An overview of chronic urticaria

Acknowledging urticaria as a symptom of mast cell degranulation is stressed. The biology of the mast cell, and the recognized immunologic and non-immunologic mast cell secretagogues are individually discussed, along with mechanisms of activation and mediators released. The major, preformed mediator histamine in the skin produces a prototypic, short-lived urticaria, however, the clinical spectrum and pattern of “hives” indicate that other mediators contribute to the polymorphism and variable behavior of this symptom. The clinical assessment is almost exclusively restricted to the history and physical examination. Features to review and examine are presented. The cause of “acute” urticaria is identifiable (by history) in the majority of patients, and except for hives that accompany an anaphylactic reaction, these patients rarely present to the physician for care. The persistent, or “chronic” hiver whose history cannot elicit a cause, is rarely triggered by an individual trigger, despite extensive professional evaluation. Evidence to support changing the chronological, “acute” and “chronic” classification of urticaria to “identifiable” and “non-identifiable” triggered urticaria is discussed, as is the futility of extensive, costly laboratory work-ups. The natural history of urticaria reveals that management should be directed toward allowing the patient to maintain an acceptable quality of life (with or without some urticaria), until the episode resolves.     

Reference distributions for serum iron and transferrin saturation: a comparison of a large cohort to the world's literature

The appropriate clinical use of serum iron and transferrin saturation (TSAT) requires satisfactory reference intervals from birth to old age, and for males and females. This study identified 54 publications from 1974 to 2001 that met the criteria used in three prior meta-analyses, and these were analyzed statistically. A summary of our review is presented along with our reference population data on these measurements. This analysis places previous publications in perspective and suggests possible reasons for the observed differences. Previous studies of the individual analytes, serum iron, transferrin, and TSAT values agree with the reference ranges presented in this study, although the entire experience over time and between sexes has not been available before. Our 95% reference ranges are somewhat broader than those of the smaller studies, but they agree well with those of the larger ones.     

Effects of normal saline on endotracheal suctioning

This study was designed to determine the effects of saline solution administered prior to endotracheal suctioning by nurses working in intensive care on oxygenation, heart rate and long-term pulmonary hygiene. The study was carried out on an experimental basis in the Intensive Care Unit of a university hospital in Turkey. A total of 20 patients were included, who were mechanically ventilated because of pulmonary or cardiovascular problems or trauma. Data were collected using a data form. Each patient was monitored for 5 minutes following suctioning with or without saline solution and findings of heart rate, SpO2, and blood gas measurements were recorded. Data were analysed using percentage calculations, the student's t-test and the Friedman test. The study showed that most of the patients were between 60 and 69 years and were intubated because of respiratory insufficiency. Evaluation of blood gases following suctioning with or without saline solution showed partial decreases in pO2, pCO2, HCO3, and oxygen saturation (SaO2), which did not reach a significant level. No significant difference was found between pH levels recorded prior to and 5 minutes after suctioning without saline solution; however, the increase in pH following suctioning with saline solution was significant. Patients undergoing suctioning with saline solution exhibited significantly increased heart rates in the fourth and fifth minutes, whereas no increases were detected in these undergoing suctioning without saline solution. SpO2 values obtained by pulse oxymeter did not show significant differences. Saline solution administered with suctioning resulted in undesirable, although not significant, alterations in oxygen saturation and arterial blood gas levels.     

Leptin levels are appropriate for body mass index in older men who experience involuntary weight loss

OBJECTIVES: To determine the relationship between leptin and unintentional weight loss in older adults. DESIGN: Prospective cohort study over 2 years. SETTING: University-affiliated Veterans Affairs Medical Center. PARTICIPANTS: The subjects were 105 community-dwelling male veterans aged 65 and older who had participated in a prospective cohort study on nutrition and health conducted at the Veterans Affairs Puget Sound Health Care System from 1986 to 1989. MEASUREMENTS: Anthropometric data and fasting blood specimens were collected at baseline and annually for the subsequent 2 years. Stored blood specimens were analyzed for leptin, insulin, glucose, C-reactive protein, sex hormone binding globulin, and testosterone levels. RESULTS: Over 2 years, 75 men were weight stable (weight loss <4% of baseline) and 30 men had unintentional weight loss (weight loss>4% of baseline). The baseline body mass index (BMI) and leptin levels for the two groups were not statistically different. Positive correlations existed between leptin level and BMI at each time point for weight-stable and weight-loss subjects. Furthermore, a significant relationship existed between changes in leptin and changes in BMI over 1 year in multiple regression analysis (r =.436, P <.001 after the first year; and r =.630, P =.027 after the second year). CONCLUSIONS: Like in younger adults, plasma leptin levels remained proportional to BMI, and changes in BMI were accurately reflected by changes in leptin levels in older individuals. Fasting leptin levels did not predict involuntary weight loss over 2 years of follow-up.     

