Increased erythropoiesis and subclinical inflammation as part of the metabolic syndrome.

Recent studies have suggested the insulin resistance might be accompanied by enhanced erythropoiesis. We have examined this association in individuals with the metabolic syndrome (MS) who in addition to insulin resistance harbor a chronic low grade inflammation. This study is relevant because chronic inflammation might have a suppressive effect on erythropoiesis. 280 and 554 non-smoking women and men with respective age of 46.4+/-9.3 (mean+/-S.D.) and 44.0+/-11.0 years are included. A significant correlation was noted between the numbers of the components of the MS and the inflammatory biomarkers including the white blood cell count, high sensitivity C-reactive protein, fibrinogen concentrations and the erythrocyte sedimentation rate. In addition, a significant correlation (r=0.157, p=0.008) was noted between the number of components of the MS and the number of red blood cells in the peripheral blood in women. The same was true for men (r=0.192, p<0.0005). We conclude that enhanced erythropoiesis could be a new, hitherto unrecognized component of the MS. The enhanced erythropoiesis could give an erroneous impression of general "good" health in these individuals.

Obesity-related correlation between C-reactive protein and the calculated 10-y Framingham Coronary Heart Disease Risk Score.

OBJECTIVE: To clarify the role of body mass index (BMI, kg/m(2)) adjustment in predictive models for cardiovascular events that add high-sensitivity C-reactive protein (hs-CRP) to the 10-y Framingham Coronary Heart Disease Risk Score (FCRS). DESIGN: A cross-sectional study in a group of apparently healthy individuals. SUBJECTS: In all, 1512 apparently healthy individuals (955 men and 557 women) at a respective age of 49.7+/-10.6 and 50.6+/-9.6 y. RESULTS: The Pearson correlation between hs-CRP and the calculated 10-y FCRS was lower when adjusted for BMI. This reduction was especially noted in women where it dropped from 0.247 to 0.09. The dominant role of hs-CRP concentrations was also noted in a linear regression model, again, especially noted in women (drop of the standardized coefficient from 0.517 for BMI to 0.08 for the FCRS). CONCLUSIONS: The correlation between hs-CRP and the 10-y FCRS is partly related to the presence of obesity. We raise the possibility that the addition of BMI to the predictive model of FCRS might attenuate the cost-effectiveness of CRP measurements for this specific risk assessment.

Torsade de pointes induced by psychotropic drugs and the prevalence of its risk factors.

OBJECTIVE: To investigate all published case reports of torsade de pointes (TdP) induced by psychotropic drugs (PDs) in order to examine the prevalence of risk factors for TdP prior to the drug initiation. METHOD: We found 45 reports on 70 patients with TdP induced by PDs. Each report was analyzed for the presence of risk factors for TdP: female gender, heart disease, hypokalemia, high doses of offending agent, concomitant use of a QT interval prolonging agent, and a history of long-QT syndrome. RESULTS: Female gender was the most common risk factor for TdP (71.4%). The other studied risk factors were also frequently present (34.2-14.2%). Nearly all patients had at least one and 51 (73%) patients had >2 risk factors for TdP prior to PD initiation. CONCLUSION: We wish to raise the level of awareness of risk factors for TdP in the psychiatric community.

Serum lipids as minor determinants of the degree of erythrocyte adhesiveness/aggregation in the peripheral blood of individuals with low grade inflammation and moderately increased serum lipids.

Both lipids and inflammation sensitive proteins have been reported to affect the aggregation of red blood cells yet their relative importance in this regard have not been determined. We have included high sensitive C-reactive protein, erythrocyte sedimentation, fibrinogen concentrations as well as various serum lipid concentrations and the degree of erythrocyte adhesiveness/aggregation in the peripheral blood in a linear regression analysis. Partial Pearson correlation coefficients were included as well. In a group of 674 individuals with various atherosclerotic risk factors, low grade inflammation and moderately increased serum lipids, a relatively low correlation was noted between red blood cell adhesiveness/aggregation and triglycerides concentrations. A negative correlation was noted for HDL cholesterol. None of the lipid variables turned significant in the regression analysis. In a group of individuals with atherosclerotic risk factors, low grade inflammation and moderately increased serum lipids, the degree of erythrocyte adhesiveness/aggregation in the peripheral blood correlates much better with the presence of inflammation sensitive proteins than with the presence of increased lipid concentrations.

