Breast angiosarcoma one year after adenosquamous endometrial cancer �� diagnostic pitfalls

Angiosarcoma of the breast is a rare and very aggressive tumors originated from endothelial cells lining blood vessels. We report a case of a 55-year-old postmenopausal female with a primary breast angiosarcoma diagnosed just a one year after radical hysterectomy and radiation therapy due to endometrial cancer. The patient initially presented with postmenopausal bleeding. Cytology and biopsy of the endometrium were performed and endometrial adenosquamous carcinoma was diagnosed followed by radical hysterectomy and postoperative local radiatiotherapy (50 Gy). One year later patient presented with a great painful tumorous mass in the right breast. Physical examination revealed an oval tumor, located in upper and outer quadrant of the right breast, around 15 cm in diameter. Mammography and ultrasonography were performed. The angiosarcoma of the breast was confirmed by biopsy. The patient underwent radical mastectomy. Histopathology proved the diagnosis of angiosarcoma (high-grade, numerous mitoses over 10/10 HPF, necrosis, ??blood lakes??, infiltrative borders). Differential diagnosis of a breast angiosarcoma should be considered in all painful breast tumours no mather the time and the location of the previous radiation treatment even if benign characteristics of these masses have been detected by mammography and breast ultrasound.     

Factors related to consultation time: Experience in Slovenia

Objective. Consultation time has a serious impact on physicians’ work and patient satisfaction. No systematic study of consultation time in general practice in Slovenia has yet been carried out. The aim of the present study was to measure consultation time, to identify the factors influencing it, and to study the influence of the workload of general practitioners on consultation time. Design. A total of 42 general practitioners participated in this cross-sectional study. Each physician collected data from 300 consecutive consultations and measured the length of the visit. Setting. Forty-two randomly selected general practices in Slovenia. Subjects. Patients of 42 general practices. Main outcome measures. Average consultation time in general practice in Slovenia; factors influencing consultation time in Slovenia. Results. Data from 12 501 visits to the surgery were collected. A quarter of all visits (25.5%) were administrative. The mean consultation time was 6.9 minutes (median 6.0 minutes, 5%–95% interval: 1.0–16.0 minutes). Longer consultation time was predicted by: patient-related factors (female gender, higher age, higher level of education, higher number of health problems, change of physician within the last year), physician-related factors (higher age), physicians’ workload (absence of high workload), and the type of visit (consultation and/or clinical examination). Conclusion. Consultation time in general practice is short, and depends on the characteristics of the patient and the physician, the physician's workload, and the type of visit. A reduction of high workload in general practice should be one of the priorities of the healthcare system.     

Gender-related reference intervals of urinary 8-oxo-7,8-dihydro-2′-deoxyguanosine determined by liquid chromatography-tandem mass spectrometry in Serbian population

ObjectivesAlthough there are many nucleobase modifications, 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) is one of the dominant form of oxidative modifications of DNA. Urinary 8-oxodG is potentially the best non-invasive biomarker of oxidative stress. Defining reference interval for urinary 8-oxodG is a prerequisite for its clinical use as biomarker.Design and methodsReference population included 229 healthy Serbian adults (130 males and 99 females). The spot urinary 8-oxodG was determined using high performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS). Urinary creatinine was measured by the kinetic Jaffé method.ResultsAnalytical performances of the HPLC-MS/MS: CVs within and between-run variations were 5.6% and 2.6%; LOD and LOQ were 1.65 nmol/L and 3.30 nmol/L; mean recovery and relative accuracy were 96% and 97%. Creatinine level was higher in males than in females, but no gender difference in 8-oxodG level was observed. Upon the adjustment of 8-oxodG to creatinine (8-oxodG/creatinine), higher values were obtained in females (1.38 ± 0.65 nmol/mmol) than in males (1.05 ± 0.48 nmol/mmol). Distribution of 8-oxodG/creatinine in spot urine sample was log-normal and gender-related reference intervals (estimated as the 2.5th–97.5th percentiles) were 0.45–2.22 nmol/mmol for males, and 0.54–3.11 nmol/mmol for females. Body mass index (BMI) affects excretion of the 8-oxodG in males, independently of urinary creatinine, while in females it does not. Therefore, BMI might contribute to the gender-related differences of 8-oxodG/creatinine in spot urine samples.ConclusionsThis is the first established gender-related reference intervals of spot urinary 8-oxodG/creatinine. Our results contribute to the full validation of 8-oxodG as biomarker of oxidative stress.     

