Effect of 3beta-hydroxysteroid dehydrogenase inhibition by trilostane on blood pressure in the Dahl salt-sensitive rat

The brains of rats and humans express the enzymes required for the synthesis of aldosterone from cholesterol, including the 3beta-steroid dehydrogenase that catalyzes the conversion of pregnenolone to progesterone in the pathway of adrenal steroid synthesis. Salt-induced hypertension in the Dahl inbred salt-sensitive (SS/jr) rat is associated with normal to low levels of circulating aldosterone, yet it is abrogated by the central infusion of mineralocorticoid receptor antagonists. To test the hypothesis that de novo synthesis of aldosterone in the brain has a pathophysiological role in the salt-induced hypertension of the SS rat, the 3beta-steroid dehydrogenase antagonist trilostane was infused continuously intracerebroventricularly or subcutaneously in two different cohorts of Dahl SS/jr rats, one female, the other male, during and after the development of salt-induced hypertension. The doses of trilostane used had no effect on blood pressure when infused subcutaneously. Animals receiving vehicle intracerebroventricularly experienced a 30- to 45-mmHg increase in systolic blood pressure measured by tail cuff. The intracerebroventricular, but not subcutaneous, infusion of 0.3 microg/h trilostane effectively blocked the increase in systolic blood pressure and reversed the hypertension produced by drinking 0.9% saline. Trilostane was equally effective in female and male rats. Weight gain, serum aldosterone and corticosterone concentrations, and behavior assessed subjectively and by elevated plus maze were unchanged by the trilostane treatment. These studies suggest that the synthesis in the brain of a mineralocorticoid receptor agonist, probably aldosterone, is responsible in part for the salt-induced hypertension of the inbred Dahl SS/jr rat.     

CNS regeneration: a morphogen's tale

Tissue regeneration will soon become an avenue for repair of damaged or diseased tissues as stem cell niches have been found in almost every organ of the vertebrate body including the CNS. In addition, different animals display an array of regenerative capabilities that are currently being researched to dissect the molecular mechanisms involved. This review concentrates on the different ways in which CNS tissues such as brain, spinal cord and retina can regenerate or display neurogenic potential and how these abilities are modulated by morphogens.     

The amino-terminal domain of the E subunit of vacuolar H(+)-ATPase (V-ATPase) interacts with the H subunit and is required for V-ATPase function

Vacuolar H(+)-ATPases (V-ATPases) are highly conserved proton pumps that couple hydrolysis of cytosolic ATP to proton transport out of the cytosol. Although it is generally believed that V-ATPases transport protons by a rotary catalytic mechanism analogous to that used by F(1)F(0)-ATPases, the structure and subunit composition of the central or peripheral stalk of the multisubunit complex are not well understood. We searched for proteins that bind to the E subunit of V-ATPase using the yeast two-hybrid assay and identified the H subunit as an interacting partner. Physical association between the E and H subunits of V-ATPase was confirmed in vitro by precipitation assays. Deletion mapping analysis revealed that a 78-amino acid fragment at the amino terminus of the E subunit was sufficient for binding to the H subunit. Expression of the amino-terminal fragments of the E subunits from human and yeast as dominant-negative mutants resulted in dramatic decreases in bafilomycin A(1)-sensitive ATP hydrolysis and proton transport activities of V-ATPase. Our data demonstrate the physiological significance of the interaction between the E and H subunits of V-ATPase and extend previous studies on the arrangement of subunits on the peripheral stalk of V-ATPase.     

A change in the conformation of prions accompanies the emergence of a new prion strain

To investigate the role of the pathogenic prion protein (PrP(Sc)) in controlling susceptibility to foreign prions, two Syrian hamster (SHa) prion strains, Sc237 and DY, were transmitted to transgenic mice expressing chimeric SHa/mouse PrP genes, Tg(MH2M). First passage of SHa(Sc237) prions exhibited prolonged incubation times, diagnostic of a species barrier. PrP(Sc) of the new MH2M(Sc237) strain possessed different structural properties from those of SHa(Sc237), as demonstrated by relative conformational stability measurements. This change was accompanied by a disease phenotype different from the SHa(Sc237) strain. Conversely, transmission of SHa(DY) prions to Tg(MH2M) mice showed no species barrier, and the MH2M(DY) strain retained the conformational and disease-specific properties of SHa(DY). These results suggest a causal relationship between species barriers, changes in PrP(Sc) conformation, and the emergence of new prion strains.     

Measured effects of user and clinical engineer training using a queuing model

This article puts forward a new proposal to calculate count, turnaround, response, and service time of work orders in a clinical engineering (CE) department. These are calculated by means of a queuing model as a measurement tool. This proposal was tested in a 600-bed hospital with an inventory of 1094 medical devices and with 6 full-time clinical engineers. In April 1999, a simulation (with ARENA 3.01 developed by System Modeling Corporation) of the working of this proposal was performed with desired values being applied to the queuing model. At the end of 2002, real work order data from the database was recorded. As predicted, the results showed that all the indicators of nonscheduled work orders decreased. Response and turnaround time were reduced from 27 to 0.56 hours and 27.48 to 1.13 hours, respectively. From a backlog of 22 outstanding repair orders per month between April 1999 and January 2000, the number was reduced to 4 in December 2002. The queuing model also helped to measure the positive effects on arrival and service rates when users and CE were trained. The difference between simulated and real values was under 5%.     