Comparative analysis between dextran sulfate adsorption and direct adsorption of lipoproteins in their capability to reduce erythrocyte adhesiveness/aggregation in the peripheral blood.

The purpose of this study was to compare the degree of erythrocyte adhesiveness/aggregation (EAA) reduction of two low-density lipoprotein (LDL) apheretic procedures, namely direct adsorption of lipoproteins (DALI) and dextran sulfate adsorption (DSA). A significant (P < 0.001) reduction of EAA was noted in six hypercholesterolemic patients who underwent a total of 40 apheretic sessions and no difference was noted in the degree of EAA reduction by the two techniques. Thus. being a real-time and point-of-care test, the erythrocyte adhesiveness/aggregation test can be applied in relevant situations of acute ischemia, where therapeutic LDL apheresis could improve the hemorheology of individuals with increased concentrations of cholesterol and inflammatory sensitive proteins.

Sex differences in the expression of haemorheological determinants in individuals with atherothrombotic risk factors and in apparently healthy people.

BACKGROUND: Increased red cell aggregation can be detrimental, leading to slow capillary blood flow and tissue hypoxaemia. Sex differences in the degree of erythrocyte adhesiveness/aggregation in the peripheral blood have not been clearly shown. OBJECTIVES: To determine whether there are sex differences in the expression of erythrocyte adhesiveness/aggregation in the peripheral blood in individuals with atherothrombotic risk factors and in apparently healthy people. METHODS: From a cohort of 965 participants in the Tel Aviv Medical Centre inflammation survey, 192 pairs of different sex were matched for age, body mass index, hip and waist circumferences, cardiovascular risk factors, and the intake of active cardiovascular drugs. RESULTS: Women had an enhanced degree of red cell aggregation (p < 0.0005) as well as increased concentrations of inflammation sensitive proteins including fibrinogen and C reactive protein. Women had a lower haemoglobin concentration than men, but this did not affect the degree of erythrocyte adhesiveness/aggregation. CONCLUSIONS: The significant increase in red blood cell adhesiveness/aggregation in the peripheral blood of women with atherothrombosis could be relevant to the more eventful course that some women experience during and following acute ischaemic disease.

Significant dominance of fibrinogen over immunoglobulins, C-reactive protein, cholesterol and triglycerides in maintaining increased red blood cell adhesiveness/aggregation in the peripheral venous blood: a model in hypercholesterolaemic patients.

BACKGROUND: It is not clear what is the relative importance of fibrinogen, immunoglobulins, highly sensitive C-reactive protein (hs-CRP), cholesterol and triglyceride concentrations on the appearance of aggregated red blood cells in the peripheral blood. DESIGN: Six hypercholesterolaemic patients undergoing regular LDL apheresis that were examined repeatedly before and following the procedure. RESULTS: We determined the degree of erythrocyte adhesiveness/aggregation in relation to the concentration of the above-mentioned macromolecules in 80 samples. In a linear logistic regression the respective R2 values for fibrinogen, total cholesterol, triglycerides, hs-CRP, IgG, IgM and IgA were 0.45 (P<0.0001), 0.2 (P<0.0001), 0.02 (P=0.02), 0.001 (P=NS) and 0.002 (P=NS), respectively. We further analyzed the potential of ApoA, ApoB and Lpa to participate in red cell adhesiveness/aggregation and found them to be not significant. CONCLUSIONS: In a milieu of adhesive macromolecules, lipids and inflammation-sensitive proteins including fibrinogen, total cholesterol, triglycerides, hs-CRP and immunoglobins G, M and A, fibrinogen has a dominant role in maintaining the red blood cell adhesiveness/aggregation in the peripheral venous blood. These findings are relevant for the research directed at finding new apheretic modalities to reduce the degree of red blood cell adhesiveness/aggregation in the peripheral blood.

Capillary and venous leukocyte adhesiveness/aggregation to differentiate between viral and bacterial infection.

