Targeted PEG-poly(glutamic acid) complexes for inhalation protein delivery to the lung.

Pulmonary delivery is increasingly seen as an attractive, non-invasive route for the delivery of forthcoming protein therapeutics. In this context, here we describe protein complexes with a new 'complexing excipient' - vitamin B12-targeted poly(ethylene glycol)-block-poly(glutamic acid) copolymers. These form complexes in sub-200nm size with a model protein, suitable for cellular targeting and intracellular delivery. Initially we confirmed expression of vitamin B12-internalization receptor (CD320) by Calu-3 cells of the in vitro lung epithelial model used, and demonstrated enhanced B12 receptor-mediated cellular internalization of B12-targeted complexes, relative to non-targeted counterparts or protein alone. To develop an inhalation formulation, the protein complexes were spray dried adopting a standard protocol into powders with aerodynamic diameter within the suitable range for lower airway deposition. The cellular internalization of targeted complexes from dry powders applied directly to Calu-3 model was found to be 2-3 fold higher compared to non-targeted complexes. The copolymer complexes show no complement activation, and in vivo lung tolerance studies demonstrated that repeated administration of formulated dry powders over a 3 week period in healthy BALB/c mice induced no significant toxicity or indications of lung inflammation, as assessed by cell population count and quantification of IL-1ß, IL-6, and TNF-α pro-inflammatory markers. Importantly, the in vivo data appear to suggest that B12-targeted polymer complexes administered as dry powder enhance lung retention of their protein payload, relative to protein alone and non-targeted counterparts. Taken together, our data illustrate the potential developability of novel B12-targeted poly(ethylene glycol)-poly(glutamic acid) copolymers as excipients suitable to be formulated into a dry powder product for the inhalation delivery of proteins, with no significant lung toxicity, and with enhanced protein retention at their in vivo target tissue.

Vitamin D receptor variants and uncontrolled asthma.

Summary: Background. Asthma is a common childhood respiratory disease, affecting around 20% of Irish children. In other populations, vitamin D receptor (VDR) polymorphisms have been associated with asthma risk. We aimed to investigate the association between 2 VDR polymorphisms and uncontrolled paediatric asthma. Methods. 44 asthmatic children and 57 healthy volunteers were studied. The VDR TaqI gene variant in exon 9 (T/C) (rs731236) and ApaI (rs7975232) in intron 8 (C/T) were determined, using TaqMan® Assays. The lung function, serum 25-hydroxyvitamin D (25OHD) levels and other biomarkers of allergy, immunity, airway and systemic inflammation were as-sessed. Results. The distribution of T and C alleles and genotype frequencies differed significantly between asthmatics and controls for both polymorphisms (p < 0.05). A significant association was found between both TaqI [OR = 2.37, 95% CI (1.27 - 4.45), p = 0.007] and ApaI polymorphisms, and asthma risk [OR = 2.93, 95% CI (1.62 - 5.3), p = 0.0004]. No association was observed between genotypes and 25OHD levels, lung function and other biomarkers, with the exception of Interleukin-10 (IL-10) and white blood cells count (WBC). IL-10 levels were lower in asthmatics with TC genotype for TaqI polymorphism (p < 0.01) and were higher in patients with TT genotype for ApaI (p < 0.01). WBC were higher in patients with TC and CC genotypes for TaqI (p < 0.05) and lower in TT genotype for ApaI (p < 0.05). Conclusion. TaqI and ApaI polymorphisms are associated with asthma in Irish children. Further studies are warranted to investigate the importance of decreased IL-10 levels in paediatric asthmatics with specific genotypes.

Life After the Event: A Review of Basic Life Support Training for Parents Following Apparent Life-Threatening Events and Their Experience and Practices Following Discharge.

Apparent Life-Threatening Events (ALTEs) are a common presentation to paediatric hospitals and represent a significant cause of parental anxiety. Basic Life Support (BLS) training is recommended for all caregivers following ALTEs. This study aimed to assess the rate of caregiver BLS training and reviewed parents experience following discharge. Parents were interviewed by phone following discharge. Over the study period 25 children attended the Emergency Department with ALTE, 17/25 (68%) were trained and 13/17 (76%) were contactable for interview. All parents found training decreased their anxiety level and were interested in attending for re-training. BLS resuscitation was subsequently required by 2/13 (15%) of children. Non-medical grade monitors were in use by 10/13 (77%) of caregivers following discharge. Caregivers are eager to engage in BLS training and it effectively reduces their caregiver anxiety. We recommend an increase in instructor staff and use of group re-training post discharge.

