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)     

Hypoplasia of the Posterior Leaflet as a Rare Cause of Congenital Mitral Insufficiency

A bstract A rare case of congenital mitral insufficiency characterized by the hypoplasia of the posterior leaflet is reported. At operation, the mitral valve was successfully repaired by a ring annuloplasty, which created a satisfactory surface of coaptation between the anterior leaflet and the bulky posterior muscular structure. The presence of this posterior muscular structure represents a developmental arrest at the stage of conversion from muscular chordae and leaflets to thin connective structures.     

Considerations regarding the application of capillary optics to medical radiography.

The generation of monoenergetic or quasimonoenergetic x-ray spectra has been accomplished by several methods including the use of K-edge filtration, characteristic radiation, crystal monochromators, and multilayer mirrors. In this paper some practical questions are discussed regarding the possibility of obtaining narrow-band spectra using x-ray reflection in glass capillary optics which have been reported recently in connection with the focusing and generation of parallel x-ray beams. Derivation of formulas for double and triple reflection with and without additional K-edge filtration imply that these methods are superior to the use of filtration alone. It is shown that the double reflection scheme is most sensitive to the angular divergence of the beam emanating from the capillary array used to generate the incident parallel beam. Simulations using three reflections predict output spectra which are relatively insensitive to blurring due to angular divergence. A small amount of K-edge filtration in combination with three reflections provides considerable sharpening of the x-ray spectrum. Aside from the spectral selectivity provided by the capillary array, the reduced divergence of the primary transmission may have advantages for scatter rejection in situations where the air gap between the patient and detector is increased by an amount consistent with the resolution requirements of the application. In parallel beam situations, the use of capillary arrays between the patient and detector may also be useful for the rejection of divergent scattered radiation.     

Paraimmunoblastic variant of small lymphocytic lymphoma/leukemia

We report 16 cases of a distinctive, biologically aggressive variant of small lymphocytic lymphoma/leukemia (SLL/L) that is characterized by the diffuse proliferation of cells normally comprising the pseudoproliferation centers (so-called paraimmunoblasts). Demographically, the patients differed in no significant regard from patients with SLL/L of usual type. Rapidly progressive, generalized lymphadenopathy was the dominant clinical finding in 15 of the 16 patients; one patient presented with symptoms related to lymphomatous involvement of the stomach and regional lymph nodes. Splenomegaly was observed in five patients. Seven patients, two of whom had a history of indolent-phase chronic lymphocytic leukemia, had an absolute lymphocytosis at diagnosis. In most patients, bone marrow involvement was noted at diagnosis. It consisted predominantly of small lymphocytic infiltrates indistinguishable from those observed in SLL/L of usual type; significant paraimmunoblastic infiltration was infrequent and generally occurred late in the disease course. Immunohistochemical and cytogenetic study further substantiated the hypothesized relationship of these cases to SLL/L. Findings included (a) coexpression of sIg and Leu-1 antigen in the majority of cases and (b) the presence of a t(11;14) (q13;q32) chromosome translocation in two of three cases with analyzable metaphases. Although treatment protocols were not uniform, follow-up data indicated an accelerated clinical course. Eleven patients have died of their disease between 3 and 39 months after diagnosis; the median survival was 28 months.     

Assessment of intracardiac shunts with gadolinium-enhanced ultrafast MR imaging.

Dye dilutional techniques are widely accepted for the assessment of intracardiac shunts, but current techniques require arterial access or radioisotope injection. Ultrafast (less than 500 msec) magnetic resonance (MR) imaging is ideally suited for the evaluation of an indicator during passage through the heart. Twenty patients were studied, including 13 with shunts. Four-chamber, T1-weighted images were obtained during bolus injection of gadopentetate dimeglumine. A single image was obtained in 420 msec, with repetitive images acquired after each QRS complex. After the contrast material was injected, there was pronounced signal intensity enhancement in the right atrium, followed by the right ventricular cavity, left atrium, left ventricular cavity, and descending aorta. Patients with substantial intracardiac shunts demonstrated early recirculation. First-pass contrast material-enhanced MR imaging is a promising new technique for the rapid assessment of intracardiac shunts. Combined with anatomic and functional MR imaging techniques, it can help provide a comprehensive noninvasive evaluation of suspected intracardiac shunts or provide follow-up in patients with known shunts.     

Incidence of otitis media in vitamin A-deficient guinea pigs.

