Antioxidant defense system in familial hypercholesterolemia and the effects of lipoprotein apheresis.

Oxidative stress is thought to play an important role in the pathogenesis of disorders associated with atherosclerosis. Alpha-tocopherol is considered to be an effective lipophilic antioxidant, which protects lipid membranes against peroxidation and thus prevents cell damage by reaction with free radicals. However, measurement of alpha-tocopherol concentration in serum does not reflect the content of α-tocopherol in membranes whereas erythrocyte alpha-tocopherol may be good indicator of antioxidative status. Therefore a simple isocratic reversed phase HPLC method has been developed and validated for the determination of alpha-tocopherol in human erythrocytes in a clinical setting. The content of alpha-tocopherol in human erythrocyte membrane and lipoperoxidation were studied in patients with severe hypercholesterolemia treated by lipoprotein apheresis. The group of hypercholesterolemic patients (n = 14) treated by lipoprotein apheresis was compared to healthy adult normolipidemic controls. After lipoprotein apheresis, the content of in membrane alpha-tocopherol did not change significantly despite decreased tocopherol in serum and lipoprotein fractions. We observed significantly decreased lipoperoxidation as revealed by serum TBARS, representing end products of lipid peroxidation, which increased from third day afterwards and remained significantly higher in comparison to controls until the next LDL-apheresis. We conclude that aggressive lipid lowering procedure with lipoprotein apheresis was associated with favorable transient decrease of lipoperoxidation. Simultaneously the cell membrane bound antioxidative defense mechanisms as reflected by the content of alpha-tocopherol in human erythrocyte membrane where not depressed in spite of its decreased plasma lipid carrier. Another variables involved remain to be investigated.

Lipoprotein apheresis in the treatment of dyslipidaemia - the Czech Republic experience.

In 1984, we started using therapeutic plasmapheresis (plasma exchange) as a method of extracorporeal lipoprotein elimination for the treatment of hypercholesterolemic patients. We evaluated the results of long-term therapy in 14 patients, 8 men and 6 women. The average age was 55.6+/-13.2 (range 28-70), median 59.5 years. 14 patients were diagnosed with familial hypercholesterolemia (FH): 5 homozygous, 9 heterozygous. Ten patients in the group were treated using immunoadsorption lipoprotein apheresis and 4 using hemorheopheresis. Immunoapheretic interventions decreased LDL-cholesterol (82+/-1 %), ApoB (73+/-13 %) and even Lp(a) by 82+/-19 %, respectively. Selected non-invasive methods are important for long-term and repeated follow-up. Carotid intima-media thickness showed improvement or stagnation in 75 % of the patients. Biomarkers of endothelial dysfunction such as endoglin (in the control group: 3.85+/-1.25 microg/l, in lipoprotein apheresis-treated hypercholesterolemic individuals 5.74+/-1.47 microg/l), CD40 ligand (before lipoprotein apheresis: 6498+/-2529 ng/l, after lipoprotein apheresis: 4057+/-2560 ng/l) and neopterin (before lipoprotein apheresis: 5.7+/-1.1 nmol/l, after lipoprotein apheresis: 5.5+/-1.3 nmol/l) related to the course of atherosclerosis, but did not reflect the actual activity of the disease nor facilitate the prediction or planning of therapy. Hemorheopheresis may improve blood flow in microcirculation in familial hypercholesterolemia and also in some other microcirculation disorders via significantly decreased activity of thrombomodulin (p<0.0001), tissue factor (p<0.0001), aggregation of thrombocytes (p<0.0001) and plasma and whole blood viscosity (p<0.0001). In conclusion, lipoprotein apheresis and hemorheopheresis substantially lowered LDL-cholesterol in severe hypercholesterolemia. Our experience with long-term therapy also shows good tolerance and a small number of complications (6.26 % non-serious clinical complications).

[Personalised antibiotic therapy in a surgical intensive care unit overview of current knowledge and the results of an observational kinetic study]. / Personalizovaná antibiotická terapie na chirurgické jednotce intenzivní péce prehled soucasných znalostí a výsledky observacní kinetické studie.

