Biomedical subjects
Publications and source records attributed to M Goodman.
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Since vascular tortuosity of stenosis may preclude placement of the intra-aortic balloon, 63 consecutive patients (37 men) having routine Judkins' cardiac catheterization had an aortogram prior to withdrawal of the last catheter. No patient had a history of claudication, palpable aneurysms, pulse deficit, or bruit. No complications occurred. Significant peripheral vascular disease was found in ten patients: three had aortic, one had iliac, and six had femoral stenosis or tortuosity. All were men. The age of patients with peripheral vascular disease was 61.4 +/- 7.7 years, while those without were 56.9 +/- 9.3 years (P = NS). No difficulty was encountered entering the femoral artery in any patient; there was difficulty advancing the catheter in five of ten (50%) patients with peripheral vascular disease and in three of 54 (6%) patients without (P less than 0.002). Fifteen patients without peripheral vascular disease had normal coronary arteries, while none with peripheral vascular disease was normal. In patients with coronary disease, the number of vessels involved was the same in both groups. Peripheral vascular disease that might preclude placement of the intra-aortic balloon occurs in 14% of patients undergoing cardiac catheterization and 18% of patients with coronary artery disease. Aortography may be safely performed and should be considered during routine cardiac catheterization in patients who may require intra-aortic balloon placement.
We have examined the extensive amino acid sequence data now available for five protein families - the alpha crystallin A chain, myoglobin, alpha and beta hemoglobin, and the cytochromes c - with the goal of estimating the true spatial distribution of base substitutions within genes that code for proteins. In every case the commonly used Poisson density failed to even approximate the experimental pattern of base substitution. For the 87 species of beta hemoglobin examined, for example, the probability that the observed results were from a Poisson process was the minuscule 10(-44). Analogous results were obtained for the other functional families. All the data were reasonably, but not perfectly, described by the negative binomial density. In particular, most of the data were described by one of the very simple limiting forms of this density, the geometric density. The implications of this for evolutionary inference are discussed. It is evident that most estimates of total base substitutions between genes are badly in need of revision.
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Analysis of nucleic acid sequence data of mammalian hemoglobin, yeast cytochrome c, and human interferon reveals strong biases in favor of specific codons. These biases do not appear to dissipate over time, suggesting that an indirect form of selection acts on silent mutations. The data are compatible with the "bootstrapping" hypothesis that silent mutations which alter the rate of evolution can hitchhike with traits whose appearance they facilitate. Selection involving modulating effects of codon usage on gene expression may also be involved, but the data appear to exclude simple maximization of gene expression.
A series of functionalized catecholamines (congeners) has been synthesized in which, formalistically, the N-isopropyl group of isoproterenol has been extended by a linear alkyl chain of varying length, terminated by a carboxy group or a substituted amide. The compounds were prepared generally via the reductive amination of norepinephrine with a keto acid or a preformed keto amide. An alternate synthesis of the model amide derivatives, involving activation of the carboxylic acid congeners and coupling with amines, was complicated in the case of short-chain derivatives by facile cyclization to lactams. In vitro evaluation of these compounds as potential beta-adrenergic agonists has shown that, while the carboxylic acid congeners have relatively low potencies, the model amide derivatives have potencies that are highly dependent on both the length of the alkyl chain and also the nature of the substituent on the amide. In general, aromatic amides are the most potent, although the nature and position of substituents on the aromatic group dramatically influences their potency. The implications of these studies, in terms of general beta-adrenergic drug design and also the attachment of the carboxylic acid congeners to carriers, are discussed.
Three recently isolated peptides, whose sequences have been determined--the corticotropin (adrenocorticotropic hormone)-releasing factor of ovine origin, sauvagine, from the skin of the frog Phyllomedusa sauvagei, and urotensin I from the teleost fish, Catostomus commersoni--show high (greater than 50%) sequence homology. CD spectra of the three peptides in trifluoroethanol indicate predominantly helical character for these peptides. Analysis of the secondary structures by the Chou-Fasman method predicts that the overall structural organization of the peptides is the same. All three possess a long internal helix, spanning about 25 residues, connected by a turn region to a COOH-terminal structural element that is an alpha-helix in corticotropin-releasing factor and urotensin I and a beta-sheet in sauvagine. The values for helical content estimated from the prediction method agree reasonably well with those computed from the CD spectra. This agreement as well as the CD spectra of corticotropin-releasing factor fragment 5-33 support the specific assignments of helical regions derived from the Chou-Fasman analysis. The three peptides exhibit significantly less helical structure in water than in trifluoroethanol as indicated by CD spectra. Hydrophilicity profiles provided comparison of the three peptides in terms of their overall hydrophilicity and the location of the regions of maximal hydrophilicity. A unique distribution of hydrophilic and hydrophobic residues within the internal helices is revealed by helical wheel analysis. Patches of both types of residues are formed following a heptad (four/three) rule. Since the two patches are shifted by one residue relative to one another, together they occupy only one face of the helical surface, a feature distinct from other amphiphilic structures.
