Association of childhood socioeconomic status with adulthood maximal exercise blood pressure: the Cardiovascular Risk in Young Finns Study.

PURPOSE: Socioeconomic status has been related to resting blood pressure (BP) levels at different stages of life. However, the association of childhood socioeconomic status (SES) and adulthood exercise BP is largely unknown. Therefore, we studied the association of childhood SES with adulthood maximal exercise BP. MATERIALS AND METHODS: This investigation consisted of 373 individuals (53% women) participating in the Cardiovascular Risk in Young Finns Study who had data concerning family SES in childhood (baseline in 1980, at age of 6-18 years) and exercise BP response data in adulthood (follow-up in adulthood in 27-29 years since baseline). A maximal cardiopulmonary exercise test with BP measurements was performed by participants, and peak exercise BP was measured. RESULTS: In stepwise multivariable analysis including childhood risk factors and lifestyle factors (body mass index, systolic BP, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, insulin, fruit consumption, vegetable consumption, and physical activity), lower family SES in childhood was associated with higher maximal exercise BP in adulthood (ß value ± SE, 1.63 ± 0.77, p = 0.035). The association remained significant after further adjustment with participants SES in adulthood (ß value ± SE, 1.68 ± 0.65, p = 0.011) and after further adjustment with adulthood body-mass index, systolic BP, maximal exercise capacity, and peak heart rate in exercise (ß value ± SE, 1.25 ± 0.56, p = 0.027). CONCLUSIONS: These findings suggest that lower childhood family SES is associated with higher maximal exercise BP in adulthood.

Limited data are available about the association of childhood socioeconomic status and adulthood exercise blood pressure.We prospectively examined whether childhood socioeconomic status is associated with adulthood exercise blood pressure in 373 participants aged 6­18 years at baseline (1980) from the longitudinal Cardiovascular Risk in Young Finns cohort study.In multivariable analysis, including childhood cardiovascular risk factors and lifestyle factors, lower family socioeconomic status in childhood was associated with higher maximal exercise blood pressure in adulthood.The association remained significant after further adjustment with participants socioeconomic status in adulthood and also after further adjustment with adulthood body mass index, systolic blood pressure, maximal exercise capacity and peak heart rate in exercise.Low childhood socioeconomic status predicted also higher risk of exaggerated exercise blood pressure response in adulthood, although this finding was diluted to non-significant after adjustment with adulthood body mass index and systolic blood pressure.These findings suggest that lower childhood family socioeconomic status is associated with higher maximal exercise blood pressure in adulthood.

Association of lifetime blood pressure with adulthood exercise blood pressure response: the cardiovascular risk in young Finns study.

PURPOSE: Elevated blood pressure (BP) in childhood has been associated with increased adulthood BP. However, BP and its change from childhood to adulthood and the risk of exaggerated adulthood exercise BP response are largely unknown. Therefore, we studied the association of childhood and adulthood BP with adulthood exercise BP response. MATERIALS AND METHODS: This investigation consisted of 406 individuals participating in the ongoing Cardiovascular Risk in Young Finns Study (baseline in 1980, at age of 6-18 years; follow-up in adulthood in 27-29 years since baseline). In childhood BP was classified as elevated according to the tables from the International Child Blood Pressure References Establishment Consortium, while in adulthood BP was considered elevated if systolic BP was ≥120 mmHg or diastolic BP was ≥80 mmHg or if use of antihypertensive medications was self-reported. A maximal cardiopulmonary exercise test with BP measurements was performed by participants in 2008-2009, and exercise BP was considered exaggerated (EEBP) if peak systolic blood pressure exceeded 210 mmHg in men and 190 mmHg in women. RESULTS: Participants with consistently high BP from childhood to adulthood and individuals with normal childhood but high adulthood BP had an increased risk of EEBP response in adulthood (relative risk [95% confidence interval], 3.32 [2.05-5.40] and 3.03 [1.77-5.17], respectively) in comparison with individuals with normal BP both in childhood and adulthood. Interestingly, individuals with elevated BP in childhood but not in adulthood also had an increased risk of EEBP [relative risk [95% confidence interval], 2.17 [1.35-3.50]). CONCLUSIONS: These findings reinforce the importance of achieving and sustaining normal blood pressure from childhood through adulthood.

