The proliferative response of hepatic peroxidomes of neonatal rats to treatment with SU-13 437 (nafenopin).

The repeated administration of the hypolipidemic agent Su-13 437 (nafenopin) to neonatal rats roughly doubled the number of peroxisomes in the liver tissue and caused a sixfold volumetric expansion of the peroxisomal compartment. During the proliferative response, the size-distribution of the peroxisomes was reversibly altered, enlarged particles appearing in numbers varying according to the dose given. By means of a new method for quantitative autoradiography, it was shown that (a) the concentration of silver grains over peroxisomes was comparable to that found over the endoplasmic reticulum; (b) the peak incorporation of [3H]arginine into the peroxisomes was dealyed in comparison with that into the endoplasmic reticulum; (c) the label, once incorporated into the expanding peroxisomal compartment, displayed the same shift to large particles as did the whole population. These results are compatible with the biosynthetic pathway for peroxisomal catalase proposed earlier (cf. reference 12), and with the notion that the drug-induced size-shift might have resulted from progressive growth of a particular class of peroxisomes formed in the presence of the agent. Evidence is presented to show that during the recovery period the larger peroxisomes are removed preferentially.

Continuous performance test and schizophrenia: a test of stimulus-response compatibility, working memory, response readiness, or none of the above?

OBJECTIVE: Abnormalities of attention are considered the fundamental deficits in cognitive function manifested by patients with schizophrenia. The authors administered variations of two types of cognitive tasks to patients with schizophrenia (N=20) and normal comparison subjects (N=30) to test four possible cognitive mechanisms that might account for such abnormalities. METHOD: Variations of the Continuous Performance Test were used to test the four mechanisms. Stimulus-response mapping was explored by comparing results on a task in which subjects were to make a response if the word "nine" was preceded by the word "one" with results on a task in which the required response was made explicit by the stimulus (the word "ready" followed by the word "press"). The building up of a prepotent response tendency was tested by manipulating the probability with which the cue and imperative stimulus appeared (17% or 50%). The amount of working memory required to maintain contextual information was tested by using different delay intervals (1000 msec and 3000 msec). The extent to which problems in vigilance might be attributable to problems in the "motoric" component of response readiness was operationalized by having subjects perform a secondary motor task concurrent with the attentional task. RESULTS: Patients with schizophrenia performed significantly worse than the normal comparison subjects on all tasks. However, none of the four manipulations of the Continuous Performance Test tasks had a differential impact on the patients' performance speed or accuracy. In contrast, there was a significant interaction of group, delay interval, and target probability in which patients made disproportionately more omission errors at short delay intervals and at low target probabilities. CONCLUSIONS: The findings may call into question the explanatory power of certain well-known contemporary mechanistic accounts of performance on the Continuous Performance Test in patients with schizophrenia. The findings suggest that a difficulty in rapidly encoding information (i.e., constructing a representation) in certain "unengaging" situations may be at the core of deficits on tasks associated with this attentional test.

Stress-induced mitogen-activated protein kinase signaling in the corpus luteum.

Current evidence suggests that stress-induced apoptosis is mediated through the activation of the mitogen-activated protein kinase (MAPK) signaling cascade. We hypothesize that stress-related signaling events documented in other cell lines may also occur in the corpus luteum. To test this, cultured bovine luteal cells were exposed to UV irradiation and harvested at different intervals (0, 30, 120, 240 and 360 min) for analysis of protein or apoptotic cell death. In response to UV treatment cellular levels of phosphorylated p38MAPK and jun-n-terminal kinase (JNK) were increased within 30 min and remained elevated over controls for the duration of the experiment. In contrast, the levels of the phosphorylated forms of p42MAPK and p44MAPK were dramatically reduced. The changes in MAPK signaling were similar to those observed in response to tumor necrosis factor alpha, a cytokine implicated in luteal regression. The UV-induced changes in MAPK phosphorylation were associated with an increase in caspase 3 activity and apoptotic cell death. Taken together, these data demonstrate that stress-induced signaling events in the corpus luteum are similar to those observed in unrelated cell types. Thus, stress-related signaling events may play a role in luteal regression.

Staphylococci, in vitro and in vivo.

