The 'Do not resuscitate' order. A profile of its changing use

The "do not resuscitate" (DNR) order has wide-ranging ethical, legal, and economic implications. We reviewed the course of 244 patients who died during two three-month periods, in 1982 and 1986. We found that 68% of patients who died had a DNR order written, including 94% with malignancy and half of patients with cardiovascular disease. Most orders (61%) were written within three days of death, with 64% written on medical-surgical floors and 34% in critical care units. Even among patients under the age of 60 years, 57% had a DNR order written by the time of death. Ninety-one percent of DNR orders were written by attending physicians, with accompanying explanatory note in 84%. Documentation showed only 14% of patients but 77% of families being consulted. In 1983 a new two-level DNR order system defined two levels of intensity: "all but cardiopulmonary resuscitation" and "comfort measures only." Equal numbers of patients received each order in the 1986 sample. No patient was transferred to the critical care units after a DNR order had been written. The prevalence of DNR orders written for patients dying of cardiovascular disease increased from 27% to 64% over the four years. We conclude, from study of deaths in this representative community hospital, that an explicit DNR order is now the rule rather than the exception, but decisions are made late and involve family far more than the patient.     

Pharmacokinetics of Anandron in patients with advanced carcinoma of the prostate

Summary The pharmacokinetics of total radioactivity and unchanged drug were studied in patients receiving Anandron (Nilutamide, RU 23908) after a single dose of [¹⁴C] Anandron and after q12 h dosings of unlabelled drug for 2–7 weeks. The results indicate that the radioactivity in plasma consists of unchanged drug and metabolites. The plasma decay of Anandron after the absorption phase was biexponential in all patients, with the terminal phase half-life ranging from 23.3–87.2 h. The plasma decay of total radioactivity after the absorption phase was biexponential in 3/12 and monoexponential in 9/12 patients. The calculated terminal phase half-lives for total radioactivity after [¹⁴C] Anandron were 34.5–137.3 h. The AUC_0– of the unchanged drug in plasma represented 23%–38% of the AUC_0– of total radioactivity. Urinary radioactivity consisted primarily of metabolites, the majority of which were chloroform-nonextractable. Urinary excretion of radioactivity at 120 h ranged from 49%–78% of the administered dose; the unchanged Anandron (at 72 h) was 0.6%–1.3% of the dose. In three patients studied, the fecal excretion of Anandron was 1.4%–7.0%. Steady-state plasma levels (4.4–8.5 g/ml) were attained within approximately 2 weeks from the initiation of twice daily dosing of Anandron. When the plasma pharmacokinetics of radioactivity and unchanged drug after the first single dose were compared with that during steady state, AUC_{0–12 h} of unchanged Anandron during steady state was significantly higher than the AUC_0– after the first single dose, suggesting that the plasma clearance of Anandron is lowered upon chronic administration of the drug, assuming that the bioavailability is constant.     

Chloride current activated by cyclic AMP and parathyroid hormone in rat osteoblasts

In primary cultures of rat osteoblasts, studied with the whole-cell configuration of the patch-clamp technique, 8-bromo-cyclic AMP (8BrcAMP) forskolin (FS) and 1–34 parathyroid hormone (PTH) were shown to activate a Cl conductance. This conductance shows a pronounced outward rectification, even with symmetrical Cl concentrations. It is blocked partially and reversibly by 4,4-diisothiocyanatostilbene 2,2-disulfonic acid (DIDS) or diphenylcarboxylate (DPC). The blockade induced by DIDS is time-and voltage-dependent. The Cl responses to FS and PTH develop slowly, after a delay of several seconds and are very slowly reversible. These responses were observed only in a fraction of the cells tested and their detection was favoured by cell dialysis. This Cl current should be taken into account for studying possible modulations of the voltage-gated Ca currents of osteoblasts. It is suggested that its physiological role may be related to the well-known morphological changes induced by PTH in osteoblasts. The cyclic AMP-sensitivity, the outward rectification and the sensitivity to dialysis of this Cl current are reminiscent of the properties of the cystic fibrosis-sensitive Cl channels of epithelial cells.     

Relationship of HLA to schizophrenia not supported in multiplex families.

The role of the human histocompatibility complex (HLA) in the pathogenesis of schizophrenia has been suggested in previous reports. We conducted a genetic study in 33 new families. Our linkage analysis, which used the affected sib-pair method, did not provide evidence for nonrandom assortment. Moreover, the results of an association study using the "haplotype relative risk" method failed to confirm the positive association between HLA A9 and schizophrenia. Taken together, our data did not support any relationship of HLA type to schizophrenia.     