INTRODUCTION: The current efforts of intensivists focused on individual antibiotic treatment in patients suffering from sepsis has inspired us to conduct an open prospective clinical study to assess the relationship between body fluid retention (>10 L/24 hours) and the efficiency of hydrophilic time-dependent antibiotics used in critically ill patients. Polytrauma and abdominal catastrophes are the most frequent causes of systemic inflammatory response syndrome (SIRS). Consequent body liquid retention is taken for a pathophysiological covariate modifying the pharmacokinetics (PK) and pharmacodynamics (PD) of hydrophilic time-dependent antibiotics (betalactams and carbapenems). Not only body fluid retention but also changes in renal clearance are thought to be responsible for failure in PK/PD target attainment necessary for effective antimicrobial activity. To describe the importance of the pathophysiological covariates for the individual kinetic variables of a representative antibiotic (piperacillin) is the primary goal of this kinetic observational study. MATERIAL AND METHODS: Three patients with polytrauma and SIRS admitted at the ICU of the Surgical Department, Teaching Hospital Hradec Králové, whose condition was characterized by cumulative body fluid retention (>10 L), were eligible for enrolment. As per standard hospital protocol, the patients were administered with 4 g of piperacillin in combination with tazobactam 0.5 g intravenously by 1-hour (h) infusion every 8 h. A series of blood samples were taken 1, 2.5, and 5 h after the termination of the infusion. Urine was collected over each dosing interval and for 24 h. Piperacillin was detected using a previously validated HPLC method. Individual pharmacokinetic variables were estimated using non-compartmental pharmacokinetic analysis. Cumulative body fluid retention was calculated as the difference between fluid intake and output. Creatinine clearance (Cl) was used for renal function evaluation. PK/PD target attainment was analysed according to Carlier (2013). RESULTS: In three patients with polytrauma and SIRS, great interindividual and intraindividual differences in extravascular volume expansion, i.e. cumulative body fluid retention 2030 L and changes in renal function, were recorded. In 2/3 patients these pathophysiological changes as well as the clinical interventions administered resulted in augmented piperacillin clearance and an increase in distribution volume (Vd) (>20 L) with a maximum at Day 28 after initiation of therapy. In such patients treated with a standard dose of piperacillin, only minimum PK/PD target attainment (50% Ft >MIC) was obtained. In contrast, a patient suffering from renal dysfunction attained both minimum (50% ft >MIC) and maximum PK/PD target (100% ft >MIC). CONCLUSIONS: In three critically ill patients with polytrauma and SIRS, pathophysiological changes (covariates) had a profound effect on the key determinants of the pharmacokinetics (Cl and Vd), resulting in significant intraindividual variability in pharmacodynamic /pharmacokinetic target attainment necessary for therapeutic time-dependent antibacterial activity of piperacillin. Consequently, patients with augmented clearance of piperacillin may be at risk for treatment failure, and/or bacterial resistance without dose up-titration. A subsequent clinical study will be conducted to describe personalised kinetically guided antibiotic therapy.

Prognostic significance of increased urinary neopterin concentrations in patients with breast carcinoma.

Increased serum or urinary concentrations of neopterin have been described in patients with tumors of different primary locations, but reports on neopterin in patients with breast carcinoma are relatively innumerous. We have evaluated urinary neopterin in 456 patients with breast carcinoma. Urinary neopterin was determined using high-performance liquid chromatography. Neopterin in patients was increased only in a minority of patients with breast carcinoma. Increased urinary neopterin was associated with inferior overall survival. Prognostic significance of increased urinary neopterin was evident in patients with tumors expressing hormone receptors or/and human epidermal growth factor receptor (HER)-2, but not in patients with triple negative tumors. Among other parameters determined, C-reactive protein, hemoglobin, peripheral blood neutrophil count and platelet count were significant prognostic factors. On multivariate analysis, age, expression of hormone receptors, neutrophils, stage and hemoglobin concentration were independent prognostic indicators. In conclusion, serum neopterin is increased only in a minority of patients with breast carcinoma. Increased urinary neopterin was predictive of poor survival in univariate, but not multivariate analysis. Age, expression of hormone receptors, neutrophils, stage and hemoglobin concentration were independent prognostic indicators.

Use of ultra high performance liquid chromatography-tandem mass spectrometry to demonstrate decreased serum statin levels after extracorporeal LDL-cholesterol elimination.

