Bcl-2 and adenovirus E1B 19 kDA protein prevent E1A-induced processing of CPP32 and cleavage of poly(ADP-ribose) polymerase

The E1A oncoproteins of adenovirus type 5 are potent inducers of apoptotic cell death. To manifest growth promoting and transforming properties, therefore, E1A requires the co-expression of a suppressor of apoptosis. During normal viral infection, this function is provided by the E1B 19 kDa protein. However, the cellular suppressor Bcl-2 can substitute for 19K during infection, and both proteins can effectively cooperate with E1A to facilitate transformation of primary cells in culture. How E1A induces apoptosis and at what point(s) on this pathway Bcl-2 and E1B 19K act are not presently known. Here, we demonstrate that E1A-induced apoptosis is accompanied by specific endo-proteolytic cleavage of poly(ADP-ribose) polymerase (PARP), an event that is linked to the Ced-3/ICE apoptotic pathway in other systems. PARP cleavage was also observed in p53-null cells infected with 19K- virus expressing 13S E1A. In addition to PARP cleavage, expression of E1A caused processing of the zymogen form of CPP32, a Ced-3/ICE protease that cleaves PARP and is required for apoptosis in mammalian cells. These events were prevented when E1A was co-expressed with E1B 19K or BCL-2, which places these suppressors of apoptosis either at or upstream of processing of pro-CPP32.     

Percutaneous mitral valvuloplasty with the single balloon technique. Short-term results, complications and in-hospital follow-up

The results of the ICD-10 Diagnostic Criteria for Research (DCR) field trial in German-speaking countries concerning section F0 (organic mental disorders) are reported. On the comparatively small data basis of the study, acceptance and interrater-reliability cannot be estimated satisfactorily. Despite this general problem, it can be said that section F0 of ICD-10 DCR maintains a high degree of continuity with respect to ICD-10. Some categories caused diagnostic disturbances and needed further specification, especially the criteria regarding the temporal relationship between the onset of an organic disorder and the psychiatric symptomatology. The recently published definite DCR seem to avoid most of the problems of the earlier version used in this study.     

5. Update on lasers in dermatology

A range of lasers with acceptably low rates of side effects is now available. Improved laser therapy has been made possible by combining wavelengths that are selectively absorbed by the target and pulses short enough to prevent heat transfer to surrounding tissue. Carbon dioxide (CO2) lasers are useful for treating disorders of skin surface texture and topography (wrinkles, scars, sun damage, benign skin appendages and rhinophyma). Vascular lasers, such as the flashlamp-pumped dye laser, are particularly effective for treating port-wine stains, haemangiomas, telangiectasia, rosacea and spider naevi. Q-switched lasers, which allow ultrashort high intensity pulses, are effective for treating most tattoos and some benign pigmented lesions.     

Pulmonary interstitial fibrosis and haemosiderin-laden macrophages: late following heart transplantation

Impairment of pulmonary diffusion is recognized following heart transplantation. This study was undertaken to determine the histopathological basis for the defect in pulmonary physiology. Heart transplant recipients (HTR) entered into a prospective study of post-transplant pulmonary physiology were asked to undergo bronchoscopy, bronchoalveolar lavage (BAL) and transbronchial biopsy (n = 18) in the presence of impaired gas transfer. Transbronchial biopsies were examined under light microscopy and demonstrated focal interstitial fibrosis in 12 patients, cytomegalovirus disease in four patients and Pneumocystis carinii pneumonia in three patients. Bronchoalveolar lavage differential counts were normal in HTR but BAL macrophages contained haemosiderin. The histological features of interstitial fibrosis may underlie the fall in gas transfer seen following heart transplantation. The presence of haemosiderin-laden macrophages late following heart transplantation suggests a capillary leak syndrome.     

In vitro and in vivo studies of benzisoquinoline ligands for the brain synaptic vesicle monoamine transporter

Tetrabenazine is a high-affinity inhibitor of the vesicular monoamine transporter in mammalian brain. As part of a program to develop in vivo imaging agents for these transporters in human brain, a series of 2-alkylated dihydrotetrabenazine ligands was synthesized and evaluated in vitro and in vivo for binding to the brain vesicular monoamine transporter. Additions of organometallic reagents to tetrabenazine produced 2-methyl, 2-ethyl, 2-n-propyl, 2-isopropyl, and 2-isobutyl derivatives of dihydrotetrabenazine. The stereochemistry and conformation of the addition products were thoroughly verified by two-dimensional NMR techniques. All of these alkyl derivatives displayed in vitro affinity for the vesicular monoamine transporter binding site in rat brain using competitive assays with the radioligand [3H]methoxytetrabenazine. Except for the isopropyl derivative, all compounds when tested at 10 mg/kg iv showed an ability to inhibit in vivo accumulation of the radioligand [11C]methoxytetrabenazine in the mouse brain striatum. Derivatives with small alkyl groups (methyl, ethyl) were more effective than those with large groups (propyl, isobutyl). These studies suggest that large groups in the 2-position of the benzisoquinoline structure will significantly diminish both in vitro and in vivo binding of these compounds to the vesicular monoamine transporter.     

