Atrial natriuretic peptide in alcoholic cirrhosis

Sodium retention in cirrhosis could result from a deficiency of atrial natriuretic peptide (ANP) or end-organ resistance to ANP. Venous levels of α-human ANP (αhANP) measured in 19 alcoholic cirrhotics by radio-immunoassay were in the higher end of the normal range (29.7 pg/ml, s.d. = 17.2) and tended to increase with development of ascites or varices. Arterial levels of αhANP were not related to right atrial pressure but were related inversely to pulse rate. There was significant splanchnic (mean = 37.2%, s.d. = 19.5) and non-splanchnic clearance (mean = 30.3%, s.d. = 17.1) of αhANP. The percentage extraction of αhANP across the splanchnic bed (%E ANP splanchnic) was not related to portal pressure, effective hepatic plasma flow or degree of intrahepatic shunting. The %E ANP splanchnic increased as functional liver cell mass (antipyrine clearance) decreased (r= 0.592, P= 0.034). Despite increased splanchnic clearance, αhANP levels increased with a fall in functional liver cell mass presumably due to increased release. Renal sodium retention in cirrhosis does not involve a deficiency of αhANP but increased end-organ resistance needs to be excluded.     

Inhibition of platelet function by A02131-1, a novel inhibitor of cGMP- specific phosphodiesterase, in vitro and in vivo

The effect of A02131-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl thieno (3,2-c)pyrazole], a cGMP-specific phosphodiesterase (PDE) inhibitor, on platelet function was investigated. The compound was found to inhibit the aggregation of and adenosine triphosphate (ATP) release from human platelet-rich plasma and washed platelets that were induced by aggregation inducing drugs such as arachidonic acid (AA), collagen, U46619, platelet-activating factor (PAF), adenosine diphosphate (ADP) and A23187, and the inhibitory effect was concentration-dependent. A02131-1 also disaggregated the performed platelet aggregates induced by these inducers. Thromboxane B2 (TXB2) formations caused by collagen, PAF, ADP, and A23187 were inhibited by A02131-1 at concentrations that did not affect the AA-induced formation of TXB2 and prostaglandin D2 (PGD2). A02131-1 suppressed both the generation of inositol 1,4,5- triphosphate (IP3) and the increase of intracellular Ca2+ concentration stimulated by these aggregation inducers. A02131-1 was shown to increase the cAMP and cGMP levels in platelets and the extent was found to be dependent on concentration as well as time. A02131-1 increased the cAMP level much more slowly than the cGMP level. Activities of adenylate cyclase, guanylate cyclase, and PDEs (type I and III) were not altered by A02131-1. However, the activity of cGMP-specific PDE (type V) was inhibited by A02131-1. The antiplatelet aggregation activity and the effect on raising cAMP level of A02131-1 were both potentiated by prostaglandin E1 (PGE1). In the mouse tail bleeding test, A02131-1 was clearly shown to be more effective than dipyridamole in prolonging the tail bleeding time of conscious mice. These data indicate that A02131-1 is a cGMP-specific PDE (type V) inhibitor in human platelets.     

Expression of a Common LQT1 Mutation in Five Apparently Unrelated Families in a Regional Inherited Arrhythmia Clinic

Expression of a Common LQT1 Mutation. Background: The Inherited Arrhythmia Clinic at the University of Western Ontario services a catchment area of 1.5 million people and follows families with inherited arrhythmia syndromes. Methods: Patients referred for evaluation of long‐QT Syndrome (LQTS) are evaluated with resting and standing ECGs, and treadmill exercise testing. Patients with findings consistent with LQTS are offered comprehensive genetic testing with screening of all first‐degree relatives of genotype‐positive patients. Results: Among 31 probands with disease‐causing LQTS mutations, 5 probands from apparently unrelated families of Irish descent were found to have an identical disease causing transmembrane mutation in KCNQ1 (Leu266Pro). Systematic screening of 33 first‐degree relatives of genotype‐positive individuals detected 15 unaffected and 18 asymptomatic affected family members. Symptoms in 6 patients occurred later in life than reported LQT1 populations (61 ± 18 years, range 44–89). In this cohort, several family members presented with cardiac arrest during acute myocardial ischemia (n = 2), sudden death, unexplained drowning, and torsade de pointes during exercise testing. There was no identifiable common relative for this cohort after pedigree construction of the previous 4–7 generations. Affected patients had mild QT prolongation at rest with dramatic QT prolongation with exercise. Conclusions: Genetic testing in this LQTS population suggests a common KCNQ1 Leu266Pro founder effect, with the descendants clustering in our geographical region even though no common relative has been identified. The observations highlight the utility of genotypic and phenotypic correlation and a specialized clinic. (J Cardiovasc Electrophysiol, Vol. 21, pp. 296–300, March 2010)     

Endoxin antagonist lessens myocardial ischemia reperfusion injury

Endoxin antagonist lessens myocardial ischemia reperfusion injury@柯永胜$Department of Cardiology, Yijishan Hospital, Wannan Medical College, Wuhu, 241001 China @王德国$Department of Cardiology, Yijishan Hospital, Wannan Medical College, Wuhu, 241001 C     

放免法测定746例地戈辛血药浓度分析

目的：监测地戈辛血药浓度。方法;采用放免法监测７４６例地戈辛治疗慢性心功能不全病人的血药浓度。结果;血药浓度在治疗范围者３２５例,偏低者９９例,高者３２２例,大于治疗范围者中有１２例出现中毒症状。结论：监测地戈辛血药浓度可作为判断药物疗效和中毒的客观指标。     

COX-2 expression is induced by UVB exposure in human skin: implications for the development of skin cancer