BACKGROUND: Using our statin analysis method, it was possible to uncover a significant drop in statin levels (atorvastatin, simvastatin, and metabolites) after extracorporeal LDL-cholesterol elimination (EE) in severe familial hypercholesterolemia (FH). The purpose of this work was to identify the mechanism underlying this drop and its clinical significance as well as to propose measures to optimize a pharmacotherapeutical regimen that can prevent the loss of statins. METHODS: Ultra High Performance Liquid Chromatography (UHPLC) connected to the triple quadrupole MS/MS system was used. Patients. A group of long-term treated patients (3-12 years of treatment) with severe FH (12 patients) and treated regularly by LDL-apheresis (immunoadsorption) or haemorheopheresis (cascade filtration) were included in this study. RESULTS: After EE, the level of statins and their metabolites decreased (atorvastatin before/after LDL-apheresis: 8.83/3.46 nmol/l; before/after haemorheopheresis: 37.02/18.94 nmol/l). A specific loss was found (concentration of atorvastatin for LDL-apheresis/haemorheopheresis: 0.28/3.04 nmol/l in washing fluids; 11.07 nmol/l in filters). To prevent substantial loss of statin concentrations, a pharmacotherapeutic regimen with a longer time interval between the dose of statins and EE is recommended (15 hours). CONCLUSIONS: A specific loss of statins was found in adsorbent columns and filters. The decrease can be prevented by the suggested dosage scheme.

Transforming growth factor beta and soluble endoglin in the healthy senior and in Alzheimer's disease patients.

OBJECTIVES: Senescence of the immune system and of endothelial cells can contribute to age-dependent vascular and neurodegenerative disorders including Alzheimer's disease. The aim of this study is an assessment of putative relationships of serum levels of transforming growth factor beta (TGFß) and soluble endoglin (sCD105) and neurodegeneration, and of changes of these molecules in the course of ageing. DESIGN: The subjects of the study consisted of three groups, the first one was 63 otherwise healthy middle - aged participants, 31 females, 32 males, of average age 35 years. The second group was formed by 58 healthy, self-dependent inhabitants of nursing homes, 44 females and 14 males, average age 83.5 years. The third group comprised of 129 Alzheimer's disease patients, 86 females, 43 males, of average age 80 years, with MMSE score that ranged from 16 to 20. MEASUREMENT: Serum levels of TGF beta and soluble endoglin were measured by the ELISA method in samples of peripheral blood using commercial kits. RESULTS: The serum level of TGFß was 34,339 ± 6,420 pg/ml in the healthy younger group, 37,555 ± 11,944 pg/ml in the healthy seniors, and 29,057 ± 11,455 pg/ml in Alzheimer's disease patients. Compared to healthy seniors, the serum level of TGFß was significantly decreased in Alzheimer's disease patients (p < 0.01). The serum level of endoglin were 4.88 ± 0.95 µg/ml in the healthy younger group; 6.11 ± 1.38 µg/ml in healthy seniors, and 7.20 ± 1.72 µg/ml in patients with Alzheimer's disease, respectively. The serum level of endoglin was significantly higher (p < 0.001) in senescent healthy persons compared to the younger control group. When compared with healthy seniors, patients with Alzheimer's disease had significantly elevated (p < 0.001) serum level of endoglin. CONCLUSIONS: Decreased levels of TGF ß in Alzheimer's disease may result in impairment of cerebral circulation reflected in the increased endoglin levels. These findings may indicate involvement of the immune system in Alzheimer's disease pathogenesis.

Effect of comorbidity on urinary neopterin in patients with breast carcinoma.

Urinary neopterin is increased in less than 20% of patients with breast carcinoma. Moderately increased neopterin concentrations are also known to accompany comorbid conditions commonly observed in patients with breast carcinoma, for example, diabetes mellitus or complications of atherosclerosis. In the present study, we evaluated the effect of the presence of comorbid conditions on urinary neopterin. A trend for higher neopterin concentrations was observed in patients with most of the comorbid conditions, but significantly higher neopterin was observed only in patients aged 70 years or older and in a heterogeneous group of patients with comorbidity other than diabetes mellitus, thyroid disorder, hyperlipidaemia, cardiac disorder or other malignancy. Significantly higher neopterin levels were noted in patients with two or more comorbid conditions. In conclusion, present data demonstrate an association between systemic immune activation reflected in increased urinary neopterin concentrations and age or presence of comorbid diseases in patients with breast carcinoma. A cumulative effect was observed with the presence of two or more comorbid conditions resulting in significantly increased urinary neopterin. These observations should be taken into account when interpreting the changes of parameters of systemic immune and inflammatory response in patients with breast carcinoma.

