Acute effect of ursodeoxycholic acid on gallbladder volume in healthy subjects

The features of time domain and power spectrum of high frequency electrocardiogram (HF-ECG) were studied in normal Kunming mice using a microprocessor ECG system. The results were as follows (mean +/- SD): (1) P-R interval was 34.9 +/- 4.7 ms (n = 58), about one third of the cardiac cycle. (2) The duration and peak-to-peak amplitude of QRS complex were 9.2 +/- 1.2 ms and 1.456 +/- 0.480 mV (n = 74) respectively. (3) The duration and amplitude of T wave were 10.2 +/- 3.2 ms and 0.336 +/- 0.115 mV, respectively (n = 58). (4) Q-T interval was 19.4 +/- 3.2 ms (n = 58), about one fifth of the cardiac cycle. (5) The total number of notches and slurs of leads II of 73 mice were 3 and 26 respectively. (6) The relative power content of each frequency range was: 0-80 Hz: 45.48 +/- 15.32%; 80-200 Hz: 43.97 +/- 9.95%; 200-300 Hz: 8.89 +/- 7.83%; 300-1000 Hz: 1.66 +/- 2.74%; 80-1000 Hz: 54.52 +/- 15.32%.     

Clonal expansion of hypermutated measles virus in a SSPE brain

Nucleotide sequence analysis was carried out to study genes encoding the matrix (M) protein of measles virus (MV) from several regions of the brain of a case of subacute sclerosing panencephalitis. This analysis revealed the presence of MV with "wild-type" sequences as well as variants which had undergone at least five biased hypermutation events (U to C and A to G in the positive strand sequences). Despite the presence of MV variants with genes encoding the intact matrix protein open reading frame, M protein could not be detected in any of the brain regions. The distribution of virus variants was studied by cDNA cloning and sequence analysis and by in situ hybridization. The hypermutated viruses appeared to expand clonally throughout the brain of patient B.     

Long-term intravenous hydroxyurea infusions in patients with advanced cancer. A phase I trial

BACKGROUND: Hydroxyurea is an S-phase specific drug. Constant exposure of tumor cells with a low S-phase fraction to the agent may result in improved cell kill. Because of its short half-life, a continuous intravenous infusion may result in better tumor exposure than intake by mouth. The goal of this trial was to find the longest tolerable duration of a continued intravenous infusion of hydroxyurea (HU) given at escalating doses. METHODS: Eligible patients had histologically confirmed cancer without effective alternate therapy, normal blood counts, liver and kidney function. After giving informed consent, the infusion began via a permanent indwelling catheter utilizing a portable pump. Dose levels (in g/m2/d) were 0.5 for level I, 1.0 for level II, 1.66 for level III, and 2.5 for level IV. RESULTS: Fourteen patients were entered. Five were men. Median age was 56 years of age (range: 32-67), median performance status 1 (range: 0-2). Diagnoses were as follows: colorectal cancer, seven; unknown primary site, three; breast cancer, two; melanoma, one; and adenoid-cystic carcinoma, one. Nine patients were pretreated with chemotherapy. Three patients were entered per dose level, except on level I, were five were entered. The mean duration of infusion was 12 weeks on level I, 5 weeks on II, 3 on III, 1 on IV. Toxicity included leukopenia below 2.0 K/mm3 in one patient each on levels III and IV, thrombocytopenia below 100 K/mm3 in one patient each on levels II and IV, and stomatitis in three patients (one on level II and two on IV). This toxicity was dose limiting. One patient on level III, with an unknown primary, had an objective response. HU levels were measured by a modification of the Fabricius-Rajewsky method. Mean plasma levels in micrograms per milliliter (SEM) were as follows: level I, 3.6 (0.23); level II, 5.1 (0.57); level III, 10.1 (1.55); and level IV, 16.7 (one point). Fetal hemoglobin rose two-fold and five-fold in two patients on level I after 9 and 16 weeks on therapy, respectively. CONCLUSIONS: HU as a continuous intravenous infusion is well tolerated; the maximum duration of therapy is related inversely with the dose given. No major antitumor activity was seen. The greatest interest in the drug rests in its future use as a modulator and radiation potentiator. The increase in hemoglobin F was of interest and may be important in the treatment of sickle cell disease.     