Metabolism of methyl-branched iodo palmitic acids in cultured hepatocytes

The metabolic fate of methyl-branched iodo fatty acids was studied in primary culture of rat hepatocytes. We compared 16-iodo-2-R,S-methyl palmitic acid (2-Me), which can be oxidized, with 16-iodo-3-R,S-methyl palmitic acid (3-Me) which can be oxidized only after an initial oxydation and with 16-iodo-2,2-dimethyl palmitic acid (2,2-Me₂) and 16-iodo-3,3-dimethyl palmitic acid (3,3-Me₂) which cannot be oxidized at all. The normal fate of natural fatty acids was given by comparative experiments with [1-¹⁴C] palmitic acid. Monomethyl-branched iodo fatty acids were taken up in the same range as palmitic acid but more than dimethyl-branched iodo fatty acids. After a 15-h incubation, acido-soluble products (ASP) accounted for 75% of the radioactivity taken up as 16-iodo-2-methyl palmitic acid, 50% as other methyl-branched iodo fatty acids and only 30% as palmitic acid, which indicated that all the methyl-branched iodo fatty acids underwent a strong deiodination process. Fatty acids were esterified in the following order: palmitic acid >16-iodo-3-R,S-methyl palmitic acid>16-iodo-2-R,S-methyl palmitic acid>16-iodo-2,2-dimethyl palmitic acid>16-iodo-3,3-dimethyl palmitic acid. Cultured hepatocytes, labelled for 3 h with the various fatty acids and reincubated for 12 h without fatty acid, secreted large amounts of free dimethylbranched iodo fatty acids as compared to the monomethyl ones and palmitic acid. Only hepatocytes prelabelled with 16-[¹²⁵I]iodo-2,2-dimethyl palmitic acid exhibited an appreciable secretion of labeled triglycerides, but at a lower rate than with [1-¹⁴C] palmitic acid. Conversely, the 16-iodo-monomethyl palmitic acids remained chiefly in hepatocyte triglycerides. Minute amounts of 16-iodo-methyl-branched-palmitic acids were found in hepatocyte or secred phospholipids as compared with palmitic acid. This metabolic fate of methyl-branched iodo palmitic acids argues against their utilization as imaging probes to monitor in vivo the synthesis and the secretion of triglycerides by the liver.     

Epidermal growth factor receptor regulates normal urothelial regeneration

Members of the epidermal growth factor (EGF) family and their receptors are involved in many cellular processes, including proliferation, migration, and differentiation. We have previously reported that these growth factors are expressed and have specific regulatory functions in an organ-like culture model of normal human urothelial cells. Here, we used this model to investigate the involvement of EGF receptor (EGFR) in human urothelial regeneration. Three 4-mm-diameter damaged areas were made in confluent normal human urothelial cell cultures with a biopsy punch. Regeneration was measured, on fixed stained cultures, with an image analyzer, at 4, 24, and 48 hours after injury. Cell proliferation was assessed by 5-bromo-2-deoxyuridine incorporation. To identify EGF family factors potentially involved in the healing process, we studied the effect of these factors on damaged confluent cultures and the level of expression of mRNAs extracted from these cultures. EGFR inhibition of the proliferation and migration of urothelial cells was tested with (1). a specific tyrosine kinase inhibitor (AG1478) and (2). a blocking anti-EGFR antibody (LA22). Exogenously added amphiregulin, EGF, transforming growth factor-alpha and heparin-binding EGF (HB-EGF) stimulated urothelial regeneration. The damaged areas were repaired by regrowth within 48 hours. Both AG1478 and LA22 inhibited the repair (by 50% and 30%, respectively), as well as proliferation and migration. This regeneration was accompanied by increased HB-EGF mRNA expression in cultures of cells from four of six subjects, but no corresponding change in EGFR protein level was observed. These results indicate that the EGFR signaling pathway is involved in urothelial regeneration. Our data support an autocrine role of HB-EGF in this process and suggest that the EGFR pathway is a potential therapeutic target for modulating urothelial cell proliferation.     

Chromosomes in tumors derived from mouse tumor x diploid cell hybrids obtained in vitro

Hybrids formed in vivo between Cl.1D tumor cells and host cells have been shown to carry a copy of each chromosome pair contributed by the host cell parent (1). However, in these hybrids, the tissue type of the host cell parents remained unknown. In the present study, hybrids between the malignant Cl.1D fibroblasts and either normal diploid fibroblasts (CF hybrids) or normal thymocytes (CT hybrids) were examined. These hybrids produced tumors when injected into host mice. Metaphases of growing hybrid cell tumors were analyzed. Neither CF nor CT malignant hybrids showed loss of any specific chromosome pair contributed by the normal cell parent. Since elimination of any chromosome pair contributed by the diploid fibroblast parent is not a prerequisite for CF hybrid tumoral growth, it seems unlikely that malignancy of hybrids results from nonexpression of normal alleles of those genes putatively implied in malignancy of Cl.1D cells.     

