The incidence of asthma in young adults

STUDY OBJECTIVES: Longitudinal data on adult asthma are sparse. The objectives of this study were to determine the incidence of asthma and to establish the risk factors for the development of asthma in subjects who were 12 to 41 years old over an 8-year period. DESIGN: From birth cohorts over the period 1953 to 1982 in The Danish Twin Registry, 19,349 subjects with no history of asthma, as determined by a questionnaire-based survey in 1994, answered a follow-up questionnaire in 2002. The subjects were regarded as incident asthma cases when answering "yes" to the question "Do you have, or have you ever had asthma?" in 2002, and "no" to the same question in 1994. RESULTS: A total of 838 cases (4.3%) of new asthma were identified in 2002. The incidence rates of asthma were 4.5 and 6.4 per 1,000 person-years, respectively, among male and female subjects. For all ages, the probability of adult-onset asthma was greater for female subjects (odds ratio [OR], 1.49; p < 0.001), and for both sexes there was a slow decline in probability with increasing age. There was a positive association between increasing body mass index (BMI) and risk of adult-onset asthma applying to both sexes (OR, 1.05 per unit; p < 0.001). Furthermore, positive associations were found between incident asthma and a history of hay fever (OR: male subjects, 4.2; female subjects, 3.7; p < 0.001), eczema (OR: male subjects, 3.5; female subjects, 2.0; p < 0.001), and both (OR: male subjects, 6.9; female subjects, 8.0; p < 0.001). CONCLUSIONS: There is a continuing high incidence of asthma past childhood that is most pronounced among female subjects. Increasing levels of BMI are associated with a greater likelihood of developing asthma for both sexes. A substantial portion of cases of adult asthma is preceded by upper airway allergic symptoms and/or eczema, thus indicating a shared pathogenesis.     

Enduring effects of chronic ethanol in the CNS: basis for alcoholism

This symposium focused on functional alterations in the mesolimbic dopamine system during the abstinence phase after chronic alcohol intake. Mark Brodie first described his recordings from midbrain slices prepared after chronic alcohol treatment in vivo by daily injection in C57BL/6J mice. No changes were found in the baseline firing frequency of dopaminergic neurones in the VTA (ventral tegmental area), but the excitation produced in these neurones by an acute ethanol challenge was significantly increased in neurons from ethanol-treated mice compared with those from the saline-treated controls. There was also a significant decrease in the inhibitory response to GABA by the dopamine neurones following the chronic ethanol treatment. These data suggest that the timing pattern and mode of ethanol administration may determine the types of changes observed in dopaminergic reward area neurons. Annalisa Muntoni lectured on the relationship between electrophysiological and biochemical in vivo evidence supporting a reduction in tonic activity of dopamine neurons projecting to the nucleus accumbens at various times after suspension of chronic ethanol treatment and morphological changes affecting dopamine neurons in rat VTA. Hilary J. Little then described changes in dopaminergic neurone function in the VTA during the abstinence phase. Decreases in baseline firing were seen at 6 days after withdrawal of mice from chronic ethanol treatment but were not apparent after 2 months abstinence. Increases in the affinity of D1 receptors in the striatum, but not in the cerebral cortex, were seen however up to 2 months after withdrawal. Scott Steffensen then described his studies recording in vivo from GABA containing neurones in the VTA in freely moving rats. Chronic ethanol administration enhanced the baseline activity of these neurones and resulted in tolerance to the inhibition by ethanol of these neurones. His results demonstrated selective adaptive circuit responses within the VTA or in extrategmental structures that regulate VTA-GABA neurone activity.     

Effect of gender on phenotypic expression of the S447X mutation in LPL: the Copenhagen City Heart Study

The G188E, D9N, and N291S mutations in LPL increase TG, reduce HDL cholesterol, and increase risk of ischemic heart disease. The common S447X mutation may have opposite effects. We genotyped 8451 women and men from the Danish general population, and 854 women and men with ischemic heart disease. Participants carrying G188E, D9N, or N291S were excluded. Compared with non-carriers, female heterozygotes and homozygotes presented with a 0.11 and 0.18 mmol/l decrease in plasma TG (P=0.001 and P=0.37) and a 0.07 and 0.03 mmol/l increase in HDL cholesterol (P=0.001 and P=0.99). Male heterozygotes and homozygotes presented with a 0.20 and 0.41 mmol decrease in plasma TG (P<0.001 and P=0.06), which was twice that in women, and a 0.05 and 0.17 mmol/l increase in plasma HDL cholesterol (P=0.02 and P=0.04), respectively. In meta-analyses by gender, the S447X mutation was associated with a significant l7% reduction in risk of ischemic heart disease in men (OR=0.83; P=0.01), whereas risk was unaffected in women (OR=0.97; P=0.98). The S447X mutation is associated with anti-atherogenic effects on TG and HDL cholesterol in both genders, and with a moderate protective effect on risk of ischemic heart disease in men.     

