Correlation between in vitro and in vivo parameters of commercial paracetamol tablets

Three leading and competitive commercial products of paracetamol tablets coded as brands A, B and C (A, being the innovator product) in the country were evaluated for their in vitro properties and in vivo comparative bioavailability. The studies included chemical equivalence, hardness, disintegration time, dissolution rate and systemic availability among eight healthy volunteers. The disintegration times were 2.1 min for brand A, 5.7 min for brand B and 36.2 min for brand C. The dissolution rate (T70) were 33.0 min, 74.5 min and 56.5 min for brands A, B and C, respectively. While brand A passed all the in vitro tests as specified in the official monograph, brand B failed only the dissolution rate test and brand C failed both the disintegration and dissolution tests. These significant differences observed among the products after in vitro tests were not reflected in the in vivo availability. While the absorption rate (indicated by tmax) of brand C was significantly faster (i.e. shorter) than those of Brands A and B, the extent of absorption (indicated by AUC) was comparable among the three brands. The relative bioavailabilities (with respect to brand A) were 92 and 91% for brands B and C, respectively indicating that the products were bioequivalent. Comparison of the in vitro and in vivo data suggest that the systemic absorption of paracetamol may not be dissolution--rate limited and that using in vitro dissolution rate studies alone to establish bioequivalency of paracetamol tablets should be done with caution.     

Riboflavin-mediated delivery of a macromolecule into cultured human cells

The effects of perivascular nerve stimulation and phenylephrine on osmolyte release were studied in the intact perfused rat liver and isolated liver parenchymal cells (PC) and nonparenchymal cells. In the perfused liver, electrical stimulation of perivascular nerves (20 Hz/2 ms/20 V) led to a phentolamine-sensitive increase of cell hydration by 6.5% +/- 1.2% (n = 3) and a transient phentolamine-sensitive stimulation of taurine and inositol, but not betaine, release. These nerve effects were mimicked by phenylephrine, but not prostaglandin F2alpha, and were not affected by sodium nitroprusside (SNP) or ibuprofen. Nerve stimulation-induced taurine, but not inositol, release was inhibited by 4, 4'-di-isothiocyanatostilbene-2,2'-disulphonic acid (DIDS) (50 micromol/L). Single-cell fluorescence studies with isolated liver PC, Kupffer cells (KC), sinusoidal endothelial cells (SEC), and hepatic stellate cells (HSC) revealed that phenylephrine induced an increase in cytosolic free Ca2+ only in PC and HSC, but not in KC and SEC, whereas extracellular uridine triphosphate (UTP) produced Ca2+ transients/oscillations in all liver cell types studied. Phenylephrine had no effect on osmolyte release from isolated KC and SEC, but increased taurine (but not inositol) release from PC and inositol (but not taurine) efflux from HSC. The data suggest that: 1) liver cell hydration and-consecutively-osmolyte content are modulated by hepatic nerves via an alpha-adrenergic mechanism, which does not involve eicosanoids or hemodynamic changes; 2) that PC and HSC are the primary targets for nerve-dependent alpha-adrenergic activation, whereas 3) KC and SEC probably do not express alpha-adrenoceptors coupled to Ca2+ mobilization or osmolyte efflux.     

Coordinate intracellular expression of Salmonella genes induced during infection

Salmonella typhimurium in vivo-induced (ivi) genes were grouped by their coordinate behavior in response to a wide variety of environmental and genetic signals, including pH, Mg2+, Fe2+, and PhoPQ. All of the seven ivi fusions that are induced by both low pH and low Mg2+ (e.g., iviVI-A) are activated by the PhoPQ regulatory system. Iron-responsive ivi fusions include those induced under iron limitation (e.g., entF) as well as one induced by iron excess but only in the absence of PhoP (pdu). Intracellular expression studies showed that each of the pH- and Mg2+-responsive fusions is induced upon entry into and growth within three distinct mammalian cell lines: RAW 264.7 murine macrophages and two cultured human epithelial cell lines: HEp-2 and Henle-407. Each ivi fusion has a characteristic level of induction consistent within all three cell types, suggesting that this class of coordinately expressed ivi genes responds to general intracellular signals that are present both in initial and in progressive stages of infection and may reflect their responses to similar vacuolar microenvironments in these cell types. Investigation of ivi expression patterns reveals not only the inherent versatility of pathogens to express a given gene(s) at various host sites but also the ability to modify their expression within the context of different animal hosts, tissues, cell types, or subcellular compartments.     

The trithorax group gene moira encodes a brahma-associated putative chromatin-remodeling factor in Drosophila melanogaster

The genes of the trithorax group (trxG) in Drosophila melanogaster are required to maintain the pattern of homeotic gene expression that is established early in embryogenesis by the transient expression of the segmentation genes. The precise role of each of the diverse trxG members and the functional relationships among them are not well understood. Here, we report on the isolation of the trxG gene moira (mor) and its molecular characterization. mor encodes a fruit fly homolog of the human and yeast chromatin-remodeling factors BAF170, BAF155, and SWI3. mor is widely expressed throughout development, and its 170-kDa protein product is present in many embryonic tissues. In vitro, MOR can bind to itself and it interacts with Brahma (BRM), an SWI2-SNF2 homolog, with which it is associated in embryonic nuclear extracts. The leucine zipper motif of MOR is likely to participate in self-oligomerization; the equally conserved SANT domain, for which no function is known, may be required for optimal binding to BRM. MOR thus joins BRM and Snf5-related 1 (SNR1), two known Drosophila SWI-SNF subunits that act as positive regulators of the homeotic genes. These observations provide a molecular explanation for the phenotypic and genetic relationships among several of the trxG genes by suggesting that they encode evolutionarily conserved components of a chromatin-remodeling complex.     

