Early atopic disease and early childhood immunization – is there a link?

Background: There are frequent concerns about early immunizations among the parents of children at heightened risk for atopy. The study assessed the effect of vaccine immunization before the first birthday on eczema severity and allergic sensitization in the second year of life. Methods: A total of 2184 infants, aged 1–2 years, with established atopic dermatitis and a family history of allergy, from 97 study centres in 10 European countries, South Africa and Australia were included. Exposure to vaccines (diphtheria, tetanus, pertussis, polio, Haemophilus influenzae Type B, hepatitis B, mumps, measles, rubella, varicella, BCG, meningococci and pneumococci) and immunization dates were recorded from immunization cards. Immunoglobulin E (IgE) was determined by RAST and eczema severity was assessed by scoring atopic dermatitis (SCORAD). Results: Immunization against any target was not associated with an increased risk of allergic sensitization to food or inhalant allergens. Varicella immunization (only 0.7% immunized) was inversely associated with total IgE > 30 kU/l (OR 0.27; 95% CI 0.08–0.87) and eczema severity (OR 0.34; 95% CI 0.12–0.93). Pertussis immunization (only 1.7% nonimmunized) was inversely associated with eczema severity (OR 0.30; 95% CI 0.10–0.89). Cumulative received vaccine doses were inversely associated with eczema severity (P = 0.0107). The immunization coverage of infants before and after the onset of atopic dermatitis was similar. Conclusion: In children at heightened risk for atopy, common childhood immunization in the first year is not associated with an increased risk of more severe eczema or allergic sensitization. Parents of atopic children should be encouraged to fully immunize their children.     

Allergen immunotherapy: where is it now?

The scientific basis and the proof of clinical effectiveness of allergen immunotherapy administered by subcutaneous injection (SCIT) are well established. It is effective treatment for sensitivity to Hymenoptera venom and for allergic rhinitis and allergic asthma. SCIT administered in the proper setting reduces the development of new sensitivities and progression from rhinitis to asthma. Further, the beneficial effects persist long after completion of a course of treatment. Although many people enjoy the benefits of SCIT, extension of its use to the many others who might be candidates for this treatment is limited by its drawbacks of safety concerns and the inconvenience of repeated clinic visits over several years to receive the injections. There are many attempts underway to improve on the safety and convenience while still retaining the benefits of SCIT. These include approaches using current allergen extracts, especially by administering them sublingually. Alternatively, through recombinant technology, extracts are being modified to reduce their allergenicity without reducing their immunogenicity. They are being linked to immunostimulatory DNA sequences that will modify their in vivo processing resulting in an enhanced nonallergic response or they are being incorporated into fusion proteins with inhibitory properties for mast cells and basophils.     

Allergen‐specific immunotherapy: is it vaccination against toxins after all?

IgE‐mediated allergies, in particular allergic rhinoconjunctivitis and asthma, have reached epidemic proportions, affecting about one‐third of the population in developed countries. The most effective treatment for allergies is specific immunotherapy (SIT), which involves the injection of increasing doses of an allergen extract to allergic individuals. The current form of SIT was first introduced in 1911 and recently celebrated its 100th birthday for the treatment of hay fever. The concept of this therapy at the time was straightforward, as it was believed that pollen contained toxins against which the patient could be vaccinated. However, the understanding became blurred with the discovery that IgE antibodies were the effector molecules of the allergic response. Subsequent research focused on the idea that SIT should induce tolerance keeping the IgE antibodies at bay. In this review, we will discuss the various hypotheses for the mechanism of SIT and we will put forward the concept that allergens may be viewed as ‘protoxins’ which need to be activated by IgE antibodies. Within this framework, protoxin‐neutralizing antibodies are the key effector molecules while a shift to Th1 or Treg cells mainly contributes to the efficacy of SIT by helping B cells to produce neutralizing IgG antibodies.     

Ultrasound screening: how effective is the service?

This study describes the standards, training and audit systems in units offering ultrasound screening services in Ireland. A national survey of 21 of all maternity units offering an obstetric ultrasound service in Ireland was undertaken. The questionnaire used was designed by the UK Screening committee and sought information on nine key areas associated with service provision including protocols for screening, the antenatal ultrasound package available and management following the identification of a fetal abnormality. This paper reports on the availability of information for women, record keeping, standards and training, and monitoring of quality. All units responded to the survey. Deficiencies in the Irish service include limited information available for women who are participating in screening, poor monitoring of ultrasound programmes, suboptimal equipment and a lack of guidelines and standards relating to the conduct of ultrasound examinations Significant improvements are required in order to deliver a national service of a satisfactory standard. Key recommendations include establishing a national working group to develop national standards to audit the service, and to guarantee that staff training is sufficient to ensure effective practice.     

