CD74 regulates complexity of tumor cell HLA class II peptidome in brain metastasis and is a positive prognostic marker for patient survival.

Despite multidisciplinary local and systemic therapeutic approaches, the prognosis for most patients with brain metastases is still dismal. The role of adaptive and innate anti-tumor response including the Human Leukocyte Antigen (HLA) machinery of antigen presentation is still unclear. We present data on the HLA class II-chaperone molecule CD74 in brain metastases and its impact on the HLA peptidome complexity.We analyzed CD74 and HLA class II expression on tumor cells in a subset of 236 human brain metastases, primary tumors and peripheral metastases of different entities in association with clinical data including overall survival. Additionally, we assessed whole DNA methylome profiles including CD74 promoter methylation and differential methylation in 21 brain metastases. We analyzed the effects of a siRNA mediated CD74 knockdown on HLA-expression and HLA peptidome composition in a brain metastatic melanoma cell line.We observed that CD74 expression on tumor cells is a strong positive prognostic marker in brain metastasis patients and positively associated with tumor-infiltrating T-lymphocytes (TILs). Whole DNA methylome analysis suggested that CD74 tumor cell expression might be regulated epigenetically via CD74 promoter methylation. CD74high and TILhigh tumors displayed a differential DNA methylation pattern with highest enrichment scores for antigen processing and presentation. Furthermore, CD74 knockdown in vitro lead to a reduction of HLA class II peptidome complexity, while HLA class I peptidome remained unaffected.In summary, our results demonstrate that a functional HLA class II processing machinery in brain metastatic tumor cells, reflected by a high expression of CD74 and a complex tumor cell HLA peptidome, seems to be crucial for better patient prognosis.

Race, response to chemotherapy, and outcome within clinical breast cancer subtypes.

The effect of race on breast cancer outcome is confounded by tumor and treatment heterogeneity. We examined a cohort of women with stage II-III breast cancer treated uniformly with neoadjuvant chemotherapy to identify factors associated with racial differences in chemotherapeutic response and long-term survival. Using a prospective database, we identified women with stage II-III breast cancer treated with neoadjuvant chemotherapy from 1998 to 2011. Race was categorized as African-American (AA) or non-AA. Preplanned subtype analyses were stratified by hormone receptor (HR) and HER2. Pathologic response to chemotherapy (pCR), time to recurrence (TTR), and overall survival (OS) were assessed using logistic regression, Kaplan-Meier method, and Cox proportional hazards regression analyses. Of 349 women identified, 102 (29 %) were AA, who were younger (p = 0.03), more obese (p < 0.001), and less likely to have HR+/HER2- tumors (p = 0.01). No significant differences in pCR rate by race were found. At median follow-up of 6.5 years, AA had worse TTR (hazard ratio 1.51, 95 % CI 1.02-2.24), which was attenuated in multivariable modeling, and there was no significant difference in OS. When stratified by HR, worse outcomes were limited to HR+AA (TTR hazard ratio 1.85, 95 % CI 1.09-3.14; OS hazard ratio 2.42 95 % CI 1.37-4.28), which remained significant in multivariable analysis including pCR rate and BMI. With long-term follow-up, racial disparity in outcome was limited to HR+ breast cancer, with no apparent contribution of chemotherapy sensitivity. This suggests that disparity root causes may be driven by HR+ factors such as unmeasured molecular differences, endocrine therapy sensitivity, or adherence.

Individual goal-directed intraoperative fluid management of initially hypovolemic patients for elective major urological surgery.