Pulse wave velocity is related to exercise blood pressure response in young adults. The Cardiovascular Risk in Young Finns Study.

Purpose: High pulse wave velocity (PWV), a marker of increased arterial stiffness, and an exaggerated exercise blood pressure (EEBP) response during an exercise test have both been related to an increased risk of hypertension and cardiovascular events. Contradictory results have been published about the association between these two parameters, and their relation in healthy young adults is unknown.Materials and methods: This study consisted of 209 young adults (mean age 38 years) who participated in the ongoing Cardiovascular Risk in Young Finns Study between 2007 and 2009. We measured resting PWV with impedance cardiography in 2007, and participants performed a maximal cardiopulmonary exercise test with blood pressure (BP) measurements at rest, during exercise and during recovery in 2008-2009.Results: High PWV (≥age- and sex-specific median) at baseline was associated with EEBP (SBP >210 mmHg for men and >190 mmHg for women) an average of 14 months later and with systolic BP during different stages of exercise from rest to peak and recovery (during peak exercise, ß ± SE was 4.1 ± 1.1, p < 0.001). The association between high PWV and systolic BP remained after adjustment for traditional cardiovascular risk factors and other exercise parameters (during peak exercise, ß ± SE was 2.3 ± 1.1, p = 0.04).Conclusions: Increased arterial stiffness predicts EEBP during a maximal exercise test in young adults during all stages of exercise from rest to peak and recovery. PWV could provide an additional tool for EEBP risk evaluation.

Determinants of exercise peak arterial blood pressure, circulatory power, and exercise cardiac power in a population based sample of Finnish male and female aged 30 to 47 years: the Cardiovascular Risk in Young Finns Study.

BACKGROUND: Novel parameters derived from peak maximal oxygen uptake (VO2) and exercise arterial blood pressure, such as peak circulatory power (CP) and exercise cardiac power (ECP), can be used in the risk assessment of cardiovascular disease and stroke. However, the determinants of these factors are poorly characterized in the general population. METHODS: We assessed peak arterial blood pressure, CP and ECP with standardized cardiopulmonary exercise test (CPET) on 281 female and 257 male participants of the Cardiovascular Risk in Young Finns Study. The subjects were aged 30-47 years. Peak VO2 as well as systolic and diastolic arterial blood pressures were measured to calculate peak mean arterial pressure, CP and ECP. These parameters were assessed for correlation with sex, age, height, weight, waist-to-hip ratio, smoking, physical activity index (PAI), fasting insulin and glucose levels as well as the use of antihypertensive treatment. RESULTS: Sex, age and weight explained 36% of the variation in peak systolic blood pressure, and these factors in combination with height and the use of antihypertensive treatment explained 13% of the variation in peak diastolic blood pressure. Sex, height, weight, waist-to-hip ratio, PAI and smoking explained 49% - 52% of the variation in peak CP. Sex, age, height, weight, waist-to-hip ratio, PAI, smoking and insulin levels explained 21% - 49% of variation in ECP. CONCLUSIONS: Subject demographics and lifestyle-related factors should be taken into account when exercise blood pressure response, CP and ECP are used to evaluate patients' cardiac function in CPET.

Coronary artery disease-associated locus on chromosome 9p21 and early markers of atherosclerosis.

