Influence of anticoagulant therapy with vitamin K antagonists on plasma levels of coagulation factor VIII

Vitamin K-antagonists (VKA) decreases vitamin K coagulation factors. To counterbalance this effect, it has been postulated that non-vitamin K proteins increase during VKA treatment. To investigate if VKA affect FVIII, a cohort of 1772 patients referred from Jan 1997 to Oct 2008 to our Thrombosis Center for a thrombophilia screening after at least 3 months from diagnosis of first venous thrombosis was studied. At the time of blood sampling, 1303 patients had discontinued VKA for at least one month, whereas the remaining 469 were still taking VKA. FVIII was significantly higher in patients on VKA than in those who had discontinued VKA (mean±SD: 144 ± 41 IU/dL and 134 ± 40 IU/dL, respectively, p < 0.0001), also after adjustment for sex, age, body mass index, thrombophilia and time elapsed from thrombosis in a multiple linear regression analysis. In order to avoid overestimation of FVIII levels, patients should be preferentially tested after VKA discontinuation.     

晚发性维生素K缺乏性颅内出血56例临床分析

目的 探讨婴儿期维生素K缺乏的病因及预防措施。方法 对本院收治56例晚发性维生素K缺乏性出血进行回顾性分析。纯母乳喂养45例，有腹泻病史18例，抗生素用药史16例，有肝病史2例为主要病因。发病年龄25d～2月52例，2～3月4例，经静注或肌注维生素Kl及降颅内高压、抗惊厥、纠正贫血等对症处理。其中7例硬脑膜下出血给予硬脑膜下穿刺放血治疗。结果 治愈49例(4．9／56)，死亡2例(2／56)，放弃5例(5／56)，存活病例有神经系统后遗症34例(34／49)。结论 对纯母乳喂养、腹泻、使用抗生素及有肝病的患儿，在常规预防的同时应注意强化预防措施。     

Rise in Late Onset Vitamin K Deficiency Bleeding in Young Infants Because of Omission or Refusal of Prophylaxis at Birth

BackgroundNewborns are at risk for vitamin K deficiency and subsequent bleeding unless supplemented at birth. Vitamin K deficiency bleeding is an acquired coagulopathy in newborn infants because of accumulation of inactive vitamin K–dependent coagulation factors, which leads to an increased bleeding tendency. Supplementation of vitamin K at birth has been recommended in the United States since 1961 and successfully reduced the risk of major bleeding. Refusal or omission of vitamin K prophylaxis is increasing and puts newborn infants at risk for life-threatening bleeding.PatientsOver an eight month period, we encountered seven infants with confirmed vitamin K deficiency; five of these patients developed vitamin K deficiency bleeding.ResultsThe mean age of the seven infants with vitamin K deficiency was 10.3 weeks (range, 7-20 weeks); manifestations ranged from overt bleeding to vomiting, poor feeding, and lethargy. None of the infants had received vitamin K at birth, and all were found to have profound derangement of coagulation parameters, which corrected rapidly with administration of vitamin K in IV or intramuscular form. Four of the seven infants had intracranial hemorrhage; two of these infants required urgent neurosurgical intervention.ConclusionSupplementation of vitamin K at birth for all newborns prevents major hemorrhagic complications, such as intracranial bleeding, due to vitamin K deficiency. Parental refusal of vitamin K is increasingly common. It is critical that health care providers and the public be made aware of the varied presentation of this preventable acquired coagulopathy.     

Discovery of glycyrrhetinic acid as an orally active,direct inhibitor of blood coagulation factor xa

Introduction

Factor Xa (FXa) plays an important role in blood coagulation. This study investigated glycyrrhetinic acid, a small molecule derived from Chinese herbs, and whether it has a direct inhibitory effect on FXa to display its anticoagulant activity.

Materials and Methods

Enzyme activities of FXa, plasmin, trypsin and thrombin, inhibition of FXa enzyme kinetics and plasma clotting time by glycyrrhentinic acid were performed in vitro. A rat tail-bleeding model and a rat venous stasis model were also used to evaluate in vivo tail-bleeding time and thrombus formation, respectively.

