Cerebral vasomotor responses after recombinant interleukin 2 infusion.

The effects of systemic human recombinant interleukin 2 (rIL-2) infusion upon both the vasoconstrictor effect of hypocapnia and the endothelium-dependent vasodilator effect of acetylcholine (Ach) were examined in anesthetized rats equipped with cranial windows. Prior to the functional studies, each of six animals received an i.v. infusion of rIL-2 (6 x 10(5) IU/kg) every 8 h for 3 days. At the same time, six control animals received infusions of equivalent volumes of sterile water. Eight h after the final infusion, each animal was anesthetized and equipped with a cranial window for the observation of pial arterioles overlying the left frontoparietal cortex. Pial arteriolar diameters were measured before and after the topical application of Ach which in normal cerebral arterioles elicits the release of endothelium-dependent relaxing factor, causing vasodilation. When arteriolar diameters returned to base line, they were measured again both before and during hyperventilation-induced hypocapnia. Following functional assessments, these same pial vessels were processed for study by transmission electron microscopy to determine if any observed functional changes correlated with morphological abnormality. Results of the statistical analyses suggested that normal Ach-induced endothelium-dependent vasodilation was absent in the rIL-2-infused group. Additionally, these animals exhibited reduced reactivity to the vasoconstrictive effects of arterial hypocapnia. The control group exhibited normal responsiveness to both Ach and hyperventilation. Ultrastructural studies revealed occasional morphological alterations of both vascular smooth muscle and endothelial cells in some vessels of rIL-2-infused animals but not in controls. These data suggest that repeated systemic rIL-2 infusion results in altered vasomotor responsiveness within the cerebral microcirculation. The data also suggest that the observed vasomotor changes are not always accompanied by overt morphological alterations of either endothelial or smooth muscle cells.

Blood-brain barrier dysfunction in cats following recombinant interleukin-2 infusion.

The effects of systemic human recombinant interleukin-2 (rIL-2) infusion upon blood-brain barrier status and cerebral vascular ultrastructure were examined in cats. Each of eight animals received a single bolus i.v. infusion of rIL-2 (100,000 units/kg). Six control animals were infused with rIL-2 excipient only. Following a 1-h postinfusion survival time, the brain tissue of five rIL-2 infused and three excipient infused animals was processed and examined by light microscopy and electron microscopy for evidence of altered cerebrovascular permeability to systemically circulating horseradish peroxidase. The brain tissue of three additional rIL-2 infused animals and three excipient infused animals, sacrificed 4 h postinfusion, was examined at the light microscopic and electron microscopic levels for the presence of extravasated endogenous IgG. All animals infused with rIL-2 and four of six excipient infused animals showed increased cerebrovascular permeability to the probe used. Altered blood-brain barrier permeability, when present, was recognized in multiple loci throughout the brain, being most prominent within white matter regions. Horseradish peroxidase and IgG were observed within perivascular basal laminae and within the interstices of the brain parenchyma. Numerous endothelial lesions were observed as was flooding of endothelial cytoplasm by horseradish peroxidase or IgG. Every animal studied, regardless of permeability status, showed, within the perivascular brain parenchyma, numerous disrupted neuronal and glial processes as well as expanded intercellular spaces. This study suggests that a single systemic infusion of rIL-2 profoundly alters blood-brain barrier integrity and cerebrovascular morphological integrity. The data also suggest that some of the observed cerebrovascular effects of systemic rIL-2 infusion are due to components of the vehicle for rIL-2.

Examination of the blood-to-brain transfer of alpha-aminoisobutyric acid and horseradish peroxidase: regional alterations in blood-brain barrier function following acute hypertension.