A series of monodisperse oligopeptide conjugates related to the catecholamine, isoproterenol, has been synthesized. The peptide carrier molecules used were synthesized by stepwise and fragment condensation techniques and ranged in size from a single, blocked amino acid derivative to isomeric pentapeptides. The amino acid compositions and sequences of the carriers were chosen so as to provide specific information concerning the effects of molecular weight, hydrophilic/hydrophobic balance, charge, etc., on the biological activity of the final conjugates. The common point of attachment for the drug in all carriers was a p-aminophenylalanine residue. The peptide-catecholamine conjugates were prepared via the attachment of carboxyl-containing catecholamine congeners, to the peptide carriers by techniques described previously. The conjugates were purified rigorously by chromatographic techniques and characterized by high-field n.m.r. spectroscopy.
Partial retro-inverso modification of biologically active peptides is described as a topochemical alteration of the backbone to prevent enzymatic degradation. The preparation of gem-diaminoalkyl residues from peptide amides using the reagent [bis(trifluoroacetoxy)iodo]benzene (TIB) is discussed. Treatment of N-t-butyloxycarbonyl tyrosine and N-t-butyloxycarbonyl tryptophan with this reagent led to decomposition of the protected amino acids. Protecting the tyrosine and tryptophan residues by t-butyl ether and Nin-formyl groups, respectively, prevented decomposition and led to good yields of the desired products. Racemic 2-alkylmalonyl diastereomers were found to be separable by HPLC. The chiral stability of peptides containing optically active malonyl residues was investigated under simulated physiological conditions. Synthetic considerations for the incorporation of gem-diaminoalkyl and 2-alkylmalonyl residues into larger peptides to yield partially modified retro-inverso peptide analogs are presented.
From 1978 to 1981, 151 patients with nasopharyngeal carcinoma (NPC) were enrolled in a prospective, collaborative study of North American patients, most of them white. Thirty-seven had World Health Organization (WHO) type 1 tumors, and 114 had WHO types 2 and 3 tumors. The anti-Epstein-Barr virus (EBV) profile of elevated antibody titers directed against viral capsid antigen and early antigen was seen in 85% of the patients with WHO types 2 and 3 tumors but in only 16% of the patients with WHO type 1 tumors. Geometric mean titers tended to be higher in higher stages of the disease in several staging systems. Low antibody-dependent cellular cytotoxicity at diagnosis appears to reflect a poorer prognosis, and the determination of antibody titers by this assay may prove to be useful for identifying persons in whom recurrent disease is likely to develop after conventional therapy. Anti-EBV titers can aid in diagnosis and treatment planning in patients with NPC, particularly those with occult primary NPC.
Forty female patients with pituitary adenomas were studied retrospectively to determine whether factors could be identified that would help predict outcome from operation. Twenty-five patients had a normal prolactin level (less than or equal to 30 ng/ml) during the early postoperative period (less than or equal to 3 months) and 15 patients had persistent disease (prolactin greater than 30 ng/ml). Nine of the 25 patients who initially had normal prolactin levels during the early postoperative period were found to have elevated prolactin levels during the late postoperative period (greater than 3 months). As has been shown previously, tumor size and preoperative prolactin levels were important factors in predicting surgical outcome. Patients with smaller (Hardy Grades I and II) tumors had significantly better outcome than those with larger (Hardy Grades III and IV) tumors. Patients with successful surgical outcomes had significantly lower preoperative prolactin values (204 ng/ml) than those with operative failures (524 ng/ml). In addition to the known factors, the patient's age at the time of operation, the length of amenorrhea, and the patient's growth hormone response to insulin hypoglycemia were newly identified as factors that helped predict surgical outcome. Patients who were less than or equal to 26 years of age and who had had amenorrhea for less than or equal to 6 years at the time of operation had significantly better surgical outcomes. Patients with normal growth hormone responses to stimulation testing had significantly better surgical outcomes than those with a blunted preoperative growth hormone response. The data suggest that prolactin-secreting pituitary tumors may cause a progressive disorder for which operative cure may be obtained only early in the disease.
