Pathophysiological aspects of brain edema

Summary Two mayor types of brain edema, related to two different pathomechanisms, can be recognized: 1)cytotoxic type-where the main feature is the swelling of cellular elements of brain parenchyma and 2)vasogenic type-where an increased vascular permeability leading to accumulation of edema fluid inthe extracellular spaces plays the principal role. In this type of edema, there is a close interrelationship between extravasation of serum proteins and retention of water in the brain tissue. In theischemic brain edema both cytotoxic and vasogenic mechanisms are involved. A biphasic opening of the blood-brain barrier, associated with vasogenic edema, is observed following release of major cerebral artery occlusion. The first opening of the barrier is related to a reactive hyperemia which follows promptly recirculation. The second opening, recognizable after a delay, is associated with a severe ischemic brain tissue injury.Dedicated to Prof. F. Seitelberger on the occasion of his seventieth birthday     

Selective Postsynaptic Inhibition of Tonic-firing Neurons in Substantia Gelatinosa by μ-Opioid Agonist

Background: Spinal substantia gelatinosa (SG) is a site of action of administered and endogenous opioid agonists and is an important element in the system of antinociception. However, little is known about the types of neurons serving as specific postsynaptic targets for opioid action within the SG. To study the spinal mechanisms of opioidergic analgesia, the authors compared the action of [mu]-opioid agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) on SG neurons with different intrinsic firing properties.

Methods: Whole cell patch clamp recordings from spinal cord slices of Wistar rats were used to study the sensitivity of SG neurons to DAMGO.

Results: Three groups of neurons with distinct distributions in SG were classified: tonic-, adapting-, and delayed-firing neurons. DAMGO at 1 [mu]m concentration selectively hyperpolarized all tonic-firing neurons tested, whereas none of the adapting- or delayed-firing neurons were affected. The effect of DAMGO on tonic-firing neurons was due to activation of G protein-coupled inward-rectifier K+ conductance, which could be blocked by 500 [mu]m Ba2+ and 500 [mu]m Cs+ but increased by 50 [mu]m baclofen. As a functional consequence of DAMGO action, a majority of tonic-firing neurons changed their pattern of intrinsic firing from tonic to adapting.     

Pretransplant survival is shorter in HIV-positive than HIV-negative subjects with end-stage liver disease.

Despite improved survival after liver transplantation (OLTX) in HIV-positive individuals treated with highly active antiretroviral therapy (HAART), some transplant candidates do not survive to OLTX. To determine if pretransplant outcome is related to severity of liver disease and/or HIV infection, we prospectively evaluated 58 consecutive HIV-positive candidates seen at a single center from 1997-2002. Of the 58, 15 (25.9%) were transplanted, whereas 21 (36.2%) died before OLTX, a median one month of evaluation, with more than half of those (12 of 21, 57.1%) dying from infection. By contrast, of 1,359 HIV-negative candidates, 860 (63.3%) were transplanted, whereas 211 (15.5%) died before OLTX (P < 0.001). The cumulative survival following initial evaluation was significantly shorter among HIV-positive than HIV-negative candidates (880 vs. 1,427 days, P = 0.035, Breslow) but was not related to the initial pretransplant MELD score (16 vs. 15), INR (1.5 vs. 1.5), creatinine (1.3 vs. 1.3 mg/dL), or total bilirubin (6.6 vs. 5.7 mg/dL), respectively, all P > 0.05. Among untransplanted HIV-positive candidates, the 21 who died did not differ from the 22 surviving in initial MELD (15 vs. 13), CD4 (230 vs. 327/microL), HIV load (both < 400 copies/mL), HAART intolerance (10/21, 47.6% vs. 10/22, 45.4%), or HCV infection (16/21, 76.2% vs. 16/22, 72.3%), all P > 0.05. Further, the 21 did not differ from the 15 transplanted in pre-OLTX CD4, HIV load, or MELD score, all P > 0.05. In conclusion, pretransplant survival appears shorter in HIV-positive OLTX candidates and is unrelated to severity of liver or HIV disease. Further study is warranted to determine risk factors for poorer pretransplant outcomes.     

Characterization of Aerosols of Human Recombinant Deoxyribonuclease I (rhDNase) Generated by Jet Nebulizers

Recombinant human deoxyribonuclease I (rhDNase) is a new therapeutic agent developed to improve clearance of purulent sputum from the human airways. It is delivered by inhalation. Four jet nebulizers, T Up-Draft II (Hudson), Customized Respirgard II (Marquest), Acorn II (Marquest), and Airlife Misty (Baxter), were evaluated in vitro for their ability to deliver aerosols of rhDNase. The aerosols were generated from 2.5-mL aqueous solutions of rhDNase, at concentrations of either 1 or 4 mg/mL. In all experiments, the Pulmo-Aide Compressor (De Vilbiss) was used to supply the air to the nebulizers. Between 20 and 28% of the rhDNase dose initially placed in the nebulizers was delivered to the mouthpiece in the respirable range (1-6 µm). Evaluation of the rhDNase following nebulization in all four devices indicated that there was no loss in enzymatic activity and no increase in aggregation. Circular dichroism spectrophotometry indicated there was no change in either the secondary or the tertiary structure in rhDNase following nebulization. These results show that all four nebulizers are essentially equivalent in their ability to deliver respirable doses of rhDNase in an intact, fully active form. Changing the concentration of the solution in the nebulizer from 4 to 1 mg/mL rhDNase leads to a proportional reduction in the respirable dose delivered to the mouthpiece.     