BACKGROUND: The impact of different approaches to fluid management during intraoperative volume resuscitation in patients undergoing major elective surgery is poorly defined. We compared volume effectiveness of crystalloid and colloid substitution aimed to maintain the cardiac index (CI) between 2.6 and 3.8 l/min/m(2) as measured by transesophageal Doppler (TED). METHODS: A total of 115 urological patients were enrolled in the prospective randomized trial and then randomized into 2 groups, one with volume therapy based on crystalloids (n = 57) and the other with colloids (n = 58). A TED probe was inserted and then hemodynamic optimization (therapy with Ringer's solution or hydroxyethyl starch 6 % 130/0.4 and administration of vasoactive drugs) was started according to TED variables to maintain the CI between 2.6 and 3.8 l/min/m(2). RESULTS: We observed high incidence of CI < 2.6 l/min/m(2) after induction of anesthesia (75 %) in both groups. There were no significant differences in demographic characteristics, ASA classification, length of surgery, estimated blood loss and the CI during surgery. To maintain the CI within the requested interval, significantly different amounts of crystalloids were needed as compared to colloid (median: 5000 ml vs 1500 ml). In the CRY group, more patients were treated by vasodilatators (40.4 vs 20.7 %). CONCLUSIONS: The study confirmed that crystalloids and colloids are effective in correcting flow-related perfusion abnormalities. The significant difference between volumes of crystalloids and colloids proved their different characteristics such as unequal distribution between compartments. The expansion of therapeutic algorithm by using vasoactive drugs allows us to avoid adverse events resulting from fluid overload (Tab. 1, Fig. 5, Ref. 35).

[Serious sepsis treatment in intensive care departments in the Czech Republic -  EPOSS Project pilot results]. / Lécba tezké sepse na pracovistích intenzivní péce v Ceské republice -  pilotní výsledky projektu EPOSS.

INTRODUCTION: Severe sepsis is still associated with significant morbidity and mortality, which is however different, as well as its management, depending on the region. What is the situation in the Czech Republic and what is the character of patients with severe sepsis is currently not known. The aim of the project is to describe the processes of care, outcome and characteristics of patients with severe sepsis admitted to the intensive care department of the Czech Republic. METHODS: This is a multicentre and observational project with retrospective enrollment of patients who meet the criteria for severe sepsis before or within 24 hours after admission to selected intensive care units (ICU EPOSS). RESULTS: 394 patients were analyzed. Median age at admission was 66 (56- 76) years, males predominated (58.9%) and the median APACHE II score on admission was 25 (19- 32). Patients were predominantly medical (56.9%) and most were secondary admitted from other ICU (53.6%). Meeting the criteria of severe sepsis was most frequently within the period (± 4 hours) of admission the EPOSS ICU (77.6%). Median total fluid intake during the first 24 hours was 6,680 (4,840- 9,450) ml. Most patients required mechanical ventilation (58.4%). Compliance with the resuscitation bundle of severe sepsis in our group was very good and was associated with lower mortality of patients. Most frequently, the EPOSS ICU length of stay (LOS) was 7 (3- 15) days and median hospital LOS was 13 (8- 28) days. Hospital mortality in our cohort was 35.8%. CONCLUSION: Introducing the project, which in its first stage obtained valuable and internationally comparable data about patients with severe sepsis admitted to the involved ICU in the Czech Republic.

Ifosfamide, carboplatin and etoposide in recurrent malignant glioma.

After failure of temozolomide, there is no established standard salvage chemotherapy for patients with recurrent glioblastoma (GBM). Two phase II trials combining ifosfamide, carboplatin and etoposide chemotherapy (ICE) showed favorable results. We therefore applied the ICE protocol to 13 patients (10 GBM, 3 anaplastic astrocytomas). Partial or complete remissions were not observed. None of the 13 patients survived progression-free for 6 months. Our retrospective analysis suggests that the ICE regimen is not effective in patients with recurrent high-grade glioma if applied at second or third relapse.

Exogenous surfactant as a component of complex non-ECMO therapy of ARDS caused by influenza A virus (2009 H1N1).

During the pandemy caused by novel influenza A virus (subgroup H1N1), a significant number of patients became critically ill from respiratory failure. In the most severe cases of primary pneumonia, patients develop refractory hypoxemic acute respiratory distress syndrome (ARDS) with typical computed tomographic findings of multi-lobar alveolar opacities and extremely reduced pulmonary airspace. To reduce the risk of injurious ventilation and promote survival, some authors recommend the use of extracorporeal membrane oxygenation (ECMO). Unfortunately, ECMO is expensive, associated with serious complications, and available at very few centers. Other therapeutic options are clearly needed. Here we report three patients with severe influenza pneumonia who recovered following treatment with porcine surfactant (Tab. 1, Fig. 3, Ref. 6). Full Text in free PDF www.bmj.sk.