Urinary Tract Infection in Childhood and Inflammatory Markers>.

Acute urinary tract infections are common in children. Our aim was to establish whether peripheral blood tests correlate with urinary culture. We also examined the relationship between peripheral blood results and the length of stay (LOS) in children and adolescents with UTI. We studied 135 patients admitted with UTI, mean (SD) age 3.0 (4.1) years. Of these 135 patients, 16 (11.9%) had combined normal serum WCC, normal neutrophil count and CRP < 5 mg/L. In this group of patients, there was no significant association between LOS and serum WCC, serum neutrophil values, E. coli infection or CRP values (p value 0.51, 0.98, 0.87, 0.82, respectively).

Special care dentistry: how prepared are we?

AIM: To assess and evaluate the confidence of the undergraduate dental team in Irish dental schools regarding their training in the field of special care dentistry (SCD). METHOD: A questionnaire was distributed amongst the undergraduate dental teams within Cork University Dental School and Hospital (CUDSH) and Dublin Dental University Hospital (DDUH). The data were analysed to assess for differences between the median responses of the various groups. RESULTS: A total of 139 students participated in the study; 82 from DDUH (59 dental science students, seven dental hygiene students and 16 dental nursing students) and 57 from CUDSH (43 dental science students and 14 dental hygiene students). Twenty-two per cent (n = 30) of respondents agreed that their training had been sufficient in providing treatment or assistance for patients requiring SCD. Seventy-five per cent agreed that more emphasis should be placed on clinical training in SCD (n = 76). Thirty-one per cent of students anticipated a high level of confidence in treating patients requiring SCD upon graduation (n = 43), with dental science students feeling the least prepared amongst the dental team. CONCLUSION: Confidence levels of the undergraduate dental team were low with regard to SCD. The existing hands-on clinical training in SCD was deemed insufficient by the respondents. Students believed more emphasis should be placed on SCD training in the undergraduate curriculum.

Does this child really have a penicillin allergy?

Penicillins, the most prescribed paediatric medications worldwide, are also the most commonly reported cause of medication allergy, although this is rarely confirmed. An oral penicillin challenge is considered the gold standard in assessing children with suspected allergy but is seldom performed due to lack of appropriately trained staff and insufficient facilities. We introduced a standardised nurse-led protocol to evaluate children with suspected penicillin allergy fulfilling low risk criteria. In total, 40 children participated, including 22 girls and 18 boys, of which 38 met study criteria. There were 36 (95%) negative challenges completed, allowing these children to be safely prescribed oral penicillin in the future. There were 2 (5%) positive challenges developing similar signs to their initial reaction. This standardised protocol appears to be safe for use and efficient in the evaluation of low risk children with suspected penicillin allergy.

Infants with FPIES to solid food proteins--chicken, rice and oats.

We present two cases of Food Protein Induced Enterocolitis Syndrome (FPIES), a non-IgE mediated food hypersensitivity. FPIES induces severe vomiting 1.5-to-3 hours post ingestion of the offending food, and may be associated with diarrhoea, hypovolemic shock and acidosis. Avoidance of that food will lead to resolution of symptoms and prevents further episodes.

Isoparaffin poisoning in an 18-month-old girl.

We report on an 18 month girl who presented having ingested and aspirated a mouthful of Isoparaffin stored in a bottle of mineral water served to her unwittingly by her grandmother. The patient subsequently developed respiratory distress and multiple bilateral lung abscesses.

Are hospital based notifications enough? Achieving accurate case ascertainment--the Southern Ireland Cerebral Palsy Register (SICPR).

