Icatibant in angiotensin-converting enzyme (ACE) inhibitor-associated angioedema.

BACKGROUND: Angioedema occurs in up to 2% of those taking angiotensin-converting enzyme (ACE) inhibitors. Upper airway angioedema may potentially require endotracheal intubation or cricothyrotomy, and is usually unresponsive to adrenaline. The bradykinin receptor antagonist icatibant is proven to be effective in the treatment of acute attacks of hereditary angioedema, and has also been reported effective in the treatment of angioedema associated with ACE inhibitors. AIM: To describe the use of icatibant for ACE inhibitor-associated airway angioedema. METHODS: We treated 13 consecutive emergency department (ED) patients, who had not improved with adrenaline and/or corticosteroids, with icatibant 30 mg subcutaneously for ACE inhibitor-associated upper respiratory tract angioedema according to an agreed protocol. RESULTS: Four patients were intubated in the ED either before or after receiving icatibant; three of these were extubated within 24 h of treatment. Eight patients received early icatibant and did not require intubation. The time from onset of airway angioedema to ED presentation ranged from 1 h to 3 days (median 4 h); from ED presentation to receiving icatibant, from 30 minutes to 3 days (median 3 h); and to onset of symptom improvement after icatibant, 15 minutes to 7 h (median 2 h). One patient received a second dose of icatibant. CONCLUSION: All patients improved after receiving icatibant, consistent with its bradykinin receptor blocking mechanism. Icatibant rapidly reversed symptoms, and appeared to avert the need for intubation or expedite extubation. Timely use of icatibant in ACE inhibitor-associated angioedema may avert the need for invasive airway procedures and intensive care unit admission.

Recommendations for locus-specific databases and their curation.

Expert curation and complete collection of mutations in genes that affect human health is essential for proper genetic healthcare and research. Expert curation is given by the curators of gene-specific mutation databases or locus-specific databases (LSDBs). While there are over 700 such databases, they vary in their content, completeness, time available for curation, and the expertise of the curator. Curation and LSDBs have been discussed, written about, and protocols have been provided for over 10 years, but there have been no formal recommendations for the ideal form of these entities. This work initiates a discussion on this topic to assist future efforts in human genetics. Further discussion is welcome.

A structured simple form for ordering genetic tests is needed to ensure coupling of clinical detail (phenotype) with DNA variants (genotype) to ensure utility in publication and databases.

Researchers and clinicians ideally need instant access to all the variation in their gene/locus of interest to efficiently conduct their research and genetic healthcare to the highest standards. Currently much key data resides in the laboratory books or patient records around the world, as there are many impediments to submitting this data. It would be ideal therefore if a semiautomated pathway was available, with a minimum of effort, to make the deidentified data publicly available for others to use. The Human Variome Project (HVP) meeting listed 96 recommendations to work toward this situation. This article is planned to initiate a strategy to enhance the collection of phenotype and genotype data from the clinician/diagnostic laboratory nexus. Thus, the aim is to develop universally applicable forms that people can use when investigating patients for each inherited disease, to assist in satisfying many of the recommendations of the HVP Meeting [Cotton et al., 2007]. We call for comment and collaboration in this article.

Interdisciplinary dissemination and implementation research to advance translational science: Challenges and opportunities.

INTRODUCTION: Interdisciplinary collaboration is a critical component of translation, dissemination, implementation, and improvement (TDII) science. Yet, little is known about effective frameworks and practices regarding interdisciplinary research in TDII. METHODS: This study drew on data collected from an expert panel during a regional symposium. RESULTS: Findings highlight facilitators and barriers to stimulating interdisciplinary TDII research in different domains: intrapersonal, interpersonal, organizational, power and hierarchy, physical environment, and communication and language. CONCLUSIONS: Findings have significant implications for TDII of clinical practices.

Gene flow versus local adaptation in the northern acorn barnacle, Semibalanus balanoides: insights from mitochondrial DNA variation.

