Biomedical subjects
Publications and source records attributed to B Hall.
Overall we are pleased to find that what sometimes seemed like hopeless space restrictions could be overcome by a combination of prudent compromise and innovative design. Even though the process consumed much time, the design of this new ICU turned out to be a satisfying process, marked by a true cooperative spirit among a group with diverse backgrounds and skills, all working toward a common goal.
BACKGROUND: Many patients who have been treated successfully for childhood cancer with regimens that contain one or more mutagenic chemotherapeutic agents are concerned that their own treatment during childhood or adolescence may adversely affect their children. METHODS: To determine the effect of chemotherapy for cancer during childhood and adolescence on the outcome of subsequent pregnancies, we reviewed the records of 306 men and women who had been treated for pediatric cancer and who responded to our questionnaire. One hundred of the 306 patients reported 202 pregnancies. Among the patients who had received chemotherapy as part of their treatment for cancer, 60 patients or wives of patients had had one or more pregnancies of 20 or more weeks' gestation. The 60 former patients had a total of 100 live-born and 2 stillborn children. RESULTS: The frequency of congenital anomalies was 8.1 percent (5 of 62) among the live-born children of the women and 7.9 percent (3 of 38) among the live-born children of the men. Structural congenital cardiac defects were identified in 10.0 percent (2 of 20) of the children of women who had been treated with dactinomycin, as compared with 0.6 percent (144 of 24,153) among the children in a multicenter survey of fetal anomalies (P = 0.0126). We found no relation between the number of mutagens received or the cumulative dose of any agent received and the frequency of congenital anomalies in the children. CONCLUSIONS: These data suggest that treatment of children and adolescents with mutagenic chemotherapeutic agents, in the dose ranges we examined, does not increase the frequency of congenital anomalies in the children subsequently born to the former patients. However, the possible adverse effect of dactinomycin on the children of such patients requires further study.
To assess the impact of the diagnosis and modern treatment of childhood cancer on achievement of adult goals, the authors evaluated employment, health and life insurance coverage, marriage, divorce, and reproduction in 227 former pediatric cancer patients. Each area was evaluated in relation to a common set of disease and demographic factors that included age at follow-up, age at diagnosis, gender, marital status, history of disease recurrence, and diagnosis. Patients were younger than 20 years of age at diagnosis, and their diagnoses were made between January 1, 1960, and December 31, 1984. The median age at diagnosis was 11.4 years, and the median age at follow-up was 26.6 years. The percentage of unemployed male respondents did not differ from population norms. The percentage of unemployed female respondents, however, was slightly higher than that of the United States population. Approximately 11% of the survivors reported some form of employment-related discrimination, a level significantly lower than that of prior reports. Company-offered health insurance was provided to 92.4% of full-time and 90.0% of part-time employed respondents. Life insurance was purchased by 60% of full-time employed men and 55% of women. These percentages were lower than those reported for the United States population. Twenty-four percent of those with life insurance had difficulty obtaining it. Fifty-eight percent of the subjects were married or lived as married. The percentages of married men and women were significantly lower than United States norms. Twenty percent of those who were married or lived as married have divorced or separated or no longer live as married. Women aged 20 to 24 years were less likely to marry, and women aged 35 to 44 years had a significantly higher frequency of divorce than similarly aged United States women. In general, the history of childhood cancer did not influence the decision to marry or live as married but was occasionally (20%) important in the decision to dissolve a marital relationship. Many former patients indicated that their diagnosis and treatment for childhood cancer influenced their decision to have children. The current study suggests that most former pediatric cancer patients achieve adult life goals. Additional research is necessary to define those populations at greatest risk of failure to achieve these goals.