The Southern Ireland Cerebral Palsy Register (SICPR) attempts to identify all cases of cerebral palsy in the Southern Health Board region. Multiple sources of case ascertainment are necessary to achieve a complete register. The aims of the study were to ensure the accuracy of case ascertainment to this register. A postal survey to all general practitioners in the Southern Health Board region did not confirm any new cases of cerebral palsy to the register. We encourage all health professionals to notify our register of any child with suspected cerebral palsy.

Parents' Evaluation of Developmental Status in the Australian day-care setting: developmental concerns of parents and carers.

OBJECTIVE: To trial the Parents' Evaluation of Developmental Status (PEDS) as an instrument for reporting developmental concerns for Australian preschool children. METHOD: A cross-sectional survey of parents and carers of 262 children attending five day-care centres and two kindergartens in Melbourne was conducted between October and November 1999. Parents and carers completed the written PEDS questionnaire, comprising 10 questions eliciting concerns about learning, development and behaviour, and answered questions about the acceptability and use of the PEDS. RESULTS: Of 445 children, 389 were eligible for inclusion. Complete parent and carer PEDS data were available for 262 children (67% response: 47% boys; 53% girls) aged from 18 months to 5 years, 9 months. Most parents found the PEDS questionnaire easy to complete (98%) and likely to be useful to health professionals (89%). Twenty-four children (9%) were classified as being at high-risk of disabilities and 49 (19%) were classified as being at medium-risk of disabilities. Parents of 125 children (48%) reported no concerns. The prevalence of parental concerns was similar to the USA norming sample. Carers reported similar prevalences of concerns. Although overall agreement was high, parent/carer kappa-values were modest, being highest for the gross motor (kappa = 0.40) and social-emotional (kappa = 0.37) domains. CONCLUSIONS: The PEDS is acceptable to parents of Australian preschool children, with a prevalence of significant concerns (i.e. children at high- and medium-risk of developmental problems) that is similar to those in the USA. Further research is needed to assess what factors differentially influence whether a concern is felt in a particular domain for a particular child.

Hereditary cerebral cavernous angiomas: presentation as idiopathic familial epilepsy.

In cavernous angiomas of the brain, abnormally dilated blood vessels are tightly clustered together with no intervening neural parenchyma. Commonly recognised as a sporadic finding, these lesions may also be inherited in an autosomal dominant fashion. This disorder was recognised as a common entity with the advent of MRI. As lesions were often not detected on CT imaging, symptomatic patients presenting with seizures were mistakenly diagnosed with an idiopathic seizure disorder. Seizures are the commonest presenting symptom followed by haemorrhage and focal neurologic deficit. We present another cause of familial epilepsy that also emphasises the importance of MRI as the modality of choice in investigating seizures in children.

New aspects of the blood coagulation cascade, anticoagulants and vein thrombosis in Asia.

PURPOSE: This review describes recent views on blood coagulation and abnormalities of its physiological control that predispose to thrombosis, suggests that venous thrombosis and pulmonary embolism are more prevalent in Asia than was previously thought, and examines recent trials of novel anticoagulants for thrombosis prevention. SOURCES: 'Medline' was used to search for publications in English or with English language abstracts. CONTENT AND CONCLUSIONS: The study of blood coagulation is basic to understanding clotting and bleeding disorders, their prevention and treatment. Tissue factor, factor Xa, and thrombin are pivotal; together with physiological controls (positive and negative feedback loops, and natural anticoagulants) that first enhance thrombin generation but then preserve vessel patency by limiting haemostatic plug formation to areas of injury. Abnormalities in these mechanisms can increase thrombosis risk (thrombophilia). The traditional impression that venous thromboembolism is rare in Asia has been reinforced by the rarity of thrombophilic genetic polymorphisms outside of European populations. Nevertheless, there is increasing evidence for an increasing prevalence of symptomatic vein thrombosis and pulmonary embolism in Asia, and that thrombosis rates in 'high risk' clinical settings among elderly patients (as after major joint surgery or a stroke) now approach levels reported from the West. This indicates the need for greater clinical awareness of these conditions. Drugs now used routinely for thrombosis prevention in the West (especially low molecular weight heparins) are effective and relatively safe. New anticoagulants were even more effective in recent trials. There is urgent need for studies in Asia that define the locally relevant benefits and hazards of the increasing range of agents now available.