Strains of Staphylococcus aureus were grown in broth and by the membrane technique; both drug-free media and media containing cloxacillin were used. The staphylococci grown in broth containing cloxacillin showed one thick cross wall and were larger than those grown in drug-free broth: 1.6 micron in diameter as opposed to 0.9 micron. The staphylococci grown on membranes placed on agar containing cloxacillin were 2-3 microns in diameter and contained three or more cross walls. Mice were infected intraperitoneally with staphylococci. After treatment with cloxacillin, the peritoneal fluid and spleens contained staphylococci that were 2-3 microns in diameter with three or more cross walls. A staphylococcal endocarditis was induced in rabbits that were then treated with cloxacillin. The staphylococci in the vegetation of the treated rabbits were 2-3 microns in diameter and contained multiple cross walls. Large staphylococci with multiple cross walls were observed in specimens from patients with respiratory infections treated with beta-lactam antibiotics. It appears, therefore, that the ultrastructure of staphylococci in vivo is comparable to that of staphylococci grown on a solid support medium such as a membrane, and different from that of staphylococci grown in a liquid medium.

Pyridoxine megavitaminosis produces degeneration of peripheral sensory neurons (sensory neuronopathy) in the dog.

Pyridoxine, a water-soluble vitamin, produces a sensory neuronopathy when administered in high doses to dogs. Beagles who received a daily oral dose of 300 mg/kg of pyridoxol hydrochloride developed a swaying gait within 9 days. They eventually became unable to walk, but were not weak. Animals were sacrificed at intervals up to 78 days. Morphological examination revealed widespread neuronal degeneration in the dorsal root ganglia and the Gasserian ganglia. Cytoplasmic changes were first observed after 8 days and consisted of small, electronlucent vacuoles that subsequently coalesced leading to death of the cells. Degeneration of sensory nerve fibers in peripheral nerves, dorsal columns of the spinal cord and the descending spinal tract of the trigeminal nerve was apparent. The pathogenesis of these changes is unclear, but may, in part, reflect the selective permeability of blood vessels in the peripheral ganglia. It is apparent that the peripheral neuropathy previously attributed to pyridoxine actually represents a toxic, peripheral sensory neuronopathy.

Performance of distributed multiscale simulations.

Multiscale simulations model phenomena across natural scales using monolithic or component-based code, running on local or distributed resources. In this work, we investigate the performance of distributed multiscale computing of component-based models, guided by six multiscale applications with different characteristics and from several disciplines. Three modes of distributed multiscale computing are identified: supplementing local dependencies with large-scale resources, load distribution over multiple resources, and load balancing of small- and large-scale resources. We find that the first mode has the apparent benefit of increasing simulation speed, and the second mode can increase simulation speed if local resources are limited. Depending on resource reservation and model coupling topology, the third mode may result in a reduction of resource consumption.

[Criteria for determining whether to offer compensation in cases of whiplash injury to the spine (neck area). A study of cases in which compensation or cash settlement has been granted (author's transl)]. / Gutachterliche Aspekte bei Schleuderverletzungen der Halswirbelsäule. Eine Studie von Fällen, die eine Rente oder Kapitalabfindung erhielten.

We compared two groups of patients with whplash injury. The first group of 17 patients received a life annuity or a cash settlement, whereas the second group, comprised of 84 people, received no compensation at all. This comparison revealed some considerable differences. However, with regard to statistically significant factors, the 2 groups differ only in neurological symptoms, giddiness, and degenerative changes revealed by X-ray. In the first group, 11 patients who received compensation showed two of the statistically significant factors; 5 patients showed one factor; and 1 showed none. The criteria which govern the granting of compensation are being discussed in detail on the basis of our own cases and the literature. It is an exception when permanent damage due to whiplash is accepted. In individual cases, however, continuous complaints and objective findings years after the trauma are justification for a moderate compensation.

[Acute febrile state]. / Akuter Status febrilis.

A 34 year old airline pilot, who had spent nine days in Cameroon (Westafrica) presented for his yearly physical examination two weeks later. The physical examination and routine laboratory tests were within normal limits. The patient complained about mild pain of joints and extremities and about not feeling quite well. The same evening (a few hours after the physical examination) he experienced chills and fever (up to 39.5 degrees Celsius). He was seen subsequently by a tropical medicine specialist, who diagnosed Plasmodium falciparum on blood smears. The patient was immediately placed on Riamet, fever and symptoms disappeared completely within a few days.

Radicular myelinopathy in aging rats.

Naturally occurring degenerative lesions of nerve fibers in the spinal cord, spinal roots and peripheral nerves in nine male rats 877 days old were swollen myelin sheaths, forming "myelin bubbles." The myelin swellings were distributed throughout the spinal tracts and the peripheral nerves, but most frequently in the lumbar ventral spinal roots. Although most axons surrounded by swollen myelin were intact, some were constricted and degenerated, while others showed signs of remyelination.

Evaluation of the bactericidal activity of beta-lactam antibiotics on slowly growing bacteria cultured in the chemostat.

