Platelet HDL(3) binding sites are not related to integrin alpha(IIb)beta(3) (GPIIb-IIIa)

Early studies considered that fibrinogen receptor (glycoprotein [GP] IIb-IIIa or platelet integrin alpha(IIb)beta(3)) is the binding site for low-density lipoprotein (LDL) and high-density lipoprotein type 3 (HDL(3)). Recent data, however, do not support the hypothesis that the binding of LDL to human intact resting platelets is related to integrin alpha(IIb)beta(3). In this study we present evidence that platelet integrin alpha(IIb)beta(3) is also not involved in the interaction of HDL(3) and human intact resting platelets. Firstly, specific ligands for platelet integrin alpha(IIb)beta(3), such as fibrinogen, vitronectin, von Willebrand factor and fibronectin, were unable to inhibit the binding of HDL(3) to intact resting platelets. Secondly, the HDL(3) binding characteristics (K(d) and B(max) values), the activation of protein kinase C (PKC) and the inhibition of thrombin-induced inositoltriphosphate (IP(3)) formation and calcium (Ca(2+)) mobilization mediated by HDL(3) particles were similar in platelets from control subjects and patients with type I and type II Glanzmann's thrombasthenia, which are characterized by total and partial lack of GPIIb-IIIa and fibrinogen, respectively. In contrast, nitrosylation of tyrosine residues of HDL(3) by tetranitromethane fully abolished both the ability of particles to interact with its specific binding sites and the functional effects. Thirdly, polyclonal antibodies against the GPIIb-IIIa complex (edu-3 and 5B12), human antiserums against platelet alloantigens (anti-Bak(a/B) and anti-PL(A1/2)), anti-integrin subunits (anti-alpha(V) and anti-beta(3)), and a wide panel of monoclonal antibodies (mAbs) against well-known epitopes of GPIIb (M3, M4, M5, M6, M8 and M95-2b) and GPIIIa (P23-7, P33, P37, P40, and P97) did not affect the binding of HDL(3) particles to human intact resting platelets. Overall results show that neither the GPIIb-IIIa complex nor GPIIb or GPIIIa individually are the membrane binding proteins for HDL(3)on intact resting platelets.     

Obamacare's (3) Day(s) in Court

Before the oral arguments in late March, the vast majority of legal scholars felt confident that the Supreme Court of the United States would uphold the individual mandate against the constitutional challenge that 26 states have levied against it. Since the oral arguments, that confidence has been severely shaken. This article asks why legal scholars were so confident before the argument and what has made us so concerned since the argument. The article posits that certain fundamental characteristics of health insurance, particularly its unusual role in steering health-care consumption decisions, which distinguishes health insurance from standard kinds of indemnity insurance, should make the constitutional question easy, but the Obama Administration's legal team was understandably hesitant to highlight those unique characteristics in its arguments. Because the Supreme Court justices seemed not to understand the uniqueness of health insurance without the government's help and because the justices seemed unusually willing to adopt a new constitutional constraint in this case, the individual mandate appears to be in far greater jeopardy than we legal scholars anticipated.     

类风湿关节炎患者红细胞C3b受体数目改变及基因多态性分析

目的　分析类风湿关节炎（ＲＡ） 患者Ｃ３ｂ受体（Ｃ３ｂＲ） 表达数目及Ｃ３ｂＲ 基因多态性分布规律,探讨Ｃ３ｂＲ 数目改变的可能原因。方法　分别测定６３ 例ＲＡ 患者及健康献血员６０ 人的红细胞Ｃ３ｂ 受体花环率（Ｃ３ｂＲＲ） 及免疫复合物花环率（Ｃ３ｂＩＣＲ） 。用限制性片段长度多态（ＲＦＬＰ） 分析及Ｓｏｕｔｈｅｒｎ ｂｌｏｔｔｉｎｇ 杂交技术检测Ｃ３ｂＲ基因多态性。结果　ＲＡ 患者红细胞Ｃ３ｂＲＲ 和Ｃ３ｂＩＣＲ 分别显著低于和高于正常对照组。Ｃ３ｂＲ基因的两个等位基因基因型和表现型频率在ＲＡ 组和对照组均无显著差异。结论　ＲＡ 患者Ｃ３ｂＲ数目下降可能与基因变异无关,可能是受体基因转录和翻译过程异常所致。设法增加红细胞Ｃ３ｂＲ 数目以加速免疫复合物的清除,可能是治疗ＲＡ的有效途径之一。     