BACKGROUND: Genome-wide association studies have recently identified a locus on chromosome 9p21 that influences risk of coronary artery disease (CAD). The effect of the locus on early markers of atherosclerosis is unknown. We examined its association with carotid intima-media thickness (CIMT) and brachial flow-mediated dilatation (FMD). METHODS AND RESULTS: We genotyped 2277 individuals, age 24 to 39 years, from the Cardiovascular Risk in Young Finns Study with CIMT and FMD measurements and 1295 individuals, age 46 to 76 years, from the Health 2000 Survey with CIMT for rs1333049, the chromosome 9p21 variant showing the strongest association with CAD. Both mean and maximum CIMT were significantly higher (P<0.001) in the older subjects of the Health 2000 Survey compared with the Young Finns Study. However, there was no association of the rs1333049 genotype with either mean or maximum CIMT at either age (P=0.959 and 0.977 for the 2 phenotypes in the Young Finns Study and P=0.714 and 0.725 in the Health 2000 Survey). Similarly, there was no association of the locus with variation in FMD in the Young Finns cohort (P=0.521). CONCLUSIONS: The chromosome 9p21 locus does not influence CAD risk through a mechanism that also affects CIMT or induces early changes in FMD.

Elevated serum neuron-specific enolase in patients with temporal lobe epilepsy: a video-EEG study.

Established markers of brain damage, neuron-specific enolase (NSE) and S-100b protein (S-100), may increase after status epilepticus, but whether a single tonic-clonic or complex partial seizure induces elevation of these markers is not known. Furthermore, it is unclear whether the risk of seizure-related neuronal damage in temporal lobe epilepsy (TLE) differs from that in extratemporal lobe epilepsies (XTLE). The aim of this study was to analyze NSE and S-100 in patients with TLE and XTLE after acute seizures. The levels of NSE and S-100 were measured in serum before (0h) and at 3, 6, 12, and 24h after acute seizures in 31 patients during inpatient video-EEG monitoring. The patients were categorized into the TLE and the XTLE group based on video-EEG recordings and MRI findings. Fifteen patients had TLE and 16 XTLE. Index seizures were mainly complex partial seizures (n=21). In TLE mean+/-S.D. values for NSE levels (mug/L) were 8.36+/-2.64 (0h), 11.35+/-3.84 (3h), 13.48+/-4.49 (6h), 12.95+/-5.46 (12h) and 10.33+/-3.13 (24h) (p=0.006, ANOVA). In XTLE the changes were not significant (p=0.3). There was less increase in the levels of S-100 in TLE (p=0.05) and no significant change in XTLE (p=0.4). The levels of markers of neuronal damage were increased in patients with TLE, not only after tonic-clonic but also after complex partial seizures. These data suggest that TLE may be associated with brain damage.

Cardiorespiratory Fitness and Risk of Fatty Liver: The Young Finns Study.

PURPOSE: Fatty liver is an expanding health concern associated with metabolic disturbances and increased risk of cardiovascular disease. Experimental studies in animals have shown associations between fatty liver and cardiorespiratory fitness but limited data exist in humans. The aim of this study was to analyze the links between cardiorespiratory fitness and fatty liver in a population-based sample of adults. METHODS: Participants were 463 adults (48% men) from the Cardiovascular Risk in Young Finns Study. Cardiorespiratory fitness was measured with a cycle ergometer exercise test as peak oxygen uptake (V˙O2peak [mL·kg·min]) in 2008 to 2009. Hepatic ultrasonographic imaging was performed in 2011 to determine fatty liver. RESULTS: Cardiorespiratory fitness was associated with lower risk of fatty liver (1 mL·kg·min increase in V˙O2peak: risk ratio, 0.90; 95% confidence interval, 0.88-0.93, P < 0.0001; adjusted for age and sex). This association remained significant after further adjustments with physical activity, adiposity, smoking, alcohol consumption, serum lipids, insulin, glucose, and C-reactive protein. Participants who were obese (waist circumference, >80 cm in women and >94 cm in men) but fit (V˙O2peak in the upper age- and sex-specific median) had lower prevalence of fatty liver than participants who were obese and unfit (below median), (11.7% vs 34.8%, P = 0.0003). CONCLUSIONS: In a population-based sample of adults, cardiorespiratory fitness is strongly, inversely and independently related with the risk of fatty liver. Importantly, the association is evident also among obese.

