Biomedical subjects
Publications and source records attributed to J M Milstein.
We describe three infants with large congenital arteriovenous malformations, two intracranial and one intrathoracic, who have high output congestive heart failure but normal pulse pressures. The theoretical basis of these pulse pressure findings in contrast to those in infants with shunting secondary to the patent ductus arteriosus is presented.
We describe the clinical presentation and course of two girls with cerebrovascular disease and mixed connective tissue disease. One developed rapid onset hemiparesis and aphasia secondary to left internal carotid artery occlusion. She experienced a complete recovery after treatment with prednisone and cyclophosphamide. The other patient was diagnosed as having mixed connective tissue disease but had acute neurologic deterioration. She died due to an intracerebral hemorrhage. Autopsy demonstrated small-vessel fibrinoid necrosis. Although cerebrovascular disease secondary to central nervous system vasculitis is a manifestation of systemic lupus erythematosus, this is the first description of cerebrovascular disease as a primary sign in mixed connective tissue disease. These cases demonstrate the range of cerebrovascular disease observed in children with mixed connective tissue disease.
Left ventricular dysfunction has been observed in human infants with pulmonary hypertension. The purpose of this study was to establish whether mechanically increased right ventricular afterload alters left ventricular performance by altering its contractility, configuration, or both. Six neonatal 3- to 7-d-old lambs were acutely instrumented with micromanometer-tipped catheters and two pairs of ultrasonic crystals to measure left ventricular pressure and anterior-posterior and septal-free wall dimensions. The product of these two dimensions, denoted left ventricular area, was used as an index of left ventricular volume. Two levels of mechanically increased right ventricular afterload were induced with a closed pericardium under three levels of left ventricular preload produced by whole-blood transfusions. Four brief increases in left ventricular afterload were induced by constricting the aorta under each right ventricular afterload and preload condition. Using multiple linear regression, we found that the slope of the end-systolic pressure-area relationship, an index of contractility, was unchanged [0.90 +/- 0.11 mm Hg/mm2 (SEM)], and stroke area (65.8 +/- 7 mm2) and cardiac output (the product of stroke area and heart rate) (13,400 +/- 1,660 mm2/min) were maintained. However, the area intercept of the pressure-area line at zero pressure (499 +/- 13 mm2) shifted significantly to the left in the presence of both levels of increased right ventricular afterload (by -39.2 +/- 13 and -76.2 +/- 15 mm2, respectively). Mechanically increased right ventricular afterload alters left ventricular configuration and causes a shift in the operating volume (area) range of the ventricle with no change in contractility in 3- to 7-d-old lambs.
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The latent period to forelimb paresis following photon irradiation of the cervical spinal cord was evaluated in Sprague-Dawley rats ranging in age from 9 days to adulthood. The radiation was administered dorsally in single fractions, and in 15-day-old animals, to different lengths of the rostral cord and in doses ranging from 16 to 38 Gy. The duration of the latent period was found to be directly proportional to the age of the animal at the time of irradiation, and independent of radiation dose or the volume of the cervical cord which was irradiated. In the majority of paretic animals, the irradiated segment of the spinal cord demonstrated white matter necrosis. The results indicate that in the developing rat, the manifestations of radiation myelopathy are delayed by an interval determined in part by the age of the animal at the time of irradiation.
Over a two year interval, we have treated five children with neurofibromatosis who developed brainstem gliomas. They had an insidious onset of symptoms and other indicators of low grade tumor despite several features that have been ascribed to rapidly progressive brainstem gliomas. Following standard radiation therapy a more protracted improvement was observed with the persistence of preradiation findings for several months. This experience confirms the better prognosis in brainstem glioma associated with neurofibromatosis.
A premature female infant born of a consanguineous union exhibited joint contractures and signs and symptoms of perinatal asphyxia. A muscle biopsy examined by light microscopic, histochemical, and electron microscopic techniques exhibited changes of muscle phosphorylase deficiency and glycogenosis, identical to those of McArdle's disease. Postmortem ultrastructural examination of liver and heart did not reveal lysosomal storage. This case and one previously reported example of fatal infantile phosphorylase deficiency suggest that the clinical spectrum of McArdle's disease may be broader than previously recognized.