3'-Azido-2',3'-dideoxyuridine (AzddU): comparative pharmacokinetics with 3'-azido-3'-deoxythymidine (AZT) in monkeys

The pharmacokinetics of the anti-human immunodeficiency virus type 1 nucleosides, 3'-azido-2',3'-dideoxyuridine (AzddU) and 3'-azido-3'-deoxythymidine (AZT) were characterized in rhesus monkeys. Half-life, total clearance, and steady-state volume of distribution were similar for both compounds. The observed pharmacokinetic parameters for AZT were comparable to those previously reported in humans. Oral absorption of AzddU and AZT was virtually complete after 60 mg/kg. However, bioavailability of both nucleosides was markedly lower (less than 50%) after 200 mg/kg, possibly indicating the involvement of a saturable absorption mechanism. The nucleosides were also well absorbed after subcutaneous administration. AzddU and AZT penetrated the cerebrospinal fluid (CSF) with concentration ratios in CSF:serum ranging from 0.05 to 0.25 one hour after drug administration. The glucuronides of AZT and AzddU were readily detected in urine. Hemogram and blood chemistry values for animals receiving short-term treatment (3 doses) with either AZT or AzddU did not exhibit any significant changes when compared with untreated control monkeys. The similar pharmacokinetic characteristics of AzddU compared with AZT suggest that clinical trials of AzddU are warranted.     

Missense mutations in the beta(3) subunit have a different impact on the expression and function between alpha(IIb)beta(3) and alpha(v)beta(3).

Alpha(IIb)beta(3) and alpha(v)beta(3) belong to the beta(3) integrin subfamily. Although the beta(3) subunit is a key regulator for the biosynthesis of beta(3) integrins, it remains obscure whether missense mutations in beta(3) may induce the same defects in both alpha(IIb)beta(3) and alpha(v)beta(3). In this study, it is revealed that thrombasthenic platelets with a His280Pro mutation in beta(3), which is prevalent in Japanese patients with Glanzmann thrombasthenia, did contain significant amounts of alpha(v)beta(3) (about 50% of control) using sensitive enzyme-linked immunosorbent assay. Expression studies showed that the His280Probeta(3) mutation impaired alpha(IIb)beta(3) expression but not alpha(v)beta(3) expression in 293 cells. To extend these findings, the effects of several beta(3) missense mutations leading to an impaired alpha(IIb)beta(3) expression on alpha(v)beta(3) function as well as expression was examined: Leu117Trp, Ser162Leu, Arg216Gln, Cys374Tyr, and a newly created Arg216Gln/Leu292Ser mutation. Leu117Trp and Cys374Tyr beta(3) mutations did impair alpha(v)beta(3) expression, while Ser162Leu, Arg216Gln, and Arg216Gln/Leu292Ser mutations did not. With regard to ligand binding function, Ser162Leu mutation induced especially distinct effects between 2 beta(3) integrins: it markedly impaired ligand binding to alpha(IIb)beta(3) but not to alpha(v)beta(3) at all. These data clearly demonstrate that the biosynthesis and the ligand binding function of alpha(IIb)beta(3) and those of alpha(v)beta(3) are regulated in part by different mechanisms. Present data would be a clue to elucidate the regulatory mechanism of expression and function of beta(3) integrins.     

Icosahedral quasicrystals as twins of cubic crystals containing large icosahedral clusters of atoms: The 1012-atom primitive cubic structure of Al(6)CuLi(3), the C-phase Al(37)Cu(3)Li(21)Mg(3), and GaMg(2)Zn(3)

Single-grain precession x-ray diffraction photographs of Al₆CuLi₃ have been successfully indexed on the basis of icosahedral twinning of cubic crystals with a 1012-atom primitive cubic unit with edge 25.70 Å, giving support to the proposal that the so-called icosahedral quasicrystals are twins of crystals containing eight large icosahedral clusters in the β-W arrangement. In this compound two of the clusters consist of 104 atoms and six consist of 136 atoms, with 24 atoms shared. The same structure is assigned to the C-phase, Al₃₇Cu₃Li₂₁Mg₃, and to GaMg₂Zn₃. A theory of icosahedral quasicrystals and amorphous metals is described.     