CD80 antigen expression as a predictor of ex vivo chemosensitivity in chronic lymphocytic leukemia.

We investigated the correlation between expression of 31 surface membrane antigens and chemosensitivity of peripheral blood mononuclear cells from 36 patients with CLL. The sensitivity of CLL cells to nine drugs (2'-chlorodeoxyadenosine, cisplatin, chlorambucil, cyclosporin A, doxorubicin, fludarabine, prednisolone, verapamil and vincristine) and two types of irradiation (gamma and UV-irradiation) was determined from dose-response curves of 4-day cultures ex vivo. The results indicated that the CLL cases responding to purine analogs (2'-chlorodeoxyadenosine and fludarabine) can be identified according to CD80 expression: all resistant cases had low or negative CD80 expression. No other correlations were revealed. CD80 may be a surrogate chemosensitivity marker for purine analogs.

The balance of inhibitory and excitatory cytokines is differently regulated in vivo and in vitro among therapy resistant epilepsy patients.

PURPOSE: Excessive neuronal activity and seizures directly stimulate cytokine expression. In this study we investigated cytokine production in circulating blood and peripheral blood mononuclear cells (PBMC) in order to assess the cellular origin of these cytokines in patients with therapy resistant epilepsy. METHODS: We compared the levels of plasma IL-1beta, IL-1Ra and IL-6 in 10 patients with therapy resistant localization-related epilepsy and in healthy volunteers. The spontaneous and exogenously stimulated production of these cytokines was studied in PBMC cultures using EIA. Moreover, cell-specific cytokine production was studied using flow cytometry. RESULTS: Highly pro-inflammatory cytokine profile (high IL-6, low IL-1Ra and low IL-1Ra/IL-1beta ratio) was observed in plasma from patients with epilepsy. Spontaneous and LPS stimulated cytokine release was similar in PBMC cultures of patients and control subjects. When cells were stimulated with OKT3 the cytokine response profiles in patients with epilepsy were almost opposite (anti-inflammatory) to the profile which was observed in circulating blood. Low IL-6 was observed in cell cultures of patients when stimulated with PDBu + A23187. Flow cytometric analysis revealed that the percentages of IL-1beta, IL-1Ra and IL-6 positive monocytes were similar in patients and control subjects. CONCLUSIONS: Patients with therapy resistant epilepsy display a pro-inflammatory profile of plasma cytokines without any evidence of increased production from PBMC. These results suggest that the most likely origin for these cytokines is the brain, where cytokines can exert neuromodulatory functions.

The effect of mannan-binding lectin variant alleles on coronary artery reactivity in healthy young men.

Mannan-binding lectin (MBL) is a serum acute-phase protein and a complement component secreted by the liver. Its deficiency caused by point mutations in the MBL gene has recently been associated with severe atherosclerosis. In this study, we investigated the effect of MBL variant alleles on coronary artery reactivity, which is an early marker of coronary dysfunction and predicts the development of atherosclerosis and coronary artery disease. The study population consisted of 51 apparently healthy, normo- or mildly hypercholesterolemic young men. Myocardial blood flow was measured at baseline and during adenosine-induced hyperemia with positron emission tomography (PET), and MBL genotyping was performed using restriction fragment-length polymorphism. As a result, MBL variant alleles had no effect on coronary artery reactivity. This finding suggests that MBL deficiency is not an independent risk factor for coronary dysfunction and early atherogenic changes but rather a co-factor in the development of atherosclerosis. Thus, the connection of MBL variant alleles with environmental risk factors in atherosclerosis should further be assessed.