Mapping location of excitation during magnetic stimulation: Effects of coil position

We determined the location of excitation for different positions of a round and butterfly coil duringin vitro magnetic stimulation of cut peripheral nerves. We analyzed the conditions under which excitation occurs, either at the termination or at the peak of the field gradients (first spatial derivative of the electric field). These results were then compared to predictions about the location of excitation sites from a theoretical model of magnetic stimulation of finite neuronal structures. Excitation along a straight nerve occurred at terminations when 1) a coil was positioned close to the end of a nerve (at least one diameter length from the end), 2) a nerve ended in a finite terminating impedance much greater than the axial resistance of the nerve, 3) the induced electric field was of sufficient magnitude, pointing in a direction away from the axis of a nerve. Excitation occurred at the negative peak of the field gradients along a nerve when 1) a coil was positioned far away from the ends of a nerve, 2) there were no geometric or volume conductor inhomogeneities around a nerve, and 3) it was of sufficient magnitude. Threshold strengths for excitation at terminations were significantly lower than that for field gradient excitation and comparable to that due to geometric and volume conductor inhomogeneities.     

Regulation of skeletal muscle development by the central nervous system in the fetal pig

The effect of upper motor neuron regulation on skeletal muscle development was studied in the fetal pig. A region of the spinal cord at the level of the upper cervical vertebrae was destroyed by cauterization at 45 days of gestation in four pig fetuses. Five fetuses with intact spinal cords served as controls. Innervation and enzyme activities in the longissimus muscle, the ultrastructure and quantitation of satellite cells in the sartorius muscle, and plasma composition were evaluated at 110 days of gestation. The terminal innervation ratios were similar (P greater than 0.05) for muscles from control and cauterized fetuses. Endplate morphology was also similar. Therefore, innervation of newly formed primary fibers is not controlled by upper motor neurons after 45 days of gestation. Mean values for body weight, percentage of muscle dry weight, percentage of myofibers with myonuclei and plasma levels of protein, glucose, triglycerides, lactate, and creatine phosphokinase activity were similar (P greater than 0.05) between the two groups of fetuses. All but one muscle fiber examined was of the secondary fiber type. These observations suggest that the physiological maturity of the muscle was not appreciably altered even though glucose-6-phosphate dehydrogenase activity was higher (P greater than 0.05) and total phosphorylase activity was lower (P greater than 0.05) in the spinal cauterized fetuses than in the control group. The percentage of satellite cells was lower when based on the number of myofibers observed (P greater than 0.005) or on the number of nuclei contained within the basal lamina (P greater than 0.001) in the muscle of the spinal cauterized fetuses than in the control fetuses. The cytoplasm of satellite cells from the muscles of control fetuses was rich in organelles indicative of metabolic and mitotic activity whereas a paucity of such organelles was observed in the satellite cells of cauterized fetuses. Since the percentage of myofibers that had myonuclei was similar (P greater than 0.05) for the control and cauterized fetuses, it appeared that the myonuclear population was maintained by direct incorporation of the parent satellite cell.     

Combination of WAGR and Potocki-Shaffer contiguous deletion syndromes in a patient with an 11p11.2-p14 deletion

Aniridia, Wilms tumor, genitourinary abnormalities, growth and mental retardation are the cardinal features of the WAGR 11p13 deletion syndrome. The Potocki-Schaffer syndrome or proximal 11p deletion syndrome (previously DEFECT11 syndrome) is a contiguous gene syndrome associated with deletions in 11p11.2, principal features of which are multiple exostoses and enlarged parietal foramina. Mental handicap, facial dysmorphism and craniosynostosis may also be associated. We report a patient with combined WAGR and Potocki-Shaffer syndromes, and obesity. She presented with aniridia, cataract, nystagmus, corneal ulcers and bilateral congenital ptosis. A left nephroblastoma was detected at 15 months. Other features included moderate developmental delay, growth deficiency, facial dysmorphism, multiple exostoses and cranial lacunae. High-resolution and molecular cytogenetics confirmed a del(11)(p11.2p14.1) deletion with a proximal breakpoint between the cosmid DO8153 and the BAC RP11-104M24 to a distal breakpoint between cosmids CO8160 (D11S151) and F1238 (D11S1446). The deletion therefore includes EXT2, ALX4, WT1 and PAX6. This case appears to be the second patient reported with this combined deletion syndrome and confirms the association of obesity in the WAGR spectrum, a feature previously reported in four cases, and for which the acronym WAGRO has been suggested. Molecular and follow-up data on the original WAGRO case are briefly presented.