A European consensus statement on the use of four-factor prothrombin complex concentrate for cardiac and non-cardiac surgical patients

Modern four-factor prothrombin complex concentrate was designed originally for rapid targeted replacement of the coagulation factors II, VII, IX and X. Dosing strategies for the approved indication of vitamin K antagonist-related bleeding vary greatly. They include INR and bodyweight-related protocols as well as fixed dose regimens. Particularly in the massively bleeding trauma and cardiac surgery patient, four-factor prothrombin complex concentrate is used increasingly for haemostatic resuscitation. Members of the Transfusion and Haemostasis Subcommittee of the European Association of Cardiothoracic Anaesthesiology performed a systematic literature review on four-factor prothrombin complex concentrate. The available evidence has been summarised for dosing, efficacy, drug safety and monitoring strategies in different scenarios. Whereas there is evidence for the efficacy of four-factor prothrombin concentrate for a variety of bleeding scenarios, convincing safety data are clearly missing. In the massively bleeding patient with coagulopathy, our group recommends the administration of an initial bolus of 25 IU.kg^-1. This applies for: the acute reversal of vitamin K antagonist therapy; haemostatic resuscitation, particularly in trauma; and the reversal of direct oral anticoagulants when no specific antidote is available. In patients with a high risk for thromboembolic complications, e.g. cardiac surgery, the administration of an initial half-dose bolus (12.5 IU.kg^-1) should be considered. A second bolus may be indicated if coagulopathy and microvascular bleeding persists and other reasons for bleeding are largely ruled out. Tissue-factor-activated, factor VII-dependent and heparin insensitive point-of-care tests may be used for peri-operative monitoring and guiding of prothrombin complex concentrate therapy.     

Effect of ethanol on dynamic visual acuity during vertical body oscillation in healthy volunteers

Visual orientation is the most important sensory input during locomotion (e.g. walking, driving a car, riding a bicycle). We investigated dynamic visual acuity (DVA) during vertical body-oscillations (amplitude 5 cm; frequency 1.5 Hz) in 12 healthy subjects before and twice after ethanol consumption. During oscillation, vertical eye movements were recorded under two test conditions: with eyes closed (EC) and during DVA testing. A significant increase in vertical eye-amplitude after ethanol ingestion occurred only during EC tests, as a possible sign of vestibular hyperreaction. During vestibular stimulation alone (EC), ethanol did not affect the phase shift between stimulus and eye movements. However, when the subjects were given an additional visual stimulus (DVA), the post-alcohol phase shift rose significantly. Surprisingly, the post-alcohol phase shift values for the two test conditions showed no significant differences. After ethanol ingestion we found no changes in static visual acuity but a significant loss of DVA. Volunteers with a change of DVA threshold (DVAT) showed significantly (P = 0.004) higher post-alcoholic changes in the phase shift. In summary, low doses of ethanol disturbed the visually guided oculomotor response during fixation of an earth-fixed target while the observer was subject to linear vertical acceleration. This effect led to an increasing delay between the beginning of body and eye movements. The consequence was an increasing phase shift and thus a decrease in DVA during whole-body oscillation which was comparable to movements during human locomotion. Received: 8 March 2000 / Accepted: 18 April 2000     

微乳液反应法制备磺胺嘧啶银均匀微晶及其质量评价

目的：应用微乳液反应法制备磺胺嘧啶银均匀微晶,并评价其质量。方法：利用磺胺嘧啶钠微乳和硝酸银微乳混合后反应的方法,制备磺胺嘧啶银均匀微晶,用透射电镜观察其形态和大小,以Ｘ－射线衍射分析、红外光谱、核磁共振、差热分析等手段检测磺胺嘧啶银均匀微晶各种理化特性。结果：磺胺嘧啶银均匀微晶的粒径大小约为２～４μｍ,均匀微晶的结晶性好,纯度高。体外抑菌实验表明该品比市售磺胺嘧啶银具有更好的抑菌效果。结论：用微乳液反应法能获得磺胺嘧啶银均匀微晶。     