Factors of risk and maintenance for eating disorders: psychometric exploration of the cross-cultural questionnaire (CCQ) across five European countries

Objective: To explore the psychometric properties of the Cross‐Cultural Questionnaire (CCQ), a new self‐report tool for assessing factors of risk and maintenance for eating disorders (ED). Method: Data was collected during a multi‐centre case‐control study. The sample included 854 ED patients and 784 healthy participants from the UK, Spain, Austria, Slovenia and Italy. Exploratory factor analyses examined the factor structure of each section of the CCQ, and Cronbach's alpha coefficients valued the internal consistency of each derived scale score. Logistic regression and receiver operating characteristic (ROC) curve procedure assessed the screening accuracy and predictive validity of the empirical factors. Results: Based on a total of 127 items, nine dimensions emerged, with satisfactory internal consistency and high congruence between countries. CCQ scores demonstrated satisfactory accuracy for discriminating between ED cases and controls (area under the ROC curve = 0.88). Most of the items achieved discriminative accuracy. Conclusions: This study offers preliminary evidence that the CCQ, available in five languages, is a useful and valid tool to assess factors of risk and maintenance for EDs. Copyright © 2010 John Wiley & Sons, Ltd. Key Practitioner Message: ? The CCQ is a new self‐report questionnaire for assessing factors of risk and maintenance for eating disorders. ? The CCQ is available in five languages (Spanish, English, German, Italian and Slovenian) and is free of charge for research purposes. ? CCQ scores demonstrated satisfactory accuracy for discriminating between ED cases and controls.     

Influence of war on quantitative and qualitative changes in drug-induced mortality in Split-Dalmatia County, Croatia

Aim

To study drug-induced mortality and characteristics of overdose deaths in the war (1991-1995), pre-war (1986-1990), and post-war period (1996-2000) in Split-Dalmatia County.

Methods

We retrospectively searched through Databases of the Department of Forensic Medicine, University Hospital Split, the national register of death records, the archives of the Split-Dalmatia County Police, and the Register of Treated Drug Addicts of the Croatian National Institute of Public Health, covering the period from 1986 to 2000, according to drug poisoning codes IX and X of the International Classification of Diseases. The indicators were statistically analyzed.

Results

There were 146 registered drug-induced deaths, with 136 (93%) deceased being men. The median age of all cases was 27 years (interquartile range 8). Most of them were single (70.6%), unemployed (44.6%), and secondary school graduates (69.2%). In the war period, there were 4.8 times more deaths than in the pre-war period (P = 0.014), and in the post-war period there were 5.2 times more deaths than in the pre-war period (P = 0.008). The most common site of death was the deceased person’s home. The toxicological analyses showed that 59 (61%) deaths were heroin related, alcohol use was found in 62 cases (42.5%), and multi-substance use was found in more than a half of the cases. In 133 (91.1%) cases, deaths were classified as unintentional, whereas 13 (8.9%) were classified as suicides.

Conclusion

The war, along with other risk factors, contributed to unfavorable developments related to drug abuse in Split-Dalmatia County, including the increase in the drug-induced mortality rate.Drug abuse is among the main causes of health problems and deaths of young people in Europe (1). Drug abuse-related mortality is one of the epidemiological indicators used for the assessment of prevalence and health-consequences of drug abuse (2). When compared with general population of the same age and sex, drug addicts have an increased risk of death (2). This implies both drug-induced deaths and deaths caused by illnesses linked to years-long drug abuse or risk behavior. An important drug-related cause of death is overdose. According to the definition of the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), drug-induced deaths refer to the deaths caused by the use of one or more substances, at least one of which is a psychoactive drug (3). Although there are differences among countries, the number of drug-induced deaths in the world has significantly increased in the recent few years (2-8).At the beginning of the War in Croatia 1991-1995, there was an outbreak of addiction epidemics and an increase in the prevalence of drug addiction (9). In the period from 1991 to 1999, the number of drug-addicts increased more than twice. In addition to this, official data on drug-induced deaths for the last few years show a constant increase (10). The increase in the number of drug addicts and fatal drug poisonings since the 1990s has been observed in Split-Dalmatia County as well (11,12).Several risk factors are identified as related to drug-induced deaths, such as sex, age, comorbid diseases, and pattern and method of drug-taking (taking of more drugs, intravenous use) (13-15).Since the war has been established as a cause of high and growing rates of morbidity and mortality (16-18), this article examines the changes in the drug-induced mortality rates in the war, pre-war, and post-war period, and analyses the characteristics of drug addicts and the circumstances involved.     