Results

Glycyrrhetinic acid in vitro directly inhibited FXa uncompetitivly with IC₅₀ of 32.6 ± 1.24 μmol/L, and displayed 2-, 14- and 20-fold selectivity for FXa when compared to plasmin, thrombin and trypsin, respectively. The plasma clotting time was increased in a dose-dependent manner. The prothrombin time doubled (PT₂), when the concentration of glycyrrhetinic acid reached 2.02 mmol/L. During in vivo experiments intragastric administration of glycyrrhetinic acid caused a dose-dependent reduction in thrombus weight on the rat venous stasis model (all P < 0.05). 50 mg/kg glycyrrhetinic acid resulted in 34.8% of venous thrombus weight lost, compared to the control. In addition, 200, 300 and 400 mg/kg doses of glycyrrhetinic acid caused a moderate hemorrhagic effect in the rat tail-bleeding model by prolonging bleeding time 1.1-, 1.5- and 1.9-fold compared to the control, respectively.

Conclusions

Glycyrrhetinic acid is a direct inhibitor of FXa that is effective by oral administration, and with further research could be used to treat blood coagulation disorders.     

An intracellular study of thalamocortical synapses in the orbito-insular cortex

Intracellular recordings were made in multimodal orbito-insular cortex in response to electrical stimulation of thalamic association nuclei. Four types of responses were observed: One was short latency excitation; another was short latency excitation followed by inhibition; the third was long latency inhibition followed by excitation; the fourth was rhythmic afterdischarge. The initial excitatory response is viewed as being due to direct thalamocortical input and the later inhibitory ones to intracortical inhibition. The results resemble those obtained in lemniscal systems having specific thalamic relay nuclei, and they provide correlates for recent anatomical reports concerning the projections of the frontal orbital cortex.     

丙戊酸钠和卡马西平对癫痫患者血同型半胱氨酸、叶酸、维生素B12水平的影响

目的探讨丙戊酸钠(VPA)和卡马西平(CBZ)对癫痫患者血同型半胱氨酸(Hcy)、叶酸、维生素(Vit)B12水平的影响。方法检测VPA组、CBZ组、未服药组患者和正常对照组血Hcy、叶酸、VitB12浓度,并对结果进行比较。结果与未服药组及正常对照组比较,VPA组和CBZ组的血浆Hcy水平显著升高(均P<0.01),血清叶酸水平显著降低(均P<0.05);且VPA组血清VitB12水平有升高趋势,CBZ组血清VitB12水平有降低趋势,但差异均无统计学意义。结论 VPA和CBZ可引起癫痫患者的血浆Hcy水平升高和血清叶酸水平降低,对血清VitB12水平无显著影响。     

Carbon dioxide as a reciprocal inhibitor in the treatment of neurosis

A patient with long standing ‘panic’ attacks was successfully treated using a variant of systematic desensitization with a carbon dioxide-oxygen mixture as a reciprocal inhibitor.     

Clearance of activity‐evoked K+ transients and associated glia cell swelling occur independently of AQP4: A study with an isoform‐selective AQP4 inhibitor

The mammalian brain consists of 80% water, which is continuously shifted between different compartments and cellular structures by mechanisms that are, to a large extent, unresolved. Aquaporin 4 (AQP4) is abundantly expressed in glia and ependymal cells of the mammalian brain and has been proposed to act as a gatekeeper for brain water dynamics, predominantly based on studies utilizing AQP4‐deficient mice. However, these mice have a range of secondary effects due to the gene deletion. An efficient and selective AQP4 inhibitor has thus been sorely needed to validate the results obtained in the AQP4^?/? mice to quantify the contribution of AQP4 to brain fluid dynamics. In AQP4‐expressing Xenopus laevis oocytes monitored by a high‐resolution volume recording system, we here demonstrate that the compound TGN‐020 is such a selective AQP4 inhibitor. TGN‐020 targets the tested species of AQP4 with an IC₅₀ of ~3.5 μM, but displays no inhibitory effect on the other AQPs (AQP1‐AQP9). With this tool, we employed rat hippocampal slices and ion‐sensitive microelectrodes to determine the role of AQP4 in glia cell swelling following neuronal activity. TGN‐020‐mediated inhibition of AQP4 did not prevent stimulus‐induced extracellular space shrinkage, nor did it slow clearance of the activity‐evoked K⁺ transient. These data, obtained with a verified isoform‐selective AQP4 inhibitor, indicate that AQP4 is not required for the astrocytic contribution to the K⁺ clearance or the associated extracellular space shrinkage.     

