247. Das lysosomale Enzymspektrum und Proteinaseninhibitoren menschlicher Leukocyten

Zusammenfassung In experimentellen Untersuchungen wurden Zusammenhänge zwischen posttraumatischen leukocytären Infiltrationen des Lungeninterstitiums und ödematösen Lungenveränderungen aufgezeigt. Aus menschlichem Frischblut wurden Leukocytenkonzentrate hergestellt, deren Lysosomen isoliert und Enzyme extrahiert. Vier neutrale Proteinasen konnten nachgewiesen und durch ihre spezifischen Substrate Bowie ihr Inhibitorspektrum charakterisiert werden. Die leukocytäre Kininogenase ist durch den therapeutisch anwendbaren polyvalenten Proteinaseninhibitor Trasylol®, hemmbar. In Tierversuchen wurde die pathogenetische Bedeutung der Kinine für die Ödembildung nachgewiesen. Der polyvalente leukocytäre Proteinaseninhibitor ist nur in geringer Menge nachweisbar.

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Lysosomal enzymes and proteinase inhibitors of human leukocytes

Summary Experimental investigations were carried out to correlate posttraumatic leukocyte infiltration of lung interstitium and edema formation. From human leukocyte lysosomes, four different neutral proteinases could be extracted and characterized by means of their specific substrates and their inhibitor spectra. Granulocyte kininogenase was sensitive to inhibition by Trasylol®, a polyspecific therapeutic proteinase inhibitor. In morphologic experiments on rabbits, the participation of kinins in the events leading to pulmonary edema is made obvious. The existence of small amounts of a polyvalent proteinase inhibitor of leukocyte origin could be shown.

     

Acute and embryo-larval toxicity of phenolic compounds to aquatic biota

Because of the prevalence of phenolic compounds in various types of effluents, both acute and embryo-larval bioassays were performed on eight phenolic compounds with rainbow trout, fathead minnows andDaphnia pulicaria. In flow-through bioassays, the 96-hr LC₅₀ values for rainbow trout and fathead minnows ranged from <0.1 mg/L for hydroquinone to >100 mg/L for resorcinol.Daphnia pulicaria was consistently the least sensitive species tested as measured in 48-hr bioassays, while fathead minnows and rainbow trout varied in their relative sensitivity to phenolics as measured in 96-hr tests. Fathead minnows were more sensitive to phenol at 25°C than at 14°C.In embryo-larval bioassays with phenol, fathead minnow growth was significantly reduced by 2.5 mg/L phenol, while rainbow trout growth was significantly reduced by 0.20 mg/L phenol. For both species the embryolarval effects concentration was 1.1% of the 96-hr LC₅₀. Another embryolarval bioassay was attempted withp-benzoquinone, a highly toxic phenolic compound found in fossil fuel processing wastewaters, which was discontinued because the compound was rapidly degraded chemically or biologically in the headtank and aquaria.Work funded under an Interagency Agreement between the U.S. Department of Energy and the U.S. Environmental Protection Agency under Contract No. DE-AS20-79 LC 01761 to the Rocky Mountain Institute of Energy and Environment, University of Wyoming.     

Successful treatment of mastodynia with the prolactin inhibitor bromocryptine (CB 154).

Mastodynia has previously been treated with gestagens or gestagen-based ovulation inhibitors with only marginal success. No other satisfactory therapy was available and in the search for a better treatment, the effectiveness of long term administration of the prolactin inhibitor bromocryptine (CB 154) to 15 patients was evaluated. Five of the subjects exhibited mammary secretion as well as mastodynia which, accorind to palpatorial, cytological and X-ray criteria, was not caused by intraductal pathology. After two to four weeks treatment with 5 mg CB 154 per day ten patients recovered fully, three showed some improvement and two were totally resistant to the treatment. Plasma prolactin levels during the follicular stage measured prior to treatment were in the normal range. All the patients continued to ovulate during the course of treatment despite the irrefutable fact that prolactin release from the pituitary was inhibited. Since there was a similar inhibition of prolactin secretion in the two patients who were resistant to treatment, it would seem that prolactin though probably very important, cannot be the only decisive factor in the hormonal control of mystodynia. Further observations showed that the premenstrual syndrome can also be successfully treated with CB 154. Upon withdrawal of treatment the possibility or relapse must be considered.     

Early complications in children with acute lymphoblastic leukemia presenting with hyperleukocytosis

BACKGROUND: The optimal management of childhood acute lymphoblastic leukemia (ALL) with hyperleukocytosis is unclear, largely because the risk of leukostasis-related complications is poorly characterized. PROCEDURE: We reviewed the presenting characteristics, initial management, and frequency and type of complications in all children seen at St. Jude Children's Research Hospital with previously untreated ALL and an initial leukocyte count >200 x 10(9)/L. RESULTS: A total of 178 children, representing 8% of all children with ALL, had an initial leukocyte count >200 x 10(9)/L; 67 patients had a leukocyte count >400 x 10(9)/L. Sixteen patients (9%) had neurological complications with 12 of these patients experiencing symptoms at presentation. Four patients (2%), all with initial leukocyte counts >400 x 10(9)/L, suffered a CNS hemorrhage. Pulmonary leukostasis occurred in 11 patients (6%). The degree of hyperleukocytosis was significantly predictive of neurological (P = 0.006) and respiratory (P = 0.014) complications. The majority of complications occurred at presentation. Cytoreduction (94 patients) decreased the leukocyte count but delayed initiation of chemotherapy (P = 0.013). CONCLUSIONS: Serious leukostasis-related complications are relatively uncommon in childhood ALL and most occur at presentation. Their incidence increases in proportion to the leukocyte count. A large subset of cases can be managed successfully without cytoreduction. Cytoreduction may be considered for patients with leukocyte counts >400 x 10(9)/L or patients who have complications at presentation.     