Arachidonic Acid-induced Platelet Aggregation ex vivo in Patients with Acute Ischaemic Heart Disease

The threshold concentrations of arachidonic acid (AA) required to induce platelet aggregation were measured in platelet-rich plasma (PRP) from patients with acute ischaemic heart disease and healthy controls. The analytical precision of the test was very good (coefficient of variation 0-4%). Analytical accuracy was evaluated by comparing the results with threshold values for collagen-induced platelet aggregation, and a significant correlation was found (r = 0.56; p<0.01). When comparing the serum levels of thromboxane B(2) to threshold values for AA-induced platelet aggregation an inverse relationship was found (r = -0.37; p<0.01). In the clinical study significantly increased aggregability to AA was seen in patients with unstable angina pectoris (n = 13) compared to patients with stable angina pectoris (n = 14), (p<0.01), and both groups had hyperaggregating platelets compared to healthy controls (n = 27), (p<0.01). The patients with acute myocardial infarction (n = 10) had nearly normoaggregating platelets for the first 2-3 days after admission, but after a week and at day 14 their platelets showed significant hyperaggregability compared to healthy controls (p<0.01). Thus studies of AA-induced aggregation ex vivo suggest that patients with unstable angina pectoris and acute myocardial infarction, in whom coronary thrombus is frequently present, have increased platelet aggregability compared to patients with stable angina pectoris and healthy controls.     

Prothrombin and risk of venous thromboembolism,ischemic heart disease and ischemic cerebrovascular disease in the general population

ObjectiveWe tested the hypotheses that Prothrombin G20210A heterozygosity associate with increased risk of venous thromboembolism (VTE), ischemic heart disease (IHD), and ischemic cerebrovascular disease (ICVD) in the general population and re-tested risk of IHD and ICVD in two case-control studies.Methods9231 individuals from the Danish general population were followed for VTE (VTE = DVT + PE), deep venous thrombosis (DVT), pulmonary embolism (PE), IHD, myocardial infarction (MI), ICVD, and ischemic stroke (IS) for a median of 24 years. Case-control studies included 2461 IHD cases and 867 ICVD cases.ResultsIn the general population, Prothrombin G20210A heterozygotes had1.3 (95% CI:0.6–2.9) fold risk for VTE, 0.6 (0.2–2.0) for DVT, 1.7(0.6–4.8) for PE, 1.5(1.1–2.1) for IHD, 1.7(1.1–2.7) for MI, 1.1(0.6–1.9) for ICVD, and 1.1(0.5–2.1) for IS compared to non-carriers. Double heterozygotes for Prothrombin G20210A and Factor V Leiden versus double non-carriers had a multifactorially adjusted hazard ratio for IHD of 6.0(2.0–19). In case-control studies, multifactorially adjusted odds ratios for Prothrombin G20210A heterozygotes versus non-carriers were 2.0(1.1–3.4) for IHD, 2.0(1.0–3.8) for MI, 1.4(0.7–3.1) for ICVD, and 2.1(0.8–5.4) for IS.ConclusionProthrombin G20210A heterozygosity alone and in combination with Factor V Leiden R506Q heterozygosity predicts 1.5 and 6.0 fold risk of IHD compared to non-carriers.     

Plasma HER2 amplification in cell-free DNA during neoadjuvant chemotherapy in breast cancer

Purpose

Measurement of human epidermal growth factor receptor 2 (HER2) gene amplification in cell-free DNA (cfDNA) is an evolving technique in breast cancer, enabling liquid biopsies and treatment monitoring. The present study investigated the dynamics of plasma HER2 gene copy number and amplification in cfDNA during neoadjuvant chemotherapy.

Patients and methods

The study included 50 patients from a prospective cohort analyzed during neoadjuvant chemotherapy. Fifty healthy women with no history of cancer served as control group and 15 patients with metastatic breast cancer were used to validate the assay. Total cfDNA and HER2 gene amplification were measured by quantitative real-time polymerase chain reaction.