Apolipoprotein E polymorphism and serum lipid response to plant sterols in humans

BACKGROUND: The apolipoprotein E polymorphism may influence the absorption of cholesterol from the intestine and thus the response of serum cholesterol to diet. We decided to use plant sterols to investigate this and studied whether the cholesterol-lowering effect of plant sterols differed between subjects with different apolipoprotein E genotyes. DESIGN: Thirty-one healthy subjects with the E3/4 or E4/4 genotype and 57 with the E3/3 genotype were fed sterol-enriched margarine or control margarine for 3 weeks each in a blind randomised cross-over design. The sterol margarine provided 3.2 g of plant sterols daily, was low-fat, and had the same fatty acid composition as the control margarine. Subjects used the margarines as part of their usual diet, which was fairly low in cholesterol (mean, 175 mg per day). The mean (+/- standard deviation) age of the subjects was 25 (+/- 11) years. RESULTS: The apolipoprotein E polymorphism did not significantly affect the responses of total and LDL cholesterol. The decrease in total cholesterol was 0.36 mmol L-1 (7.4%) in the E3/3 subjects and 0.31 mmol L-1 (5.7%) in the epsilon 4 subjects (P = 0.50) and that in LDL cholesterol was 0.34 mmol L-1 (12.2%) in the E3/3 subjects and 0.32 mmol L-1 (9.8%) in the epsilon 4 subjects (P = 0.68). CONCLUSION: The serum cholesterol response to plant sterols is not affected by the apolipoprotein E polymorphism in healthy subjects who consume a low-cholesterol diet.     

Effect of metamizol on promyelocytic and terminally differentiated granulocytic cells. Comparative analysis with acetylsalicylic acid and diclofenac

Metamizol is an analgesic and antipyretic agent that can induce agranulocytosis in certain patients. However, its effects on granulocyte viability and differentiation have been poorly evaluated. Here we analysed the effects of metamizol and its active metabolite, 4-methylaminoantipyrine (MAA), on the viability of HL60 promyelocytes and their dimethyl sulphoxide-induced differentiated granulocytes. Metamizol and MAA at 75 microM (above the peak of plasmatic concentration after 2g intake) did not alter granulocytic differentiation of HL60 cells. Only at concentrations above 100 microM, well over the pharmacological range, metamizol-induced apoptosis in about 30% of the HL60 promyelocytes, while HL60-granulocytic terminally differentiated cells were more resistant to this apoptotic action. When the effects of metamizol were compared with those of acetylsalicylic acid (ASA) and diclofenac on cell viability, at equivalent concentrations used in analgesic and antipyretic therapy (75 microM for metamizol, and ASA and 3 microM for diclofenac) their apoptotic effects were similar. Again, the HL60 promyelocytes were more sensitive to apoptosis than granulocytic differentiated cells, as measured by the percentage of sub-G(1) cells detected by flow cytometry and by determination of caspase activity as a function of poly(ADP-ribose) polymerase cleavage. Furthermore, when human blood-derived granulocytes were treated with metamizol, MAA, and ASA at 75 microM or diclofenac at 3 microM, less than 10% of apoptotic granulocytes were detected, whereas at toxicological/suprapharmacological concentrations (10mM), about 90% of granulocytes were apoptotic. These results demonstrate that metamizol, MAA, ASA, and diclofenac, at pharmacological concentrations, neither affect the granulocytic differentiation process nor induce relevant apoptosis on terminally differentiated granulocytes.     

Tumor acidity, ion trapping and chemotherapeutics. I. Acid pH affects the distribution of chemotherapeutic agents in vitro

Resistance to anti-cancer chemotherapies often leads to regional failure, and can be caused by biochemical and/or physiological mechanisms. Biochemical mechanisms include the overexpression of resistance-conferring proteins. In contrast, physiological resistance involves the tumor microenvironment, and can be caused by poor perfusion, hypoxia and/or acidity. This communication investigates the role of tumor acidity in resistance to a panel of chemotherapeutic agents commonly used against breast cancer, such as anthracyclines, taxanes, anti-metabolites and alkylating agents. The effects of pH on the cytotoxicity of these agents were determined, and ion trapping was confirmed by monitoring the effect of pH on the cellular uptake of radiolabeled anthracyclines. Furthermore, pH-dependent cytotoxicity and uptake were compared between parental drug sensitive MCF-7 cells and variants overexpressing p-glycoprotein (MDR-1) and Breast Cancer Resistance Protein. These data indicate that the magnitude of physiological resistance from pH-dependent ion trapping is comparable to biochemical resistance caused by overexpression of drug efflux pumps. Hence, microenvironment-based ion trapping is a significant barrier to anthracycline-based chemotherapy and can itself be a therapeutic target to enhance the efficacy of existing chemotherapies.     