Quantitative ballistocardiography (Q-BCG) for measurement of cardiovascular dynamics.

In the seventies of the past century ballistocardiography had been thought to be obsolete in cardiology for impossibility of objective calibration. In the present work the quantitative ballistocardiography (Q-BCG) for measurement of systolic force (F) and minute cardiac force (MF) in sitting subject was described. The new principle of piezoelectric transducer enabled to register the force caused by the heart and blood movement, which was not measured before. The calibration proved that the action of the force on the transducer was expressed quantitatively without the amplitude-, time-, and phase deformation. The close relationship of skeletal muscle force and F was proved. The F and MF changed under different physiological conditions (age, partial pressure of oxygen, body weight, skeletal muscle force). It was shown that the systolic force (F) and minute cardiac force (MF) are the physiological parameters neurohumorally regulated similarly as the heart rate or systolic volume.

[Ventilator-associated pneumonia]. / Ventilátorová pneumonie.

Ventilator-associated pneumonia (VAP) is defined as pneumonia occurring in a patient after intubation with an endotracheal tube or tracheostomy tube lasting for 48 hours or more. It is also one of the most common and fatal infections of patients in ICUs. The diagnostic process in VAP is still underestimated and precise criteria for diagnosis are inconsistent. Delayed diagnosis and subsequent delay in starting appropriate therapy are associated with worse outcomes in patients with VAP. Appropriate dose, adequate route of administration and reasonable length of antibiotic therapy together with de-escalation are the fundamental principles of therapy. Supportive care is also an integral part of the treatment. Implementing preventive procedures according to the local ICU standards is needed for reducing the incidence of VAP effectively.

A response to infection in patients with severe sepsis--do we need a "stage-directed therapy concept"?

Excessive forms of the response of organism to infection play an important role in the pathogenesis of severe sepsis. They may consist of either local pro-inflammatory response with a massive release of cytokines into the systemic circulation, or may be presented as an excessive systemic anti-inflammatory response. In the first case, the result is a systemic pro-inflammatory state, characterised by natural stages of the inflammatory response, in which dysfunction of macrocirculation is followed by microcirculation derangement and mitochondrial alteration at the end. These mechanisms are responsible for the development of remote organs failure. The result in the second case is a deactivation of local immunocompetent cells, which results in the risk of uncontrollable growth of microorganisms, especially in organs with an impaired antimicrobial barrier. This may explain the clinically observed recurrence of septic episodes, when a resolution of infection at one site is later replaced with an outbreak of sepsis from another site. A number of therapeutic interventions aimed on the management of causes and consequences of systemic pro-inflammatory state was clinically tested (e.g. antibiotics, goal directed hemodynamic support and inhibitors of coagulation) with surprisingly different effectiveness. The cause of this difference may lie, apart from the frequently discussed inhomogeneity of the studied patient population, also in an incorrect timing of the therapeutic interventions, which does not respect natural stages of the inflammatory response (Fig. 1, Ref. 40).

New clearance evaluation method for hepatological diagnostics.

Pulse dye densitometry (PDD) enables the evaluation of hemodynamic state as well as liver function. A repeated examination, even after a short pause (or under stress condition), enables to follow safely the dynamics of liver pathology. From presented parameters we have evaluated as reliable the C5-clearance, an expression of equilibrium state in the two compartment liver system. Furthermore, T-index expresses ratio of C5 value to cardiac output, it is a sensitive indicator of the blood pole, i.e. sinusoidal uptake, which is in very good correlation with staging of hepatopathies. The isolated h constant in correlation to T-index is valuable For functional grading. The Japanese automatic analyzer of indocyanine green (ICG) dilution and elimination curves, after incorporation of a two compartment mathematical model, becomes more useful for complex hepatological diagnostics. Non-invasive PDD is becoming of uppermost importance to clinical interest, yielding comparable results as other complicated and invasive examinations and may be, therefore, repeated in short time intervals for different indications with minimal stress of examined patient.