BACKGROUND: A simple capillary leukocyte adhesiveness/aggregation test (CAPLAAT) might be helpful in determining the intensity of inflammation in acute viral and bacterial infections. PATIENTS AND METHODS: We included 30 patients with acute bacterial infections, 14 with viral infections as well as 48 healthy controls. The leukocyte adhesiveness/aggregation test (LAAT) test was performed using a simple slide test and image analysis. RESULTS: The CAPLAAT had a similar discrimination power between bacterial and viral infections as both the white blood cell count (WBC) and the erythrocyte sedimentation rate (ESR). It was more sensitive than the WBC and the ESR (77%, 68% and 66%, respectively) for the detection of bacterial infections and had a comparable negative predictive value. By analyzing the size distribution of the aggregated leukocytes, we found that a venous leukocyte adhesiveness/aggregation test (VLAAT) of four cells and more had the best positive predictive value (94%) and specificity (95%) for diagnosis of an acute bacterial infection (from all the acute phase response variables examined). CONCLUSION: The CAPLAAT might be attractive for the detection of inflammation and for the assessment of its severity at points of care where the services of a clinical laboratory are not available around the clock.

Prognostic implications of admission inflammatory profile in acute ischemic neurological events.

OBJECTIVE: To reveal the potential prognostic implications of admission inflammatory markers in patients with acute ischemic neurological events. PATIENTS AND METHODS: Sixty patients with an acute ischemic neurological event who were examined within 24 h from the appearance of symptomatology. We determined the high-sensitive C-reactive protein (hs-CRP) concentrations, erythrocyte sedimentation rate (ESR), fibrinogen concentrations and degree of erythrocyte adhesiveness/aggregation. RESULTS: A significant correlation was noted between baseline hs-CRP concentrations, ESR as well as adhesiveness/aggregation and the outcome of the ischemic neurological event as determined by the modified Rankin scale 8-12 months following the insult. CONCLUSION: Admission inflammatory markers have long-term prognostic implications in patients with acute ischemic neurological events. These findings are relevant in view of the new therapeutic interventions now available for reducing the inflammatory response.

The leukocyte adhesiveness/aggregation test (LAAT) conveys information of biological relevance and is not a result of chance collision. Something more than another hypothesis.

The leukocyte adhesiveness/aggregation test is a sensitive marker for the detection of inflammation and for the assessment of its intensity. This has been convincingly shown by several independent groups as well as in various models of infection/inflammation. However, it has not been settled whether the concomitant appearance of leukocytosis and aggregation is a result of chance collision or not. We recently examined a group of individuals with proven acute infection/inflammation who had absolutely the same number of white blood cells in the peripheral blood and found significantly enhanced leukocyte adhesiveness/aggregation in patients as opposed to control. These findings clearly demonstrate that the phenomenon of leukocyte adhesiveness/aggregation does not result from a simple chance collision. It probably conveys a message of biological relevance reflecting both the appearance of cell adhesive molecules during activation as well as the contribution of plasmatic sticky proteins.

The erythrocyte adhesiveness/aggregation test for the detection of an acute phase response and for the assessment of its intensity.

We have developed a simple slide test and image analysis to reveal the state of erythrocyte adhesiveness/aggregation in the peripheral blood of patients with various degrees of the humoral acute phase response. The significant correlation between the results of the erythrocyte adhesiveness/aggregation test (EAAT), the erythrocyte sedimentation rate and fibrinogen concentration support the notion that it is possible to use the EAAT as a marker for the intensity of the acute phase response. Within a group of 860 individuals, we were able to differentiate effectively between groups of patients with a different intensity of humoral acute phase response. The present study confirms previous observations that support the applicability of the EAAT to routine clinical practice.

Cutaneous involvement in a rare case of adult visceral leishmaniasis acquired in Israel.

Skin lesions are rare in visceral leishmaniasis, especially in Mediterranean countries. We describe an unusual case of visceral leishmaniasis in a 41-year-old man that began with a skin lesion. The parasites isolated from both the skin lesion and the bone marrow were typed as Leishmania donovani sensu stricto. This pathogen is not endemic in Israel or neighboring countries; its contribution to adult visceral leishmaniasis in Israel is summarized.

Retinal artery occlusion in a patient with factor V Leiden and prothrombin G20210A mutations.