Polymorphism in the IL10 promoter region and early markers of atherosclerosis: the Cardiovascular Risk in Young Finns Study.

OBJECTIVE: Inflammatory factors modify the risk of coronary heart disease. Pleiotropic cytokine interleukin-10 (IL-10) has been suggested as modifying risk for atherosclerosis. Promoter region genetic polymorphism of IL-10 gene (IL10) is known to be associated with the variation of IL-10 production. We investigated whether single-base exchange polymorphisms -1082 G>A (rs1800896), -819 C>T (rs1800871) and -592 C>A (rs1800872) at IL10 gene are associated with risk factors and early markers of atherosclerosis in young subjects. METHODS AND RESULTS: As a part of the Cardiovascular Risk in Young Finns Study, we determined carotid artery compliance (CAC), stiffness index (SI) and Young's elastic modulus (YEM), intima media thickness (IMT), IL10 genotype and atherosclerosis risk parameters for 2260 subjects aged 24-39 years. In male subjects CAC was lower in carriers of IL-10 high- to intermediate-producer haplotype -1082 G; -819 C; -592 C (GCC+, 1.96+/-0.67) than in noncarriers (GCC-, 2.10+/-0.62, %/10 mmHg, mean+/-SD, p=0.0010). An inverse association was observed in SI (GCC+, 5.76+/-2.12 and GCC-, 5.26+/-1.46, p=0.0034) and YEM (GCC+, 347+/-165 and GCC-, 305+/-110, mm Hg.mm, p=0.0005). Associations remained significant when adjusted to age, BMI, smoking and serum lipids as well as fasting glucose and insulin levels. The genetic effect size for these parameters was not significant in women. CONCLUSIONS: IL10 promoter region high- to intermediate-producer haplotype GCC associates with decreased arterial elasticity in men. These results are in disconcordance with the supposed antiatheromatous properties of IL-10.

Lifetime risk factors and arterial pulse wave velocity in adulthood: the cardiovascular risk in young Finns study.

Limited and partly controversial data are available regarding the relationship of arterial pulse wave velocity and childhood cardiovascular risk factors. We studied how risk factors identified in childhood and adulthood predict pulse wave velocity assessed in adulthood. The study cohort consisted of 1691 white adults aged 30 to 45 years who had risk factor data available since childhood. Pulse wave velocity was assessed noninvasively by whole-body impedance cardiography. The number of conventional childhood and adulthood risk factors (extreme quintiles for low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, body mass index, and smoking) was directly associated with pulse wave velocity in adulthood (P=0.005 and P<0.0001, respectively). In multivariable regression analysis, independent predictors of pulse wave velocity were sex (P<0.0001), age (P<0.0001), childhood systolic blood pressure (P=0.002) and glucose (P=0.02), and adulthood systolic blood pressure (P<0.0001), insulin (P=0.0009), and triglycerides (P=0.003). Reduction in the number of risk factors (P<0.0001) and a favorable change in obesity status (P=0.0002) from childhood to adulthood were associated with lower pulse wave velocity in adulthood. Conventional risk factors in childhood and adulthood predict pulse wave velocity in adulthood. Favorable changes in risk factor and obesity status from childhood to adulthood are associated with lower pulse wave velocity in adulthood. These results support efforts for a reduction of conventional risk factors both in childhood and adulthood in the primary prevention of atherosclerosis.

Cerebrospinal fluid tau as a marker of neuronal damage after epileptic seizure.