Cortisol regulates eel (Anguilla anguilla) aquaporin 3 (AQP3) mRNA expression levels in gill

Previous studies in eel (Anguilla anguilla) gill have shown that the expression of the aquaporin 3 (AQP3) water and small solute channel is dramatically decreased (mRNA abundance decreased by up to 97%) when these euryhaline fish are acclimated from freshwater (FW) to seawater (SW). However, AQP3 mRNA expression levels in the intestine following SW-acclimation do not change. The SW-acclimating corticosteroid hormone, cortisol has previously been shown to regulate the expression of aquaporins (particularly AQP1) in eel osmoregulatory tissues in a tissue-specific and isoform-specific fashion. AQP1 is up-regulated in intestine and oesophagus, but down-regulated in kidney, following SW-acclimation in these fish. This study extends knowledge of the regulation of aquaporin expression by cortisol in the eel and shows that elevated levels of this hormone down-regulate AQP3 mRNA expression in the gill in a similar manner to SW-acclimation. However, the smaller magnitude of the changes in branchial AQP3 expression induced by cortisol-infusion (around a 60% decrease), in comparison to those occurring following SW-acclimation, suggest that other factors must also contribute to AQP3 down-regulation. In a similar fashion to the regulation of AQP1 by cortisol, changes in AQP3 expression following hormone infusion appear to be tissue-specific, as little effect was seen on the level of AQP3 expression in the intestine. Again the apparent lack of change in intestinal AQP3 expression following cortisol-infusion mimicked the invariant level of intestinal AQP3 mRNA abundance following SW-acclimation.     

Robin Goodfellow (43-3)

As winter turns to spring and Robin can examine his garden oncemore, he turns his attention to examination in general. MichaelDocherty in Nottingham has made a special issue out of the paucityof examination of the musculoskeletal system in inpatients;White and two Alcolados in Wales ( Postgrad Med J 2003;79:588–9[Abstract/Free Full Text])are more specific and note that examination of the hands israrely recorded. Having said that, their population shows notunexpected findings; the commonest abnormalities in men wereHeberden's nodes, Dupuytren's contractures and staining withcoal dust. Robin awaits comment on his previous remarks on the role ofarthoscopy—much overdone, in his opinion—but meanwhilenotes Oakley and Lassere's     

Robin Goodfellow (42-3)

Hi-de-hi. Robin's managers are in the dog-house, as they tryto meet targets to reduce waits in the Accident & EmergencyDepartment by opening a new fast-track unit of 22 beds (butfail to fund the essential physiotherapists and occupationaltherapists) and compensate for this necessary bed expansionby closing a 28-bed ward to save money. Their delays have alsoresulted in Robin's proposed rheumatology nurse specialist posthitting the buffers because the under-managers couldn't gettheir act together to do the paperwork, even though money wasnot an issue. R is not a happy bunny, taking consolation onlyfrom the knowledge that     

Pheochromocytoma and pregnancy (3 cases)

In this paper, a review of pregnancy and pheocromocytoma is shown. The importance of early diagnostic and adequate management is essential in this patients. When this associations exists the management must be very carefully considered to avoid high mortality risks for both, fetus and mother. 56 cases of pheocromocytoma were studied at the Instituto Nacional de Cardiología, three of them were pregnant women which are described in this work.     

Robin Goodfellow (44-3)

Robin remains grateful to his surgical colleagues for continuingto send interesting referrals. The latest was an ischial bursitisconfirmed on MRI (the Robin approach, of course, is inject firstand ask questions when it doesn't work). The surgeon wrote ‘AlthoughI do not myself inject bursars ...’ – well, neitherhas Robin, and he would only consider doing so if they werefrom an Oxbridge college. Robin has, with the recent and most welcome arrival of a specialistnurse, started to do some tidying up and the first job was toweed out from the database all those who had not been seen inclinic for two years or more. It is a sad testament to communicationsthat of just over