The evolutionary history of 12 Chironomus thummi thummi (CTT) haemoglobins of known primary structures was reconstructed by the maximum parsimony method. This reconstruction demonstrates that the 12 CTT haemoglobin lineages originated monophyletically from a common ancestor within early Insecta and have the lineage to monomeric blood worm haemoglobin as their closest sister group. It can be further deduced that the earliest ancestral CTT haemoglobins were monomers and that a branch to all extant dimeric CTT haemoglobins emerged later in phylogeny near the base of Chironomidae, but perhaps still before Chironomus itself evolved. This ancient, pre-Chironomus history suggests that among insect taxa, now lacking expressed globins, remnants of globin genes might exist as unexpressed pseudogenes. By the parameter of base replacement frequencies, CTT haemoglobins appear as relatively slow-evolving proteins, showing a preponderance of guanine in equilibrium adenine transitions at the first nucleotide position of the codons but not at the second. The most conservatively-evolving amino acid positions are haem contacts; the next most conservative are in interhelical contacts and interior positions involved in stabilization of tertiary structure. Further elucidation of the phylogenetic origins and adaptive evolution of the multiple haemoglobins found in Chironomus will be possible by the maximum parsimony method once haemoglobins or, in their absence, haemoglobin pseudogenes are sequenced in species throughout Chironomidae and related taxa.
Skeletal muscle myoglobin of the aardvark (Orycteropus afer) was isolated and its primary structure determined. The amino-acid sequence was then used in conjunction with previously established myoglobin sequences to evaluate the phylogenetic relationships of the aardvark. The most parsimonious trees constructed from this myoglobin sequence data either alone or when combined with lens alpha-crystallin A sequence data depict the aardvark lineage as one of the most ancient among Eutheria.
Generally the elderly are identified as a stigmatized subculture victimized by society's denial or avoidance of their physical problems, social needs and psychological issues. So much more the case for the nursing home resident, who is characterized as helpless, passive and socially insensible. The article questions the efficacy of recreational activities as they exist in the nursing home milieu today. Does therapeutic recreation take into account the physical, social and emotional needs of the nursing home resident? What is the basis for rationale in building therapeutic recreation programs? Where is the didactic emphasis in university programs designed to educate the recreational therapist? It is concluded that recreational activities become therapeutic only when they have evolved from a detailed knowledge of the problems germane to a given population.
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Conjugates of low molecular weight amines with inert peptide carriers can be made to preserve some pharmacologic effects of the ligand. No previous studies of conjugates have systematically derivatized the ligand to optimize its activity or affinity to receptors; or have pharmacophores been selected for conjugation on the basis of their effects making them particularly interesting as ligands. Chemically pure and characterizable conjugates ranging from single blocked amino acid derivatives to isomeric pentapeptides were constructed and tested for beta adrenergic properties. Sixteen conjugates with varying water solubility, amino acid composition and sequence, charged groups and spacer length between ligand and carrier showed potencies and duration of action widely different from isoproterenol. In the in vitro S-49 mouse lymphoma assay a range of relative potencies (as compared to isoproterenol) from 10(-6) to 1 time as potent was obtained, whereas in the in vivo rat blood pressure assay these compounds were shown to be from one-fifth to 4 times as potent as isoproterenol. The most potent compound tested, Boc-Phe(NH)-Gly-NHCH3, was also tested in a guinea-pig atrial preparation as well as in an anesthetized cardiovascular dog preparation. The results indicated that the compound was approximately 3.5 times more potent in producing an inotropic response than isoproterenol. In some instances, ostensively trivial changes quite distant from the pharmacophores in amino acid sequence of the carrier made major changes in potency and efficacy of the compound.
In this study, 10 congeners of isoproterenol were systematically synthesized and pharmacologically tested in both in vitro and in vivo systems. The aim was to produce compounds that were more potent and had effects different from those of the parent compound and that could ultimately be attached covalently to inert peptide carriers offering versatility in size, pK, and other physicochemical properties. The congeners synthesized were tested in the S49 mouse lymphoma assay for their ability to stimulate cyclic AMP accumulation and were shown to have potencies relative to isoproterenol ranging from 4 orders of magnitude less potent to 4 orders of magnitude more potent than isoproterenol in eliciting this response. Some of the congeners were also tested in a guinea pig isolated atrial preparation, a rat blood pressure assay, a guinea pig bronchodilation assay, and an anesthetized dog preparation. In these assays, the congeners were shown to have the same types of activities as in the S49 cell assay. The results of these studies indicate that structural modifications distant from the catecholamine moiety dramatically alter the pharmacological profile of the congeners versus the parent compound, resulting in a series of ligands with a wide range of activities.