Central respiratory chemoreception

By definition central respiratory chemoreceptors (CRCs) are cells that are sensitive to changes in brain PCO₂ or pH and contribute to the stimulation of breathing elicited by hypercapnia or metabolic acidosis. CO₂ most likely works by lowering pH. The pertinent proton receptors have not been identified and may be ion channels. CRCs are probably neurons but may also include acid‐sensitive glia and vascular cells that communicate with neurons via paracrine mechanisms. Retrotrapezoid nucleus (RTN) neurons are the most completely characterized CRCs. Their high sensitivity to CO₂ in vivo presumably relies on their intrinsic acid sensitivity, excitatory inputs from the carotid bodies and brain regions such as raphe and hypothalamus, and facilitating influences from neighboring astrocytes. RTN neurons are necessary for the respiratory network to respond to CO₂ during the perinatal period and under anesthesia. In conscious adults, RTN neurons contribute to an unknown degree to the pH‐dependent regulation of breathing rate, inspiratory, and expiratory activity. The abnormal prenatal development of RTN neurons probably contributes to the congenital central hypoventilation syndrome. Other CRCs presumably exist, but the supportive evidence is less complete. The proposed locations of these CRCs are the medullary raphe, the nucleus tractus solitarius, the ventrolateral medulla, the fastigial nucleus, and the hypothalamus. Several wake‐promoting systems (serotonergic and catecholaminergic neurons, orexinergic neurons) are also putative CRCs. Their contribution to central respiratory chemoreception may be behavior dependent or vary according to the state of vigilance. J. Comp. Neurol. 518:3883–3906, 2010. © 2010 Wiley‐Liss, Inc.     

Fracture behaviour of zirconia FPDs substructures

Summary The purpose of this study was to evaluate the occurrence of superficial flaws after machining and to identify fracture initiation and propagation in three‐unit heat‐treated machined fixed partial dentures (FPDs) substructures made of hot isostatic pressed (HIPed) yttria‐stabilized tetragonal zirconia polycrystal (Y‐TZP) after loaded to fracture. Four three‐unit HIPed Y‐TZP‐based FPDs substructures were examined. To evaluate the occurrence of superficial flaws after machining, the surfaces were studied utilizing a fluorescent penetrant method. After static loading to fracture, characteristic fracture features on both mating halves of the fractured specimens were studied using a stereomicroscope and a scanning electron microscope. Grinding grooves were clearly visible on the surfaces of the machined FPDs substructures, but no other flaws could be seen with the fluorescent penetrant method. After loading to fracture, the characteristic fracture features of arrest lines, compression curl, fracture mirror, fracture origin, hackle and twist hackle were detected. These findings indicated that the decisive fracture was initiated at the gingival embrasure of the pontic in association with a grinding groove. Thus, in three‐unit heat‐treated machined HIPed Y‐TZP FPDs substructures, with the shape studied in this study, the gingival embrasure of the pontic seems to be a weak area providing a location for tensile stresses when they are occlusally loaded. In this area, fracture initiation may be located to a grinding groove.     

Re: Propranolol Treatment for Hemangioma of Infancy: Risks and Recommendations

Letters to the Editor are welcomed for publication (subject to editing). Letters must be signed by all authors, and must not exceed two pages of text including references. Letters should not duplicate material submitted or published in other journals. Prepublication proofs will not be provided.     

Activation and inhibition of G protein-coupled inwardly rectifying potassium (Kir3) channels by G protein beta gamma subunits

G protein-coupled inwardly rectifying potassium (GIRK) channels can be activated or inhibited by different classes of receptors, suggesting a role for G proteins in determining signaling specificity. Because G protein betagamma subunits containing either beta1 or beta2 with multiple Ggamma subunits activate GIRK channels, we hypothesized that specificity might be imparted by beta3, beta4, or beta5 subunits. We used a transfection assay in cell lines expressing GIRK channels to examine effects of dimers containing these Gbeta subunits. Inwardly rectifying K(+) currents were increased in cells expressing beta3 or beta4, with either gamma2 or gamma11. Purified, recombinant beta3gamma2 and beta4gamma2 bound directly to glutathione-S-transferase fusion proteins containing N- or C-terminal cytoplasmic domains of GIRK1 and GIRK4, indicating that beta3 and beta4, like beta1, form dimers that bind to and activate GIRK channels. By contrast, beta5-containing dimers inhibited GIRK channel currents. This inhibitory effect was obtained with either beta5gamma2 or beta5gamma11, was observed with either GIRK1,4 or GIRK1,2 channels, and was evident in the context of either basal or agonist-induced currents, both of which were mediated by endogenous Gbetagamma subunits. In cotransfection assays, beta5gamma2 suppressed beta1gamma2-activated GIRK currents in a dose-dependent manner consistent with competitive inhibition. Moreover, we found that beta5gamma2 could bind to the same GIRK channel cytoplasmic domains as other, activating Gbetagamma subunits. Thus, beta5-containing dimers inhibit Gbetagamma-stimulated GIRK channels, perhaps by directly binding to the channels. This suggests that beta5-containing dimers could act as competitive antagonists of other Gbetagamma dimers on GIRK channels.     

Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S

Protein S deficiency is a recognized risk factor for venous thrombosis. Of all the inherited thrombophilic conditions, it remains the most difficult to diagnose because of phenotypic variability, which can lead to inconclusive results. We have overcome this problem by studying a cohort of patients from a single center where the diagnosis was confirmed at the genetic level. Twenty-eight index patients with protein S deficiency and a PROS1 gene defect were studied, together with 109 first-degree relatives. To avoid selection bias, we confined analysis of total and free protein S levels and thrombotic risk to the patients' relatives. In this group of relatives, a low free protein S level was the most reliable predictor of a PROS1 gene defect (sensitivity 97.7%, specificity 100%). First-degree relatives with a PROS1 gene defect had a 5.0-fold higher risk of thrombosis (95% confidence interval, 1. 5-16.8) than those with a normal PROS1 gene and no other recognized thrombophilic defect. Although pregnancy/puerperium and immobility/trauma were important precipitating factors for thrombosis, almost half of the events were spontaneous. Relatives with splice-site or major structural defects in the PROS1 gene were more likely to have had a thrombotic event and had significantly lower total and free protein S levels than those relatives having missense mutations. We conclude that persons with PROS1 gene defects and protein S deficiency are at increased risk of thrombosis and that free protein S estimation offers the most reliable way of diagnosing the deficiency. (Blood. 2000;95:1935-1941)     

Carriage of Haemophilus influenzae and Streptococcus pneumoniae in healthy Chinese and Vietnamese children in Hong Kong

Nasopharyngeal carriage of Haemophilus influenzae and Streptococcus pneumoniae was studied in 621 healthy Chinese children and 300 healthy Vietnamese children aged from 2 months to 5 years in Hong Kong. The carriage rate of H, influenzae type b in Vietnamese children was 1.3% (CI 0.04-2.63%); it was zero in Chinese. The carriage rate of non-typable H. influenzae was 5.8% (CI 1.4-7.6%) in Chinese and 65.4% (CI 58.9-69.8%) in Vietnamese. The carriage rates of S. pneumoniae were 10.8% (CI 8.3-13.2%) and 55.7% (CI 50.1-61.3%) in Chinese and Vietnamese children, respectively. Univariate and multivariate logistic regression analyses were performed to search for factors associated with differences in carriage rates of both H. influenzae and S. pneumoniae between Chinese and Vietnamese children. Although older age, smaller living area and parental smoking were associated with higher carriage rates, these could not explain the remarkably low carriage rates of both bacteria in Chinese children.     

Genetic Engineering and Medical Ethics

In the introduction I express the need of introducing the point of view of Ethics when we are dealing with problems of science, technology, and especially medicine. In the first part of my presentation I deal with the problem of the value of human life, coming to the conclusion that human life might not be completely absolute, but is extremely important and “ceteris paribus” should be respected, and the problem of when it starts. Some of the main arguments are discussed. In this connection the question of abortion is briefly discussed. In the second part I deal with some problems related to human reproduction. Most people will be willing to support programmes for treating individuals with genetic disease; but at the same time the dangers of increasing depersonalization of the reproductive process are pointed out. In the third part I take up the problem of In Vitro Fertilisation. IVF has certainly brought benefits to some couples suffering from infertility, but at the same time it has raised quite a few human and moral problems. Is it permissible to fertilise an egg with a donor sperm, replacing the embryo in the womb? What about fertilising a donor egg with the husband's sperm? Is it acceptable to store or freeze embryos for future use? Is it moral to implant such an embryo in a woman who has no genetic relationship with the embryo? Is it moral to use surrogate mothers? Is it moral for ‘spare’ embryos to be killed or used as tissue for research? At the end I stress the need of dialogue between life sciences and ethics.     

贴报-P2临床毒理学、药理学和疗效研究

5-Flourouracil（5-FU） is one of well known anti-cancer drugs, but its toxicity in normal lymphocytes remains a major problem in chemotherapy. The eastern traditional drug, Bupleuri radix（BR）, has been used for the treatment of liver diseases and contains series of triterpene saponins.