Regulation of hematopoietic stem cell aging in vivo by a distinct genetic element

Until recently, stem cells were thought to be endowed with unlimited self-renewal capacity and, thus, assumed exempt from aging. But accumulating evidence over the past decade compellingly argues that a measurable and progressive replicative impairment in the hematopoietic, intestinal, and muscle stem cell activity exists from adulthood to old age, resulting in a decline in stem cell function and rendering stem cell aging as the possible link between cellular aging and organismal aging. By using a previously uncharacterized congenic animal model to study genetic regulation of hematopoietic stem cell aging, we have demonstrated definitively that a locus on murine chromosome 2 regulates hematopoietic stem cell aging. In addition to demonstrating that hematopoietic stem cell aging is regulated by a distinct genetic element, experimental evidence links the response of hematopoietic stem cells to DNA double-strand breaks to cellular aging, suggesting DNA integrity influences stem cell aging.     

Purine level regulation during energy depletion associated with graded excitatory stimulation in brain

OBJECTIVES: The formation and release of adenosine following graded excitatory stimulation of the brain may serve important physiological functions such as sleep regulation, as well as an early resistance mechanism against excitotoxicity. However, adenosine at high levels may reflect merely the results of obstructed energy metabolism. METHODS: We examined the extent to which levels of adenosine and adenylate energy charge are affected in vivo by graded excitatory stimulations of brain using unilateral intrastriatal injections of glutamatergic agents and head-focused high energy microwaving for accurate and precise measures of purines. RESULTS: Our results confirmed that adenosine levels rise when adenylate energy charge decreases and showed that these increases occurred in three distinct phases with the rate of adenosine formation in each phase increasing as tissue adenylate energy charge was further depleted. In addition, we observed that, in most cases, the effects of focal excitatory stimulation on changes in tissue purine levels were restricted spatially within the immediate vicinity of the injection site; however, when strongly depolarizing stimuli were used, changes in purine levels could be observed in adjacent and, occasionally, even in contralateral brain regions. DISCUSSION: These results provide new insight into purine regulation that occurs under physiologically relevant conditions, such as sleep and during the early stages of brain insults that induce excitotoxicity.     

Delayed versus immediate surgery in acute appendicitis: do we need to operate during the night?

Background/purpose

Over the last 4 years, the authors changed their management of acute nonperforated appendicitis from emergent surgery within the first 2 to 6 hours of admission to initiation of antibiotic therapy with operation within 24 hours of admission in those seen in the late evening or early morning. They examined, therefore, whether a delay in operation for acute appendicitis would affect outcome measures of patient morbidity and resource use.

Methods

The medical records of 126 patients with acute appendicitis occurring between 1998 and 2001 were retrospectively reviewed. Incidence of perforation at surgery, length of stay (LOS), hospital charges, operating time, and complications as a function of duration between emergency room (ER) triage and operation (ER-OR) or admission and operation (Admit-OR) were analyzed by Student’s t test, and regression analysis with P less than .05 considered significant.

Results

Thirty-eight children (26%) were operated on within 6 hours of ER triage, whereas the remaining 88 children (74%) were operated on between 6 and 24 hours from ER triage. No significant difference was noted in perforation rate, LOS, costs, or operative time, nor were substantial changes in complications noted between those with an ER-OR ≤6 hours and greater than 6 hours. Likewise, no significant differences in these outcome measures were noted for Admit-OR greater than 6 when compared with ≤6 hours. Only costs with ER-OR greater than 12 hours and LOS with Admit-OR greater than 6 hours were significantly (without Bonferroni correction) different than ≤ 6 hours. Multivariable linear regression analysis identified only LOS as a significant predictor of time to OR.

Conclusions

In children with acute appendicitis, delaying surgery until the daytime hours did not significantly affect operating time, perforation rate, or complications. Delayed management allows greater efficiency and effective use of physician and hospital resources, including decreased resident involvement in operations during the night.     

Polyomavirus simian virus 40 infection associated with nephropathy in a lung-transplant recipient

BACKGROUND: Between 1955 and 1963, millions of individuals worldwide received vaccines contaminated with polyomavirus simian virus (SV)40. Recent data suggest that some individuals may develop renal dysfunction related to SV40 infection, including individuals too young to have received contaminated vaccines. CASE REPORT AND RESULTS: Three years after bilateral lung transplantation, a 32-year-old man with cystic fibrosis developed nephrotic syndrome and progressed to end-stage renal failure over 1.5 years. He was shown to have nephropathy caused by SV40. The diagnosis was documented by detecting and confirming sequences of SV40 (but not BK or JC virus) in his kidney biopsy and urine by polymerase chain reaction, Southern blot, and DNA sequencing. Positive immunohistochemistry for SV40 was found in his kidney, and neutralizing antibodies for SV40 were detected in his serum, before and after the onset of renal dysfunction. A source for the virus was not determined. His household contacts did not have serologic or molecular evidence of SV40 infection. No serum or tissue samples were available from his 27-year-old donor. DISCUSSION: This report shows that SV40 is circulating in the community and can cause nephropathy in transplant patients.