To investigate the interactions between methotrexate (MTX) and irradiation of the central nervous system, adult rats were infused with MTX via the lateral cerebral ventricle either before, during, or following single fraction irradiation to the cervical spine. Single doses ranging from 1600 cGy to 3200 cGy were administered and the dose-response curve for forelimb paralysis was compared with that seen in irradiated animals which did not receive MTX. There was no effect on the dose-response curve when MTX was administered simultaneously with or following irradiation compared to radiation alone. When MTX was given prior to irradiation, however, the entire dose-response curve shifted in the direction of radioprotection by approximately 225 cGy. Histopathologic examinations were consistent with this observation, with animals pretreated with methotrexate demonstrating significantly less white matter necrosis than observed in untreated controls. Protection of normal CNS tissue from radionecrosis, and from the associated paralysis, may be achieved with preradiation methotrexate.
The toxicity of a new chemotherapeutic regimen for CNS tumors using eight anticancer agents administered in a 12-hour period was evaluated in 34 children with newly diagnosed and recurrent tumors treated at the Children's Hospital and Medical Center in Seattle. The chemotherapy included methylprednisolone, vincristine, lomustine (CCNU), procarbazine, hydroxyurea, cisplatin (CDDP), and either cyclophosphamide or imidazole carboximide (DTIC). The first five patients additionally received high-dose methotrexate (HDMTX), but because of excessive toxicity this was replaced by cytarabine. Of 125 courses administered without HDMTX, red cell transfusions were required in 15% of the courses and platelet transfusions were required in 8%. Hospitalization for empiric treatment of fever associated with neutropenia occurred in 6% of courses. Three episodes of documented sepsis occurred. Virtually all hematologic toxicity occurred in patients with recurrent disease. Renal toxicity occurred in 14% of patient courses. One patient died of renal failure and sepsis following therapy. Neurologic and hepatic complications were infrequent. High-frequency hearing loss above the voice range was common, but clinically significant hearing loss occurred in only three patients. Severe nausea and vomiting were infrequent. Overall, the toxicity of "eight in one" chemotherapy in newly diagnosed patients was minimal; toxicity was greater in patients with recurrent disease.
A 16-year-old male with a 9-year history of spontaneously arrested hydrocephalus was noted to have hydrosyringomyelia and increased intracranial pressure shortly after sustaining minor head trauma. His symptoms resolved completely following ventriculoperitoneal shunt replacement. Hydrosyringomyelia may occur in the setting of long-standing, apparently arrested hydrocephalus.
This report describes a laboratory model that permits study of the radiochemotherapy interactions in the CNS. Rats are stereotaxically implanted with a cerebroventricular cannula attached to an osmotic minipump, which slowly infuses a chemotherapeutic agent into CSF for up to 14 days. The cervical cord is irradiated, and forelimb paralysis develops 4-6 months later at an effective dose for paresis in 50% of the animals; the doses with radiotherapy alone are 2,125 cGy for a single fraction and 2,950 cGy for split fractions. Investigations with the model indicate that mature CNS tissue is not sensitized to either single-fraction or split-dose irradiation with either simultaneous or post-radiation exposure to high concentrations of methotrexate.
The effects of acutely increased right ventricular afterload induced by mechanical constriction of the main pulmonary artery or with alveolar hypoxia on function of the left ventricle were assessed in six and nine lambs, respectively (aged 1 to 3 days). Mechanical constriction of the main pulmonary artery in newborn lambs compromised left ventricular function with significant decreases in systemic blood flow and the peak first derivative of left ventricular pressure when considered simultaneously and as single variables. In contrast, alveolar hypoxia augmented left ventricular function with significant increases in systemic blood flow and the peak first derivative of left ventricular pressure when considered simultaneously or as single variables. Interaction appears to exist between the right and left ventricles during the newborn period. The mechanically increased afterload may have compromised left ventricular function by altering its end-diastolic size, inotropic state, or both. On the other hand, the augmented left ventricular function in the presence of hypoxia may have been due to an increase in inotropic background. The clinical implications in some infants with pulmonary hypertension and left ventricular dysfunction are raised.