[Influence of haemorheopheresis in the dry form of the age related macular degeneration]. / Moznost ovlivnení suché formy vekem podmínené makulárni degenerace hemorheoferézou.

INTRODUCTION: The age related macular degeneration (ARMD) is the most common cause of practical blindness in the population older than 60 years of age. Usually it starts as a dry form with soft drusen.The progression of the dry form is difficult to control-promising seems to be the influence of rheologic factors in the choroid and the retina and thus improvement of their blood flow. AIM: By means of haemorheopheresis to improve blood rheology and thus micocirculation in the choroid and retina. The authors describe the development of the dry form of the ARMD in the sensitive stage with soft drusen and the eventual presence of retinal pigment epithelium detachment (RPED) after haemorheopheresis. The treated patients were compared with a control group (natural course of the ARMD) with the same number of patients. METHODS: In a prospective, randomized study, comprising of 16 patients with the dry form of ARMD were treated with haemorheopheresis (cascade filtration) and 16 patients in the control group. Haemorheopheresis treatment comprised of 8 cycles in 10 weeks. Plasma obtained by separator was filtered by the Evaflux 4A (Japan) separator, where, the defined spectrum of high molecular proteins was captured. This lead to a decrease in blood and plasma viscosity and thus to improvement of rheologic conditions of the retina. RESULTS: Results show a positive influence on the absorption of soft drusen, reduction of the retinal pigment epithelium detachment, and the possibility to improve the visual acuity of the treated patients. CONCLUSION: Comparing to the worsening of clinical signs and visual functions in natural course of the ARMD development, the rheopheresis as well tolerated method may cause the retardation or stop of the unfavorable course of the disease.

Comparison of a novel ultra-performance liquid chromatographic method for determination of retinol and alpha-tocopherol in human serum with conventional HPLC using monolithic and particulate columns.

Retinol and alpha-tocopherol are biologically active compounds often monitored in blood samples because of their evident importance in human metabolism. In this study a novel ultra-performance liquid chromatographic (UPLC) method used for determination of both vitamins in human serum has been compared with conventional HPLC with particulate and monolithic C(18) columns. In UPLC a sub-two-micron particle-hybrid C(18) stationary phase was used for separation, in contrast with a five-micron-particle packed column and a monolithic column with a highly porous structure. Methanol, at flow rates of 0.48, 1.5, and 2.5 mL min(-1), respectively, was used as mobile phase for isocratic elution of the compounds in the three methods. Detection was performed at 325 nm and 290 nm, the absorption maxima of retinol and alpha-tocopherol, respectively. Analysis time, sensitivity, mobile-phase consumption, validation data, and cost were critically compared for these different chromatographic systems. Although cost and mobile-phase consumption seem to make UPLC the method of choice, use of the monolithic column resulted in almost the same separation and performance with a slightly shorter analysis time. These methods are alternatives and, in routine laboratory practice, more economical means of analysis of large numbers of biological samples than use of a traditional particulate column.

Urinary neopterin in patients with advanced colorectal carcinoma.

In previous studies, mostly in patients with early stage colorectal carcinoma, neopterin, an indicator of systemic immune activation, has been associated with poor prognosis. The aim of the present study was to evaluate urinary neopterin in patients with advanced or metastatic colorectal carcinoma treated with chemotherapy. A retrospective analysis was performed of urinary neopterin, determined by high-performance liquid chromatography, in 88 patients with advanced or metastatic colorectal carcinoma. Peripheral blood cell count and serum carcinoembryonic antigen (CEA) were determined in 72 patients before the start of chemotherapy. Urinary neopterin in colorectal carcinoma patients was significantly increased compared to controls, but lower than in patients with inflammatory bowel disease. Neopterin correlated significantly with serum CEA, age, peripheral blood leukocyte and platelet counts. The median survival of colorectal carcinoma patients with urinary neopterin below 214 micromol/mol creatinine was significantly longer compared to that of patients with higher neopterin concentrations (median 18 vs 5 months, log-rank test p=0.003). CEA and hemoglobin were also associated with survival in univariate analysis, but in multivariate analysis only urinary neopterin and serum CEA were independent predictors of survival. High urinary neopterin during follow-up was also predictive of poor prognosis.

Neopterin as an indicator of immune activation and prognosis in patients with gynecological malignancies.