AT1 antagonism by eprosartan lowers heart rate variability and baroreflex gain

INTRODUCTION: Blockade of the renin-angiotensin system (RAS) by ACE inhibitors has been demonstrated to reduce total mortality in cardiovascular diseases. This advantage was attributed in part to changes of autonomic cardiovascular control, exemplified by an increase of heart rate variability (HRV) and baroreflex gain (BRG). We sought to assess the effects of the angiotensin type 1 (AT1) receptor blocker eprosartan on HRV and BRG. MATERIALS AND METHODS: In a double-blind randomized cross-over design 25 young males took eprosartan (600 mg/day) and placebo each for a period of 7 days with a wash-out period of at least 4 weeks in between. At the end of the intake phases simultaneous recordings of arterial blood pressure (AP; Finapres) and electrocardiogram (ECG) were taken. Power spectra of HRV and arterial blood pressure variability (APV) were calculated by fast Fourier transform (FFT) and served to calculate BRG. Ang-II levels were measured by radioimmunoassay. RESULTS: Eprosartan tended to lower mean AP, it slightly increased heart rate (HR) (p<0.05), and markedly increased circulating Ang-II levels (p<0.01). Eprosartan diminished the total power of HRV (p<0.05) and the BRG (p<0.01). The low/high frequency (LF/HF) ratio of HRV and the APV were not altered. CONCLUSIONS: AT1 antagonism by eprosartan lowers heart rate variability and baroreflex gain. We speculate that these findings are due to the marked increase in circulating angiotensin II (Ang II). Further studies are needed to clarify whether angiotensin type 1 (AT1) blockers with potential actions inside the blood-brain barrier (BBB) may have different effects on HRV and BRG.     

Clinical significance of detecting elevated serum DcR3/TR6/M68 in malignant tumor patients

TR6/DcR3/M68 is a soluble receptor that belongs to the TNF receptor family. It is expressed in malignant cells of several tumor types and has been postulated to help tumor cells to gain survival advantage by inhibiting apoptosis and by interfering with immune surveillance. In our study, we assessed for the first time serum TR6 in tumor patients to explore its diagnostic and prognostic value. We examined serum TR6 levels with ELISA in 146 tumor patients, 19 patients with acute infection, 5 patients with liver cirrhosis and 29 healthy individuals. TR6 expression in tumor mass was studied with immunohistochemistry. TR6 gene copy number in tumor tissues was evaluated by real time PCR. Ninety-seven point nine percent (47 of 48 cases) of healthy individuals and patients with acute infection were serum TR6-negative. In contrast, 56.2% (82 of 146 cases) of the tumor patients were serum TR6-positive. Almost all serum TR6-positive individuals (98.8%, 82 out of 83 cases) had malignancy, excluding the cases of liver cirrhosis. In gastric carcinomas, serum TR6 levels were closely correlated with tumor differentiation status and TNM classification. Tumor mass was the source of serum TR6 because its levels decreased drastically after curative tumor resection. TR6 gene amplification occurred in about half of liver carcinomas, but not in gastric or pancreatic carcinomas, indicating plural mechanisms of TR6 upregulation. Our study demonstrated that serum TR6 should be considered as a novel parameter for the diagnosis, treatment and prognosis of malignancies.     

Induction of apoptosis in estrogen dependent and independent breast cancer cells by the marine terpenoid dehydrothyrsiferol

Breast cancer (BCA) represents the highest incidence of death in 35- to 60-year-old women. Above all, hormone unresponsive BCA is still associated with poorer prognosis than hormone receptor expressing malign, mammary tumors. There is a consistent need for effective compounds to treat especially the first variant of this disease. Therefore, we investigated the cytotoxic effects of the marine polyether triterpenoid dehydrothyrsiferol (DT) in four BCA cell lines. Annexin V labeling revealed higher rates of DT-induced apoptosis in hormone insensitive than in estrogen receptor expressing cells. Flow cytometric analysis of combined DNA fragmentation and total DNA labeling allowed us to ascribe apoptotic cells to their cell cycle stage. Although, high cell mortality was detected in mitogen dependent G(1)-phase, time, concentration, and cell line dependent populations of apoptotic cells were also found to be of S-phase and G(2)/M-phase origin. These results suggest that the induction of apoptosis by DT might be transduced through more than one effector pathway. Cell cycle distributions and 5-bromo-2'-deoxyuridine incorporation varied in a treatment dependent manner and differed from control experiments with colchicine and doxorubicin which exclude that DT functions as a mitosis inhibitor. In summary, we propose that DT might be an interesting candidate for an antitumor drug development regimen.