PURPOSE: Whether repeated brief seizures can cause neuronal damage is controversial. Cerebrospinal fluid (CSF) total tau (T-tau) and phosphorylated tau (P-tau) measurements have been suggested for the diagnosis of Alzheimer's disease, and T-tau may also be a marker of axonal damage and neuronal degeneration. We studied T-tau and P-tau levels and P-tau/T-tau ratio in CSF after epileptic seizures in order to determine whether they are increased after seizures. METHODS: A total of 54 patients with tonic-clonic or partial secondarily generalized seizures due to various etiologies were studied and CSF obtained within 48h after the seizure. RESULTS: There were no statistical differences in the levels of T-tau (p=0.09, ANOVA) or P-tau (p=0.60) between different etiologic groups or controls. No patients with epilepsy of unknown origin had abnormal CSF T-tau whereas 11 patients with acute or remote symptomatic seizures had abnormal T-tau levels and the P-tau/T-tau ratio showed significant differences between the groups and controls (p=0.003). CONCLUSIONS: Epileptic seizures with unknown etiology did not increase CSF tau levels. Abnormal tau levels were associated with either acute or remote symptomatic seizures with known etiology. The presence of elevated CSF tau increases the probability of symptomatic cause in a patient with a seizure.

Polymorphism in the IL6 promoter region is associated with the risk factors and markers of subclinical atherosclerosis in men: The Cardiovascular Risk in Young Finns Study.

OBJECTIVE: Inflammatory factors modify the risk of coronary heart disease. Promoter region genetic polymorphism of inflammatory cytokine interleukin-6 (IL6 -174 G>C) is associated with the variation of IL-6 production. We investigated whether IL6 -174 G>C associates with the risk factors of atherosclerosis and carotid artery compliance (CAC) in young subjects. METHODS AND RESULTS: As part of the Cardiovascular Risk in Young Finns Study, we performed carotid artery ultrasound examinations, IL6 -174 G>C genotyping and coronary heart disease risk factor determination for 2228 subjects aged 24-39 years. In men CAC was higher for IL6 -174 GG (2.10+/-0.65) than for GC (2.00+/-0.68) or CC (1.95+/-0.63, %/10mmHg, mean+/-S.D., p=0.0221). A similar association was observed for HDL cholesterol (GG 1.22+/-0.29, GC 1.15+/-0.27 and CC 1.14+/-0.28mmol/L, p=0.0015) and apolipoprotein A1 (apoA1) (GG 1.44+/-0.21, GC 1.40+/-0.20, CC 1.38+/-0.21mmol/L, p=0.0118). The opposite genotype effect was present in systolic (GG 127+/-13.1, GC 129+/-13.1, CC 130+/-14.3mmHg, p=0.0382) and diastolic blood pressure (GG 73.8+/-9.14, GC 75.1+/-8.68, CC 75.9+/-9.70mmHg, p=0.0374). The genetic effect size for these parameters was not significant in women. CONCLUSIONS: IL6 -174 allele G homozygozity associates with beneficial profile of early predictors of atherosclerosis such as high CAC, HDL-C and apoA1 as well as low systolic and diastolic blood pressure in men.

Interleukin-6 promoter polymorphism and cardiovascular risk factors: the Health 2000 Survey.

OBJECTIVE: Inflammatory factors modify the risk of cardiovascular diseases and atherosclerosis. The single base genetic polymorphism in the promoter region of inflammatory cytokine interleukin-6 (IL6 -174 G>C, rs1800795) is associated with the variation of IL-6 production. The aim of this study was to investigate whether IL6 -174 G>C is associated with the risk factors and early markers of atherosclerosis. METHODS: As part of Finnish Health 2000 Study, we performed carotid artery ultrasound examinations, IL6 -174 G>C genotyping and cardiovascular risk factor determination for 1334 subjects aged 46-76 years. RESULTS: In men, serum total cholesterol was higher in IL6 -174 GG (5.70+/-0.88mmol/L) than in the GC (5.51+/-0.98mmol/L) or CC (5.38+/-0.97mmol/L, mean+/-SD, p=0.0059) groups. The same order was seen in LDL-C (GG 3.64+/-0.83mmol/L, GC 3.41+/-0.88mmol/L, CC 3.30+/-0.91mmol/L, p=0.0017). The opposite association was observed with plasma fasting glucose levels (GG 5.93+/-0.97, GC 6.11+/-1.34, CC 6.34+/-1.59mmol/L, p=0.043) and BMI (GG 26.8+/-3.42, GC 27.5+/-4.32, CC 28.0+/-3.81kg/m(2), p=0.027). IL6 -174 allele C homozygous men indicated a trend towards higher systolic blood pressure. IL6 -174 G>C was not associated with carotid artery compliance, intima media thickness or CRP. The effect size of IL6 -174 G>C on cardiovascular risk factors was not significant in women. These results suggest that IL6 -174 G>C modifies the levels of several metabolic risk factors of atherosclerosis in men.