A 3D biomechanical model of the hand for power grip

A three-dimensional scalable biomechanical model of the four fingers of the hand to evaluate power grip is proposed. The model has been validated by means of reproducing an experiment in which the subjects exerted the maximal voluntary grasping force over cylinders of different diameters. The model is used to simulate the cylinder grip for two hand sizes and for five different handle diameters. The reduction of the muscle forces using different handle diameters has been studied. The model can be applied to the design and evaluation of handles for power grip and to the study of power grasp for normal and abnormal hands.     

Abietane diterpenoids from the roots of some Mexican Salvia species (Labiatae): chemical diversity, phytogeographical significance, and cytotoxic activity

From the roots of some Mexican Salvia species, classified in subgenus Jungia, several diterpenoids belonging to abietane (i.e., 3-7), salvifolane (9-->20,10-->6)-diabeoabietane) (i.e., 2), and totarane (i.e., 10) carbocyclic skeletons were isolated together with two 20-nor- and one 6,7-secoabietane derivatives, 1 and 9, and 8, respectively. While compounds 2-10 were previously known from different sources, compound 1 is a new 20-norabietane derivative, whose structure was deduced by spectroscopic means and confirmed by X-ray-diffraction analysis. The phytogeographical significance of the distribution of 20-norabietanic diterpenoids in the genus suggested an evolutionary link between the Chinese and New-World Salvias. Compounds 2 and 8 were tested for cell-growth inhibition activity against several human cancer cell lines and human normal lymphocytes, while 2 showed a moderate cytotoxic activity, 8 exhibited a moderate yet selective activity against leukemia cell line.     

Intestinal motor disorders associated with cyclical bacterial overgrowth in a rat model of enteritis

The aims of this study were: 1) to obtain an experimental model reproducing the characteristics of chronicity and spontaneous relapses found in inflammatory bowel disease (IBD) and 2) to correlate these changes with intestinal motility and bacteria translocation. For this purpose, two groups of Sprague-Dawley rats were used: a treated group that received two subcutaneous injections of indomethacin (7.5 mg/kg) 48 h apart and a control group that received saline. Blood leukocytes, TNF, and fecal parameters were monitored for 90 days after treatment. In treated rats, a cyclic oscillation of blood leukocytes and TNF concomitant with an inverse correlation of fecal output was observed. Treated rats were then selected either during their highest or lowest blood leukocyte values for motor activity and microbiological evaluation. Controls were obtained in age-matched rats. Rats with high leukocyte levels showed a decrease of motor activity. In contrast, animals with low leukocyte levels presented hypermotility. Bacterial overgrowth accompanied by bacterial translocation was found in the group with high leukocytes, whereas no differences were observed between the control and indomethacin groups during the lowest leukocyte phase. We obtained a model of IBD characterized by a chronic cyclic oscillation of intestinal motility, flora, and inflammatory blood parameters. During the high-leukocyte stage, motor activity decrease is related to bacterial translocation. This phase is followed by a reactive one characterized by hypermotility associated with a decrease in both bacterial growth and leukocytes. However, as in IBD, this reaction seems unable to prevent a return to relapse.     

Identification of a Golgi-localised GRIP domain protein from<Emphasis Type="Italic"> Arabidopsis thaliana</Emphasis>

A family of Golgi-localised molecules was recently described in animals and fungi possessing extensive coiled regions and a short (~40 residues) conserved C-terminal domain, called the GRIP domain, which is responsible for their location to this organelle. Using the model plant Arabidopsis thaliana, we identified a gene (AtGRIP) encoding a putative GRIP protein. We demonstrated that the C-terminal domain from AtGRIP functions as a Golgi-targeting sequence in plant cells. Localisation studies in living cells expressing the AtGRIP fused to a DsRed2 fluorescent probe, showed extensive co-location with the Golgi marker -mannosidase I in transformed tobacco protoplasts. GRIP-like sequences were also found in genomic databases of rice, maize, wheat and alfalfa, suggesting that this domain may be a useful Golgi marker for immunolocalisation studies. Despite low sequence identity amongst GRIP domains, the plant GRIP sequence was able to target to the Golgi of mammalian cells. Taken together, these data indicate that GRIP domain proteins might be implicated in a targeting mechanism that is conserved amongst eukaryotes.Abbreviations -ManI -Mannosidase I - AtGRIP Arabidopsis GRIP domain protein - GCC Golgi-localized coiled-coil protein - GFP Green fluorescent protein - MES 2-(N-Morpholino)ethanesulfonic acid - TGN Trans-Golgi network     

Reduction mammaplasty with superior-lateral dermoglandular pedicle: another alternative

During a period of 7.5 years, reduction mammaplasty using a superior-lateral dermoglandular pedicle was performed in 213 mammary glands in 112 patients. This procedure is a modification of the original technique by Skoog that takes advantage of its benefits but adds two basic premises: (1) to preserve the integrity of the galactophorous ducts for future nursing and (2) to cause less innervation injury. Patients were followed for an average of 28 months (range, 3 months to 7.5 years). The quantity of extirpated tissue ranged from 310 to 1380 g, with a median of 520 g. The nipple-areola complex migrated 5 to 14.5 cm (median, 7.8 cm). The most severe complication was partial necrosis of the nipple-areola complex, which occurred in five cases (four patients). This complication occurred only during the first 2 years of the study, in breast resections larger than 800 g, and with migrations larger than 10 cm. This problem resulted in a modification of the technique, and the complication has not occurred for the past 5 years. There were no important alterations in the sensibility of the nipple-areola complex nor in the integrity of the galactophorous ducts. The long-term satisfaction of the patients was high. The authors present an easily designed and accomplishable technique that is applicable to patients with severe hypertrophy and gigantomastia. The technique has a high security index, and the integrity of the mammary gland is maintained to the maximum.