Retinal artery occlusion is rare in young adults, and may be associated with hereditary thrombophilia. We present a 19-year-old male who was evaluated for central retinal artery occlusion and found to be homozygous for the factor V Leiden mutation and heterozygous for the prothrombin G20210A mutation. Anterior chamber paracenthesis resulted in dramatic improvement, but recurring loss of vision necessitated repeated paracenthesis and the addition of aspirin to standard anticoagulation treatment. The literature concerning hereditary thrombophilia and retinal artery occlusion is reviewed, and the synergistic effect of multiple risk factors is emphasized. Screening for hereditary thrombophilia should be considered for young people presenting with unexplained retinal artery occlusion.

Rheological determinants of red blood cell aggregation in diabetic patients in relation to their metabolic control.

AIMS: To determine whether increased red blood cell adhesiveness/aggregation in diabetic patients is related to the extent of their metabolic control. METHODS: We measured erythrocyte adhesiveness/aggregation in a group of 85 adult patients with diabetes mellitus by using citrated venous whole blood and a simple slide test. The erythrocyte adhesiveness/aggregation was determined by measuring the size of the spaces that are formed between the aggregated erythrocytes. We divided the patients into those with either low or high erythrocyte adhesiveness/aggregation values. RESULTS: The erythrocyte adhesiveness/aggregation values of the two groups differed significantly in terms of their fibrinogen concentration, erythrocyte sedimentation rate, high sensitive C-reactive protein (CRP), total cholesterol and triglyceride concentrations. There was no difference between the two groups regarding the concentrations of HbA(1c). Logistic regression was applied to construct a model to predict the belonging of a patient in the low or high erythrocyte adhesiveness/aggregation group. A linear regression was applied to construct a model to predict the erythrocyte adhesiveness/aggregation values. Both models turned out to include gender, age, fibrinogen, triglyceride, retinopathy, coronary artery disease and age and gender interaction. Neither HbA(1c) nor CRP entered the models. CONCLUSIONS: The degree of erythrocyte adhesiveness/aggregation and several variables of the acute-phase response in patients with diabetes mellitus are not directly related to the degree of metabolic control as evaluated by means of HbA(1c) concentration. Diabetic patients might benefit from rheological or anti-inflammatory interventions regardless of their metabolic control.

The picture of inflammation: a new concept that combines the white blood cell count and erythrocyte sedimentation rate into a new hematologic diagnostic modality.

BACKGROUND: Physicians who work in small clinics, far away from medical centers, cannot obtain relevant information regarding the acute phase response at low cost and real time. METHODS: We adopted a simple slide test and image analysis to determine the number of white blood cells in the peripheral blood, their degree of adhesiveness/aggregation as well as that of the red blood cells. Three independent observers scored the images into categories of no (1), mild (2), moderate (3) or severe (4) inflammation. RESULTS: A substantial interobserver agreement was noted for all three observers. No patient classified as having no (1) inflammation was given a score of moderate (3) or severe (4) inflammation and vice versa. The one-way analysis of variance (age- and gender-adjusted) confirmed that the data obtained from the image analyzer are significantly different between the above-mentioned four categories. CONCLUSIONS: It is possible to use a simple slide test and image analysis to discriminate effectively between various degrees of inflammation intensity. Since it is possible to send the pictures via telephone, Inter- or Intranet to a physician somewhere else, it might be attractive for medical personnel who work in small clinics not equipped with sophisticated laboratory facilities. This technique is currently being evaluated for possible Telemedicine and E-Health uses.

Increased erythrocyte adhesiveness and aggregation in peripheral venous blood of women with pregnancy-induced hypertension.

OBJECTIVE: To study the state of erythrocyte adhesiveness/aggregation in the peripheral blood of women with pregnancy-induced hypertension as well as in matched controls using a simple slide test and image analysis. METHODS: We recruited 25 women with pregnancy-induced hypertension. Twenty-five age- and gestational age-matched normotensive volunteers took part in the study and served as controls. Blood smears were evaluated by an image analysis system (INFLAMET). Quantitative measures of erythrocyte aggregation were used to describe the state of erythrocyte adhesiveness/aggregation such as vacuum radius, which measures the spaces between the aggregated erythrocytes. The number of participants was established by power analysis (given alpha of 0.05 and 80% power and considering a minimum difference to detect 4 microm in vacuum radius with a standard deviation of approximately 5). RESULTS: A significant (P =.002) increment in the state of erythrocyte aggregation was noted in the study group compared with the controls, the vacuum radius values being 16.1 +/- 1.3 and 10.3 +/- 1.2, respectively. Erythrocyte sedimentation rate but not fibrinogen concentration was significantly elevated in the study group. The increased aggregation correlated significantly with fibrinogen concentration, systolic, and diastolic blood pressures. CONCLUSION: We observed increased aggregability of red blood cells in hypertensive conditions of pregnancy. Our findings are significant in that they reveal blood pressure-related increment in red cell adhesiveness/aggregation despite there being no significant increment in clottable fibrinogen concentrations.

