Twenty-four-hour pharmacokinetics of rectal acetaminophen in children: an old drug with new recommendations

Oxidized low density lipoprotein (LDL) and acetyl LDL are recognized by the scavenger receptor class A type I/II (SR-AI/II) on macrophages and liver endothelial cells. Several investigators have suggested that there are additional receptors specific for oxidized LDL, but characterization of these alternate receptors for oxidized LDL and evaluation of their quantitative importance in uptake of oxidized LDL has been difficult because of overlapping ligand specificity with SR-AI/II. The purpose of this study was to determine the importance of SR-AI/II in the removal of modified LDL from the bloodstream in vivo. The clearance rate of oxidized LDL from plasma in normal mice was very rapid, and > 90% of injected dose was removed from the blood within 5 min. Clearance rates of oxidized LDL were equally high in SR-AI/II knockout mice, indicating that this receptor is not required for removal of oxidized LDL from plasma. Surprisingly, there was no difference in the clearance rate of acetyl LDL in wild-type and SR-AI/II knockout animals. The plasma clearance of radioiodinated acetyl LDL was almost fully blocked by a 50-fold excess of unlabeled acetyl LDL, but the latter only inhibited oxidized LDL clearance by approximately 5%. Both modified LDLs were cleared mostly by the liver, and there was no difference in the tissue distribution of modified LDL in control and knockout mice. Studies in isolated nonparenchymal liver cells showed that Kupffer cells accounted for most of the uptake of oxidized LDL. Extensively oxidized LDL and LDL modified by exposure to fatty acid peroxidation products were efficient competitors for the uptake of labeled oxidized LDL by SR-AI/II-deficient Kupffer cells, while acetyl LDL and malondialdehyde-modified LDL were relatively poor competitors.     

Hierarchically coupled ultradian oscillators generating robust circadian rhythms

Ensembles of mutually coupled ultradian cellular oscillators have been proposed by a number of authors to explain the generation of circadian rhythms in mammals. Most mathematical models using many coupled oscillators predict that the output period should vary as the square root of the number of participating units, thus being inconsistent with the well-established experimental result that ablation of substantial parts of the suprachiasmatic nuclei (SCN), the main circadian pacemaker in mammals, does not eliminate the overt circadian functions, which show no changes in the phases or periods of the rhythms. From these observations, we have developed a theoretical model that exhibits the robustness of the circadian clock to changes in the number of cells in the SCN, and that is readily adaptable to include the successful features of other known models of circadian regulation, such as the phase response curves and light resetting of the phase.     

Breast cancer diagnosis using N2 laser excited autofluorescence spectroscopy

Carbonic anhydrase VI (CA VI) is a secreted enzyme produced predominantly by serous acinar cells of submandibular and parotid glands. We have investigated the developmental pattern of CA VI production by these glands in the sheep, from fetal life to adulthood, using immunohistochemistry. Also, a specific radioimmunoassay for CA VI was used to measure changes in enzyme expression in the parotid gland postnatally. CA VI is detectable by immunohistochemistry in parotid excretory ducts from 106 days gestation (term is 145 days), in striated ducts from 138 days and in acinar cells from 1 day postnatal. The duct cell content of CA VI declined as the acinar cell population increased, a feature also of CA VI immunoreactivity in the submandibular gland. Production of CA VI by submandibular duct cells was detectable initially at 125 days gestation, and acinar production was not seen before 29 days post-natal. Apart from the differing ontogeny of CA VI production in ducts and acini of parotid and submandibular glands, there was a parallel pattern of CA VI expression during the development of these major salivary glands. With the development of the acinar tissues in the postnatal lamb, there was a dramatic increase (about 600-fold) in the level of expression of CA VI in the parotid gland between days 7 and 59 as measured by radioimmunoassay.     

Late-onset life-threatening angioedema and upper airway obstruction caused by angiotensin-converting enzyme inhibitor: report of a case

Angioedema is a rare but potentially lethal adverse effect when associated with upper airway obstruction. Sporadic cases of angioedema secondary to angiotensin converting enzyme inhibitors (ACEI) have been reported in the literature. The overall incidence is around 0.1% to 0.2%, and the time of onset is usually during the first week of ACEI therapy. Late-onset angioedema secondary to treatment with ACEIs is much more frequent than appreciated, and is largely unrecognized because of the absence of temporal correlation between ACEI therapy and the development of angioedema. Since angioedema may progress to upper airway obstruction, otolaryngologists must be aware of this association. Most importantly, late-onset angioedema should alert the clinician to discontinue the ACEI immediately to prevent further morbidity. This report presents an example of late-onset angioedema which was precipitated by taking a double dose of captopril incidentally. The case is discussed, and the literature, pathophysiology and treatment of angioedema are reviewed.     