The development of a new multidrug chemotherapy regimen for primary brain tumors was based upon the cellular heterogeneity within individual tumors, the Goldie-Coldman and Price-Goldie-Hill hypotheses, and known agonistic effects of certain drug combinations and sequences. Eight drugs (vincristine [VCR], hydroxyurea, procarbazine, CCNU, cisplatin, cytosine arabinoside [Ara-C] high-dose methylprednisolone, and either cyclophosphamide or dacarbazine) were administered within 12 hours in an attempt to minimize myelosuppression. Courses were repeated at 2- to 4-week intervals. The regimen was devised to include lipid and water soluble drugs, polar and nonpolar agents, phase-specific and cell-cycle independent agents, and antineoplastics with different mechanisms of action. More than 330 courses of the regimen were administered to 107 children with brain tumors whose tumor had recurred or had been incompletely resected at diagnosis. Tumor response according to protocol-specified criteria and independent review was evaluable in 78% of the patients. After just two cycles of chemotherapy and within a 4- to 6-week interval, 50% had an objective tumor response including 15.5% who had a complete response (CR). Nephrotoxicity and high-frequency hearing losses were noted after three to five courses of therapy in approximately half of the patients. Transfusions with red cells or platelets and use of antibiotics for fever and neutropenia were required in 10% to 25% of patients. The regimen appears satisfactory for preradiation chemotherapy in newly diagnosed patients with residual tumor after surgery, but it must be compared with standard therapeutic approaches in prospective controlled trials before its relative value can be established.
The hemodynamic effects of N2O and N2O plus hypoxia were studied in six lambs (0-3 days of age) that were instrumented with pulmonary artery flow probes and catheters, as well as aortic and left atrial catheters. N2O was administered to the awake lambs through a mask in mixtures of 75% N2O:25% O2 and 75% N2O:11% O2:14% N2. Pulmonary arterial pressure and resistance increased significantly upon exposure to N2O both during normoxia and hypoxia, and nitrous oxide also significantly elevated left atrial pressure and decreased pulmonary artery blood flow during normoxia. Aortic pressure was essentially unchanged by nitrous oxide. The data indicate that in newborn lambs the pulmonary vasculature responds to N2O with vasoconstriction.
The neurologic examination is important in the early diagnosis of brain tumors in children. Only in brain stem gliomas may the neurologic examination be better than computed tomographic scans in determining the progression. However, in general, the traditional neurologic examination has little or no value for prognosis. Reversible, associated features of brain tumors such as seizures or increased intracranial pressure may alter the patient's ability to function neurologically, but may not influence the prognosis regarding the tumor status. The Karnofsky functional status, to a large extent, reflects an adult's ability to work and has prognostic value but is largely inapplicable to children. Thus, a quality-of-life scale for children is needed.
Balloon distention of the left pulmonary artery (PA) was produced in 14 lambs (aged 1 to 3 days) to assess whether an increase in systemic vascular resistance results from such distention. The lambs were anesthetized with chloralose and instrumented to enable measurement of systemic blood flow, PA pressure, aortic pressure, heart rate and right atrial pressure. PA distention resulted in an increase in systemic vascular resistance and aortic pressure (p less than 0.05). This result was probably due to a systemic vasoconstrictor response, since systemic blood flow and right atrial pressure did not change significantly. Limited trials using autonomic blocking agents suggested that the response is either a reflex under autonomic control or a response to humoral release of alpha-adrenergic substances. In conclusion, some interdependence appears to exist between the systemic and pulmonary vascular beds. It is postulated that such changes may be important in fetal life when they may affect redistribution of cardiac output during adaptation to hypoxemia.
Four newborns had tracheal agenesis and numerous features of the VATER (vertebral defects, imperforate anus, tracheoesophageal fistula, and radial and renal dysplasia) association. Forty-two additional reported cases of tracheal agenesis have been reviewed to establish whether this defect usually occurs in association with other VATER abnormalities. Since tracheal agenesis usually is accompanied by other VATER-associated defects and since similar abnormalities in embryological mechanisms and timing are implicated, according to current theories of development, we propose that tracheal agenesis should be considered a component of the VATER association.
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