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Glucagon stimulates flux through the glycine cleavage system (GCS) in isolated rat hepatocytes (Jois, M., Hall, B., Fewer, K., and Brosnan, J. T. (1989) J. Biol. Chem. 264, 3347-3351. In the present study, flux through GCS was measured in isolated rat liver perfused with 100 nM glucagon, 1 microM epinephrine, 1 microM norepinephrine, 10 microM phenylephrine, or 100 nM vasopressin. These hormones increased flux through GCS in perfused rat liver by 100-200% above the basal rate. The possibility that the stimulation of flux by adrenergic agonists and vasopressin is mediated by increases in cytoplasmic Ca2+ which in turn could regulate mitochondrial glycine catabolism was examined by measuring flux through GCS in isolated mitochondria in the presence of 0.04-2.88 microM free Ca2+. Flux through GCS in isolated mitochondria was exquisitely sensitive to free Ca2+ in the medium; half-maximal stimulation occurred at about 0.4 microM free Ca2+ and maximal stimulation (7-fold) was reached when the free Ca2+ in the medium was 1 microM. The Vmax (nanomoles/mg protein/min) and Km (millimolar) values for the flux through GCS in intact mitochondria were 0.67 +/- 0.16 and 20.66 +/- 4.82 in the presence of 1 mM [ethylenebis(oxyethylenenitrilo)]tetraacetic acid and 3.28 +/- 0.76 and 10.98 +/- 1.91 in presence of 0.5 microM free Ca2+, respectively. The results show that the flux through GCS is sensitive to concentrations of calcium which would be achieved in the cytoplasm of hepatocytes stimulated by calcium-mobilizing hormones.
The major aim of this study was to further investigate the fine specificity of myeloma proteins recognizing epitopes on fructans. Our studies showed that UPC 61, EPC 109, and a hybrid antibody composed of the heavy chain from UPC 61 and the light chain from EPC 109, UPC 61H:EPC 109L, not only bind to inulin which is a linear fructan of beta (2----1) fructofuranosyl linkages, but also bind to sinistrin, a branched molecule consisting of a beta (2----1) fructofuranosyl backbone with beta (2----6) branch points. The fine binding specificity of these three antibodies for the beta (2----1) fructofuranosyl linkages found in inulin-BSA can be further studied by their binding to fructan oligosaccharides isolated from asparagus roots. From a comparative analysis of the amino acid sequences and the apparent affinity constants (aKa) of UPC 61, EPC 109, and the hybrid for various fructan oligosaccharides, it appears that the light chain of the immunoglobulin molecule makes an important contribution to the binding specificity. Finally we report for the first time that a monoclonal antibody specific for beta (2----6) fructans can also bind specifically to inulin-BSA with a lower affinity. This antibody derives its VH and VL from the VHX24 and Vk10b gene families, respectively, which are different from the gene families utilized by UPC 61 and EPC 109 (VHJ606 and Vk11 gene families).
Tomato polygalacturonase is a cell wall enzyme secreted in large amounts during tomato fruit ripening. Polygalacturonase is synthesized as a glycoprotein precursor that undergoes numerous cotranslational and post-translational processing steps during its maturation, yielding three isozymes in tomato fruit, PG1, PG2A, and PG2B. To investigate the physiological roles of the three isozymes and the functional significance of the polygalacturonase processing domains in its intracellular transport and activity, we have examined polygalacturonase expression in transgenic tobacco plants. A full-length polygalacturonase cDNA was placed under control of the cauliflower mosaic virus 35S promoter and introduced into tobacco by way of Agrobacterium-mediated transformation. Analysis of transgenic tobacco plants indicated that (1) immunologically detectable polygalacturonase can be extracted from leaves, roots, and stems of transgenic tobacco plants; (2) only PG2A and PG2B were detectable in transgenic tobacco; (3) the polygalacturonase isozymes present in transgenic tobacco were electrophoretically indistinguishable from the tomato isozymes; (4) the N-terminal sequence, degree of N-linked glycosylation, and extent of oligosaccharide processing were similar in polygalacturonase from transgenic tobacco and tomato; (5) polygalacturonase was properly localized in cell walls of transgenic tissue; (6) the protein was enzymatically active in vitro; however, (7) accumulation of PG2A and PG2B in cell walls of transgenic tobacco did not result in pectin degradation in vivo. These results indicated that tomato polygalacturonase was properly processed and transported to the cell wall of tobacco. However, accumulation of the two polygalacturonase isozymes expressed in this heterologous host was insufficient to promote polyuronide degradation in tobacco leaf tissue.
The hepatic glycine cleavage system (GCS) is the principal route for the metabolism of glycine in mammals. Flux through the GCS in isolated rat hepatocytes was stimulated by about 100% by glucagon (10(-7) M), forskolin (10(-4) M), and dibutyryl cAMP (10(-4) M). The stimulation of flux through the GCS by these agents was accompanied by marked elevation of cellular cAMP levels. A significant correlation was observed between increased cellular cAMP levels induced by glucagon and stimulation of flux through the GCS by glucagon. Exclusion of calcium from the incubation medium reduced the basal flux by 38%, but did not affect the degree of stimulation of flux through the GCS by glucagon. A single intraperitoneal injection of glucagon to rats prior to isolation of hepatocytes resulted in a 76% stimulation of flux through the GCS. These hepatocytes with stimulated flux through the GCS showed reduced sensitivity for further stimulation by glucagon. Half-maximal stimulation of flux through the GCS occurred at 3.8 +/- 1.1 and 8.5 +/- 1.4 nM glucagon in hepatocytes isolated from control and glucagon-injected rats, respectively. We conclude that cAMP is involved in the regulation of flux through the GCS by glucagon.