The anaerobic oxidation of ammonium

From recent research it has become clear that at least two different possibilities for anaerobic ammonium oxidation exist in nature. 'Aerobic' ammonium oxidizers like Nitrosomonas eutropha were observed to reduce nitrite or nitrogen dioxide with hydroxylamine or ammonium as electron donor under anoxic conditions. The maximum rate for anaerobic ammonium oxidation was about 2 nmol NH4+ min-1 (mg protein)-1 using nitrogen dioxide as electron acceptor. This reaction, which may involve NO as an intermediate, is thought to generate energy sufficient for survival under anoxic conditions, but not for growth. A novel obligately anaerobic ammonium oxidation (Anammox) process was recently discovered in a denitrifying pilot plant reactor. From this system, a highly enriched microbial community with one dominating peculiar autotrophic organism was obtained. With nitrite as electron acceptor a maximum specific oxidation rate of 55 nmol NH4+ min-1 (mg protein)-1 was determined. Although this reaction is 25-fold faster than in Nitrosomonas, it allowed growth at a rate of only 0.003 h-1 (doubling time 11 days). 15N labeling studies showed that hydroxylamine and hydrazine were important intermediates in this new process. A novel type of hydroxylamine oxidoreductase containing an unusual P468 cytochrome has been purified from the Anammox culture. Microsensor studies have shown that at the oxic/anoxic interface of many ecosystems nitrite and ammonia occur in the absence of oxygen. In addition, the number of reports on unaccounted high nitrogen losses in wastewater treatment is gradually increasing, indicating that anaerobic ammonium oxidation may be more widespread than previously assumed. The recently developed nitrification systems in which oxidation of nitrite to nitrate is prevented form an ideal partner for the Anammox process. The combination of these partial nitrification and Anammox processes remains a challenge for future application in the removal of ammonium from wastewater with high ammonium concentrations.     

Hydrochloric acid and pepsin secretion and the structure of the stomach in experimental protein malnutrition

In adult male rats submitted during 12 weeks to a diet containing 2,5% protein the amount of hydrochloric acid and of pepsin was determined and the macro and microscopic morphology of the stomach was studied. A group fed a diet containing 20% protein was used as control. The statistical analysis of the data obtained showed that the apparent differences in the secretion of acid as well as pepsin could be attributed to the different body weights of the two groups. The morphological examination showed papillomas, frequently ulcerated occurring in the forestomach of the undernourished rats. In these areas, histological examination revealed hyperkeratosis and acanthosis. The glandular epithelium showed neither macroscopic nor microscopic alterations.     

Increased sensitivity of the cough reflex in progressive systemic sclerosis patients with interstitial lung disease

Cough is a common presenting symptom of interstitial lung disease (ILD). The aim of this study was to examine the cough reflex in patients with progressive systemic sclerosis (PSS), with and without associated ILD. The cough reflex to inhalation of chloride deficient solutions and capsaicin was determined in patients with PSS with associated ILD (n=12), compared to patients with PSS without ILD (n=12). In addition, patients with a chronic dry cough (n=12) and healthy subjects (n=10) without cough were studied. Cough responses to inhalation of isotonic solutions containing 150, 75, 37.5 and 0 mM Cl- ions and of capsaicin (0.9-500 mM) were measured. PSS patients with ILD reported a significantly higher cough score than PSS patients without ILD (p<0.03). ILD patients coughed more than those without ILD to Cl- of 37.5 and 0 mM (19.1+/-5.0 vs 6.2+/-1.9 coughs x min(-1) (p<0.03), and 29.2+/-5.0 vs 14.1/-4.1 coughs x min(-1) (p<0.04), respectively). The log concentration of capsaicin causing two or five coughs was lower in PSS with ILD compared to PSS without ILD (0.74+/-0.15 mM vs 2.12+/-0.26 mM; p<0.002). Patients with chronic dry cough had a similar degree of response to low-chloride and capsaicin solutions as patients with PSS and ILD, whilst healthy controls had a similar degrees of response to PSS patients. There is an increased cough reflex in patients with interstitial lung disease, which may represent sensitization of airway sensory nerves. This may be the basis for the chronic dry cough in patients with interstitial lung disease.     