Blood-brain barrier (BBB) alterations following acute hypertension were studied in rats, employing as tracers in each animal both horseradish peroxidase (HRP) (MW 40,000) and [14C]alpha-aminoisobutyric acid ([14C]AIB) (MW 104). Eighteen animals were subjected to acute hypertension induced by the intravenous infusion of norepinephrine bitartrate (NE) (Levophed). Five animals injected with both tracers but not infused with NE served as controls. The brain of each animal was serially sectioned with adjacent sections processed either for macroautoradiography or for light microscopic visualization of HRP reaction product via histochemical reaction with tetramethylbenzidine. Quantitative blood-to-brain transfer constants for AIB were determined in each of 14 brain regions. Qualitative comparisons were also made between the AIB and HRP blood-to-brain extravasation patterns in each group. Acute hypertension increased cerebrovascular permeability to both AIB and HRP in most animals. Topographically, the sites of the most highly elevated AIB transfer corresponded with sites of HRP extravasation. Conversely, all sites of protein passage corresponded spatially to sites of elevated AIB transfer. Brain regions commonly showing increased permeability to both tracers included the cerebral cortices, corpus callosum, and thalamus. Importantly, some brain regions showed elevated AIB transfer constants where protein extravasation was absent. These regions included the caudate-putamen, hippocampus, basal forebrain, and cerebellum. These observations suggest that following acute hypertension, alterations in BBB permeability are not limited to vascular segments allowing protein extravasation.

Appearance of cytokine-associated central nervous system myelin damage coincides temporally with serum tumor necrosis factor induction after recombinant interleukin-2 infusion in rats.

Endogenous tumor necrosis factor (TNF) activity, assessed by L-929 fibroblast bioassay, was determined in serum samples from rats infused intravenously with recombinant interleukin-2 (rIL-2) or rIL-2 vehicle. Parallel studies of cerebral ultrastructure were conducted in additional rats, comparably infused. Rats received rIL-2 or vehicle either one time only or 3 times daily for 3 days. TNF activity was assessed at 2, 4, and 8 h after the single or final infusion. Rats employed for ultrastructural studies were sacrificed at 4 h after the single or final infusion. Every rIL-2-infused rat exhibited unusual abnormalities of axonal ultrastructure, identical to those previously described after in vitro TNF application to living spinal cord slices. Serum samples drawn during and after the development of axonal changes revealed significantly elevated circulating TNF activity. Controls exhibited neither TNF activity nor altered axons. These studies demonstrate that, following rIL-2 infusion in rats, endogenous TNF circulates at elevated levels during the development of rIL-2-related central nervous system abnormalities similar to those produced in vitro by recombinant TNF. Whether rIL-2-induced circulating TNF is causally-related to the observed myelin damage remains to be determined but merits further investigation, particularly since blood-brain barrier function has been shown to be compromised following rIL-2 infusion.

Differential central nervous system responses following single and multiple recombinant interleukin-2 infusions.

The effects of systemic recombinant human interleukin-2 (rIL-2) infusion on cerebrovascular permeability to an endogenous circulating macromolecule, immunoglobulin G (IgG), were assessed in rats after single and multiple rIL-2 infusions. Ultrastructural detail of the cerebral vasculature and the related brain parenchyma was also examined for rIL-2-related changes following single and multiple infusions. Animals examined 6 and 24 h after a single rIL-2 infusion exhibited moderately increased permeability to IgG that was not observed in those animals examined 6 h after 5 days of rIL-2 infusion. Alterations of cerebrovascular morphology were evident as early as 6 h after a single infusion and were accompanied by occasional axonal degeneration and demyelination. Such structural changes persisted, becoming more widespread after 5 days of rIL-2 infusion, at which time they were associated with other neuronal as well as glial alterations.

When perfectly HLA-matched kidneys are refused for transplant: implications for a national cooperative sharing system.