XMAP215 polymerase activity is built by combining multiple tubulin-binding TOG domains and a basic lattice-binding region

XMAP215/Dis1 family proteins positively regulate microtubule growth. Repeats at their N termini, called TOG domains, are important for this function. While TOG domains directly bind tubulin dimers, it is unclear how this interaction translates to polymerase activity. Understanding the functional roles of TOG domains is further complicated by the fact that the number of these domains present in the proteins of different species varies. Here, we take advantage of a recent crystal structure of the third TOG domain from Caenorhabditis elegans, Zyg9, and mutate key residues in each TOG domain of XMAP215 that are predicted to be important for interaction with the tubulin heterodimer. We determined the contributions of the individual TOG domains to microtubule growth. We show that the TOG domains are absolutely required to bind free tubulin and that the domains differentially contribute to XMAP215's overall affinity for free tubulin. The mutants' overall affinity for free tubulin correlates well with polymerase activity. Furthermore, we demonstrate that an additional basic region is important for targeting to the microtubule lattice and is critical for XMAP215 to function at physiological concentrations. Using this information, we have engineered a "bonsai" protein, with two TOG domains and a basic region, that has almost full polymerase activity.     

The role of α1 and α5 subunit-containing GABAA receptors in motor impairment induced by benzodiazepines in rats

Benzodiazepines negatively affect motor coordination and balance and produce myorelaxation. The aim of the present study was to examine the extent to which populations of γ-aminobutyric acid A (GABAA) receptors containing α1 and α5 subunits contribute to these motor-impairing effects in rats. We used the nonselective agonist diazepam and the α1-selective agonist zolpidem, as well as nonselective, α1-subunit and α5-subunit-selective antagonists flumazenil, βCCt, and XLi093, respectively. Ataxia and muscle relaxation were assessed by rotarod and grip strength tests performed 20 min after intraperitoneal treatment. Diazepam (2 mg/kg) induced significant ataxia and muscle relaxation, which were completely prevented by pretreatment with flumazenil (10 mg/kg) and βCCt (20 mg/kg). XLi093 antagonized the myorelaxant, but not the ataxic actions of diazepam. All three doses of zolpidem (1, 2, and 5 mg/kg) produced ataxia, but only the highest dose (5 mg/kg) significantly decreased the grip strength. These effects of zolpidem were reversed by βCCt at doses of 5 and 10 mg/kg, respectively. The present study demonstrates that α1 GABAA receptors mediate ataxia and indirectly contribute to myorelaxation in rats, whereas α5 GABAA receptors contribute significantly, although not dominantly, to muscle relaxation but not ataxia.     

Suitability of isolated rat jejunum model for demonstration of complete absorption in humans for BCS-based biowaiver request

The objective of this study was to evaluate the suitability and acceptance criteria of isolated rat jejunum model for Biopharmaceutics Classification System (BCS)-permeability classification. The evaluation followed recommended procedures including investigation of tissue integrity by applying damage triggers (nitrogen gassing, elevated temperature, azide addition), characterization of transporter functionality, and expression and development of correlation between rats' apparent permeability coefficient (P(app) ) versus humans' and versus oral fraction absorbed (f(a) ) in humans. Firstly, damage triggers caused a decrease in transepithelial resistance and potential difference and increase in lucifer yellow (LY) and fluorescein isothiocyanate (FITC)-dextran P(app) . However, only FITC-dextran P(app) 's increase was considered significant in all treatment groups, making FITC-dextran a better indicator of jejunum integrity than LY. Secondly, the expression level of selected intestinal transporters highly correlated between rat and human and functionality of P-glycoprotein was confirmed. P(app) of investigated drugs correlated with human f(a) (R(2) = 0.85, n = 20) and with human permeability coefficients (R(2) = 0.86, n = 13). Utility of described model for BCS classification was shown on levetiracetam, where significantly higher permeability of levetiracetam as compared with internal standard metoprolol was determined (t-test, p = 0.005). In conclusion, isolated rat jejunum model is a useful tool not only for mechanistic investigation, but also for permeability classification according to BCS and consequently for BCS-based biowaiver procedures.     

Disorders of hemostasis in chronic renal failure and renal transplantation

The presence of end-stage renal disease (ESRD) has been associated with profound clinical effects on hemostasis ranging from thrombosis to bleeding complications. The pathogenesis of uremic bleeding is multifactorial. It has been attributed to platelet dysfunction, the most important feature, particularly platelet-platelet and platelet-vessel wall interactions. Renal replacement therapy has helped reduce bleeding episodes, but the risk of morbidity and mortality due to hemorrhage persists. Abnormalities of blood coagulation and fibrinolysis predispose uremic patients to hypercoagulable state carrying the risk of atherosclerotic cardiovascular disease and thrombotic complications such as thrombosis of the vascular access wall. There are differences in the measurement of various hemostatic parameters in patients with ESRD concerning treatment with either hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Hemostatic disturbances are overlapped by changes in the coagulation/fibrinolytic system after renal transplantation (RT). Despite the etiology, renal transplant patients are at an increased risk of thromboembolic events as a consequence of prothrombotic clotting and fibrinolytic abnormalities. This hypercoagulable state is to a large extent associated with immunosuppressive drugs. This review will give a summary of views on hemostasis in patients with ESRD and after RT.