The bactericidal activity of 23 beta-lactam antibiotics was compared in slowly growing bacteria cultured in a chemostat. In an attempt to mimic possible in vivo conditions, slowly growing cultures were produced by limitation of iron, glucose, phosphate, or magnesium. Only select antibiotics remained effectively bactericidal against slowly growing cells. For these compounds, the rate of antibiotic-induced loss of viability was a constant when killing was expressed per generation (in contrast to absolute time) in that slowly growing bacteria were killed proportionately more slowly. Individual antibiotics differed greatly, however, in their specific bactericidal activities against slowly growing cells, i.e., in the absolute degree of killing elicited during exposure of the bacteria to MIC equivalents of the drugs. Specific bactericidal activities varied not only with drug structure but also with the bacterial strains and, to a lesser extent, with the nature of the growth-limiting nutrient. In slowly growing cultures exposure to the low drug concentrations studied here (near MIC) caused killing without detectable lysis. Antibiotics with high specific bactericidal activities were capable of rapidly killing cultures of slowly growing pathogens despite extremely long generation times approaching those reported for in vivo growth rates.

Adjustment of the myelin sheath to axonal atrophy in the rat spinal root by the formation of infolded myelin loops.

Atrophy of the L4 dorsal and ventral spinal roots was experimentally induced by unilateral sciatic neurectomy in groups of young (2 and 4 months) and older (12 months) albino rats. During the 4 months following neurectomy, the occurrence of infolded myelin loops (IMLs) was quantitatively examined in transverse sections prepared using perfusion fixation with glutaraldehyde and embedding in epoxy resin. The number of IMLs was higher on the operated side and increased with the time of survival and the age of the animals. The formation of IMLs is a characteristic early response of a large-caliber myelin sheath to axonal atrophy, probably reflecting the presence of redundant myelin.

Mediators of interferon gamma-initiated signaling in bovine luteal cells.

Interferon gamma (IFNgamma) has been implicated as a mediator of luteal steroidogenesis and cell fate. IFNgamma-initiated signaling events, although implied by studies in cell lines, have yet to be described in primary luteal cells. The objective of these studies was to begin to characterize IFNgamma-initiated signaling within luteal cells. Dispersed bovine luteal cell cultures were challenged with increasing levels of bovine recombinant IFNgamma (0-1000 U) or IFNgamma (200 U) in the presence or absence of tumor necrosis factor alpha (TNFalpha, 10 ng/ml) over time (short term, 0-60 min; long term, 0, 24, 48 h). Fractionated or total cell lysates were evaluated by the Western blotting technique to determine the changes in the levels of signal transducers and activators of transcription (STAT), interferon regulatory factor 1 (IRF-1), and I kappa B alpha (IkappaB-alpha). Utilizing antibodies that recognize the nonphosphorylated forms of STAT-1 and STAT-3, it was determined that levels of STAT-1 and STAT-3 in total cell lysates were constitutively expressed and did not change in response to treatment with IFNgamma or TNFalpha. In contrast, nuclear levels of STAT-1 and phosphorylated STAT-3 were elevated in a time-dependent manner in response to IFNgamma treatment. Furthermore, IFNgamma and TNFalpha treatment elevated levels of IRF-1 within 2 h. TNFalpha-induced increases in the levels of IRF-1 were transient, whereas the levels of IRF-1 in response to IFNgamma treatment remained elevated at 48 h. These data suggest that IFNgamma treatment can activate members of the STAT pathway, resulting in increased levels of IRF-1. TNFalpha treatment induced a rapid decrease in the levels of IkappaB-alpha. IFNgamma treatment did not alter the levels of IkappaB-alpha and failed to inhibit the TNFalpha-initiated decrease in the levels of IkappaB-alpha. The present experiment demonstrates that the steroidogenic cells of the corpus luteum have the capacity to respond to IFNgamma via activation of STAT and IRF-1, providing further evidence that IFNgamma may be involved in the luteolytic process. These data also suggest that IFNgamma does not signal through the nuclear factor kappa B cell survival signaling pathway.

Effect of interleukin-1 gene polymorphisms on gingival inflammation assessed by bleeding on probing in a periodontal maintenance population.