Fourteen cases of acute lobar atelectasis were alternately allocated to one of two chest physiotherapy regimens for treatment. Treatment in group 1 comprised positioning, vibrations, hyperinflation, and suction, and in group 2, treatment consisted of hyperinflation and suction alone. Treatment in either group was given hourly for six hours. Patients in group 1 had a significantly higher mean percentage resolution of their atelectasis (mean value, 60.1 percent), as seen on chest roentgenogram, after one treatment intervention than patients in group 2 (mean value, 7.6 percent; p less than .006). After the intensive six-hour treatment period, the difference between the groups was marginally statistically significant, still favoring group 1 over group 2 (p less than .055). Follow-up roentgenograms at 24 and 48 hours revealed no significant difference between the treatment groups (p greater than .10 and greater than .20, respectively). These results suggest that, at least initially in the course of acute lobar atelectasis, positioning and vibrations add to the efficacy of a treatment of hyperinflation and suction alone.
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Marfan syndrome is infrequently diagnosed early in infancy. The experience of the authors with 22 severely affected infants diagnosed as having Marfan syndrome in the first 3 months of life is described and the literature on 32 additional infants with Marfan syndrome is reviewed. It was found that serious cardiac pathology (82% of the patients described in the article, 94% of those described in the literature) may be present at birth, and that congenital contractures (64% of our cases, 47% of literature cases) are often an associated finding. Other useful clinical findings included arachnodactyly, dolichocephaly, a characteristic facies, a high-arched palate, micrognathia, hyperextensible joints, pes planus, anterior chest deformity, iridodenesis, megalocornea, and dislocated lenses. Echocardiography was useful as a noninvasive method for defining the extent of cardiovascular involvement and following its course. Characteristic cardiac findings in early life included mitral valve prolapse, valvular regurgitation, and aortic root dilation. Cardiac function ranged from normal to poor, with a tendency to worsen. Of the 22 cases 3 infants died during the first year of life. Morbidity and mortality may be high when Marfan syndrome is diagnosed during infancy, and prompt recognition of this phenotype can facilitate management and counseling. Most such severe cases appear to be due to a sporadic mutation in a single germ cell of one parent. Many familial cases may have milder manifestations, be more difficult to detect during infancy, and have a better prognosis.
To evaluate gonadal function and pregnancy outcome after treatment for acute lymphoblastic leukemia during childhood or adolescence, 44 former patients who were less than 20 years of age at diagnosis, 5 or more years from diagnosis, and 18 or more years of age were contacted. Thirty-nine (88%) provided information regarding pregnancy outcome. Gonadal function as estimated by the ability to conceive or sire a pregnancy, was not impaired despite treatment with substantial cumulative doses of methotrexate, 6-mercaptopurine, vincristine, and 1-asparaginase. Twelve patients reported a total of 27 pregnancies. There were four spontaneous abortions, one stillborn, and 22 liveborn infants. The birthweights were 1928 to 4536 g (median, 3430 g). Two infants had congenital anomalies. The childrens' ages ranged from 1 month to 10 years, 2 months (median, 6 years, 1 month). None has been diagnosed with any type of childhood cancer. The results of this study suggest that pregnancy outcome is not affected adversely by treatment received during childhood or adolescence for acute lymphoblastic leukemia.
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Glucagon stimulates 14CO2 production from [1-14C] glycine by isolated rat hepatocytes. Maximal stimulation (70%) of decarboxylation of glycine by hepatocytes was achieved when the concentration of glucagon in the medium reached 10 nM; half-maximal stimulation occurred at a concentration of about 2 nM. A lag period of 10 min was observed before the stimulation could be measured. Inclusion of beta-hydroxybutyrate (10 mM) or acetoacetate (10 mM) did not affect the magnitude of stimulation suggesting that the effects of glucagon were independent of mitochondrial redox state. Glucagon did not affect either the concentration or specific activity of intracellular glycine, thus excluding the possibilities that altered concentration or specific activity of intracellular glycine contributes to the observed stimulation. The stimulation of decarboxylation of glycine by glucagon was further studied by monitoring 14CO2 production from [1-14C]glycine by mitochondria isolated from rats previously injected with glucagon. Glycine decarboxylation was significantly stimulated in the mitochondria isolated from the glucagon-injected rats. We suggest that glucagon is a major regulator of hepatic glycine metabolism through the glycine cleavage enzyme system and may be responsible for the increased hepatic glycine removal observed in animals fed high-protein diets.
