HCMR interview: Montague Brown.
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Biomedical subjects
Publications and source records attributed to M Brown.
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A patient with sickle cell trait and pernicious anemia in relapse may appear to have sickle thalassemia because HbA2 levels can be elevated and the peripheral blood smear may contain target cells, teardrop cells, and eliptocytes. A normal hemoglobin alpha:beta chain ratio, a megaloblastic bone marrow, and correction of the abnormal hematologic morphology after administration of vitamin B12 will establish the correct diagnosis.
The fluid-bridge test (FBT) detects the entry of urine into the proximal urethra during coughing. In this study it was applied in the investigation of incontinent patients when they were first supine and then standing up. The test results in 76 women with urinary incontinence and 27 women with normal urinary control are reported. When the test was performed erect at 0.5 cm from the urethrovesical junction, it was positive in 68 (90%) of the study group and 4 (15%) of the controls. The difference between the results in the 2 groups is highly significant (P less than 0.001). In 12 (16%) of the incontinent group the test at 0.5 cm became positive only when the subject was standing up, indicating that erect testing adds to the diagnostic efficiency of the method. Erect testing seems more relevant to the investigation of stress urinary incontinence. This study has shown that this is possible using simple urodynamic apparatus.
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Somatostatin-28 (SS-28) is 380 times as potent as somatostatin-14 (SS-14) to inhibit acutely insulin secretion induced by arginine in vivo; SS-28 is only 3 times as potent as SS-14 to inhibit glucagon secretion induced by arginine. D-Trp substitution in position 28 of SS-28 increase potency to 2600 times that of SS-14 for inhibition of arginine induced insulin secretion. SS-28 in 10 and [D-Trp22]-SS-28 is 100 times as potent as SS-14 to act within the central nervous system to inhibit bombesin induced hyperglycemia. SS-28 compared to SS-14 shows pancreatic beta-cell and brain selectivity of action.
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Several neural peptides have been demonstrated to influence central nervous system control of nutrient metabolism. The principal mechanism by which these peptides influence peripheral nutrient metabolism is by altering the secretion of adrenal epinephrine. Bombesin or its mammalian counterpart, gastrin releasing peptide, and TRF act within the brain to stimulate the secretion of epinephrine from the adrenal gland. Associated with these changes in epinephrine secretion is a reduction of plasma insulin and elevation of plasma glucagon and glucose. Somatostatin and various somatostatin analogs act in the brain to inhibit adrenal epinephrine secretion stimulation by a variety of stimuli.
Thyrotropin-releasing factor (TRF), somatostatin, and bombesin-like peptide are present in the brain and may be involved in central nervous system (CNS) control of visceral functions. All three peptides exert potent actions to modify animal thermoregulation. TRF and somatostatin or somatostatin analogs act within the brain to influence parasympathetic and sympathetic outflow resulting in changes of adrenal epinephrine secretion, gastric acid secretion, heart rate, and blood pressure. Bombesin acts within the brain to increase adrenal epinephrine secretion and to inhibit gastric acid secretion without influencing other sympathetic or parasympathetic activities. These peptides and others may be important physiological regulators of CNS information processing related to a variety of visceral systems.
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Strategic planning and marketing for regional multihospital systems requires aids far greater in scope than those needed by single institutions. In the first place, planners for a regional system must be able to determine effects of its actions throughout the region, taking into account competitive interactions among a large number of institutions. This requires a much greater degree of sophistication than is usually found at the level of the single institution. Moreover, this greater sophistication cannot be bought at the expense of speed or demands on the time of the decisionmakers, nor can it be achieved through more sophisticated managerial skills. The aids must also be able to handle expeditiously a far larger volume of inquiry. Those two considerations shaped the design of the Multihospital Strategic Planning Model. Because of its comprehensiveness, the ease with which management can use it, and the speed with which it can answer a large volume of questions, it has become a permanent part of the ongoing corporate-level planning and marketing activities of the Maryland Health Care System in Baltimore. The planning staff can quickly analyze a wide variety of "What if?" questions by making selected changes--on an objective or a subjective basis--in the data files that represent the input variables of the system. By storing such changes in new data files, the staff can piggyback future "What if?" questions onto those asked in the past. The system includes on-line software to change data and create new files. Designed in an interactive mode, the system may be used by the planning staff, in the planning office, at any time.