Malignant tumors may contribute to host response that involves both the adaptive and innate immune systems. Among other biochemical indicators of systemic immune and inflammatory activity, activation of macrophages by interferon-gamma induces a marked increase in the production of neopterin. Neopterin production by activated macrophages is also associated with tryptophan degradation. In addition to tumors of other primary locations, increased urinary and serum neopterin concentrations have been reported in patients with gynecological cancers, including epithelial ovarian carcinoma, cervical carcinoma, endometrial carcinoma, uterine sarcomas, and vulvar carcinoma, but not in women with benign neoplasms or precancerous disorders. Increased neopterin concentrations have been associated with poor prognosis. Elevated levels of neopterin have also been observed in the tumor microenvironment. Systemic (urinary or serum) or local (ascitic fluid) neopterin concentrations increased after therapeutic administration of cytokines. Elevated neopterin concentrations have been associated with anemia of chronic disease and increased urinary zinc loss in patients with gynecological malignancy. Elevated neopterin has also been connected with depressed function of peripheral blood lymphocytes and a decrease in CD4+ T-cell numbers.

Biochemical profile and survival in nonagenarians.

OBJECTIVES: Old age is associated with an increase in frequency of disorders involving virtually all organ systems, resulting in a rise of mortality. The aim of the project was to study the relationship between biochemical markers and all-cause mortality in a defined age group. DESIGN AND METHODS: Thirty-eight nonagenarians, aged 92 +/- 2 (range 90-100) years entered the study. At the start of the study, a sample of peripheral blood and urine were obtained for analysis of 50 basic biochemical, hematologic and biologic parameters. The assessment was then repeated in 6 to 12 months intervals. The significance of difference between surviving subjects and those who died was examined by Mann-Whitney U test and the correlation between the variables was studied by Spearman rank correlation coefficient. RESULTS: During the observation period, 21 of the studied subjects died leaving 17 persons still alive at the end of the study. The mean time from the first measurement to the death was 12 +/- 10 (range 0-33) months. The mean follow-up time in surviving subjects was 31 +/- 12 (range 4-45) months. Serum vitamin E and calcium were significantly higher, and serum alanine aminotransferase (ALT) and urinary neopterin were significantly lower in survivors compared to the subjects who died. No other parameters were significantly different in survivors and in persons who died. Urinary neopterin exhibited a significant negative correlation with serum sodium concentration (RS = -0.50, p < 0.01), but the other parameters did not correlate significantly. CONCLUSION: In conclusion, among the parameters studied, differences between survivors and nonsurvivors were observed only for serum vitamin E, calcium, ALT and urinary neopterin. These findings may form a basis for prospective interventional trials in this group of patients.

CD4+ T-lymphocytopenia and systemic immune activation in patients with primary and secondary liver tumours.

Using flow cytometry, we evaluated peripheral blood leucocyte subsets in 84 patients with primary and secondary liver cancer. The patients had significantly lower absolute (659+/-386 vs. 906+/-360 cells per microl, p=0.004) numbers of CD3+ CD4+, relative (9+/-5 vs. 12+/-4%, p=0.02) and absolute (154+/-115 vs. 221+/-83 cells per microl, p=0.02) numbers of CD8+ CD28+, absolute numbers of CD3+ and relative and absolute numbers of CD19+. Relative and absolute numbers of CD3+ DR+, CD3+ CD69+ and CD14+ CD16+ cells were significantly elevated in patients compared to controls. The phenotype was similar in 54 patients exposed to chemotherapy compared to 30 untreated patients. Urinary neopterin, a marker of systemic immune activation, was significantly higher in patients with liver tumours compared to controls. A negative correlation was observed between urinary neopterin and the absolute numbers of CD3+ CD4+ (Spearman rank correlation coefficient, rs = -0.54, p<0.0025) and CD19+ (rs = -0.49, p<0.01) in untreated patients. We conclude that, independently of prior chemotherapy, patients with liver present with markedly decreased numbers of CD3+ CD4+ lymphocytes as well as with other abnormalities of peripheral blood leukocyte phenotype. Similar to patients with human immunodeficiency virus infection, the decrease in CD3+ CD4+ lymphocytes is associated with systemic immune activation.

Intestinal permeability in patients with chemotherapy-induced stomatitis.

