Francis A. Neelon

Renal Cyclic Adenosine Monophosphate: An Accurate Index of Parathyroid Function

Measurement of total urine cyclic 3:5-adenosine monophosphate (cyclic AMP) only incompletely discriminates between normal, hyperparathyroid, and nonparathyroid hypercalcemic patients. Only a fraction of total urine cyclic AMP is contributed by parathyroid hormone (PTH) action on the proximal nephron (renal cyclic AMP); the remainder is derived from plasma by glomerular filtration. We dtermined total urine and plasma cyclic AMP and PTH (by carboxy-terminal specific radioimmunoassay) in control, hyperparathyroid, nonparathyroid hypercalcemic, and surgically hypoparathyroid patients. Renal cyclic AMP was calculated as total urine cyclic AMP minus the filtered component. Of these determinations, only renal cyclic AMP segregated normal from hyperparathyroid, and hyperparathyroid from nonparathyroid hypercalcemic patients with complete accuracy. These data suggest that measurement of renal cyclic AMP provides an accurate index of parathyroid activity and allows clinical discrimination and appropriate treatment of the sub-groups of patients with malignancy and nonparathyroid hypercalcemia from those with hyperparathyroidism.

The impact of psychologic factors on measurement of functional status. Assessment of the sickness impact profile.

In this study the relationship between four psychologic health constructs (depression, anxiety, patient response bias, and hostility) and the Sickness Impact Profile (SIP) measurement of functional status was evaluated. The SIP, Carroll Depression Rating Scale (CDRS); and the Minnesota Multiphasic Personality Inventory (MMPI) were administered to 332 patients hospitalized for treatment of combined medical and psychiatric problems. Pearsons product-moment correlation was high between CDRS and SIP Total score (r = 0.67) and between CDRS and SIP Psychosocial subscale (r = 0.72); correlation was lower between CDRS and SIP Physical subscale (r = 0.44). Six MMPI scales (depression, anxiety, psychasthenia, lie, K, hostility) correlated with SIP Total score (r = 0.18 to 0.50), with SIP Psychosocial score (r = 0.28 to 0.65) and less well with SIP Physical subscale (r = 0.07 to 0.25). Factor analysis of the SIP categories showed two factors with eigenvalues greater than 1. Promax factor rotation showed all SIP Psychosocial categories and all measured psychologic variables loaded most heavily on factor 1. SIP Physical categories loaded most heavily on factor 2. Stepwise multiple regression analysis showed that psychologic variables account for 49% of the SIP total variance, 62% of SIP Psychosocial subscale variance, but only 19% of SIP Physical subscale variance. The CDRS accounts for the major portion of the explained variance with only minor additional contributions from the MMPI scales. We conclude that 1) the SIP discriminates psychosocial and physical dysfunction even in medical patients with extensive psychiatric comorbidity; 2) the SIP measures at least two dimensions of health, one of which is strongly related to depression; and 3) constructs measured by MMPI scales do not have substantial independent contribution to SIP variance.

Observer variability in the pulmonary examination

Observer variability in the pulmonary examination was assessed by having four blindfolded observers (two medical students and two pulmonary physicians) twice examine 31 patients with abnormal pulmonary findings. Examiners were consistent in the repetitive detection of pulmonary abnormalities in 74–89% of the examinations; conversely, 11–26% of the time they disagreed with themselves. Although pulmonary specialists recorded fewer (55% of observations) abnormal findings than did medical students (74%), they were significantly (p=0.008) less self-consistent than were the students. There was no clear trend in agreement between examiners (kappa=0.20−0.49). Each examiner’s findings were compared with those of physicians specially trained in pulmonary examination. Dichotomous variables (wheezes, crackles, rubs) were more reliably detected (kappa=0.30−0.70) than graded variables (tympany, dullness, breath sound intensity), where kappa=0.16−0.43. The authors suggest that dichotomous variables deserve greatest clinical reliance; that time in training, alone, does not improve clinical performance; and that there is a disconcertingly large amount of inter- and intraobserver disagreement in this fundamental clinical task.

Stimulation of cartilage amino acid uptake by growth hormone-dependent factors in serum. Mediation by adenosine 3':5'-monophosphate.

The effects of growth hormone-dependent serum factors on amino acid transport and on cartilage cyclic AMP levels in embryonic chicken cartilage were studied in vitro. Cartilages incubated in medium containing rat serum showed a significantly greater uptake of alpha-amino [1-14C] isobutyrate or [1-14C] cycloleucine than control cartilages incubated in medium alone. Normal rat serum (5%) added to the incubation medium also caused an increase in cartilage cyclic AMP content (from as little as 23% to as much as 109%). The factors in serum which increase cartilage cyclic AMP and amino acid uptake are growth hormone dependent, since neither growth hormone itself nor serum from hypophysectomized rats restores these serum factors. Studies comparing the ability of sera with varying amounts of growth hormone-dependent factors to stimulate amino-aminoisobutyrate transport and to increase cartilage cyclic AMP show a striking linear correlation between the two effects (r=0.977). Theophylline and prostaglandin E1, WHICH RAISE CARTILAGE CYCLIC AMP also increase amino-aminoisobutyrate transport. Exogenous cyclic AMP, N6-monobutyryl cyclic AMP and n6, 02-dibutyryl cyclic AMP increase cartilage amino-aminoisobutyrate transport. The data are compatible with the thesis that growth hormone-dependent serum factors increase cartilage amino acid transport by elevating cartilage cyclic AMP.