Setleis syndrome, an autosomal recessive disorder characterized by "coarse" face, temporal cutis aplasia, double upper eyelashes, absent lower eyelashes, chronic conjunctivitis, and prominent thick lips, was reported previously in 8 Puerto Rican children. We report on 3 unrelated children (one mentally retarded) with Setleis syndrome who are not of Puerto Rican descent. Two of our patients had imperforate anus, which has not previously been reported. The evolution of the phenotype over time is illustrated.
Mimicry of the nonthrombogenic surface of the erythrocyte has been advocated as the starting point for the development of nonthrombogenic biomaterials. Phosphorylcholine forms 88% of the outer surface of the erythrocyte, and so materials containing it should be nonthrombogenic. We have evaluated the thrombogenicity of such materials and compared them with Dacron and PTFE. Three materials containing phosphorylcholine were used: a naturally occurring phospholipid (dipalmitoylphosphatidylcholine, DPPC), a polymerized phospholipid (diacetylenic phosphatidylcholine, DAPC) and a polyester polyurethane (Polyester G). The thrombogenic potential of these materials was assessed by material thrombelastography (MTEG). This technique uses human whole blood at 37 degrees C, without an air interface, and records the elasticity of the blood clot produced. Since each material is evaluated with a control surface, extraneous differences due to factors other than the test material are eliminated. Analysis, and examples of the MTEG traces are shown and discussed. The phosphorylcholine containing materials were found to have a reduced amount of clotting factor activation, but only DPPC was better than Dacron and PTFE. MTEG demonstrated the known thrombogenicity of Dacron towards platelets. A striking reduction in platelet activation was shown for the three phosphorylcholine containing materials. These three materials show only 25% of the platelet activation of PTFE. These materials warrant further investigation as potentially very useful biomaterials.
Our approach to the design of haemocompatible biomaterials is based upon the concept that coating a polymer or metal surface with phosphatidylcholine polar groups (corresponding to the major phospholipid of the human erythrocyte outer cell membrane) will improve their haemocompatibility. We have examined the effect on blood coagulation of a number of substrates: those normally used in prosthetic devices such as polyethylene terephthalate (Dacron), expanded polytetrafluoroethylene, silicone and new polymers which contain the phosphatidylcholine head group (phosphorylcholine). The effect on coagulation of blood exposed to these substrates was determined by the technique of material thrombelastography, a relatively new method for the in vitro screening of biomaterial thrombogenicity. The results obtained with Dacron, polytetrafluoroethylene and silicone are compared with those obtained with a phospholipid-dipalmitoyl-phosphatidylcholine, a polymerized phospholipid-diacetylenicphosphatidylcholine, and a range of recently synthesized polyesters, each of which contains the phosphorylcholine polar head group.
We have determined the nucleotide sequence of the murine immunoglobulin gamma 2a membrane 3' untranslated region (1413 nucleotides) and approximately 679 nucleotides of downstream sequence. Two AATAAA hexanucleotide sequences are present in the 2092 nucleotide interval. The first one functions as the major polyA signal, directing cleavage and polyadenylation at a site 20 nucleotides downstream. Within 41 nucleotides downstream of the major membrane polyA signal are two sequences with 75% homology to the consensus sequence, (C/T)GTGTT(C/T)(C/T), identified by McLauchlan et al. [Nucl. Acids Res. 13, 1347-1365 (1985)]. An 80% homology match to the Berget consensus sequence, CA(C/T)TG, begins five nucleotides 3' of the major polyA site (used 20 times more than the second, downstream polyA site) [Berget Nature 309, 179-182 (1984)]. The second AATAAA, located 73 nucleotides 3' of the first, directs cleavage and polyadenylation 18 nucleotides downstream at a minor polyA site. One match with 75% homology to the McLauchlan consensus sequence begins 17 nucleotides 3' of the second (weaker) polyA site. No matches to the Berget consensus sequence are located near this second, weaker polyA site.