Bilateral lower limb oedema due to a distended urinary bladder

A 91-year-old Chinese man developed bilateral lower limb oedema due to venous obstruction resulting from a distended urinary bladder. After the bladder was decompressed by urethral catheterisation, the bilateral lower limb oedema promptly subsided. Although a distended urinary bladder is a rare cause of bilateral lower limb oedema, it can be easily recognised by palpation of the lower abdomen and the relief of symptoms by urethral catheterisation is most rewarding.     

Kinetochores distinguish GTP from GDP forms of the microtubule lattice

During prometaphase in mitotic cell division, chromosomes attach to the walls of microtubules and subsequently move to microtubule ends, where they stay throughout mitosis. This end-attachment seems to be essential for correct chromosome segregating. However, the mechanism by which kinetochores, the multiprotein complexes that link chromosomes to the microtubules of the mitotic spindle, recognize and stay attached to microtubule ends is not understood. One clue comes from the hydrolysis of GTP that occurs during microtubule polymerization. Although tubulin dimers must contain GTP to polymerize, this GTP is rapidly hydrolysed following the addition of dimers to a growing polymer. This creates a microtubule consisting largely of GDP-tubulin, with a small cap of GTP-tubulin at the end. It is possible that kinetochores distinguish the different structural states of a GTP- versus a GDP-microtubule lattice. We have examined this question in vitro using reconstituted kinetochores from the yeast Saccharomyces cerevisiae. We found that kinetochores in vitro bind preferentially to GTP- rather than GDP-microtubules, and to the plus-end preferentially over the lattice. Our results could explain how kinetochores stay at microtubule ends and thus segregate chromosomes correctly during mitosis in vivo. This result demonstrates that proteins exist that can distinguish the GTP conformation of the microtubule lattice.     

Suppressor gene analysis reveals an essential role for sphingolipids in transport of glycosylphosphatidylinositol-anchored proteins in Saccharomyces cerevisiae

Sphingolipids are normally necessary for growth of Saccharomyces cerevisiae cells, but mutant strains that bypass the need for sphingolipids have been identified. Such bypass mutants fail to grow under stressful conditions, including low pH (pH 4.1), when they lack sphingolipids. To begin to understand why sphingolipids seem to be necessary for coping with low-pH stress, we screened a genomic library and selected a suppressor gene, CWP2 (cell wall protein 2), that when present in multiple copies partially compensates for the lack of sphingolipids and enhances survival at low pH. To explain these results, we present evidence that sphingolipids are required for a normal rate of transport of glycosylphosphatidylinositol (GPI)-anchored proteins, including Cwp2 and Gas1/Gpg1, from the endoplasmic reticulum (ER) to the Golgi apparatus. The effect of sphingolipids is specific for transport of GPI-anchored proteins because no effect on the rate of transport of carboxypeptidase Y, a non-GPI-anchored protein, was observed. Since the Gasl protein accumulated in the ER with a GPI anchor in cells lacking sphingolipids, we conclude that sphingolipids are not necessary for anchor attachment. Therefore, sphingolipids must be necessary for a step in formation of COPII vesicles or for their transport to the Golgi apparatus. Our data identify the Cwp2 protein as a vital component in protecting cells from the stress of low pH.     

Interaction of prion peptide HuPrP106-126 with nucleic acid

Synthetic prion peptide PrP106-126 has been used as a model to understand prion diseases. The conformation of the peptide depends on the environmental conditions and it forms amyloid in vitro. The potential of this prion peptide to interact with nucleic acids has been studied using a fluorescent labelled nucleic acid by kinetic and equilibrium methods. A decrease in the fluorescence of the labelled DNA induced by the peptide with time is observed which is pH, ionic strength and temperature dependent. The activation energy of the reactions is approximately 100 kJ mol-1. Lysine tripeptide and spermidine, carrying the same number of positive charges as the prion peptide, do not show an appreciable effect on the DNA. The binding constant between the prion peptide and DNA has a value of > 10(6) M-1 in phosphate buffer, pH 8 which is of the same order of magnitude as the binding of a retroviral protein, p10, with model nucleic acids. It is tempting to speculate that this interaction might play a role in the prion diseases.