Family History of Alcoholism Does Not Predict Neuropsychological Performance in Alcoholics

We examined the relationship of history of alcoholism in first-degree relatives to neuropsychological performance of alcoholics abstinent from several weeks to several years. Eighty-four men were assigned to four groups based on "strength" of family history of alcoholism. The groups were: (1) "strong history," a parent plus another first-degree relative positive; (2) "moderate," parent only positive; (3) "weak," nonparent first-degree relative only positive; and (4) "negative," no first-degree relative positive. There were no significant between-group differences in NP performance. In other analyses there were no NP differences between alcoholics classified positive or negative purely on basis of paternal alcoholism, and no differences between subjects who had multigenerational versus unigenerational versus negative familial histories of alcoholism. It is concluded that genetic loading for alcoholism does not significantly affect the NP status of abstinent alcoholic groups equated for education, drinking history, and medical risk.     

The evolving face of human immunodeficiency virus-related progressive multifocal leukoencephalopathy: Defining a consensus terminology

There is a need for consistent definition of human immunodeficiency virus (HIV)-associated cases of progressive multifocal leukoencephalopathy (PML), especially following the profound disease changes that have resulted from the use of highly active antiretroviral therapy (HAART). According to the criteria used for diagnosis, PML cases should be either referred to as “histology-confirmed,” with evidence of JC virus (JCV) infection in brain, “laboratory-confirmed,” with detection of JCV DNA in cerebrospinal fluid (CSF), or “possible,” in the presence of typical clinical and radiological picture, but no demonstration of JCV infection. Disease outcome should be defined by the evidence or lack of evidence of disease activity, rather than using survival or other variables. Disease activity should be based on clinical (scored neurological examination), radiological (magnetic resonance imaging), and virological (JCV DNA levels in CSF) indicators, to be assessed regularly, e.g., every 3 months until evidence of disease arrest or death. Furthermore, parallel assessments of other HIV-associated manifestations, including CD4+ cell counts and viral load, are required. A standard patient classification would be helpful for clinical management of PML patients, for their inclusion in clinical studies, and also will increase our current knowledge of PML and its evolution in relation with HAART.     

Different proliferative activity of the glandular and myoepithelial lineages in benign proliferative and early malignant breast diseases.

The aim of the present study was to explore cell biological characteristics of normal breast, benign proliferative breast diseases and noninvasive breast malignancies based on the recently published adult progenitor cell concept from our group. Here, we investigated the proliferative activity of CK5/14(+), CK8/18/19(+) and alpha-smooth muscle actin(+) cellular phenotypes encountered in normal mammary gland, in a series of usual ductal hyperplasias and early malignant breast diseases, such as atypical ductal and lobular hyperplasias, as well as ductal and lobular in situ carcinomas. Immunohistochemical double labeling was performed on frozen sections from diagnostic breast biopsies by using antibodies to basal cytokeratins (CK5/14), glandular cytokeratins (CK8/18/19), smooth muscle actin and the Ki-67 antigen (MIB1). Normal breast tissues and usual ductal hyperplasias were characterized by a heterogeneous cellular composition of the growth fraction. The proliferative cell compartment consisted of CK8/18/19(+) glandular and, in a variable proportion, CK5/14(+) progenitor phenotypes. In contrast, noninvasive breast malignancies were composed of a monotonous proliferation of CK 8/18/19(+) neoplastic glandular cells. These findings indicate a significant role of progenitor cells in the development of benign proliferative breast diseases and lend support to the view that malignant transformation in the human breast usually occurs in a cell committed to the glandular lineage. Our results provide cell kinetic support to the functional progenitor cell hypothesis, and we propose this concept as an operative model for understanding benign proliferative and malignant breast diseases.     

Gastric ulceration caused by heater probe coagulation

A double-contrast upper gastrointestinal examination on a woman who had undergone endoscopic heater probe therapy one day earlier for multiple arteriovenous malformations revealed shallow, irregular, and linear ulcers at the sites of heater probe coagulation. Multiple shallow ulcers may therefore develop as a direct complication of heater probe therapy. Radiologists should be aware of this complication to avoid diagnostic confusion in these patients.