[Pathogenesis of severe sepsis--from macrocirculation to mitochondria]. / Patogeneze teké sepse--od makrocirkulace k mitochondriím.

Severe sepsis is at present serious medical and social problem. In contrast to many other diseases its incidence shows an upward tendency and so does mortality due to sepsis. From the point of view of pathogenesis the cause of this complaint is a disturbed response to infection. The basis of this disruption is either a huge local inflammation that goes hand in hand with the penetration of proinflammatory cytokines into systemic circulation or an excessive proinflammatory systemic response. In the first instance the consequence is a systemic proinflammatory response accompanied by a disruption of macrocirculation, later also of microcirculation and finally mitochondrial failure. These mechanisms are responsible for the gradual failure of distant organs. In the second instance the consequence is a deactivation of systemic and local immunocompetent cells accompanied by the risk of uncontrolled proliferation of microorganisms. Affected are organs with a disturbed antimicrobial barrier, especially the lungs du ring mechanical ventilation, the bloodstream or the urinary system during catheterization. A large group of selectively acting preparations has been clinically tested in the management of this disorder, but only very few of these preparations were efficacious. We may postulate that the great diversity of the investigated population of patients was responsible for this lack of success.

[Hair whorl--a genetically bound phenomenon in testing of right-handedness and hemispheric dominance]. / Vír vlasu--geneticky vázaný jev pri vysetrováiní fenotypu praváctví a hemisferální dominance.

BACKGROUND: The importance of normal development of hemispheric dominance and its significance for the development of an individual is sufficiently known. The internationally not well known procedure according to Zlab (1) represents one of the most suitable examinations for right-handedness and laterality testing. METHODS AND RESULTS: In our study we used one of the most popular questionnaires for phenotype testing of handedness- Edinburgh's Inventory (2). According to this questionnaire we have examined 65 children 10 years of age (+/- one year), and classified them into 3 groups: a) pure right-handed (n = 51), b) pure left-handed (n = 5) (all have fulfilled +90-100% resp. -90-100% of answers on corresponding ten questions) and c) a group of mixed laterality--ambidextrous (n = 9). The questionnaire we have accomplished by means of objective testing of hair whorl direction presupposed clockwise in right-handed and counter clockwise in lefthanded. Some of other tests we used turn to be more reliable than lid opening and using a broom (upper hand) by "dominant" hand used in Edinburg's Handedness Inventory. We have examined also hand, elbow, knee and leg joints excursibiliy (enlarged passivity and/or diminished muscle tonus) to define cerebellar dominance: right cerebellar hemisphere in right-handed and left cerebellar hemisphere in left-handed. In the group of pure right-handers we found clockwise hair whorl in 23 of 25 boys. In girls (probably due tu various hair combing) we found clockwise hair whorl only in 12 of 26 children. CONCLUSIONS: Examination of the hair whorl direction seems to be enrichment for a quick clinical phenotype and genotype laterality testing.

[Contribution and selected risks of blood transfusion]. / Prínos a vybraná rizika krevních prevodu.

AIM: Overview of recent knowledge about risks and benefits of blood transfusion. TYPE OF STUDY: Review article. SETTING: Department of Anaesthesiology and Intensive Care, University Hospital, Ostrava. METHODS: Summary of previously published data. CONCLUSION: Transfusion of blood and blood products remains controversial in clinical practice. Neither indication and timing nor benefit of this procedure is clearly determined. Previously often reported complications as blood-group incompatibility and infection are less frequent now, and new transfusion's side effects as TRIM (transfusion-related immunomodulation) and TRALI (transfusion-related lung injury) are reported with growing evidence. This risk (often underestimated in the past) is discussed in the article, and compared with blood transfusion benefits. Either restrictive or more open approach to blood transfusion are supported as well as criticised by different groups of clinicians and "good clinical practice" definition remains open for the future.

[Traffic accidents from the view of neurologist]. / Dopravní nehody z hlediska neurologa.