Structural requirements for PAK activation by Rac GTPases

The Rho family GTPases, Rac1 and Rac2, regulate a variety of cellular functions including cytoskeletal reorganization, the generation of reactive oxygen species, G1 cell cycle progression and, in concert with Ras, oncogenic transformation. Among the many putative protein targets identified for Rac (and/or Cdc42), the Ser/Thr kinase p21-activated kinase (PAK) is a prime candidate for mediating some of Rac's cellular effects. This report shows that Rac1 binds to and stimulates the kinase activity of PAK1 approximately 2- and 4-5-fold, respectively, better than Rac2. Mutational analysis was employed to determine the structural elements on Rac and PAK that are important for optimal binding and activation. The most notable difference between the highly homologous Rac isomers is the composition of their C-terminal polybasic domains. Mutation of these six basic residues in Rac1 to neutral amino acids dramatically decreased the ability of Rac1 to bind PAK1 and almost completely abolished its ability to stimulate PAK activity. Moreover, replacing the highly charged polybasic domain of Rac1 with the less charged domain of Rac2 (and vice versa) completely reversed the PAK binding/activation properties of the two Rac isomers. Thus, polybasic domain differences account for the disparate abilities of Rac1 and Rac2 to activate PAK. PAK proteins also contain a basic region, consisting of three contiguous lysine residues (Lys66-Lys67-Lys68), which lies outside of the previously identified Cdc42/Rac-binding domain. Mutation of these Lys residues to neutral residues decreased PAK binding to activated Rac1 and Rac2 (but not Cdc42) and greatly reduced PAK1 activation by Rac1, Rac2, and Cdc42 proteins in vivo. In contrast, mutation of lysines 66-68 to basic Arg residues did not decrease (and in some cases enhanced) the ability of Rac1, Rac2, and Cdc42 to bind and activate PAK1. Our studies suggest that the polybasic domain of Rac is a novel effector domain that may allow the two Rac isomers to activate different effector proteins. In addition, our results indicate that a basic region in PAK is required for PAK activation and that binding of Rac/Cdc42 to PAK is not sufficient for kinase activation.     

Genetic risks of in vitro fertilization

In-vitro fertilization (IVF) with embryo transfer is a well established therapy in infertility. With the increase of andrological problems as reasons for IVF the question of possible genetic risks is gaining additional attention. For the patients, the incidence of congenital malformations in their offspring resulting from IVF as well as the incidence of spontaneous abortions are of particular interest. In this review population genetic data of congenital malformations are compared to those found in IVF populations. On average, congenital malformations occur in 3% of all livebirths in an unselected population, whereas there were 1.5% newborns with congenital malformations reported in the IVF population. This is well within this basic background risk for congenital malformations. Bearing maternal age and especially careful follow-up of early pregnancies after IVF in mind, the rate of spontaneous abortions after IVF (21 to 27%) is also not significantly increased above the rate of 15% in the unselected general population. The introduction of microinvasive techniques into IVF has given the question of possible genetic risks for the offspring from IVF using these techniques, a great deal of topical interest. The range of indications of subzonal or intracytoplasmatic sperm injection (ICSI) includes andrological problems to a high degree which themselves could be the result of chromosomal anomalies or hereditary disorders. One example is the vas deferens aplasia in one form of CF mutations. Cytogenetic and clinical genetic evaluation should be recommended especially in cases of andrological or idiopathic sterility and infertility. Some examples of autosomal dominant syndromes in which clinical genetic evaluation and genetic counselling are advisable are listed in a summarizing table.     

Triggering of L-selectin (gp90MEL-14) induces homotypic lymphocyte adhesion by a mechanism independent of LFA-1

The L-selectin adhesion receptor plays a central role in regulating leukocyte adhesion to endothelial cells. The data presented in this report demonstrate that triggering of L-selectin results in a rapid and vigorous homotypic adhesion among normal lymphocytes as well as lymphoblastoid cells, thereby providing evidence for a novel cell-cell adhesion function of L-selectin. The cellular adhesion event induced by mAb MEL-14 was dependent on metabolic energy, an intact cytoskeleton, and the activation of intracellular protein kinases. Cell clustering did not require cross-linking of L-selectin molecules and occurred in the complete absence of divalent cations. Analysis of adhesion receptor expression and antibody inhibition experiments indicated that cluster formation did not involve LFA-1, alpha 4 integrins, beta 1 integrins, beta 7 integrins, or CD44.