PURPOSE: Mucositis represents one of the most common side effects of chemotherapy, and may affect any part of the gastrointestinal tract, resulting in stomatitis, dysphagia, dyspepsia, or diarrhea. The aim of the present study was to evaluate intestinal permeability in patients with stomatitis during treatment with oral granulocyte-monocyte colony-stimulating factor (GM-CSF, Leucomax). METHODS: Ten patients with chemotherapy-induced stomatitis and 21 control cancer patients were included in the study. Intestinal permeability in patients with stomatitis was evaluated before and after the treatment with oral GM-CSF (200 micrograms for 4 consecutive days) by measuring urinary lactulose, D-xylose, and mannitol after oral challenge in collected urine using capillary gas chromatography. RESULTS: Mean grade of stomatitis (3, range 2-3) improved during treatment by a mean of 1 grade (range 0-2, sign test P < 0.05) with an improvement observed in eight of ten patients. Lactulose excretion, lactulose/mannitol, and lactulose/xylose ratios were markedly elevated in the patients with mucositis compared with 21 control cancer patients (1.60 +/- 1.04%, 0.2446 +/- 0.2937, and 0.3877 +/- 0.6808 vs 0.35 +/- 0.20%, 0.0332 +/- 0.0148, and 0.0255 +/- 0.0086, respectively, Mann Whitney U-test, P < 0.001). After treatment, lactulose excretion, lactulose/mannitol, and lactulose/xylose ratio decreased significantly (1.60 +/- 1.04 vs 0.63 +/- 0.42%; 0.2446 +/- 0.2937 vs 0.1303 +/- 0.1149; and 0.3877 +/- 0.6808 vs 0.1126 +/- 0.1146, respectively, P < 0.05). CONCLUSIONS: Lactulose excretion after oral challenge, lactulose/mannitol, or lactulose/xylose ratio may be useful markers for intestinal involvement in chemotherapy-induced mucositis. Improvement of oral mucositis was associated with a significant decrease of intestinal permeability to lactulose. Testing of intestinal permeability by the present method may be useful to evaluate the effect of therapeutic interventions in patients with chemotherapy-induced mucositis.

Bioanalysis of age-related changes of lipid metabolism in nonagenarians.

The aim of the present study was the bioanalysis of lipid metabolism in the aged patients and to study the relationship between these biochemical markers and longevity. Eleven nonagenarians, nine women and two men, aged 94+/-3 years and ten control patients, six women and four men, aged 84+/-5 years, followed at the Department of Metabolic Care and Gerontology, Charles University, Teaching Hospital entered the study. All subjects were self-sufficient, without major illnesses and free living. At the start of the project the free fatty acids (FFA), thiobarbituric reactive substances (TBARS), retinol, alpha tocopherol, ascorbic acid, cholesterol, triacylglycerols, phospholipids in serum, in lipoprotein fractions and fatty acids (FA) and phospholipids in erythrocyte membrane were determined. We used capillary gas chromatography for determination of fatty acids. Retinol and alpha tocopherol were analysed by reversed-phase high-performance liquid chromatography, other parameters were determined spectrophotometrically or spectrofluorometrically. We found significantly higher LDL polyunsaturated fatty acids (PUFA) 22:4n--3 (P=0.028) and 22:6n--3 (P=0.018) and a significant increase of HDL alpha tocopherol/cholesterol ratio (P=0.034) in nonagenarians. There were not any significant differences in erythrocyte membrane fatty acids and phospholipids. In serum we found significantly higher level of TBARS (3.22+/-1.22 vs 1.98+/-0.71 micromol/l, P=0.012) in nonagenarians, other parameters were not changed significantly. The higher concentration of PUFAs in LDL and alpha tocopherol in HDL might be parameters related to longevity.

Intraarterial chemotherapy of malignant melanoma metastatic to the liver.

BACKGROUND/AIMS: The prognosis of malignant melanoma metastatic to the liver is poor. The aim of the present report was to analyze retrospectively the effectiveness of regional chemotherapy and biologic therapy in patients with hepatic metastases of malignant melanoma. METHODOLOGY: Seven patients with hepatic metastases of malignant melanoma were treated by intraarterial administration of the combination of cisplatin, vinblastine and dacarbazine, or melphalan, with or without interleukin-2, interferon-alpha and interferon-gamma. RESULTS: The median survival of 4 patients with metastatic involvement initially limited to the liver is 19+ months in contrast to a median survival of 5 months in patients with concurrent extrahepatic disease. Intraarterial administration of cytokines led to an initial decrease in circulating lymphocyte numbers, with subsequent return to pretreatment levels, and to an increase in urinary neopterin, a marker of immune activation. CONCLUSIONS: Regional intraarterial administration of chemotherapy with or without cytokines may be effective for controlling hepatic metastases of malignant melanoma in patients with disease limited to the liver, but little benefit is evident in patients who present with concurrent extrahepatic disease.

