ATP-induced tetramerization and cooperativity in hemoglobin of lower vertebrates

The importance of intraerythrocytic organic phosphates in the allosteric control of oxygen binding to vertebrate hemoglobin (Hb) is well recognized and is correlated with conformational changes of the tetramer. ATP is a major allosteric effector of snake Hb, since the absence of this nucleotide abolishes the Hb cooperativity. This effect may be related to the molecular weight of about 32,000 for this Hb, which is compatible with the dimeric form. ATP induces a pH-dependent tetramerization of deoxyHb that leads to the recovery of cooperativity. This phenomenon may be partially explained by two amino acid replacements in the beta chains (CD2 Glu-43 --> Thr and G3 Glu-101 --> Val), which result in the loss of two negative charges at the alpha1beta2 interface and favors the dissociation into dimers. The ATP-dependent dimer left arrow over right arrow tetramer may be physiologically important among ancient animal groups that have similar mutations and display variations in blood pH that are governed by these animals' metabolic state. The enormous loss of free energy of association that accompanies Hb oxygenation, and which is also observed at a much lower intensity in higher vertebrate Hbs, must be taken into consideration in allosteric models. We propose that the transition from a myoglobin-like protein to an allosteric one may be of evolutionary significance.     

Exposure to atmospheric radon

To determine if persons with the Prader-Willi syndrome (PWS) have increased psychopathology when compared with matched controls, and whether there is a specific behavior phenotype in PWS, the behavior of 46 persons with PWS was compared with that of control individuals derived from a community sample (N = 454) of persons with mental retardation (MR). Behaviors were studied using the Developmental Behaviour Checklist, an instrument of established validity in the evaluation of behavioral disturbance in individuals with MR. PWS subjects were found to be more behaviorally disturbed than controls overall, and especially in antisocial behavior. In addition, some individual behaviors were more common in PWS subjects than controls. When these behaviors are considered together with findings from other studies using acceptably rigorous methods, a consensus behavior phenotype for PWS can be formulated. This will provide a valid foundation for studies of the mechanism of genetic pathogenesis of behavior in PWS.     

Integrin-associated protein is a ligand for the P84 neural adhesion molecule

P84 (also known as SHPS-1, BIT, and SIRP) is a heterophilic adhesive membrane protein involved in receptor tyrosine kinase signaling that is found at synapses in the mammalian central nervous system and in non-neural tissues. We have identified a binding partner for P84 using an expression cloning strategy. Here we report that integrin-associated protein (IAP/CD47) is a predominant binding partner of P84. Immunohistochemistry reveals a virtually identical distribution of P84 and IAP in a variety of adult brain regions. Because IAP has been implicated in cell signaling in cells of the immune system, P84 and IAP represent a heterophilic binding pair that is likely to be involved in bi-directional signaling at the synapse and in other tissues.     

Heterocyclic amides: inhibitors of acyl-CoA:cholesterol O-acyl transferase with hypocholesterolemic activity in several species and antiatherosclerotic activity in the rabbit

A series of heterocyclic amides were synthesized and evaluated as inhibitors of acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and for cholesterol lowering in cholesterol-fed rats. Compounds were evaluated for cell-based macrophage ACAT inhibition, bioactivity, and adrenal toxicity. Candidates were selected for evaluation in cholesterol-fed dogs and, ultimately, the injured cholesterol-fed rabbit model of atherosclerosis. The heterocyclic amides potently inhibited rabbit liver ACAT (IC50's = 0.014-0.11 microM), and the majority of compounds significantly lowered plasma cholesterol (42-68%) in an acute cholesterol-fed rat model at 3 mg/kg. The most efficacious compounds in the rat were evaluated for bioactivity in vivo and arterial ACAT inhibition in a cell-based macrophage ACAT assay. Two highly bioactive analogs, (+/-)-2-(3-dodecylisoxazol-5-yl)-2-phenyl-N-(2,4,6-trimethoxypheny l) acetamide (13a) and (+/-)-2-(5-dodecylisoxazol-3-yl)-2-phenyl-N-(2,4,6-trimethoxypheny l) acetamide (16a), were selected for further study and were found to be nontoxic in a guinea pig model of adrenal toxicity. Compounds 13a and 16a lowered total cholesterol in the cholesterol-fed rat, rabbit, and dog models of pre-established hypercholesterolemia. Compound 13a in the injured cholesterol-fed rabbit model of atherosclerosis was effective in slowing the development of cholesteryl ester-rich thoracic aortic lesions, reducing lesion coverage by 53% at a dose of 1 mg/kg.     