Results

Plasma HER2 gene copy number (p = 0.794), HER2 gene amplification (p = 0.127) and total cfDNA (p = 0.440) did not differ significantly from the levels in the control group. Eighteen patients (36 %) obtained pathological complete response (pCR). HER2 gene copy number before the operation was significantly higher than the baseline level (p < 0.0001), but there was no difference between patients with and without pCR (p = 0.569). Likewise, there was no difference in plasma HER2 gene amplification between tissue HER2-positive and -negative patients (p = 0.754).

Conclusions

The results indicate that neither total cfDNA nor HER2 gene copy number is elevated in primary breast cancer patients compared to healthy controls. The level of both parameters increased during neoadjuvant chemotherapy, but without any relation to treatment effect. There was no indication of plasma HER2 gene amplification in the HER2-positive patients in the neoadjuvant setting.     

Risk factors for asthma in young adults: a co-twin control study

Background: The liability to asthma is influenced both by genetic and environmental factors. The objective of this study was to identify risk factors for asthma in young adult twin pairs during an 8‐year period. Methods: From the birth cohorts 1953–1982 of the Danish Twin Registry, 6090 twin pairs who were initially unaffected with respect to asthma at a nationwide questionnaire‐based study in 1994 participated in a similar follow‐up study in 2002. Subjects were regarded incident asthma cases when responding affirmatively to the question ‘Do you have, or have you ever had asthma'? in 2002. Pairs in which only one twin developed asthma – discordant pairs – were identified and conditional logistic regression was applied to detect effects of risk factors. Results: A total of 126 monozygotic (MZ) and 273 dizygotic (DZ) discordant twin pairs were identified. In MZ twins hay fever (OR = 3.16, 95% CI: 1.29–7.73, P = 0.007) and exercise (OR for inactivity = 0.35, 95% CI: 0.13–0.91, P = 0.023) were significantly associated with asthma, whereas in DZ twins, hay fever (OR = 2.44, 95% CI: 1.44–4.13, P = 0.001), eczema (OR = 1.96, 95% CI: 1.02–3.78, P = 0.040), female sex (OR between males and females = 0.54, 95% CI: 0.36–0.80, P = 0.002), and increasing levels of body mass index (BMI; OR per unit = 1.11, 95% CI: 1.02–1.20, P = 0.009) were significant predictors of asthma. Conclusions: Hay fever, eczema, female sex, exercise and increasing levels of BMI were risk factors for asthma in young adults. The different risk profile observed in MZ twins compared with DZ twins may reflect an underlying genetic vulnerability shared between those risk factors and asthma.     

Prognostic impact of placenta growth factor and vascular endothelial growth factor A in patients with breast cancer

Placenta growth factor (PlGF) and vascular endothelial growth factor A (VEGF-A) are angiogenic growth factors interacting competitively with the same receptors. VEGF-A is essential in both normal and pathologic conditions, but the functions of PlGF seem to be restricted to pathologic conditions such as ischemic heart disease, arthritis and tumor growth. Angiogenesis is a complex process with several growth factors involved. Because PlGF modulates VEGF-A responses, we investigated their mutual relationship and impact on breast cancer prognosis. Quantitative PlGF and VEGF-A levels were measured in 229 tumor tissue specimen from primarily operated patients with unilateral breast cancer. Non-malignant breast tissue was also dissected near the tumor and quantitative measurements were available for 211 patients. PlGF and VEGF-A protein levels in homogenized tissue lysates were analyzed using the Luminex system. We found significantly higher median levels of PlGF and VEGF-A in tumor tissue compared to non-malignant tissue (PlGF: 69.8 vs. 31.4 pg/mg, p < 0.001 and VEGF-A: 1148.2 vs. 163.5 pg/mg, p < 0.001). PlGF and VEGF-A were correlated in both malignant tissue (r = 0.41, p < 0.001) and in non-malignant tissue (r = 0.69, p < 0.001). The proportion of node positive patients was higher with high PlGF expression (61.4%) than with low PlGF expression (45.6%) in tumor tissue, p = 0.024. High levels of PlGF and VEGF-A in tumor tissue were associated with significant shorter recurrence-free survival (RFS) in both univariate analysis (PlGF: p = 0.023; VEGF-A: p = 0.047) and in multivariate analysis (PlGF: p = 0.026; VEGF-A: p = 0.036). Neither PlGF nor VEGF-A expression in non-malignant tissue were predictors for RFS. In conclusion, our results support the mutual relationship between PlGF and VEGF-A and encourage further investigations as prognostic markers in breast cancer patients.