BACKGROUND: The transplant community attempts to maximize overall renal graft survival rates through nationwide sharing of perfectly-matched cadaveric kidneys. Although the number of such transplants is determined annually, the number available but not transplanted has never been assessed. There has also been no verification of the widespread claim that kidneys transplanted as paybacks for perfect matches are inferior. STUDY DESIGN: From records of the United Network for Organ Sharing, a complete accounting of six-antigen-matched kidney disposition was obtained, including a frequency distribution of reasons for refusal given when kidneys were refused for matched patients. Actuarial graft survival (GS) rates for matched, payback, and other cadaveric renal transplants were determined. RESULTS: Of the six-antigen-matched kidneys available, 97 percent were transplanted; 71 percent of those were accepted for matched patients. The two-year GS rate for matched patients was 84 percent, significantly higher than that for kidneys available for matched patients but transplanted into other patients (71.3 percent) and that for all other cadaveric kidneys (75.5 percent). Most reasons for refusal were related to donor quality. Kidneys refused for such reasons showed a 67.7 percent two-year GS rate in nonmatched patients and the highest rates of acute and chronic rejection and primary failure. The two-year GS rate for kidneys accepted as paybacks for matched kidneys (75.7 percent) was equivalent to that for all non-matched cadaveric kidneys (75.5 percent). CONCLUSIONS: If all normal-quality grafts refused for perfectly matched patients during 1990 through 1992 had been accepted for those patients, the number of transplants with typically superior survival rates could have increased by 25 percent, from 1,365 to 1,704. The payback requirement of the United Network for Organ Sharing does not seem to reduce the overall benefits of sharing perfectly matched kidneys nationwide.

Avoidance of primary post-tonsillectomy hemorrhage in a teaching program.

OBJECTIVE: To determine the incidence of primary post-tonsillectomy hemorrhage in a teaching institution by using a uniform technique, including a 3-minute relaxation of retraction before case termination and the use of bismuth subgallate. DESIGN: Case series. SETTING: Tertiary care academic pediatric center. PATIENTS: A 7-year retrospective study was performed by using the medical records of 1286 children without a bleeding abnormality who underwent tonsillectomy (with or without adenoidectomy). A uniform technique, proposed to reduce hemorrhage, was used for 705 children and was not used for 581 children. RESULTS: No episodes of primary hemorrhage (onset < or = 24 hours after surgery) occurred, and the incidence of delayed hemorrhage (onset >24 hours after surgery) was 1.1% in the study group. The primary hemorrhage rate of the study group was significantly lower (P = .007) than the rate for the reference group (0.0% vs 1.0%), as was the total hemorrhage rate (1.1% vs 4.1%) and the delayed hemorrhage rate (1.1% vs 3.1%). CONCLUSION: A uniform technique including the use of bismuth subgallate and reassessment of the tonsillar fossae after a 3-minute observation period reduces the incidence of primary tonsillar hemorrhage in a teaching institution setting.

Report of the first case of invasive fungal sinusitis caused by Scopulariopsis acremonium: review of scopulariopsis infections.

Scopulariopsis acremonium is a species of saprophytic fungus not previously reported to cause invasive disease in humans, although invasive infections from other species of Scopulariopsis have been reported and are reviewed. Deep infection with this fungus is associated with a high mortality rate. Invasive fungal sinusitis, in general, is a potentially fatal disease that typically affects immunocompromised patients, such as those receiving intensive chemotherapy or undergoing bone marrow transplantation. We report a case of invasive fungal sinusitis caused by Scopulariopsis acremonium in a patient with leukemia, who was successfully treated with amphotericin B, itraconazole, endoscopic sinus surgery, and granulocyte colony-stimulating factor.

Screening for cancers of the head and neck: addressing the problem.

More than 90% of upper aerodigestive tract (UADT) cancers occur in people with specific lifestyle risks, including tobacco and alcohol use. More than 90% of tumors occur in easily examined parts of the head and neck, therefore, there is the possibility of identifying the vast majority of patients through selective screening. Physicians should keep in mind that the mucosa's sojourn from visually suspicious (and possibly malignant) tissue is most likely less than two years, and frequent examination of asymptomatic patients is necessary. When patients wait to bring symptoms to medical attention, their cancers will be advanced 60% of the time when the chance of cure is less than 30%. Given the difficulty of implementing regular examinations in a poorly compliant, high risk population, genetic and molecular screening tools may allow very high risk individuals to be identified.