4-Chloro-m-cresol, an activator of ryanodine receptors, inhibits voltage-gated K(+) channels at the rat calyx of Held

4-Chloro-m-cresol (4-CmC) is thought to be a specific activator of ryanodine receptors (RyRs). Using this compound, we examined whether the RyR-mediated Ca(2+) release is involved in transmitter release at the rat calyx of Held synapse in brainstem slices. Bath application of 4-CmC caused a dramatic increase in the amplitude of excitatory postsynaptic currents (TIFCs) with the half-maximal effective concentration of 0.12 mm. By making direct patch-clamp whole-cell recordings from presynaptic terminals, we investigated the mechanism by which 4-CmC facilitates transmitter release. 4-CmC markedly prolonged the duration of action potentials, with little effect on their rise time kinetics. In voltage-clamp recordings, 4-CmC inhibited voltage-gated presynaptic K(+) currents (I(pK)) by 53% (at +20 mV) but had no effect on voltage-gated presynaptic Ca(2+) currents (I(pCa)). In simultaneous pre- and postsynaptic recordings, 4-CmC had no effect on the TIFC evoked by I(pCa). Although immunocytochemical study of the calyceal terminals showed immunoreactivity to type 3 RyRs, ryanodine (0.02 mm) had no effect on the 4-CmC-induced TIFC potentiation. We conclude that the facilitatory effect of 4-CmC on nerve-evoked transmitter release is mediated by its inhibitory effect on I(pK).     

XIAP过度表达对未成熟脑急性放射损伤后脑组织硝基酪氨酸和4-羟基壬烯醛表达的影响

目的探讨急性放射损伤对未成熟脑高增殖细胞的影响以及X-染色体连锁的凋亡抑制剂(XIAP)过度表达对放射后氧化应激产物硝基酪氨酸(NT)和4-羟基壬烯醛(4-HNE)形成的影响。方法新生10日龄XIAP过度表达转基因C57BL/6小鼠(XIAP组)及同期野生型10日龄C57BL/6小鼠在8Gy单一剂量放射线照射后6h或7d处死取脑,进行脑组织硝基酪氨酸和4-羟基壬烯醛免疫组化染色,以及海马齿状回、侧脑室下区面积测量。结果照射后7d海马齿状回、侧脑室下区面积较对照组明显下降,照射后脑组织硝基酪氨酸和4-羟基壬烯醛免疫活性明显增加,照射后6hXIAP过度表达组大脑海马齿状回、侧脑室下区硝基酪氨酸和4-HNE的阳性细胞数明显低于野生组(P<0.05,P<0.001)。结论放射线照射可导致活性氧、活性氮基团过度表达,进而引起高增殖细胞损伤;XIAP过度表达可能抑制照射后硝基酪氨酸和4-HNE的形成。     

Sexual arousal as a sympathetic inhibitor in the treatment of claustrophobia

A 21-yr-old female who had been suffering from severe claustrophobic anxiety was treated by using sexual arousal as the incompatible response. Following thirteen weeks of treatment the client was able to enter and remain in the three situations that had previously produced intense anxiety. In addition, the client's daily dosage of Valium had decreased from 40 mg to almost complete elimination of the drug. At a one year follow-up all therapeutic gains had been maintained.     

有氧运动对大鼠骨骼肌线粒体Na+，K+-ATP酶和Ca2+-ATP酶及线粒体肿胀的影响

背景：研究表明有氧运动可提高线粒体功能,但在不同时期的作用特点还不明确。 目的：观察不同周期有氧运动对大鼠骨骼肌线粒体Na+,K+-ATP酶和Ca2+-ATP酶以及线粒体肿胀的影响。 方法：将SD大鼠随机分为正常对照组,有氧运动2,4和6周组。正常对照组不进行有氧运动,其余3组则参照BedfordTG标准,采用跑台运动方式,建立有氧运动模型进行相应的运动周期锻炼。测定各组大鼠骨骼肌线粒体Na+,K+-ATP酶和Ca2+-ATP酶的活性以及线粒体肿胀程度。 结果与结论：有氧运动2周组各指标与对照组比较无差异。有氧运动4和6周组线粒体Na+,K+-ATP酶、Ca2+-ATP酶活性均增高(P < 0.05),线粒体肿胀程度降低(P < 0.05)。实验结果表明,有氧运动可保护线粒体Na+,K+-ATP酶、Ca2+-ATP酶的活性,提高线粒体功能,但需要一定的时间积累。     