The state of leukocyte adhesiveness/aggregation in the peripheral blood of patients with type 2 diabetes and ischemic vascular disease.

White blood cells have a potential role in the pathogenesis of vasculopathy in diabetic patients. We studied the circulating peripheral blood in a cohort of patients with documented ischemic heart or brain disease with and without type 2 diabetes by means of image analysis and flow cytometry. Our study showed that the state of leukocyte adhesiveness/aggregation is slightly increased in those who had concomitant diabetes but that there was no difference regarding the expression of CD11b/CD18 and CD62L antigens on the surface of the peripheral blood white blood cells. The finding of a significantly increased number of white blood cells in the peripheral blood of patients with ischemic vascular diseases is important insofar as it is associated with a poorer prognosis.

A leukocyte and erythrocyte adhesiveness/aggregation test to reveal the presence of smoldering inflammation and risk factors for atherosclerosis.

The number of white blood cells in the peripheral blood, the presence of inflammation, increased fibrinogen concentrations and hyperlipidemia are established risk factors for atherosclerosis. It is known that hyperfibrinogenemia and hyperlipidemia cause increased erythrocyte aggregation, that inflammation will confer increased adhesive properties upon white blood cells and that the increased number of white blood cells can be detected in the peripheral blood. Therefore, we adopted a simple slide test and image analysis to determine the number of peripheral blood leukocytes and their state of adhesiveness/aggregation together with an erythrocyte adhesiveness/aggregation test to reveal the presence of these risk factors. The significant correlation between the fibrinogen and cholesterol concentration and the erythrocyte aggregation, between the white blood count and the number of leukocytes on the slides, and between the concentration of C-reactive protein and leukocyte adhesiveness indicate that we have succeeded in designing a simple one-step screening test that will identify patients at risk for atherosclerosis.

The feasibility of estimating the erythrocyte sedimentation rate within a few minutes by using a simple slide test.

The acute phase response is accompanied by the appearance of aggregated red blood cells in the peripheral blood. The Westergren erythrocyte sedimentation rate (ESR) is an indirect measurement of this enhanced aggregability. We adopted a simple slide test and image analysis to reveal the adhesiveness/aggregation of red blood cells. A significant correlation was found between the erythrocyte adhesiveness/aggregation test (EAAT) and the ESR. A predictive model for ESR based on EAAT and the age of the patients was created. This new approach will enable us to obtain within a few minutes a good estimate of whether a given individual has a mild moderate or significant acute phase response. With further development, we will be able to use a bedside small cartridge that will deliver the extrapolated ESR at low costs and within a couple of minutes.

Reduced leukocyte adhesiveness in response to viral versus nonviral infection/inflammation.

BACKGROUND: Viral infection differs from nonviral infection/inflammation by not producing a significant acute phase response. Since inflammation can cause increased adhesiveness of peripheral white blood cells (WBC), we compared these adhesive properties in individuals with viral infection to those with nonviral infection/inflammation. PATIENTS AND METHODS: The state of leukocyte adhesiveness/aggregation in the peripheral blood of patients with viral versus nonviral infection/inflammation was examined in 101 consecutive patients with acute febrile disease. RESULTS: A significant difference was found between the two groups; 13.6 +/- 7% for viral infection versus 22.8 +/- 8.5% for nonviral infection/inflammation (p < 0.0001). There was also a significant difference in the concentration of fibrinogen (361 +/- 109 mg/dl vs 554 +/- 172 mg/dl, p < 0.0001), and in the CD11b/CD18 cell surface expression (175 +/- 66 vs 210 +/- 100 in peripheral blood polymorphonuclear leukocytes). CONCLUSION: The results of this study could explain, at least in part, the differential adhesive behavior of the WBC in the peripheral blood in the two populations.