Review article deals with traffic accidents in our country and the problems of their causes. In comparison with economically developed countries traffic accidents prevalence raised since 1990 till 1995 and with small decline in 2004 it remains on a high level of 140 deaths in traffic accidents for I million of inhabitants, which makes the Czech Republic one of the worst among the compared countries. In agreement with present views, the main course of accidents is the human error. Attention is given to traffic accidents prevalence of young men versus young women, and to the evaluation of psycho-physiologic functions in elderly drivers. Personal qualities are among the most important in the neglecting of traffic rules, in the aggressivity, non-tolerance and disrespect to the freedom of others. Besides the building of the more perfect infrastructure, it is necessary to improve the register of accident recidivist drivers and for accidents and repeated accidents to promote compulsory psycho-neurological examination. Similarly to preventive check outs for alcohol, it s necessary to introduce similar measures to cope with growing effects of drugs.

The new clearance method for hepatic diagnostics.

New multiparametric analysis and method of their evaluation were derived. The bolus dye injection is used for evaluation of ICG (indicyaningreen) and BSP (bromsulphophtalein) kinetics. This arrangement is a form of spectrophotometric measurement of BSP in plasma and/or pulse dye densitometry of ICG. Clearance values enable to differentiate liver diseases and to add their clinical staging. Pathophysiology of dye kinetics is discussed from two points of view i.e. sinusoidal and canalicular membrane transfer.

[Prion neuroinfections]. / Prionové neuroinfekce.

Prion neuroinfections represent an emergent problem namely after the epidemic brake out of the bovine spongiform encephalopathies, which culminated in 1993. Isolated cases can still emerge. The next case was the discovery of a new variant of Creutzfeldt-Jakob disease in the comparatively young persons with proved alimentary infection route--about 140 cases has been described. Physiological prions are glycoproteins, affixed to the rafts of cell membranes (namely in neurons) by glycosylphosphatidylinositol anchor. They act as signalling molecules and participate in the cooper metabolism. Despite the intensive study in many prestigious laboratories, the way how the pathogenic isoform of prions, given by the prevalence of beta-conformations in the polypeptide chain develops has not been proved yet. Pathogenic isoforms are formed intracellulary after the precedent endocytosis. Aggregations of abnormal prion molecules build up prion amyloid deposits in the form of fibrils or plaques. The loss of neurons brings about the neurological symptoms, which are not directly related to the amounts of amyloid deposits. Characteristic findings of spongiosis and the immunohistochemical evidence of protease-resistant prions belong to the only reliable tests. Reliable intravital test in the blood or urine is not yet available. All forms of human and animal transmissible spongiform encephalopathies develop only in genetically sensitive individuals. A brief overview of clinical forms and some biochemical and genetic aspects of the disease are given.

Electrocardiographic body surface maps (BSM) in patients with ischemic heart disease examined by coronary angiography.

ECG body surface maps (BSM) is one of the noninvasive methods for the detection of ischemic heart disease. In the present work we registered the BSM in 25 patients, 18 men, mean age 56.8 (31-83) years, 7 women, mean age 58.7 (43-72) years with coronary artery disease and in 23 healthy persons, 17 men, mean age 55 (46-60) years, 6 women, mean age 57 (42-70) years. Using diagnostic system Cardiag we measured 32 parameters of heart electric field (ECG, VCG, isopotential, isointegral, and isoarea maps). The results of BSM examination were compared with the results of coronary angiography (CAG) and other noninvasive methods. Twenty-four patients were BSM positive, 5 of them with negative CAG. In one case both BSM and CAG were negative. None of persons with positive CAG were BSM negative. The values of positive BSM in patients with negative CAG approached more to the values of positive CAG persons than to controls. Despite of small number of persons examined in our study one can conclude that the BSM method detects the damage of myocardium by another way than the CAG.

[Somatognosis, body schema and the phenomena of somatic and visceral phantoms and phantom pain]. / Somatognózie, telesné schéma, fenomén telového a viscerálního fantomu a fantomové bolesti.