Sex differences in academic advancement. Results of a national study of pediatricians

BACKGROUND: Although the numbers of women in training and in entry-level academic positions in medicine have increased substantially in recent years, the proportion of women in senior faculty positions has not changed. We conducted a study to determine the contributions of background and training, academic productivity, distribution of work time, institutional support, career attitudes, and family responsibilities to sex differences in academic rank and salary among faculty members of academic pediatric departments. METHODS: We conducted a cross-sectional survey of all salaried physicians in 126 academic departments of pediatrics in the United States in January 1992. Of the 6441 questionnaires distributed, 4285 (67 percent) were returned. The sample was representative of U.S. pediatric faculty members. Multivariate models were used to relate academic rank and salary to 16 independent variables. RESULTS: Significantly fewer women than men achieved the rank of associate professor or higher. For both men and women, higher salaries and ranks were related to greater academic productivity (more publications and grants), more hours worked, more institutional support of research, greater overall career satisfaction, and fewer career problems. Less time spent in teaching and patient care was related to greater academic productivity for both sexes. Women in the low ranks were less academically productive and spent significantly more time in teaching and patient care than men in those ranks. Adjustment for all independent variables eliminated sex differences in academic rank but not in salary. CONCLUSIONS: Lower rates of academic productivity, more time spent in teaching and patient care and less time spent in research, less institutional support for research, and lower rates of specialization in highly paid subspecialties contributed to the lower ranks and salaries of female faculty members.     

Molecular characterization of a plasmid-borne (pTC82) chloramphenicol resistance determinant (cat-TC) from Lactobacillus reuteri G4

Lactobacillus reuteri G4 contains a 7.0-kb plasmid (pTC82) encoding resistance to chloramphenicol (Cm). Determination of the nucleotide sequence of the genetic determinant (cat-TC) encoding resistance to Cm on pTC82 revealed an open reading frame for a 238-amino-acid Cm acetyltransferase (CAT) monomer. This structural cat gene, 714 bp in length, was highly related (ca. 95% nucleotide and ca. 81% amino acid identity) to the 648-bp cat gene from Staphylococcus aureus plasmid pC194. A total of 6 bp transversions and 4 bp deletions was observed along the whole DNA sequence of cat-TC compared to that of cat-pC194. To determine the activity of the putative cat-TC gene, recombinant plasmid pUC8217 containing the cat determinant from pTC82 was subjected to a maxicell analysis. The observed molecular mass of the synthesized protein, based on electrophoretic mobility, was in reasonable agreement with the 27.3 kDa predicted from the DNA sequence. This is the first reported nucleotide sequence of a Cm-resistance determinant from L. reuteri and also the first evidence of adding Lactobacillus to the list of versatile bacterial genera which naturally acquire the cat-pC194 gene in the microbial ecological system.     

Acute pancreatitis associated with the use of lisinopril

OBJECTIVE: To report a case of acute pancreatitis associated with lisinopril use. CASE SUMMARY: A 67-year-old man with no past history of pancreatitis or its associated risk factors developed acute pancreatitis after taking lisinopril for two years. To date, the use of angiotensin-converting enzyme (ACE) inhibitors and development of pancreatitis has been described in the literature with captopril, enalapril maleate, and one case temporally related to lisinopril use. CONCLUSIONS: The use of ACE inhibitors as first-line agents in controlling hypertension and congestive heart failure has increased. In addition to monitoring for efficacy and commonly reported adverse effects, clinicians need to be aware that acute pancreatitis may occur with all ACE inhibitors.     

Stimulation of inositol phosphate production and GTPase activity by compound 48/80 in rat peritoneal mast cells

Phospholipase C activity, GTPase activity and cytosolic-free calcium concentration in mast cells were stimulated by compound 48/80. Accumulation of inositol phosphates in rat mast cells was stimulated by guanosine 5'-[gamma-thio]-triphosphate. Guanosine 5'-[gamma-thio]triphosphate, however, exhibited no effect upon the purified phospholipase C activity and upon phospholipase C in the mast cell homogenate. The stimulatory effect of compound 48/80 upon phospholipase C activity of intact mast cells was observed to have been well correlated with that on GTPase activity of mast cell homogenate. Compound 48/80 exhibited no effect upon the binding of radioactive guanosine 5'-[gamma-thio]triphosphate to mast cell homogenate. Phospholipase C activity was verified by the above results to become affected by compound 48/80 through guanine nucleotide-binding regulatory protein.     

Reproductive factors and risk of brain, colon, and other malignancies in Iowa (United States)

The influence of parity on the risk of cancers of the female breast and reproductive organs is well established. However, non-reproductive sites have received less attention. Mail questionnaire data gathered from incident female cases (169 brain; 332 colon; 260 rectal; 145 kidney; and 169 pancreas cancers), and 821 population-based controls in Iowa (United States) were used to measure the effect of parity and age at first birth on risk of these malignancies. Relative to nulliparous women, ever-parous women were at significantly decreased risk of brain cancer (odds ratio [OR] = 0.44, 95 percent confidence interval [CI] = 0.3-0.7) and of colon cancer (OR = 0.67, CI = 0.5-0.97), after adjustment for age and other risk factors. The OR for the other sites did not differ significantly from 1.0. The lower risk of brain cancer among parous women was similar in younger and older age groups, in patients diagnosed with glioblastoma and astrocytoma, and among ever- and never-smokers. The findings for colon cancer are consistent with observations from other studies. In the context of limited laboratory and clinical evidence implicating hormones in brain neoplasia, these findings may suggest a role for hormonal factors in brain cancer etiology. Hormonal factors deserve more detailed future consideration as risk factors in brain cancer.