Extensive documentation has validated the role of UV irradiation as a tumor initiator and promoter, inducing both squamous and basal cell carcinomas. Human epidermis is a tissue which undergoes active metabolism of arachidonic acid to prostaglandins which is regulated by the action of prostaglandin H synthase (also known as cyclooxygenase). One mechanism for the promotional activity of UV light may involve its ability to induce prostaglandin formation. Work in our laboratory has demonstrated that acute exposure of human keratinocytes to UVB irradiation results in increased production of prostaglandin E2 (PGE2). When cultured human keratinocytes were examined after irradiation with 30 mJ/cm2 UVB in vitro, Western blot analysis showed a 6-fold increase in COX-2 protein which was evident at 6 h and peaked 24 h after irradiation. Furthermore, when human subjects were irradiated on sun- protected skin with up to four times their minimal erythema dosage (MED) and biopsied 24 h later, upregulation of COX-2 protein expression was observed via immunofluorescence microscopy. RNAase protection assays supported this observation, showing induction of COX-2 message which peaked at approximately 12 h following irradiation in vitro. Furthermore, human squamous cell carcinoma biopsies exhibited strongly enhanced staining for COX-2 protein via immunohistochemistry and Western analysis when compared to normal non-sun-exposed control skin. Together, these data demonstrate acute upregulation of COX-2 via UVB irradiation and suggest the need for further studies of COX-2 expression as a potential pharmacological target mediating human skin tumor development.      

Evaluation of an Azo and Two Anthraquinone Dyes for Allergic Potential

Two dye mixtures and the individual component dyes were evaluatedfor the potential to induce contact or pulmonary hypersensitivity.These dye mixtures were suspect because of anecdotal reportsof both pulmonary and contact hypersensitivity in assembly workers,and because the component dyes were structurally related todyes known to be contact sensitizers. One mixture consistedof disperse blue 3 (DB3) and disperse red 11 (DR11), which areanthraquinones, and the other mixture contained DR11 and solventred 1 (SR1), an azo dye. Contact hypersensitivity was examinedusing the local lymph node assay (LLNA) and a modified mouseear swelling test (MEST). Both the MEST and the LLNA indicatedthat SR1 has weak contact-sensitizing potential. None of theother individual dye compounds or the two mixtures were identifiedas contact sensitizers by either method. To evaluate the mixturesas potential pulmonary allergens, guinea pigs were repeatedlyexposed by inhalation (300 mg/m³ 6 hr/day) 5 days/week, for1 week. Weekly exposures were repeated three times with 2 weeksof nonexposure time in between. Guinea pigs were then challengedthrough the jugular vein using a dye-dimethylsulfoxide mixture.During the challenge, breathing mechanics (dynamic complianceand resistance) were measured in mechanically ventilated animals.Changes in these measurements, indicative of bronchoconstriction,were not observed in animals exposed to either dye mixture,nor were antibodies detected in the sera of exposed animalsusing individual dye-specific enzyme-linked immunosorbent assays.In conclusion, two methods indicate that SR1 may have contact-sensitizingpotential. There was no indication of contact-sensitizing potentialfor either DB3 or DR11 and no evidence that any of the dyescaused pulmonary hypersensitivity.     

A ninth locus (RP18) for autosomal dominant retinitis pigmentosa maps in the pericentromeric region of chromosome 1

We studied a large Danish family of seven generations in which autosomal dominant retinitis pigmentosa (adRP), a heterogeneous genetic form of retinal dystrophy, was segregating. After linkage had been excluded to all known adRP loci on chromosomes 3q, 6p, 7p, 7q, 8q, 17p, 17q and 19q, a genome screening was performed. Positive lod scores suggestive of linkage with values ranging between Z = 1.58-5.36 at theta = 0.04-0.20 were obtained for eight loci on proximal 1p and 1q. Close linkage without recombination and a maximum lod score of 7.22 at theta = 0.00 was found between the adRP locus (RP18) in this family and D1S498 which is on 1q very near the centromere. Analysis of multiply informative meioses suggests that in this family D1S534 and D1S305 flank RP18 in interval 1p13-q23. No linkage has been found to loci from this chromosomal region in six other medium sized adRP families in which the disease locus has been excluded from all known chromosomal regions harbouring an adRP gene or locus suggesting that there is (at least) one further adRP locus to be mapped in the future.      

DNA diagnosis of FRAXA and FRAXE in Chinese children with neurodevelopmental disorders and fragile X syndrome

Fragile X (FraX) syndrome is the most common cause of inherited mental retardation. To see whether FRAXA or FRAXE can account for the etiology of some unexplained neurodevelopmental disorders in children, we screened for trinucleotide repeat expansion in a consecutive cohort of 73 Chinese children and their mothers seen in 1995 (group 1) referred for developmental assessment due to developmental delay, language delay, attention deficit hyperactivity disorder, autistic spectrum disorder, mental retardation and/or learning disability. We also screened DNA samples of all five previously diagnosed cytogenetically-positive FraX boys, their mothers and sisters (group 2). A control group of unrelated teenagers and adults were recruited from the community (group 3). In group 1, 3 families (2 mothers and a mother and her son) were found to carry a small premutation allele at FRAXA (premutation frequency = 2%, 3/153 independent X chromosomes), but none had any expansion at FRAXE. In group 2, all 5 FraX boys had full mutation at FRAXA and normal repeat length at FRAXE. In group 3, 1 male has a premutation allele out of 18 males and 59 females tested (premutation frequency of control = 0.7%, 1 out of 136 X chromosomes). For FRAXE screening in group 3, 2 females were carriers (1.5%, 2 out of 136 X chromosomes). Thus, FRAXA and FRAXE cannot account for the etiology of neurodevelopmental disorders in our cohort of Chinese children, and the prevalence of FRAXE mutation in normal Chinese population appears to be higher than reported in the Caucasians.