Mitogen induced activation, proliferation and surface antigen expression patterns in unmutated and hypermutated chronic lymphocytic leukemia cells.

OBJECTIVES: To determine whether the immunoglobulin V(H) gene mutational status has an effect on the activation, proliferation and surface antigen expression of chronic lymphocytic leukemia (CLL) cells when stimulated in vitro. METHODS: The proliferation and activation responses of CLL cells were studied in 22-immunoglobulin gene V(H) unmutated (UM-CLL) and 12 hypermutated (M-CLL) CLL cases in 4-day cultures. As the mitogen responses have been previously shown to be diverse in CLL, a case-specific strategy based on optimized mitogen combinations (OMCs) of interleukin-2 (IL-2), 12-O-tetradecanoylphorbol 13-acetate (TPA), Staphylococcus aureus Cowan 1 (SAC), and human recombinant tumor necrosis factor alpha (TNF) was applied in cell stimulation. The expression of 23 surface membrane antigens (CD5, CD11c, CD19, CD20, CD21, CD22, CD23, CD25, CD27, CD38, CD40, CD45, CD45RA, CD45RO, CD79b, CD80, CD95, CD124, CD126, CD130, FMC7, IgD, and IgM) was studied by flow cytometry at days 0 and 4. RESULTS: The proliferation and activation responses were similar in UM-CLL and M-CLL when OMCs contained IL-2, TPA or TNF. SAC induced faster proliferation in UM-CLL than in M-CLL. OMC stimulation induced preferential down-regulation of growth- promoting cell surface receptors CD5, CD21, and CD124 and preferential up-regulation of growth-inhibiting antigen CD80 in M-CLL. CONCLUSIONS: Difference in immunophenotypic evolution of UM-CLL and M-CLL can be demonstrated if appropriate matrix signals are provided. The pathways for CD5, CD21, CD124 (IL4R), and CD80 (B7-1) regulation should be further explored in relation with somatic hypermutation and outcome of CLL.

Surface antigen expression and correlation with variable heavy-chain gene mutation status in chronic lymphocytic leukemia.

Recent studies have demonstrated that B-cell chronic lymphocytic leukemia (CLL) consists of two clinical entities with either somatically hypermutated (M-CLL) or unmutated (UM-CLL) immunoglobulin variable heavy-chain (VH) regions. In view of the fact that the cellular biology of these two subsets of disease is currently unexplored, we performed an extensive analysis of the surface antigen expression and correlated this with the VH gene mutation status in a cohort of 32 CLL patients. Using polymerase chain reaction amplification and nucleotide sequencing, the VH genes were shown to be mutated in 10 cases (31%) and unmutated in 22 (69%). The expression of 27 surface membrane antigens in peripheral blood leukemic cells was analyzed by flow cytometry, measuring both the percentage of positive cells as well as the geometric mean fluorescence intensity (GMF). Most of the surface membrane antigens (CD5, CD11c, CD19, CD20, CD21, CD22, CD23, CD25, CD40, CD45, VD79b, CD80, CD95, CD122, CD124, CD126, CD130, CD154, IgM, and IgD) showed a similar expression pattern in both UM-CLL and M-CLL patients. The similarity of M-CLL and UM-CLL, as demonstrated here for the first time with many protein markers, indicates a considerably homogeneous phenotype in both subsets. Furthermore, CD27 was strongly expressed in all cases, which may suggest a memory cell phenotype for both M-CLL and UM-CLL. More positive cells in the UM-CLL group were observed regarding CD38, but CD38 was not a good predictor of VH gene mutation status. Seventy percent of the M-CLL cases, but only 36% of UM-CLL cases, were Ig-lambda+. The most striking differential expression, however, was observed in the two slicing variants of the common leukocyte antigen CD45, namely CD45RO and CD45RA. CD45RO expression was significantly associated with M-CLL, whereas the GMF intensity of CD45RA tended to be associated with UM-CLL. The role of these CD45 splicing variants in the pathogenesis of CLL deserves further investigation.