Physiology of the young adult Fischer 344 rat inferior colliculus: responses to contralateral monaural stimuli

This study was designed to establish the young adult (3 month) Fischer 344 (F344) rat as a model of inferior colliculus (IC) physiology, providing a baseline for analysis of changes in single unit responses as the animals age and for the study of noise induced hearing loss. The response properties of units localized to the central nucleus of the IC (CIC) and those localized to the external cortex of the IC (ECIC) were compared in order to better characterize differences between these two subnuclei in the processing of simple auditory stimuli. In vivo extracellular single unit recordings were made from IC neurons in ketamine/xylazine anesthetized young adult F344 rats. When a unit was electrically isolated, the spontaneous activity level, characteristic frequency (CF) and CF threshold were determined. Rate/intensity functions (RIFs) in response to contralateral CF tones and to contralateral noise bursts were obtained as were tone isointensity functions. The recording site was marked by ejecting horseradish peroxidase (HRP) from an electrode. Locations of recorded units were determined from electrode track marks and HRP marks in serial brain sections. Recordings were made from 320 neurons in the IC; 176 were localized to the CIC and 87 to the ECIC. Thirteen percent of the units in each subdivision were found to be poorly responsive to auditory stimulation (clicks, tones or noise), and spontaneous activity was generally low. Characteristic frequencies representative of the full rat audiogram were found in each subdivision with the mean threshold significantly higher in the ECIC (28.7 dB SPL) than in the CIC (22.3 dB SPL). The mean maximum discharge rate to CF tone bursts was near 24 spikes/s in each subdivision. Dynamic range tended to be higher in the ECIC (28.3 dB) than in the CIC (23.2 dB), reflecting the lower percentage of nonmonotonic units found in the ECIC. Most units responded more robustly with a slower tone presentation rate, displayed lower levels of discharge to noise bursts than to tone bursts, and had differently shaped tone and noise RIFs. Most units were classified as onset responders to CF tone bursts in both subdivisions, with the percentage of onset responders higher in the ECIC (68.9%) than in the CIC (57.8%). First spike latency did not differ significantly between the subdivisions, but tended to be shorter in the CIC. The breadth of the excitatory receptive fields did not differ significantly between subdivisions, although the mean was slightly larger in the ECIC. These results are generally consistent with the results of CIC studies from other species, establishing the F344 rat as a model of CIC physiology. Differences between CIC and ECIC units included a higher percentage of nonmonotonic RIFs and lower percentage of onset temporal response patterns in the CIC than in the ECIC. Some properties which have been previously used as hallmarks for differentiation between CIC and ECIC units, namely broader tuning and longer first spike latencies in the ECIC, did not reach statistical significance in this study. These may reflect species differences and/or the highly variable and largely overlapping sets of responses evident in the large sample size used in this study.     

Low lipid concentrations in critical illness: implications for preventing and treating endotoxemia

OBJECTIVES: To determine the prevalence and clinical significance of hypolipidemia found in critically ill patients, and whether the addition of a reconstituted lipoprotein preparation could inhibit the generation of tumor necrosis factor-alpha (TNF-alpha) in acute-phase blood taken from these patients. SETTING: Surgical intensive care unit (ICU) of a large urban university hospital. DESIGN: Prospective case series. PATIENTS: A total of 32 patients with a variety of critical illnesses had lipid and lipoprotein concentrations determined. Six patients and six age- and gender-matched control subjects had whole blood in vitro studies of the effect of lipoprotein on lipopolysaccharide mediated TNF-alpha production. INTERVENTIONS: Blood samples were drawn on admission to the ICU and over a subsequent 8-day period. MEASUREMENTS AND MAIN RESULTS: Mean serum lipid and lipoprotein values obtained from patients within 24 hrs of transfer to the surgical ICU were extremely low: mean total cholesterol was 117 mg/dL (3.03 mmol/L), low-density lipoprotein cholesterol 71 mg/dL (1.84 mmol/L), and high-density lipoprotein cholesterol 25 mg/dL (0.65 mmol/L). Only the mean triglyceride concentration of 105 mg/dL (1.19 mmol/L), and the mean lipoprotein(a) concentration of 25 mg/dL (0.25 g/L) were within the normal range. During the first 8 days following surgical ICU admission, there were trends toward increasing lipid and lipoprotein concentrations that were significant for triglycerides and apolipoprotein B. Survival did not correlate with the lipid or lipoprotein concentrations, but patients with infections had significantly lower (p = .008) high-density lipoprotein cholesterol concentrations compared with noninfected patients. Lipopolysaccharide-stimulated production of TNF-alpha in patient and control blood samples was completely suppressed by the addition of 2 mg/mL of a reconstituted high-density lipoprotein preparation. CONCLUSIONS: Patients who are critically ill from a variety of causes have extremely low cholesterol and lipoprotein concentrations. Correction of the hypolipidemia by a reconstituted high-density lipoprotein preparation offers a new strategy for the prevention and treatment of endotoxemia.     

Observation of single chain motion in a polymer melt

Molecular motion of single polymer chains has been investigated in a melt sample of polytetrahydrofuran and compared with results for the same polymer in dilute solution. Using a high resolution neutron scattering technique motion over distances up to 30 Å has been observed with an energy resolution of 0.01 μeV (～10⁷s^?1). The motion of the chains in the melt is described by the Rouse model and a friction factor per segment has been extracted from the data. This compares well with values obtained from viscosity and bulk relaxation measurements on similar polymers.