A case-control association study and family-based expression analysis of the bipolar disorder candidate gene PI4K2B

Bipolar disorder, schizophrenia and recurrent major depression are complex psychiatric illnesses with a substantial, yet unknown genetic component. Linkage of bipolar disorder and recurrent major depression with markers on chromosome 4p15–p16 has been identified in a large Scottish family and three smaller families. Analysis of haplotypes in the four chromosome 4p-linked families, identified two regions, each shared by three of the four families, which are also supported by a case-control association study. The candidate gene phosphatidylinositol 4-kinase type-II beta (PI4K2B) lies within one of these regions. PI4K2B is a strong functional candidate as it is a member of the phosphatidylinositol pathway, which is targeted by lithium for therapeutic effect in bipolar disorder. Two approaches were undertaken to test the PI4K2B candidate gene as a susceptibility factor for psychiatric illness. First, a case-control association study, using tagging SNPs from the PI4K2B genomic region, in bipolar disorder (n = 368), schizophrenia (n = 386) and controls (n = 458) showed association with a two-marker haplotype in schizophrenia but not bipolar disorder (rs10939038 and rs17408391, global P = 0.005, permuted global P = 0.039). Second, expression studies at the allele-specific mRNA and protein level using lymphoblastoid cell lines from members of the large Scottish family, which showed linkage to 4p15–p16 in bipolar disorder and recurrent major depression, showed no difference in expression differences between affected and non-affected family members. There is no evidence to suggest that PI4K2B is contributing to bipolar disorder in this family but a role for this gene in schizophrenia has not been excluded.     

Effects of the specific serotonin reuptake inhibitor, citalopram, upon local cerebral blood flow and glucose utilisation in the rat

The effects of the potent selective 5-HT reuptake blocking agent, citalopram (10 mg/kg, i.v.), on local cerebral blood flow (lCBF) and local cerebral metabolic rate of glucose (lCMRglu) were measured using [14C]iodoantipyrine (IAP) and [14C]2-deoxyglucose (2-DG) autoradiography, respectively. Significant decreases in lCBF were observed in nine of the 27 brain areas analysed, with significant decreases in lCMRglu observed in 17 areas. While decreases in blood flow were observed, it cannot be concluded that these were in fact the result of a direct action of 5-HT upon serotonergic receptors in cerebrovascular smooth muscle, since the dynamic relationship between flow and metabolism remains largely intact. The reductions in lCBF may be explained entirely by the secondary effects of depressed cerebral metabolic demand induced by citalopram which would, once again, question the role of specifically perivascular serotonergic nerve activity in the tonic control of cerebral blood flow.     

Influence of vitamin B12 on brain methionine adenosyltransferase activity in senile dementia of the Alzheimer's type

Summary The influence of vitamin B₁₂ on the activity of methionine adenosyltransferase (MAT) in postmortem brains of patients with senile dementia of the Alzheimer's type (SDAT) was investigated. In samples of cortex gyrus frontalis from SDAT patients with normal and low levels of serum B₁₂, MAT V_max was significantly increased by 25% and 19%, respectively. MAT V_max from a SDAT group chronically treated with B₁₂ was similar to controls. In contrast to cortex gyrus frontalis, no significant alterations were seen in MAT activity in nucleus caudatus. This study provides evidence that SDAT is associated with significant alterations in transmethylation mechanisms in specific regions of the brain. The relationship between blood levels of B₁₂ and the actual status of this vitamin in the brain influencing the rates of synthesis of both methionine and SAM may, however, be far more complex and cannot be directly clarified on the basis of the present human brain results.     

Increased activation of blood coagulation in pregnant women with the Factor V Leiden mutation

Background

The risk of venous thromboembolism is enhanced in pregnant carriers of the Factor V Leiden mutation. The primary aim of the study was to compare prothrombin fragments 1 + 2, soluble fibrin and D-dimer levels in pregnant Factor V Leiden mutation carriers with those in non-carriers. Secondary aims were to evaluate whether these biomarkers could predict placenta-mediated complications or venous thromboembolism, and to study blood coagulation after caesarean section with thromboprophylaxis and after vaginal delivery without thromboprophylaxis.

Material/Methods

Prothrombin fragments 1 + 2, soluble fibrin and D-dimer levels were studied longitudinally in 476 carriers with singleton pregnancies from gestational weeks 23–25 until 8–10 weeks postpartum.