After observing an association between vitamin A deficiency and otitis media among children in Micronesia, we sought to develop an animal model for vitamin A-deficiency-induced otitis media. Thirty juvenile guinea pigs were screened for absence for otitis and then divided into two groups. The experimental group was placed on a vitamin A-free diet, whereas control animals were fed a standard formula. The animals were followed by means of otologic examination and serum retinol determinations. When experimental animals demonstrated vitamin A deficiency, they were killed along with one control and temporal bones were harvested and prepared for histologic examination. None of the 15 controls demonstrated middle ear abnormalities. In the experimental group, 77% of temporal bones showed middle ear pathology consisting of either of subepithelial edema (27%) or frank otitis media (50%). These results indicate that the guinea pig is a suitable species for study of otitis media in association with vitamin A deficiency. We postulate that eustachian tube dysfunction is the primary mechanism for inducing middle ear inflammation in this animal model.     

Digit ratio and hand-grip strength in German and Mizos men: cross-cultural evidence for an organizing effect of prenatal testosterone on strength.

The ratio of the length of the second and fourth digits (2D:4D), a putative proxy of prenatal testosterone (PT), is correlated with measures of physical fitness. The relationship between the organizing effect of PT on physical fitness is likely to arise as a response to intrasexual male competition for females. Physical strength is also likely to be important in intrasexual conflict, but nothing is known concerning the relationship between 2D:4D and strength. The strength of an individual is strongly influenced by body size, and 2D:4D is strongly dependent on ethnicity. We present evidence that strength, as measured from hand-grip strength, is related to 2D:4D in samples from two ethnic groups (52 Caucasian men from Germany, and 88 Oriental Mizos men from northeast India) which differed markedly in size. We found that 1) the German men were heavier and stronger, but had higher 2D:4D (lower PT) than the Mizos men; 2) a median split for grip strength into low (LGS) and high (HGS) groups showed that for right-hand 2D:4D (but not left-hand 2D:4D), the LGS men had higher 2D:4D than the HGS men; and 3) the relationships between right 2D:4D and grip strength were independent of ethnicity, age, height, and weight. Measures of grip strength correlate strongly with strength in other muscle groups, so we conclude that PT may have an early organizing effect on strength in men, and this is likely to be widespread in human groups.     

Assessing blood pressure control in patients treated for hypertension: comparing different measurements and targets.

We examined how different methods and definitions of blood pressure affect the achievement of targets in general practice. There was a wide range in the proportion of treated patients achieving the different target levels recommended by the National Institute for Health and Clinical Excellence, British Hypertension Society and the general medical services contract. Among non-diabetic patients this ranged from; 10-37% (average office), 15-39% (standardised nurse measurement), 11-49% (last recorded) and 31-56% (ambulatory blood pressure). Defining targets without a clear definition of how blood pressure should be measured is largely meaningless and ignoring ambulatory blood pressure results in many patients being classified incorrectly as failing to achieve targets.     

Screening for glaucoma: age and sex of referrals and confirmed cases in England and Wales

This paper is based on a prospective survey covering 275,600 sight tests by optometrists in England and Wales. It analyses the age and sex distribution of 1402 referrals for suspected glaucoma and 456 confirmed cases of the disease. The proportion of sight tests which led to a confirmed case increased with age, for both sexes, to a maximum at approximately 70 years, and then tended to decline. Cases of glaucoma in people aged 36-51 years accounted for about a tenth of the total, which is more than is generally recognized. Wider adoption of routine tonometry for middle aged people would help to ensure that these cases are detected at an early stage. Confirmed cases of glaucoma in which raised intraocular pressure had not been given as a reason for referral, i.e. probable low tension glaucomas, increased from 5% of patients < 51 years old to 13% of patients > 75 years old. Glaucoma was found to be much more common in men.     

Identification in rodents and other species of an mRNA homologous to the human beta-amyloid precursor

The isolation and sequencing of the core peptide (beta-amyloid) found in the plaques of patients with Alzheimer's disease has allowed the identification of a cDNA for the precursor protein. Using a human cDNA clone for this beta-amyloid material, we have identified an homologous mRNA (3.8 kb) in brain tissue obtained from 8 additional species. We have also determined its distribution in 7 brain regions and 12 organs obtained from rodents. A prominent, second mRNA species (2.2 kb) has been identified in rat non-neuronal tissues. The beta-amyloid gene is amply expressed in the brain of all vertebrates tested and in most rodent organs, indicating that it encodes a highly conserved and ubiquitous protein.