The IL1A genotype associates with atopy in nonasthmatic adults.

BACKGROUND: The skin prick test is used to examine specific IgE-mediated allergic responses. Generally, results accord well with anamnestic information on atopy. Several genetic factors probably affect the strength of allergen-mediated skin test reactions. OBJECTIVE: We sought to investigate skin test findings in a population-based sample of adult asthmatic patients and control subjects and to establish whether the IL1A genotype affects allergy testing. METHODS: We analyzed the single G-to-T base exchange polymorphism in exon 5 at +4845 of the gene encoding IL-1alpha (IL1A) in adult asthmatic patients (n = 245) and nonasthmatic control subjects (n = 405). The data were assessed for correlation with data on the skin test responses of these subjects to 22 common allergens. RESULTS: The IL1A genotype distribution and allele frequencies proved similar in patients and control subjects. Surprisingly, the IL1A genotype distribution was markedly different in control subjects with positive (ie, >/=1 positive reaction) and negative skin test responses (P =.006). This difference was caused by an increase in the frequency of the rarer allele 2 in control subjects with negative skin test responses (P =.004). CONCLUSION: Our study demonstrates that the IL1 gene complex is involved in the regulation of IgE-mediated atopic reactions. The results suggest that skin test responses to specific allergens are differently regulated in nonasthmatic and asthmatic subjects. Because of the potential role of the IL1A genotype as a confounding factor in skin prick testing, these results require special attention and should be further evaluated in other clinical settings.

Allergic rhinitis and polymorphisms of the interleukin 1 gene complex.

BACKGROUND: Allergic rhinitis is a chronic inflammatory disease with a genetic background. Inflammatory reactions are regulated by cytokines. Cytokine genes are polymorphic and have been implicated as candidate genes in allergy. OBJECTIVES: To study the significance of the interleukin 1 (IL-1) gene complex in allergic rhinitis. METHODS: Population-based, cross-sectional study. We studied the polymorphisms of 3 IL-1 gene complex genes, IL1A (+4845G>T), IL1B (-511 degrees C>T), and IL1RN (variable number of tandem repeats; IVS2, 86 bp, duplicates 2 to 5), in patients with allergic rhinitis. The study group consisted of 405 nonasthmatic individuals of whom 56 had allergic rhinitis. RESULTS: The genotype distribution differed significantly in all cytokine genes studied between subjects with and without allergic rhinitis. The difference was mainly due to an increased number of IL1A allele G homozygotes (67.9% vs 43.2%; odds ratio [OR], 2.8; 95% confidence interval [CI], 1.5-5.1), IL1B heterozygotes (72.2% vs 47.4%; OR, 2.8; 95% CI, 1.5-5.3), and IL1RN allele 2 homozygotes (18.5% vs 7.5%; OR, 2.8; 95% CI, 1.3-6.2) in allergic rhinitis. Haplotype analysis revealed a significant difference in the distribution of IL-1 gene complex haplotypes between subjects with and without allergic rhinitis (P = 0.005, 10 df). CONCLUSIONS: The IL-1 gene complex polymorphism is strongly associated with allergic rhinitis in nonasthmatic individuals.