Stimulation of cartilage macromolecule synthesis by adenosine 3′,5′-monophosphate

The role of cyclic AMP in the regulation of cartilage macromolecule synthesis in vitro was studied in pelvic cartilage from 10-12 day chick embryos. Incubation of cartilages in medium containing 0.5 mM cyclic AMP resulted in a 30% inhibition of 35SO4-2, [3H]leucine and [3H]uridine incorporation into proteoglycan, total protein and RNA, respectively. Higher concentrations of cyclic AMP had no greater effects. In contrast, butyrylated cyclic AMP derivatives (0.5-5.0 mM) added to the incubation medium stimulated (50-100%) the incorporation of these radiolabeled precursors into cartilage macromolecules. Theophylline, in concentrations (0.1-0.5 mM) which raise intracellular cyclic AMP, also increases the incorporation of radiolabeled precursors into macromolecules. The data indicate that exogenous cyclic AMP and butyrylated cyclic AMP derivatives have paradoxical effects on cartilage macromolecule synthesis. Butyrylated cyclic AMP derivatives, not exogenous cyclic AMP, mimic the effects of intracellular cyclic AMP. Incubation of embryonic chicken cartilage with exogenous cyclic AMP results in the extracellular degradation of the cyclic AMP to adenosine. Adenosine (0.125 mM) inhibits precursor incorporation into cartilage macromolecules. The metabolism of exogenous cyclic AMP generates sufficient adenosine to account for the observed inhibitory effects of exogenous cyclic AMP on cartilage macromolecule synthesis. Butyrylated cyclic AMP derivatives are not degraded during incubation with cartilage. The data indicate that cartilage is a tissue in which the effect of cyclic AMP is to stimulate anabolic processes.

Acetaminophen and hepatic dysfunction in infectious mononucleosis.

Two family members developed severe hepatitic dysfunction in association with infectious mononucleosis and acetaminophen administration. Since severe hepatitis is an extremely rare complication of infectious mononucleosis, we postulate that the hepatic dysfunction was induced by acetaminophen.

Minnesota Multiphasic Personality Inventory (MMPI) Cluster Groups Among Chronically Ill Patients: Relationship to Illness Adjustment and Treatment Outcome

Cluster analysis of the MMPI has been utilized widely in the chronic low back pain literature to try to identify reliable patient subtypes predictive of treatment outcome. We extended this methodology to patients with heterogeneous chronic medical conditions by replicating prototypic MMPI cluster group profiles and by relating cluster groups to clinical baseline and outcome data. Subjects were two independent samples (n=254 and n=263) of chronically ill patients admitted to an inpatient medicine/psychiatry unit. Using a four-cluster solution, similar cluster profile groups were replicated in both samples. Consistent differences emerged between cluster groups on functional impairment, psychiatric diagnoses, depression, and psychosomatic symptoms. Cluster group membership also predicted changes in functional impairment and depression six months after treatment. Results are discussed in terms of similarities between chronic low back pain and chronic illness and tailoring treatment to different patient types.

A comparison of the structure of hamster pancreatic insulin and the insulin extracted from a transplantable hamster islet-cell carcinoma

Insulin has been isolated from pancreases of the Syrian hamster and from a transplantable islet-cell tumor of the hamster. Acid/ethanol extraction, ether precipitation, ion exchange and gel filtration chromatography gave preparations of suitable purity for structural studies. Using trypsin cleavage, automatic Edman degradation and manual Edman degradation, a complete sequence of the pancreatic insulin B chain was determined. By automatic Edman degradation, the amino-terminal 10 residues of the pancreatic A chain were assigned and the sequence of carboxy-terminal eleven residues could be deduced by homology to other mammalian and avian insulins. The sequence assigned to hamster insulin A chain is identical to that of the rat, mouse and spiny mouse. The sequence of hamster insulin B chain is identical to rabbit and spiny mouse B chain. In terms of protein evolution, hamster insulin thus appears to occupy an intermediate position between rabbit and rat insulins. Amino acid composition, tryptic peptide composition and partial sequence analysis of the hamster tumor insulin showed no differences from hamster pancreatic insulin.

Preparative solvent partition chromatography of butyrylated cyclic AMP analogues.

A simple and effective separation of cyclic adenosine-3′,5′-monophosphate (cAMP) and its butyryl-substituted analogues using partition chromatography on columns of Sephadex gel in isopropanol/0.5 m ammonium acetate (4:1) is described. The technique is suitable for preparative separations as demonstrated by revised uv spectral data obtained on butyrylated cAMPs purified by this technique. In addition, it has analytical utility in that it allows complete separation of N6-monobutyryl cAMP from O2′-monobutyryl cAMP, thereby permitting simultaneous and independent assessment of the rate of acyl substituent hydrolysis from the disubstituted derivative (N6,O2′-dibutyryl cAMP), and this is demonstrated under several conditions.