Study of the vertical transport in <Emphasis Type="Italic">p</Emphasis>-doped superlattices based on group III-V semiconductors

The electrical conductivity σ has been calculated for p-doped GaAs/Al_0.3Ga_0.7As and cubic GaN/Al_0.3Ga_0.7N thin superlattices (SLs). The calculations are done within a self-consistent approach to the theory by means of a full six-band Luttinger-Kohn Hamiltonian, together with the Poisson equation in a plane wave representation, including exchange correlation effects within the local density approximation. It was also assumed that transport in the SL occurs through extended minibands states for each carrier, and the conductivity is calculated at zero temperature and in low-field ohmic limits by the quasi-chemical Boltzmann kinetic equation. It was shown that the particular minibands structure of the p-doped SLs leads to a plateau-like behavior in the conductivity as a function of the donor concentration and/or the Fermi level energy. In addition, it is shown that the Coulomb and exchange-correlation effects play an important role in these systems, since they determine the bending potential.     

The Chemical Evolution of the La<Subscript>0.6</Subscript>Sr<Subscript>0.4</Subscript>CoO<Subscript>3−δ</Subscript> Surface Under SOFC Operating Conditions and Its Implications for Electrochemical Oxygen Exchange Activity

Owing to its extraordinary high activity for catalysing the oxygen exchange reaction, strontium doped LaCoO₃ (LSC) is one of the most promising materials for solid oxide fuel cell (SOFC) cathodes. However, under SOFC operating conditions this material suffers from performance degradation. This loss of electrochemical activity has been extensively studied in the past and an accumulation of strontium at the LSC surface has been shown to be responsible for most of the degradation effects. The present study sheds further light onto LSC surface changes also occurring under SOFC operating conditions. In-situ near ambient pressure X-ray photoelectron spectroscopy measurements were conducted at temperatures between 400 and 790 °C. Simultaneously, electrochemical impedance measurements were performed to characterise the catalytic activity of the LSC electrode surface for O₂ reduction. This combination allowed a correlation of the loss in electro-catalytic activity with the appearance of an additional La-containing Sr-oxide species at the LSC surface. This additional Sr-oxide species preferentially covers electrochemically active Co sites at the surface, and thus very effectively decreases the oxygen exchange performance of LSC. Formation of precipitates, in contrast, was found to play a less important role for the electrochemical degradation of LSC.     

Quasilinearized Regression

Estimation in nonlinear regression usually requires a considerable amount of computational work. If it is possible to linearize the original formulas, the linear regression is sometimes applied to transformed linear relations. The method of quasilinearized regression (first order approximation of nonlinear regression), comparable to linear regression, with respect to computational effort, is described in this paper. This method gives substantially better results than linear regression of linearized formula.     

Polymerase chain reaction (PCR) and its possible applications in diagnosis of infection in ophthalmology

Fecal incontinence resulting from pudendal canal syndrome has been treated by pudendal canal decompression (PCD) with satisfactory results. Considering the possible difficulty in exposing the pudendal canal and nerve by the open method, laparoscopic PCD was practiced in 9 women aged between 37 and 52 years. They were complaining of fecal incontinence; urinary stress incontinence was an additional complaint in 4/9 women. Neurologic, manometric, and EMG studies confirmed the diagnosis of pudendal canal syndrome. For laparoscopic PCD a 1-cm incision lateral to the anal orifice was performed. A balloon dilator was introduced in the ischiorectal fossa (IRF) to create a working space, and CO2 was insufflated. Under the guidance of a laparoscope, the IRF was entered and the inferior rectal nerve identified and followed to the pudendal canal. The latter was split open, releasing the pudendal nerve into the IRF. Fecal control was achieved in 7/9 patients and urinary control in 2/4. Fecal and urinary control were associated with improvement in perianal sensation, rectal neck pressure, EMG of external anal sphincter and levator ani muscle as well as in pudendal nerve terminal motor latency. Two women showed no improvement. Failure is suggested to be due to an advanced pudendal neuropathy. In conclusion, laparoscopic PCD is a simple, easy, and safe procedure. It allows for better exposure of the contents of the IRF than the open procedure, thus avoiding injury of the pudendal nerve and its branches during the performance of the PCD.     

Constitutive expression in gal7 mutants of Kluyveromyces lactis is due to internal production of galactose as an inducer of the Gal/Lac regulon

The induction process of the galactose regulon has been intensively studied, but until now the nature of the inducer has remained unknown. We have analyzed a delta gal7 mutant of the yeast Kluyveromyces lactis, which lacks the galactotransferase activity and is able to express the genes of the Gal/Lac regulon also in the absence of galactose. We found that this expression is semiconstitutive and undergoes a strong induction during the stationary phase. The gal1-209 mutant, which has a reduced kinase activity but retains its positive regulatory function, also shows a constitutive expression of beta-galactosidase, suggesting that galactose is the inducer. A gal10 deletion in delta gal7 or gal1-209 mutants reduces the expression to under wild-type levels. The presence of the inducer could be demonstrated in both delta gal7 crude extracts and culture medium by means of a bioassay using the induction in gal1-209 cells. A mutation in the transporter gene LAC12 decreases the level of induction in gal7 cells, indicating that galactose is partly released into the medium and then retransported into the cells. Nuclear magnetic resonance analysis of crude extracts from delta gal7 cells revealed the presence of 50 microM galactose. We conclude that galactose is the inducer of the Gal/Lac regulon and is produced via UDP-galactose through a yet-unknown pathway.