In reciprocal transplant experiments, Bertness and Gaines (1993) found that Semibalanus balanoides juveniles that had settled in an upper Narragansett Bay estuary survived better in that estuary that did juveniles from coastal localities. The observed pattern of survivorship led to the claim that local adaptation may result from a combination of limited gene flow between and strong selection within these habitats. Here we test the hypothesis that limited gene flow has led to habitat-specific population differentiation using sequence and restriction fragment length polymorphism analyses of the mitochondrial DNA D-loop region of S. balanoides. Samples were analyzed from replicated coastal and estuary localities in both Narragansett Bay, Rhode Island, and Damariscotta River, Maine. The patterns of F(ST) indicate that gene flow between coast and estuary is extensive (Nm > 100) and is not lower in the estuary with lower flushing rates (Narragansett Bay). Given the high estimate of genetic exchange, adaptations for unpredictable environments seem more likely than local adaptation in this species because loci that respond to selection in one generation are essentially homogenized by the next seasons' settlement. Nevertheless, these estimates of neutral gene flow can help identify the strength of selection necessary for local adaptation to accumulate in Semibalanus.

Automated linkage analysis in psychiatric disorders.

A genome-wide search for linkage of microsatellite markers to chromosomal loci containing genes responsible for the major psychoses is a laborious task which can be carried out with greater speed and economy by introducing automation to several steps in the procedure. We describe the use of the Automated Linkage Preprocessor (ALP) program for the computer analysis of the waveform generated by fluorescein-labelled markers after electrophoretic separation. (To obtain a copy send a request to A.F. Brown at the below MRC address or use Anonymous FTP to ftp.hgu.mrc.ac.uk. Software is in directory pub/ALP). The program runs on a PC in the Microsoft Windows environment, and is used in conjunction with an automated laser fluorescence (ALF) sequencer (Pharmacia) and its Fragment Manager software to detect and size the PCR products, filter out peaks of fluorescence due to nonallele fragments, and generate genotypes in a format suitable for direct input to standard linkage analysis programs. The method should offer the advantages of speed, accuracy, and reduced cost. Its use in linkage studies in a large family with manic-depressive illness is discussed.

Hormone replacement therapy for African American women: missed opportunities for effective intervention.

OBJECTIVES: Because of the potential benefits and risks of hormone replacement therapy (HRT), information about the efficacy of HRT in different groups of women is important to patients and providers. The objectives of this study were to review the evidence on the benefits and risks of HRT in African American women and to present a quantitative analysis of the potential reduction in mortality from osteoporotic fractures and coronary heart disease and the potential increase in risk of breast and endometrial cancer. METHODS: A MEDLINE search of English-language observational studies and clinical trials on the effects of HRT on osteoporotic fractures and coronary heart disease (CHD) was conducted for the time period from 1966 to September 1998. Using available CHD mortality data for African American women and white women, potential reductions in mortality with HRT were explored for African American and white women. RESULTS: In the 30 studies on CHD and HRT, African American women were known to comprise only 173 (0.1%) of 148,437 participants. In 11 studies of HRT and osteoporotic fractures, only 128 (0.4%) of 40,299 participants were known to be African American women. An analysis of CHD mortality by decade intervals indicated that African American women, aged 55 to 64, are more likely to die from CHD each year than white women. Despite a lower incidence of breast and endometrial cancer among African American women, the mortality rates of African American women with these cancers is higher compared with white women. CONCLUSIONS: With the higher underlying CHD mortality rate among African American women, HRT is an important potential preventive therapy. The absence of African American women and other non-white women from clinical studies of HRT makes it difficult to fully assess the risks and benefits of HRT in this group of women.

Design, characterisation and preliminary clinical evaluation of a novel mucoadhesive topical formulation containing tetracycline for the treatment of periodontal disease.