Bleeding on probing (BOP) is the most significant clinical parameter for the assessment of periodontal inflammation. The aim of this prospective longitudinal trial was to study the association between allelic variants of the IL-1 gene complex and gingival inflammation. Three hundred and twenty-three randomly selected periodontal maintenance patients (64.4% females) received a periodontal examination that included probing depth measurements and BOP at each of 4 supportive periodontal therapy (SPT) appointments. A blood sample taken from each subject was analysed for the presence of specific allotypes of the IL-1 gene complex. Two polymorphisms located at +4845 bp in the IL-1 alpha region and at +3954 bp in the IL-1 beta region were evaluated by a polymerase chain reaction method; 35.3% of the examined subjects were positive for specific combinations of allotypes of the IL-1 gene complex previously associated with an increased risk for severe periodontitis. The population consisted of 90 current smokers and 94 former smokers. An analysis of the association between the IL-1 genotype and BOP in the whole population (including smokers) did not reach statistical significance because of the overriding effect of smoking. A subset analysis of the 139 never smokers indicated that genotype positive patients had a significantly elevated chance of presenting an increase in the BOP% over a 4-appointment recall period (p = 0.03) after correcting for oral hygiene. In fact, patients who were genotype-negative had a 50% smaller chance of showing increases in BOP% during SPT. A further analysis explored the relationship between the genotype and the level of BOP% at the most recent recall visit. A generalized linear model showed a statistically significant effect of the genotype status after correcting for plaque accumulation and prevalence of residual pockets (> or = 5 mm). Genotype-negative subjects had significantly lower BOP% (p = 0.0097). It is concluded that the increased BOP prevalence and incidence observed in IL-1 genotype-positive subjects indicates that some individuals have a genetically determined hyper-inflammatory response that is expressed in the clinical response of the periodontal tissues.

Increase in hepatocyte and nuclear volume and decrease in the population of binucleated cells in preneoplastic foci of rat liver: a stereological study using the nucleator method.

Gamma-glutamyltranspeptidase-positive hepatocyte foci were produced in female rats given a single dose of diethylnitrosamine neonatally after birth and, after weaning, a diet containing phenobarbitone for 30 wk. The nucleator method, a new stereological approach, provided an efficient, unbiased estimate of mean cell volume in focal lesions and extrafocal areas. It also provided an unbiased sample of cells to estimate hepatocyte nuclear volume and the percentage of binucleated cells. The results showed an increase in the mean volume of mononucleated cells--from 4,700 micron3 in extrafocal areas to 12,700 micron2 in foci--and of binucleated cells--from 6,900 micron3 to 25,000 micron3. This demonstrated the hypertrophic effect of the carcinogenic treatment in focal lesions. A striking reduction in the proportion of binucleated cells was also observed in the preneoplastic lesions. Nuclear volume measurements from mononucleated and binucleated hepatocytes were used to assess ploidy. An apparent increase in nuclear ploidy, with no change in cellular ploidy, was noted in focal tissue when compared with nonfocal tissue. This appeared to be caused by an increase in mononucleated tetraploid cells and a reduction in binucleated cells with two diploid nuclei, indicating an altered mitotic mechanism in focal lesions. The significance of these changes in cell volume, apparent ploidy levels and binuclearity in preneoplastic foci is discussed in relation to the hepatocarcinogenic process.

Ultrastructural changes in chemically induced preneoplastic focal lesions in the rat liver: a stereological study.

Ultrastructural changes were investigated and quantified, using a stereological approach, in early gamma-glutamyltranspeptidase (GGT)-positive focal lesions, induced in the rat liver by treatment with a single initiating dose of diethylnitrosamine (DENA) followed by promotion with phenobarbitone (PB) for 30 weeks. Within the extra-hepatocyte environment of focal tissue, the mean volume occupied by Ito cells was markedly decreased, whilst that occupied by endothelial and Kupffer cells was increased, when compared to uninvolved tissue from the same rat livers. The bile canaliculi were dilated, but no significant differences in the mean volume occupied by the sinusoidal and Disse spaces were noted. In focal hepatocytes there was a striking overproduction of lipid droplets and proliferation of smooth endoplasmic reticulum (sER). Whorls of concentrically arranged, parallel ER membranes were found only in the hepatocytes of preneoplastic foci, in association with the proliferated sER, and never in the surrounding, uninvolved tissue. The increase in mean volume of the sER, lipid droplet and cytoplasmic matrix compartments, together with the appearance of whorls, were the major contributing factors to the marked hypertrophy seen in focal hepatocytes. The mean volume of the rough endoplasmic reticulum, mitochondrial, lysosomal, peroxisomal and nuclear compartments per hepatocyte also increased, but contributed to a lesser extent to the cellular hypertrophy. It is speculated that whorls may be structural adaptations, resulting from a possible alteration in the normal feedback control of cholesterol synthesis, for the production of sterols and the biogenesis of sER in eosinophilic-type focal cells. The significance of changes observed in focal tissue, and the high biological variation noted between foci, is discussed in relation to the hepatocarcinogenic process.