An electronic nose in the discrimination of patients with asthma and controls

BACKGROUND: Exhaled breath contains thousands of volatile organic compounds (VOCs) that could serve as biomarkers of lung disease. Electronic noses can distinguish VOC mixtures by pattern recognition. OBJECTIVE: We hypothesized that an electronic nose can discriminate exhaled air of patients with asthma from healthy controls, and between patients with different disease severities. METHODS: Ten young patients with mild asthma (25.1 +/- 5.9 years; FEV(1), 99.9 +/- 7.7% predicted), 10 young controls (26.8 +/- 6.4 years; FEV(1), 101.9 +/- 10.3), 10 older patients with severe asthma (49.5 +/- 12.0 years; FEV(1), 62.3 +/- 23.6), and 10 older controls (57.3 +/- 7.1 years; FEV(1), 108.3 +/- 14.7) joined a cross-sectional study with duplicate sampling of exhaled breath with an interval of 2 to 5 minutes. Subjects inspired VOC-filtered air by tidal breathing for 5 minutes, and a single expiratory vital capacity was collected into a Tedlar bag that was sampled by electronic nose (Cyranose 320) within 10 minutes. Smellprints were analyzed by linear discriminant analysis on principal component reduction. Cross-validation values (CVVs) were calculated. RESULTS: Smellprints of patients with mild asthma were fully separated from young controls (CVV, 100%; Mahalanobis distance [M-distance], 5.32), and patients with severe asthma could be distinguished from old controls (CVV, 90%; M-distance, 2.77). Patients with mild and severe asthma could be less well discriminated (CVV, 65%; M-distance, 1.23), whereas the 2 control groups were indistinguishable (CVV, 50%; M-distance, 1.56). The duplicate samples replicated these results. CONCLUSION: An electronic nose can discriminate exhaled breath of patients with asthma from controls but is less accurate in distinguishing asthma severities. CLINICAL IMPLICATION: These findings warrant validation of electronic noses in diagnosing newly presented patients with asthma.     

Systemic inflammatory immune signatures in a patient with CRB1 linked retinal dystrophy

Background: In this report we describe, for the first time, the activation of the peripheral immune compartment in a patient with a CRB1 linked retinal degenerative disease, masquerading as intermediate uveitis.

Methods: To monitor the immune system during systemic immunosuppressive treatment, given for the initial diagnosis of intermediate uveitis, blood samples were taken before and during therapy, for analysis of peripheral blood mononuclear cell-subsets and circulating immune mediators.

Results: The levels of various pro-inflammatory immune mediators (including MIF, TSLP, CCL2/MCP-1, CXCL9, CXCL10, IFN-β, IL-6, IL-17, IL-21, IL-22, and IL-23) were elevated in serum at the first time point, and decreased under immunosuppressive treatment. In parallel, the frequency of activated (CD86+) CD1c+ myeloid dendritic cells in blood was proportional to the central foveal thickness measured by optical coherence tomography.

Conclusions: These observations challenge the current view on the distinct pathophysiology of retinal degenerative and retinal inflammatory conditions in this patient.     

Involvement of corticosterone in cardiovascular responses to an open-field novelty stressor in freely moving rats

The aim of the present study was to investigate the modulatory action of different concentrations of circulating corticosterone occupying either predominantly mineralocorticoid receptors (MR) or both MR and glucocorticoid receptors (GR) in control of cardiovascular responses to a novelty stressor. Six groups of rats were instrumented with radiotelemetry transmitters: sham-operated controls, adrenalectomised (ADX) controls, ADX with chronic implantation of a 20-mg corticosterone pellet, ADX with chronic implantation of a 100-mg corticosterone pellet, ADX receiving acute bolus injection of 0.25 mg/kg of corticosterone, and ADX with both implantation of a 20-mg corticosterone pellet and bolus treatment. Exposure to the novelty of an open field caused an increase in blood pressure, heart rate, body temperature and exploratory locomotor activity. The pressor response was dose-dependently increased in ADX rats implanted with a corticosterone pellet. Bolus injection of corticosterone at 10 min prior to novelty had no effect. The tachycardia was reduced in ADX rats compared to sham-operated controls, and this effect was restored by implantation of a 20-mg, but not 100-mg, corticosterone pellet. Bolus injection of corticosterone facilitated the return of heart rate towards baseline levels. The increase in body temperature was reduced in ADX rats, a deficit that was normalised by implantation of either corticosterone dose but not by acute bolus treatment. Locomotor activity was not different between the groups except for a slightly more rapid decline of locomotor activity in both groups treated with a bolus injection of corticosterone. These data show an important role of putative brain MR in maintaining adequate cardiovascular and behavioural responsiveness to a mild psychological stressor, while additional acute or chronic occupation of GR has further differential and sometimes opposing effects.     

Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells

Anergic/suppressive CD4+CD25+ T cells have been proposed to play an important role in the maintenance of peripheral tolerance. Here we demonstrate that in humans these cells suppress proliferation to self antigens, but also to dietary and foreign antigens. The suppressive CD4+CD25+ T cells display a broad usage of the T cell receptor Vbeta repertoire,suggesting that they recognize a wide variety of antigens. They reside in the primed/memory CD4+CD45RO+CD45RB(low) subset and have short telomeres, indicating that these cells have the phenotype of highly differentiated CD4+ T cells that have experienced repeated episodes of antigen-specific stimulation in vivo. This suggests that anergic/suppressive CD4+CD25+ T cells may be generated in the periphery as a consequence of repeated antigenic encounter. This is supported by the observation that highly differentiated CD4+T cells can be induced to become anergic/suppressive when stimulated by antigen presented by non-professional antigen-presenting cells. We suggest that besides being generated in the thymus, CD4+CD25+ regulatory T cells may also be generated in the periphery. This would provide a mechanism for the generation of regulatory cells that induce tolerance to a wide array of antigens that may not be encountered in the thymus.     

Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS

Neurotrophin treatment has so far failed to prolong the survival of individuals affected with amyotrophic lateral sclerosis (ALS), an incurable motoneuron degenerative disorder. Here we show that intracerebroventricular (i.c.v.) delivery of recombinant vascular endothelial growth factor (Vegf) in a SOD1(G93A) rat model of ALS delays onset of paralysis by 17 d, improves motor performance and prolongs survival by 22 d, representing the largest effects in animal models of ALS achieved by protein delivery. By protecting cervical motoneurons, i.c.v. delivery of Vegf is particularly effective in rats with the most severe form of ALS with forelimb onset. Vegf has direct neuroprotective effects on motoneurons in vivo, because neuronal expression of a transgene expressing the Vegf receptor prolongs the survival of SOD1(G93A) mice. On i.c.v. delivery, Vegf is anterogradely transported and preserves neuromuscular junctions in SOD1(G93A) rats. Our findings in preclinical rodent models of ALS may have implications for treatment of neurodegenerative disease in general.     

Absence of caspase 3 activation in neoplastic cells of nasopharyngeal carcinoma biopsies predicts rapid fatal outcome.

Poor prognosis in nasopharyngeal carcinoma patients may result from resistance to the apoptosis-inducing effect of radio- and/or chemotherapy. Apoptosis depends on proper activation of caspase 3, resulting in cleavage of key proteins like PARP-1. To investigate whether disruption of the apoptosis pathway results in therapy-resistant tumour cells, we investigated whether absence of caspase 3 activation in tumour biopsies of nasopharyngeal carcinoma patients is related to poor clinical outcome. Moreover, we investigated whether absence of caspase 3 activation is related to loss of procaspase 3 expression or expression of the apoptosis regulators p53, bcl-2 and XIAP. We studied 36 Indonesian nasopharyngeal carcinoma patients without evidence of distant metastases who were treated with curative intent by radiotherapy only. Activation of caspase 3 and expression of the different markers were determined using specific antibodies. Levels of caspase 3 activation were determined by quantifying positively staining tumour cells. Nasopharyngeal carcinoma-derived C15 and C17 tumour cells were used as control. Absence of caspase 3 activation was strongly related to a poor clinical response to radiotherapy and to a higher T and N stage, resulting in a particularly poor clinical outcome with regard to progression-free (P<0.0001) and overall survival time (P<0.0001). Absence of caspase 3 activation was significantly correlated to loss of expression of procaspase 3 (P=0.04). In nasopharyngeal carcinoma patients treated with curative intent, absence of active caspase 3-positive neoplastic cells predicts rapid fatal outcome, and is associated with poor response to radiotherapy and high T and N stage at time of presentation.     

Awareness of lifestyle risk factors for cancer and heart disease among adults in the UK

Objective

To examine and compare awareness of lifestyle risk factors for cancer and heart disease in a single UK representative sample.

Methods

Two open-ended questions about cancer and heart disease risk factors were included in a population-based survey of 1747 adults. Responses were coded for four lifestyles with established links to both diseases: smoking, eating an unhealthy diet, drinking excessive alcohol and physical inactivity.

Results

Awareness of lifestyle risk factors was low for both diseases, although higher for heart disease than cancer. The average number identified by respondents was 2.1 (heart disease) and 1.4 (cancer). The strongest predictor was education (both p < 0.001). Awareness that physical inactivity is a cancer risk factor was particularly low at 7%.

Conclusion

These findings suggest that public awareness of the impact of lifestyle on commonly feared diseases, especially cancer, is low.

Practice implications

Unhealthy lifestyles make a significant contribution to ill health and mortality. Increased public awareness of the links between lifestyles and commonly feared diseases might help people understand the potential health consequences of their actions and encourage them to make much-needed lifestyle changes. Efforts are needed to improve public health messages about how lifestyle risk factors impact on the chances of developing these important diseases.     

Lessons from BWS twins: complex maternal and paternal hypomethylation and a common source of haematopoietic stem cells

The Beckwith–Wiedemann syndrome (BWS) is a growth disorder for which an increased frequency of monozygotic (MZ) twinning has been reported. With few exceptions, these twins are discordant for BWS and for females. Here, we describe the molecular and phenotypic analysis of 12 BWS twins and a triplet; seven twins are MZ, monochorionic and diamniotic, three twins are MZ, dichorionic and diamniotic and three twins are dizygotic. Twelve twins are female. In the majority of the twin pairs (11 of 13), the defect on chromosome 11p15 was hypomethylation of the paternal allele of DMR2. In 5 of 10 twins, there was additional hypomethylation of imprinted loci; in most cases, the loci affected were maternally methylated, but in two cases, hypomethylation of the paternally methylated DLK1 and H19 DMRs was detected, a novel finding in BWS. In buccal swabs of the MZ twins who share a placenta, the defect was present only in the affected twin; comparable hypomethylation in lymphocytes was detected in both the twins. The level of hypomethylation reached levels below 25%. The exchange of blood cells through vascular connections cannot fully explain the degree of hypomethylation found in the blood cell of the non-affected twin. We propose an additional mechanism through which sharing of aberrant methylation patterns in discordant twins, limited to blood cells, might occur. In a BWS-discordant MZ triplet, an intermediate level of demethylation was found in one of the non-affected sibs; this child showed mild signs of BWS. This finding supports the theory that a methylation error proceeds and possibly triggers the twinning process.