Pathological sympathoexcitation: how is it achieved?

AIM: Congestive heart failure (CHF) and obstructive sleep apnoea syndrome (OSAS) are both associated with an intense sympathoexcitation, including an increased muscle sympathetic nerve activity (MSNA). We have studied the firing characteristics of single vasoconstrictor fibres to the muscle vascular bed in CHF and OSAS patients, at rest and during transient sympathoexcitatory stimuli, to elucidate the mechanisms by which vasoconstrictor output is augmented in these conditions. RESULTS: The main alternatives for augmenting sympathetic output are an increased firing frequency of individual nerve fibres and an increased recruitment of nerve fibres. Starting with the frequency alternative, the inherent bursting character of MSNA provides two possibilities to increase the firing of individual fibres: (1) by increasing the proportion of neural bursts in which the fibre is active (increased firing probability) and (2) by increasing the number of spikes a fibre generates per burst (increased multiple within-burst firing). At rest and in cardiac sinus rhythm, an increased firing probability is seen in both CHF and OSAS patients, whereas increased multiple within-burst firing is found in OSAS but not in CHF. In response to transient sympathoexcitatory stimuli (such as pre-mature heart beats), both patient groups show marked shifts towards multiple within-burst firing. Thus, both mechanisms for augmenting discharge frequency are operating in these two pathological conditions, but the firing characteristics at rest differ significantly. During recording sessions in sympathoexcited patients, we have encountered vasoconstrictor fibres that are active almost exclusively during periods of transient sympathoexcitation, while being virtually silent at rest. This suggests that recruitment of previously inactive vasoconstrictor fibres, the second main alternative for increasing vasoconstrictor output, contributes to transient sympathoexcitatory responses in these patients. Although it seems reasonable to assume that recruitment may also contribute to the resting level of MSNA in CHF and OSAS, this issue is difficult to resolve in microneurographic studies. CONCLUSION: In conclusion, pathological sympathoexcitation appears to depend on both recruitment and increased firing frequency. A shift towards multiple within-burst firing, at rest or in response to transient stimuli, may constitute a risk factor per se as it entails neural volleys with high instantaneous firing frequencies and consequently higher release of neurotransmitters.     

Pathological sympathoexcitation: how is it achieved?

Aim: Congestive heart failure (CHF) and obstructive sleep apnoea syndrome (OSAS) are both associated with an intense sympathoexcitation, including an increased muscle sympathetic nerve activity (MSNA). We have studied the firing characteristics of single vasoconstrictor fibres to the muscle vascular bed in CHF and OSAS patients, at rest and during transient sympathoexcitatory stimuli, to elucidate the mechanisms by which vasoconstrictor output is augmented in these conditions. Results: The main alternatives for augmenting sympathetic output are an increased firing frequency of individual nerve fibres and an increased recruitment of nerve fibres. Starting with the frequency alternative, the inherent bursting character of MSNA provides two possibilities to increase the firing of individual fibres: (1) by increasing the proportion of neural bursts in which the fibre is active (increased firing probability) and (2) by increasing the number of spikes a fibre generates per burst (increased multiple within‐burst firing). At rest and in cardiac sinus rhythm, an increased firing probability is seen in both CHF and OSAS patients, whereas increased multiple within‐burst firing is found in OSAS but not in CHF. In response to transient sympathoexcitatory stimuli (such as pre‐mature heart beats), both patient groups show marked shifts towards multiple within‐burst firing. Thus, both mechanisms for augmenting discharge frequency are operating in these two pathological conditions, but the firing characteristics at rest differ significantly. During recording sessions in sympathoexcited patients, we have encountered vasoconstrictor fibres that are active almost exclusively during periods of transient sympathoexcitation, while being virtually silent at rest. This suggests that recruitment of previously inactive vasoconstrictor fibres, the second main alternative for increasing vasoconstrictor output, contributes to transient sympathoexcitatory responses in these patients. Although it seems reasonable to assume that recruitment may also contribute to the resting level of MSNA in CHF and OSAS, this issue is difficult to resolve in microneurographic studies. Conclusion: In conclusion, pathological sympathoexcitation appears to depend on both recruitment and increased firing frequency. A shift towards multiple within‐burst firing, at rest or in response to transient stimuli, may constitute a risk factor per se as it entails neural volleys with high instantaneous firing frequencies and consequently higher release of neurotransmitters.     