This study describes the formulation, characterisation and preliminary clinical evaluation of mucoadhesive, semi-solid formulations containing hydroxyethylcellulose (HEC, 1-5%, w/w), polyvinylpyrrolidine (PVP, 2 or 3%, w/w), polycarbophil (PC, 1 or 3%, w/w) and tetracycline (5%, w/w, as the hydrochloride). Each formulation was characterised in terms of drug release, hardness, compressibility, adhesiveness (using a texture analyser in texture profile analysis mode), syringeability (using a texture analyser in compression mode) and adhesion to a mucin disc (measured as a detachment force using the texture analyser in tensile mode). The release exponent for the formulations ranged from 0.78+/-0.02 to 1. 27+/-0.07, indicating that drug release was non-diffusion controlled. Increasing the concentrations of each polymeric component significantly increased the time required for 10 and 30% release of the original mass of tetracycline, due to both increased viscosity and, additionally, the unique swelling properties of the formulations. Increasing concentrations of each polymeric component also increased the hardness, compressibility, adhesiveness, syringeability and mucoadhesion of the formulations. The effects on product hardness, compressibility and syringeability may be due to increased product viscosity and, hence, increased resistance to compression. Similarly, the effects of these polymers on adhesiveness/mucoadhesion highlight their mucoadhesive nature and, importantly, the effects of polymer state (particularly PC) on these properties. Thus, in formulations where the neutralisation of PC was maximally suppressed, adhesiveness and mucoadhesion were also maximal. Interestingly, statistical interactions were primarily observed between the effects of HEC and PC on drug release, mechanical and mucoadhesive properties. These were explained by the effects of HEC on the physical state of PC, namely swollen or unswollen. In the preliminary clinical evaluation, a formulation was selected that offered an appropriate balance of the above physical properties and contained 3% HEC, 3% PVP and 1% PC, in addition to tetracycline 5% (as the hydrochloride). The clinical efficacy of this (test) formulation was compared to an identical tetracycline-devoid (control) formulation in nine periodontal pockets (>/=5 mm depth). One week following administration of the test formulation, there was a significant improvement in periodontal health as identified by reduced numbers of sub-gingival microbial pathogens. Therefore, it can be concluded that, when used in combination with mechanical plaque removal, the tetracycline-containing semi-solid systems described in this study would augment such therapy by enhancing the removal of pathogens, thus improving periodontal health.

Rheological characterization of bioadhesive, antimicrobial, semisolids designed for the treatment of periodontal diseases: transient and dynamic viscoelastic and continuous shear analysis.

This study examined the creep behavior and oscillatory and flow properties of tetracycline-containing, bioadhesive semisolid formulations, designed for localized treatment of periodontal disease. Formulations were prepared containing hydroxyethylcellulose (HEC, 1, 3, or 5% w/w), poly(vinylpyrrolidone) (PVP, 2 or 3% w/w), polycarbophil (PC, 1 or 3% w/w), and tetracycline (5% w/w, as the hydrochloride). In creep analysis, each formulation exhibited several distinct regions that were mathematically modelled using a multi-element Voigt model with a residual spring and dashpot. Increasing the concentrations of each polymeric component decreased the elastic compliance (J(0)) yet increased the residual viscosity. In oscillatory analysis, increased polymer concentrations increased the storage modulus (G'), the loss modulus (G") and the dynamic viscosity (eta'), yet decreased the loss tangent (tan delta). The relationships between G' or G" and frequency were observed to plateau at higher frequencies, which is indicative of polymer chain entanglement and network formation. With the exception of formulations containing 1% HEC, the formulations were elastic (tan delta < 1), with large G' and small J(0) values. All formulations exhibited pseudoplastic flow with thixotropy. Increasing concentrations of each polymeric component increased the zero-shear viscosity (determined using the Cross model) and was further evidence of polymer chain entanglement. Formulations containing 1% w/w HEC possessed excellent flow properties, however, their thixotropic behavior and essentially elastoviscous nature (large J(0) and tan delta) would be disadvantageous for use in the treatment of periodontal disease because of rapid removal from the pocket and relatively uncontrolled drug release. Despite their advantageous viscoelastic properties, the flow properties of formulations containing 5% w/w HEC were inappropriate, rendering administration through a periodontal syringe potentially difficult. Based on their rheological behavior, formulations containing HEC (3% w/w), PVP (2 or 3% w/w), and PC (1 or 3% w/w) would be suitable for clinical application. However, consideration of other physicochemical properties (e.g., bioadhesion, drug release kinetics) must be performed prior to selection of the most suitable formulation for clinical examination. This study has highlighted the successful complimentary application of creep analysis and oscillatory and flow rheometry for the characterization and development of bioadhesive semisolid formulations for the treatment of periodontal disease.

Examination of the physical state of chlorhexidine within viscoelastic, bioadhesive semisolids using raman spectroscopy.