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Gastrin-releasing peptide is a 27-amino acid peptide recently isolated from porcine gut. It shares a common C-terminal decapeptide homology with bombesin (except for a His/Gln interchange at residue 8 from C-terminus). Synthetic porcine gastrin-releasing peptide was shown to release gastrin 5 min after intravenous injection in rats. Given intracisternally (0.3--3 microgram), but not intravenously (1--10 micrograms), gastrin-releasing peptide caused a dose-dependent reduction in gastric secretion (volume and acidity) and elevation in plasma gastrin levels measured 2 h after peptide injection and pylorus ligation in rats. Gastrin-releasing peptide given intracisternally had long acting, reversible, and specific inhibitory effects. Gastrin-releasing peptide blocked the secretion of acid evoked by 2-deoxy-D-glucose or TRH given intracisternally or by histamine given subcutaneously. The acetylated C-terminal octapeptide fragment of gastrin-releasing peptide inhibited gastric acid secretion as effectively as gastrin-releasing peptide. Acetylated C-terminal heptapeptide did not. These results demonstrated that gastrin-releasing peptide has the capability to act in the brain to inhibit basal and stimulated gastric secretion and its antisecretory effect does not depend on a decrease in gastrin release. The presence of bombesin immunoactivity in rat brain and its ability to act through the brain to inhibit gastric acid secretion suggest that bombesinlike peptides may be chemical messengers involved in central nervous regulation of gastric secretion.
Three chemotherapeutic agents, chlorambucil, mustargen, and BCNU-409962, being investigated for their possible clinical use in conjunction with radiation therapy have been shown in vitro to dramatically affect the characteristics of standard radiation survival curves (in V79 cells and spheroids). The agent mustargen, at a concentration of 0.25 microgram/ml administered 1 hour prior to 9-MeV-electron exposure, had a significant effect in reducing D0. The 165-rad D0 observed in control curves was reduced to 105 rads in the presence of drug. One hour preincubation with BCNU (prior to radiation exposure) at a concentration of 3.0 microgram/ml was found to dramatically reduce the initial shoulder region with n number values for drug curves approximately one-half those seen for controls. No effect is seen when chlorambucil is combined with radiation in exponential or confluent cultures but an enhancement ratio of 1.8 is found when intact spheroids are pretreated with this drug.
We have characterized some of the physiology of multicellular spheroids of different sizes grown from Chinese hamster lung fibroblast (V79) cells. Among the parameters studied were oxygen tension distributions within the spheroid. This was achieved using ultramicroelectrodes with tip diameters of 1-5 mu and a perfusion system whereby environmental conditions such as flow, temperature, and chemical makeup of the milieu could be measured and controlled. Plateau pO2 values of less than 10 mm Hg were consistently obtained from spheroids under various conditions. We were able to modify these distributions by use of indirect radiation sensitizer drugs such as mechlorethamine HCl (mustargen) at nontoxic doses. We have also made determinations of the inhibitory capacities of several other drugs on the respiration rate of constituent cells of multicellular spheroids in single-cell suspensions. We have concluded that there are indeed hypoxic cells in spheroids whose radioresistance may be modified by essentially nontoxic levels of indirect radiosensitizer drugs and that the system described shows great promise for screening agents which may modify radiation response.
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A study of mastoid operations undertaken for various chronic middle ear entities, using closed and open techniques, revealed the following: 1. Marsupialized mastoid balls were found less disappointing than often considered; small cavities were dry in 90 percent and large ones in 70 percent of cases. 2. Residual disease (epidermoid cysts) appeared in 27 percent of the CAT-operated ears and in 13 percent when the open technique was employed. 3. Residual disease appeared twice as often when the primary disease involved the tympanic cavity and in young patients than when the attic and mastoid were exclusively involved or in older patients. 4. Residual disease did show up only in epidermoid ("attic") cholesteatomas, but not when the primary pathology was a retraction pocket (sinus tympani) cholesteatoma. 5. Up to 56 percent of the CAT-operated ears showed small, medium, or large retraction pockets. However, only large retraction pockets were of clinical significance. 6. The posterior wall, when preserved, atrophied to an important degree in about a tenth of the cases. 7. Significant atelectasis appeared in about a third of the ears once the membrana tensa was preserved, that is, in CAT or conservative radical operations. 8. About 10 percent of CAT operations performed in children may lead to an episode of acute mastoiditis.
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