The body scheme is a complex of memory patterns secured in the structures of the brain, where the parietal lobes play the most important role. Basic principles are given by the genetic programming of the structure and function along with the synthesis of information brought by means of sensory activity. The unitary perception of the body scheme is a dynamic image, enabling conscious and unconscious representation of our body, its parts, their functions, position, shape and/or movements. The recognition of the body scheme in humans is named somatognosia. Disorders of somatognosia include visceral and somatic phantom, phantom pain and other disorders related to the capability of communication by means of language: autotopoagnosia, hemiasomatognosia, pain asymboly, anosognosia of hemiplegia, anosognosia of blindness, deafness, neglect and other defects appearing at the neurologist's and psychiatrist's borderline of interest. Interest in the visceral phantom is usually much smaller than that in the phantom limb. The aim of this paper was to draw the to phantom phenomena in patients following rectum amputation and colostomy. A survey of contemporary knowledge about the body scheme and its disorders, cortical plasticity and the problem of cortical maladaptation are presented.

[Effect of a 10-day animal fat-free diet on cholesterol and glucose serum levels, blood pressure and body weight in 50-year-old volunteers]. / Vliv desetidenní diety bez zivocisného tuku na hladinu sérového cholesterolu, glykemie, krevní tlak a telesnou hmotnost u padesátiletých dobrovolníku.

The morbidity and mortality of cardiovascular diseases is high in developed countries including Czech Republic. The lifestyle decreases it in 50%. The aim of this work was to ascertain if the short lasting stay without stress and with vegetarian diet (without eggs) and physical activity is able to decrease the main risk factors of cardiovascular diseases. In 106 volunteers, mean age 49.1 (+/- 14.1) years, 83 women and 23 men, the body weight, blood pressure, serum cholesterol and blood glucose (Accutrend GC, Boehringer, Mannheim, BRD) have been measured before and after the stay at the same conditions. Eighty persons were healthy, seven persons with essential hypertension, eight persons with ischemic heart disease, four persons with diabetes mellitus and seven persons with other than cardiovascular diseases. In some persons the lipid spectrum was measured. Cholesterol decreased in blood serum from 4.9 to 4.3 mmol/l (11%--p < 0.01), blood glucose decreased from 4.2 to 3.3 mmol/l (p < 0.05), blood pressure systolic from 121.5 to 117.4 mm Hg (p < 0.01) and diastolic from 76.5 to 73.8 mm Hg (p < 0.05), body weight was not significantly changed. Our results showed, that 10-days lasting stay containing vegetarian diet and physical activity decreased the risk factors of cardiovascular diseases in 50 years-old volunteers.

Detection of antimicrobials in bee products with activity against viridans streptococci.

OBJECTIVES: Bee products have been studied extensively for their healing properties and have become part of cosmetic preparations and folk medicine. The major objective of this study was to examine the presence of antimicrobials in various bee products. DESIGN: Propolis, honeycomb lids, pollen, honeycombs, and honey were screened for antimicrobial compounds. Viridans streptococci were used as indicator strains. Ethanol extracts were applied onto paper disks, dried, and put on the surface of nutrient agar plates with the overlay containing viridans streptococci. The plates were then incubated and evaluated the next day for the presence of inhibition zones. The size of the inhibition zone represented a quantitative measure of antimicrobial activity in a sample. Thin-layer chromatography was used for separation of compounds in the samples and biodetection-an overlay with indicator strain-identified the antimicrobial compounds by formation of inhibition zones. RESULTS: Ethanol extracts of propolis and honeycomb lids, as well as honey containing honeycomb lids contained a mixture of antimicrobial compounds in various amounts. Thin-layer chromatography experiments with two different solvent systems differing in polarity suggested that major antimicrobials present in the samples prepared from honeycomb lids, honeycombs, pollen, and propolis have similar properties. These active compounds were not extremely hydrophobic. CONCLUSIONS: Extracts from the tested samples of bee products exhibited antimicrobial properties at various levels depending on the sample and bacterial species used for testing. Using chromatographic techniques, we demonstrated similar properties of the active compounds in various active samples. In conclusion, our results suggest that honey containing honeycomb lids may be a beneficial food supplement because of the presence of antibacterial compounds.