This study examined the effects of polymeric components on the physical state of chlorhexidine within bioadhesive, semisolid formulations using Raman spectroscopy. Semisolid formulations were prepared in which chlorhexidine base (CHX, 5%w/w, particle size <63 microm) was dispersed in aqueous (phosphate-buffered saline, pH 6.8) polymer matrices consisting of one or more polymeric components, namely HEC (3%w/w), PVP (3%), and PC (PC, 3%). Raman spectra were recorded using 785-nm excitation and were typically accumulated for 360 s. The Raman spectra were dominated by the presence of CHX. The spectra of CHX in HEC and in HEC/PVP gels were indistinguishable from that for solid CHX as a result of the insolubility of CHX in these formulations. However, in systems containing PC and CHX, there was a shift in the strongest band from 1564 cm(-1) to 1608 cm(-1), which may be accredited to protonation of the basic CHX by the numerous carboxylic acidic groups on PC. Identical shifts in the band positions were observed when this protonation was modeled using ethanoic acid, supporting the view that there was a simple acid base reaction between PC and CHX. However, there were notable differences in the relative intensities of the peaks from these samples, with the spectrum of CHX in the PC matrix displaying properties intermediate between those of CHX dissolved in ethanoic acid and solid CHX diacetate. This may be accredited to the limited solubility of the CHX-PC ion pair. In matrices containing HEC and PC, no peak was observed at 1564 cm(-1), whereas the intensity of the peak at 1608 cm(-1) was increased. Therefore, in these formulations CHX was completely converted to the di-cation as a result of the synergistic effects of PC (which protonated CHX) and HEC (which solubilized the di-cation). In the absence of either HEC or PC, complete protonation was not achieved. It is suggested that this enhancement of solubility of H(2)CHX(2+) may be due to hydrogen bonding, given the hydroxylated nature of HEC. In conclusion, this study has shown the applicability of Raman spectroscopy for both the analysis of opaque, semisolid formulations and, additionally, for the examination of the state of therapeutic agents within such matrices. In particular, using Raman spectroscopy, it was uniquely possible to identify the roles of various polymeric components on both the ionization and solubilization of CHX within aqueous semisolid systems.

Quantitative Trait Loci in Sweet Corn Associated with Partial Resistance to Stewart's Wilt, Northern Corn Leaf Blight, and Common Rust.

ABSTRACT Partial resistance to Stewart's wilt (Erwina stewartii, syn. Pantoea stewartii), northern corn leaf blight (NCLB) (Exserohilum turcicum), and common rust (Puccinia sorghi) was observed in an F(2:3) population developed from a cross between the inbred sweet corn lines IL731a and W6786. The objective of this study was to identify quantitative trait loci (QTL) associated with partial resistance using restriction fragment length polymorphic markers. Phenotypic data were collected for 2 years for Stewart's wilt, NCLB, and common rust but, due to significant family-environment interaction, analysis was conducted individually on data from each year. In 2 years of evaluation for the three diseases, a total of 33 regions in the maize genome were associated with partial resistance describing from 5.9 to 18% of the total phenotypic variability. Of six regions common in both years, three were associated with partial resistance to Stewart's wilt (chromosomes 4:07, 5:03, and 6:04), one was associated with NCLB (chromosome 9:05), and two were associated with common rust (chromosomes 2:04 and 3:04). The rust QTL on 3S mapped to within 20 cM of the rp3 locus and explained 17.7% of the phenotypic variability. Some of the QTL associated with partial resistance to the three diseases have been reported previously, and some are described here for the first time. Results suggest it may be possible to consolidate QTL from various elite backgrounds in a manner analogous to the pyramiding of major resistance genes. We also report here on two QTL associated with anthocyanin production on chromosomes 10:6 and 5:03 in the general location of the a2 gene.

Variation of glucosinolates in vegetable crops of Brassica oleracea.

Glucosinolates were evaluated in 5 groups and 65 accessions of Brassica oleracea (50 broccoli, 4 Brussels sprouts, 6 cabbage, 3 cauliflower, and 2 kale) grown under uniform cultural conditions. Glucosinolates and their concentrations varied among the different groups and within each group. The predominant glucosinolates in broccoli were 4-methylsulfinylbutyl glucosinolate (glucoraphanin), 3-butenyl glucosinolate (gluconapin), and 3-indolylmethyl glucosinoate (glucobrassicin). Glucoraphanin concentration in broccoli ranged from 0.8 micromol g(-1) DW in EV6-1 to 21.7 micromol g(-1) DW in Brigadier. Concentrations of the other glucosinolates in broccoli varied similarly over a wide range. In Brussels sprouts, cabbage, cauliflower, and kale, the predominant glucosinolates were sinigrin (8.9, 7.8, 9.3, and 10.4 micromol g(-1) DW, respectively) and glucobrassicin (3.2, 0.9, 1.3, and 1.2 micromol g(-1) DW, respectively). Brussels sprouts also had significant amounts of gluconapin (6.9 micromol g(-1) DW). Wide variations in glucosinolate content among genotypes suggest differences in their health-promoting properties and the opportunity for enhancement of their levels through genetic manipulation.