Pancreatic intraepithelial neoplasia – can we detect early pancreatic cancer?

Haugk B
(2010) Histopathology 57, 503–514
Pancreatic intraepithelial neoplasia – can we detect early pancreatic cancer? Pancreatic cancer is one of the most lethal cancers, with an incidence equalling mortality. Pancreatic cancer is a heterogeneous group in which pancreatic ductal adenocarcinoma (PDAC) is the most common. It is now established that PDAC develops through stepwise progression from precursor lesions. Detection and treatment of these precursor lesions would allow curative treatment. Three precursor lesions for PDAC have been identified. Two of these – mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMNs) – are rare, radiologically detectable, cystic precursor lesions which can be cured if treated at the preinvasive stage. The third and most common precursor lesion has recently been defined as pancreatic intraepithelial neoplasia (PanIN). PanINs are microscopic lesions with no clinical correlate. They display a spectrum of cyto‐architectural changes (PanIN‐1, PanIN‐2 and PanIN‐3) mirrored in an increasing accumulation of molecular genetic changes, with PanIN‐3 sharing many of the alterations with PDAC. Great advances in the understanding of pancreatic carcinogenesis have opened avenues for diagnosis and chemoprevention. However, access to the pancreas is limited, molecular tests are at the early stages and too little is known about the natural history of early PanINs to justify resection. Currently, screening focuses upon high‐risk individuals only.     

Biomarker-based early cancer detection: is it achievable?

A new mathematical model evaluates the power of blood-based biomarkers for early cancer detection.     

Are regulatory T cells the target of venom immunotherapy?

PURPOSE OF REVIEW: Allergen-specific immunotherapy is the only treatment that leads to lifelong tolerance to previously disease-causing allergens by restoring normal immunity against allergens. T-regulatory (TReg) cells are involved in preventing sensitization to allergens and represent a major target for venom- or other allergen-specific immunotherapy. RECENT FINDINGS: Induction of peripheral tolerance in T cells, which is characterized mainly by suppressed proliferative and cytokine responses against the T-cell epitopes of major allergens, is an essential step in specific immunotherapy. It is initiated by the autocrine action of interleukin-10 and/or transforming growth factor-beta, which are produced by antigen-specific TReg cells. Tolerized T cells can be reactivated to produce distinct T-helper-1 or T-helper-2 cytokine patterns, thus directing allergen-specific immunotherapy toward successful or unsuccessful outcomes. TReg cells directly or indirectly influence effector cells of allergic inflammation, such as mast cells, basophils and eosinophils. In addition, there is accumulating evidence that they may suppress IgE production and induce IgG4 and IgA production against allergens. In addition, histamine released from mast cells and basophils may efficiently contribute to immunoregulation during specific immunotherapy, and affect TReg cells and the production of their cytokines via histamine receptor 2. SUMMARY: By applying recent knowledge in TReg-cell-dependent mechanisms of peripheral tolerance, more rational and safer approaches to the prevention and cure of venom hypersensitivity may be developed in the future.     

The vascular network of tumours — what is it not for?

It is becoming almost a dogma that tumours cannot grow beyond 1-2 mm(3) unless they are supported by a rich vascular supply 1. It is true that tumours promote angiogenesis and that highly vascularized carcinomas have, in general, a more aggressive clinical course than carcinomas of low vascularization 23. However, a study of intratumoral angiogenesis reveals that the newly formed vessels are commonly deprived of those structural qualities that would allow them to perform an optimal oxygenation function 3. Thus, most tumours, irrespective of their angiogenic status, behave as if they were 'hypoxic', urging (via angiogenic mediators) for, what would look paradoxical at first sight, more defective angiogenesis. It is hypothesized that tumour cells can grow into solid neoplasms by exploiting the host's pre-existing vessels, without the need for new blood vessel formation. Neovascularization, however, may be important for tumours with an exophytic pattern of growth as these, by their very nature, lose the host's sheltering stroma. Shifting to anaerobic glycolysis and activation of anti-apoptotic pathways are complementary mechanisms for tumour cell survival and growth. Besides, continuous and indiscriminate production of a defective vascular network ensures an increased metastatic potential since the newly formed intratumoral vessels, simulating venular-like spaces, are easily permeable to tumour cells, facilitating metastases.