Oocyte quality and treatment outcome in intracytoplasmic sperm injection cycles of polycystic ovarian syndrome patients

Patients with polycystic ovarian syndrome (PCOS) have higher miscarriage rates. It is postulated that this is caused by a lower rate of mature oocytes, and a lower quality of embryos. Retrospectively we analysed 51 intracytoplasmic sperm injection (ICSI) cycles of 31 PCOS patients. These data were compared to age-matched controls (105 cycles) during the same period. All patients of both groups received gonadotrophin-releasing hormone (GnRH) agonists prior to gonadotrophin treatment. The rate of metaphase II oocytes (MII) was not different. However, the mean absolute number of normally fertilized oocytes was significantly higher in PCOS patients (5.00 versus 3.56, P < 0.01), due to a higher number of oocytes retrieved. More embryos were transferred by cycle in the PCOS group (2.69 versus 2.17, P < 0.05), with a higher cumulative embryo score. The overall and multiple pregnancy rate showed no differences and the clinical abortion rate was lower (21 versus 41.67%, P < 0.05) in the controls. Our findings demonstrate that negative factors unconnected to oocyte morphology must be present in PCOS patients. It is possible that only cytoplasmic, not nuclear, maturity is influenced in these patients.     

The effects of 5-HT uptake- and MAO-inhibitors on l-5-HTP-induced excitation in rats

Summary The behavioural syndrome caused by l-5-HTP in rats was used for the study of effects of selective 5-HT uptake inhibitors and inhibitors of MAO on central 5-HT receptors. A good correlation was found between the relative potencies of drugs in inhibiting the 5-HT uptake in the rat brain and in intensifying l-5-HTP-induced behavioural stimulation. The potentiation of the l-5-HTP syndrome by the MAO inhibitors correlated with the inhibition of the A- but not of the B-form of the brain monoamine oxidase.In rats treated with the maximally inhibiting dose of a 5-HT uptake inhibitor, MAO inhibitors were still able to increase the intensity of the l-5-HTP syndrome, while the combination of maximal doses of two 5-HT uptake inhibitors did not produce a more intense syndrome than that produced by one 5-HT uptake inhibitor alone.The l-5-HTP-induced behavioural syndrome in rats seems to afford an experimental model allowing the quantification and characterization of the interaction of drugs with serotonin metabolism in the brain.     

Economic costs of functional dyspepsia

Dyspepsia is defined as chronic or recurrent symptoms believed to originate in the upper gastrointestinal tract. When routine investigation results in no identifiable explanation for those symptoms patients are labelled as having functional dyspepsia. In community-based surveys, approximately 30% of the otherwise apparently healthy population report dyspeptic symptoms and the majority are believed to have functional dyspepsia. Although only 1 in 4 or 5 patients make use of healthcare resources, this patient category is one of the largest in ambulatory care (1.6 to 5% of all consultations in general practice). The annual frequency of consultations for functional dyspepsia in Sweden has been estimated at 47 per 1000 population. In consequence of its high prevalence and associated absenteeism, the total costs of functional dyspepsia are considerable. In Sweden in 1981, the costs were estimated at $US55 000 per 1000 population ($US113 630 in 1991 dollars). The most cost-effective management strategy remains to be defined. Evidence is accumulating that the traditional 'wait-and-see' policy with initial empirical therapeutic trials without investigation may not be the most cost conserving strategy.     