Results

Prothrombin fragments 1 + 2 and D-dimer levels gradually increased during pregnancy. D-dimer levels were higher in carriers, both during pregnancy and puerperium, compared to non-carriers. D-dimer levels above 0.5 mg/l were found in about 30% and 20% of the heterozygous carriers at 4–5 and 8–10 weeks postpartum, respectively. Soluble fibrin levels were mainly unchanged during pregnancy, with no difference between carriers and non-carriers. Biomarker levels were similar in carriers with uncomplicated and complicated pregnancies.

Conclusion

Higher D-dimer levels indicate increased blood coagulation and fibrinolysis activity in carriers. The high proportion of carriers with D-dimer levels exceeding 0.5 mg/l postpartum must be considered when assessing the probability of venous thromboembolism. Large overlaps in biomarker levels in normal and complicated pregnancies suggest that these biomarkers cannot be used as predictors. Thromboprophylaxis following caesarean section may prevent increased activation of blood coagulation.     

局部亚低温对脑缺血再灌注治疗时间的影响

目的观察有效再灌注时间窗内实施局部亚低温对不同时间点血管再通(再灌注)的影响,并探讨其机制。方法将150只雄性大鼠随机分为大脑中动脉闭塞(middle cerebral artery occlusion,MCAO)24h组10只;常温再灌注组50只;MCAO 2h进行亚低温再灌注组50只;MCAO 3h进行亚低温再灌注组40只。动物均于再灌注24h后处死,但MCAO 24h组大脑中动脉闭塞24h后直接处死。采用TTC染色观察梗死体积,用干-湿质量法测定脑含水量,用原位末端标记(TUNEL)观察神经细胞凋亡的变化,采用免疫组化法检测大鼠模型的Bcl-2、Bax及水通道蛋白4(aquaporin4,AQP4)的表达。结果 MCAO 24h组的梗死体积、脑含水量、TUNEL阳性细胞数、及Bcl-2、Bax、AQP4的表达相比较,常温组2～3h有统计学差异(P<0.01),4～6h没有统计学差异(P>0.05);MCAO 2h亚低温再灌注组2～5h有统计学差异(P<0.01),6h没有统计学差异(P>0.05);MCAO 3h亚低温再灌注组3～4h有统计学差异(P<0.01),5～6h没有统计学差异(P>0.05)。亚低温再灌注组各时相点的梗死体积、脑含水量、TUNEL阳性细胞数、Bax、AQP4的表达均显著低于相应常温组,Bcl-2的表达显著高于常温组(P<0.01,P<0.05)。结论实施局部亚低温可延长再灌注治疗时间窗,而且亚低温开始时间越早,其延长时间窗的效果就越显著。这为解决在时间窗内就诊的患者因检查等错过再灌注治疗这一临床难题的解决提供了重要的实验室依据。其机制可能与抑制半暗带细胞的凋亡和改善微循环有关。     

French clinical practice guidelines on the management of patients on vitamin K antagonists in at-risk situations (overdose, risk of bleeding, and active bleeding)

The present report from several French medical societies in the field and the French National Authority for Health provides an expert consensus for the management of patients on vitamin K antagonists in at-risk situations (overdose, risk of bleeding, and active bleeding). Asymptomatic VKA overdose is defined as an International Normalized Ratio (INR) value above the upper limit of the therapeutic target. In this case, the guidelines describe the rapid reduction of the INR down to the therapeutic range, either by omitting a dose or using vitamin K. Regarding the haemorrhagic complications, the guidelines address the management of these patients according to the severity of bleeding, and especially focus on the use of prothrombin complex concentrate. Finally, the consensus addresses the management of patients in cases of elective or emergency surgery or other invasive procedures, and discusses whether treatment should be continued or not, and whether VKA substitution by heparin - “bridging anticoagulation” - is needed.     

The treatment of temporomandibular joint syndrome through control of anxiety

Following a negative experience with general anesthesia, a 20-yr-old woman developed anxiety and an inability to relax concomitant with temporomandibular joint dysfunction and pain syndrome. Systematic countering of anxiety by relaxation successfully removed her anxiety and led to a complete resolution of her symptoms. Follow-up at 16 months indicated maintenance of treatment gains and no recurrence of the symptoms during the previous 12 months.