Bioanalysis of PUFA metabolism and lipid peroxidation in coronary atherosclerosis.

Twenty eight men (age 34-77 years) who underwent an elective coronary angiography for coronary artery disease (CAD), were studied. They were divided into group A (luminal narrowing < 50%; n = 11) and group B (luminal narrowing > 50%; n = 17). Capillary gas chromatography was used for determination of fatty acids. Retinol and alpha-tocopherol were analyzed by reversed-phase high-performance liquid chromatography (HPLC), other parameters were determined spectrofluorometrically and spectrophotometrically. Severe coronary atherosclerosis in group B was associated with higher serum low density lipoprotein/high density lipoprotein (LDL/HDL) cholesterol ratio, triacylglycerols, and phospholipids (P < 0.05). Erythrocyte membrane fatty acids C14:0, C16:1 and C22:6n3 were significantly higher in group B (P < 0.05). We found significantly higher plasma polyunsaturated fatty acids (PUFA) C18:3n6 in group B, whereas plasma linoleic acid was not changed significantly. There was a significant increase of IDL-C18:0, LDL-C14:0 and HDL-C22:6n3 PUFA in group B. We conclude that disturbances in saturated fatty acids (SUFA) and PUFA metabolism are associated with coronary atherogenesis. Such abnormalities may include enhanced extrahepatic transport of C14:0 SUFA via LDL and its incorporation into cell membranes, and enhanced clearance of anti atherosclerotic C22:6n3 PUFA via serum HDL.

The association between specific nutritional antioxidants and manifestation of colorectal cancer.

Determination of specific antioxidants for examination of oxidative balance and immune responses may be of value in the early diagnosis of colorectal cancer. In the present report, we investigated urinary excretion of zinc, copper, and neopterin and serum levels of vitamins A, C, and E in 30 patients (age = 64 +/- 12 y) with colorectal cancer at the time of diagnosis and in 30 control subjects (age = 61 +/- 11 y) with benign disorders not associated with a systemic inflammatory response. Urinary excretion of zinc, copper, and neopterin was significantly elevated, and serum concentration of vitamin A was decreased in patients with colorectal cancer; these changes are characteristics of systemic immune activation. These phenomena may be of use for the detection of tumor progression and immune response to neoplasm.

[Monitoring phagocyte activity and free radicals in Helicobacter pylori infections]. / Monitorace aktivity fagocytu a volných radikálu u infekce Helicobacter pylori.

The presence of infection in organism induces a lot of Immunological reactions accompanied by creating free Radicals and reactive oxygen species (ROS). These play an important role in elimination of bacteria but also in tissue injury in surrounding. The aim of presented study was to focus on monitoring of ROS and phagocyte activation in subjects infected by Helicobacter pylori (HP) and thus to contribute to our knowledge of the etiopathogenic role of HP in inflammatory gastrointestinal diseases. The results report some differences, which interpretation opens a lot of questions showing how important of role ROS in HP infection may play.

[Dyslipoproteinemia in elderly patients]. / Dyslipoproteinémie u nemocných vyssího veku.

Dyslipoproteinaemia as one among classical risk factors of atherosclerotic cardiovascular diseases has been involved also in the aged. The predictive value of total cholesterol, LDL-cholesterol, HDL-cholesterol, triacylglycerols and lipoprotein (a) is preserved. There are several objective data from post-hoc analyses of prospective clinical studies AFCAPS/TexCAPS, 4S, CARE, LIPID a WOSCOPS, which addressed the need of treatment of dyslipoproteinaemia in the aged. The guidelines are not unique, but they stress an individual approach. We usually continue to treat genetic forms of dyslipidaemia. Candidates of treatment are also patients with diagnose of coronary heart disease (CHD) and sublinic form of CHD, where the treatment has been effective within two years and lead to decrease of CHD risk up to 45%. The individuals with CHD and other CHD risk factors absent would be treated less often. The diet is an basic treatment option of hypolipidemic intervention in the elderly. We do not omit exercise. The pharmacotherapy of dyslipidaemia is used for the individuals with high risk. We usually start with lower dose of fibrates or statins and monitor for adverse effects of such therapy.