Steady-state kinetics of imipramine in patients

Steady-state plasma level kinetics were studied in 76 patients given imipramine (IP) 150 to 225 mg/day for 2–5 weeks. IP was given in three divided doses at 8.00 a.m., 1.00 p.m. and 5.00 p.m. Plasma concentrations of IP and its active metabolite desipramine (DMI) were determined by quantitative in situ thin-layer chromatography. The plasma levels of IP and DMI showed pronounced flucutations throughout the day with a ratio of about 2 between highest and lowest level. Patients with steady-state levels of IP and/or DMI below 50 g/l reached this within 1 week of treatment. Patients with higher steady-state levels reached steady-state concentrations within 2–3 weeks. There were some intraindividual fluctuations in plasma levels from week to week after steady state had been reached (coefficient of variation: 10–20%). Interindividually, the steady-state levels corrected to a dose of 3.5 mg/kg per day varied considerably: IP: 6–356 g/l, DMI: 24–659 g/l and IP+DMI: 58–809 g/l. The steady-state plasma levels showed a skew distribution that became normal by logarithmic transformation. The IP/DMI ratio ranged from 0.07 to 5.5 with a median value of 0.47. Compared to data from amitriptyline treated patients the IP/DMI ratios had significantly lower median value and larger variation than the corresponding plasma level ratios of amitriptyline/nortriptyline. Several statistically significant differences in steady-state levels between age groups were found. For IP: Women aged 30–39 had lower levels than women aged 20–29, 40–49, and 50–59, and men aged 50–59 and 60–65; men aged 30–39 had lower levels than men aged 60–65. For DMI: Women aged 30–39 had lower levels than women aged 50–59.     

Neue Perspektiven in der endokrinen Therapie gynäkologischer Malignome

Today, endocrine therapies are a mainstay in the treatment of gynaecological cancers. In spite of their significant advantages, optimisation has been necessary in order to overcome certain disadvantages, such as the development of resistance and the appearance of tissue specific agonistic effects. The modern view of the signalling mechanisms of tumour cells opens new perspectives for endocrine therapy of gynaecological cancers. In this overview, our new understanding of the non-genomic effects of oestrogen and their interaction with growth factor-signal induction will be presented, as will the resulting consequences for endocrine therapies and the perspectives for their continued development.     

Postmenopausale Hormontherapie und Mammakarzinom

Die Gynäkologie - Die Diskussion um die Hormonersatztherapie (HRT) zur Prävention von Herzerkrankungen und Osteoporose hat Auswirkungen auf die Behandlungsentscheidung, doch bisher fehlt...     

Involvement of the proliferating cell nuclear antigen (PCNA) in DNA repair induced by alkylating agents and oxidative damage in human fibroblasts

The involvement of the proliferating cell nuclear antigen (PCNA) in the process of DNA repair induced by alkylating agents or by oxidative damage was investigated in human quiescent fibroblasts by immunofluorescence and flow cytometry. Transition from soluble to the DNA-bound form of PCNA, was taken as the parameter to determine its involvement in repair DNA synthesis. Treatment with the alkylating agents methylmethane sulfonate and N-methyl-N'-nitro-N-nitrosoguanidine resulted in the rapid and dose-dependent increase in the nuclear binding of PCNA. Similar results were obtained with compounds such as hydrogen peroxide or tert-butyl hydroperoxide, which are known to induce oxidative DNA damage. Tert-butyl hydroperoxide may also generate malondialdehyde through a reaction of lipid peroxidation. This mutagenic and carcinogenic product has been previously shown to form adducts with DNA. Therefore, the possibility that tert-butyl hydroperoxide could induce DNA damage through this pathway was investigated by incubating cells directly in the presence of malondialdehyde. Such treatment resulted in an increase in immunofluorescence associated with nuclear-bound PCNA. The ability of oxidative and alkylating agents to induce the nuclear binding of PCNA was also assessed in proliferating cells. In these conditions, treatment with hydrogen peroxide or methylmethane sulfonate, resulted in an increase in nuclear-bound PCNA in the G1 and in the G2 + M compartments, but not in S phase. At longer times after treatment, PCNA immunostaining was reduced to basal levels, while an increase in nuclear binding of p21(waf1/cip1) protein was found in concomitance with cell-cycle arrest. These results indicate that agents inducing DNA base alterations in vivo, promote the nuclear binding of PCNA. These lines of evidence support the role of a PCNA-dependent reaction in the base excision repair system.