Ciguatera poisoning: an example of a public health challenge.

Ciguatera is a common form of fish poisoning, endemic in all nations of the Pacific region. Several thousand cases have been notified to Queensland authorities over a 10-year period. However, many cases remain undiagnosed and most go unreported. The public health implications include raising awareness of the condition, ensuring that ciguatera is considered in differential diagnosis and promoting better documentation and reporting.

Ciguatera poisoning: a global issue with common management problems.

Ciguatera poisoning, a toxinological syndrome comprising an enigmatic mixture of gastrointestinal, neurocutaneous and constitutional symptoms, is a common food-borne illness related to contaminated fish consumption. As many as 50000 cases worldwide are reported annually, and the condition is endemic in tropical and subtropical regions of the Pacific Basin, Indian Ocean and Caribbean. Isolated outbreaks occur sporadically but with increasing frequency in temperate areas such as Europe and North America. Increase in travel between temperate countries and endemic areas and importation of susceptible fish has led to its encroachment into regions of the world where ciguatera has previously been rarely encountered. In the developed world, ciguatera poses a public health threat due to delayed or missed diagnosis. Ciguatera is frequently encountered in Australia. Sporadic cases are often misdiagnosed or not medically attended to, leading to persistent or recurrent debilitating symptoms lasting months to years. Without treatment, distinctive neurologic symptoms persist, occasionally being mistaken for multiple sclerosis. Constitutional symptoms may be misdiagnosed as chronic fatigue syndrome. A common source outbreak is easier to recognize and therefore notify to public health organizations. We present a case series of four adult tourists who developed ciguatera poisoning after consuming contaminated fish in Vanuatu. All responded well to intravenous mannitol. This is in contrast to a fifth patient who developed symptoms suggestive of ciguatoxicity in the same week as the index cases but actually had staphylococcal endocarditis with bacteraemia. In addition to a lack of response to mannitol, clinical and laboratory indices of sepsis were present in this patient. Apart from ciguatera, acute gastroenteritis followed by neurological symptoms may be due to paralytic or neurotoxic shellfish poisoning, scombroid and pufferfish toxicity, botulism, enterovirus 71, toxidromes and bacteraemia. Clinical aspects of ciguatera toxicity, its pathophysiology, diagnostic difficulties and epidemiology are discussed.

Paediatric emergency department anaphylaxis: different patterns from adults.

BACKGROUND AND AIMS: Data on acute paediatric anaphylaxis presentations to the emergency department (ED) are limited. All allergic presentations to one Australian paediatric ED were studied to determine epidemiological, clinical, and outcome data. METHODS: Retrospective, case based study of patients under 16 years attending one metropolitan, paediatric teaching hospital ED in Australia over three years. The medical records of patients presenting with generalised allergic reactions and anaphylaxis satisfying relevant ICD-9-CM diagnostic codes were studied. The incidence, age, sex ratio, co-morbidities, likely aetiology, clinical features, management, and disposal were determined. RESULTS: A total of 526 children with generalised allergic reactions, and 57 with anaphylaxis were included in the study. This represented incidences of 9.3:1000 ED presentations for generalised allergic reactions and 1:1000 for anaphylaxis. There were no fatalities. In anaphylaxis cases, a cause was recognised in 68.4%. Cutaneous features were present in 82.5%. A past history of asthma was reported in 36.8%. Adrenaline was used in 39.3% of severe anaphylaxis cases. The ED alone definitively cared for 97.8% of all patients. Follow up was inadequate in cases of anaphylaxis. CONCLUSIONS: This is the first reported incidence figure for paediatric anaphylaxis ED presentations in Australia, and is less than that reported in adults in the same local population. However, the incidence of generalised allergic reactions of 9.3:1000 was greater than in the adults. Virtually all paediatric allergic cases may be managed in the ED alone, provided that the importance of specialist follow up, particularly for severe anaphylaxis, is recognised.

Outbreeding Depression as a Cost of Dispersal in the Harpacticoid Copepod, Tigriopus californicus.

The costs of dispersing can be evaluated in terms of genetic expenses. These costs are associated with outbreeding depression. In the supralittoral zone of the rocky shore, both outbreeding depression and inbreeding depression may be important in determining whether an organism should disperse. These genetic costs were investigated in the harpacticoid copepod, Tigriopus californicus, which inhabits supralittoral pools. Matings between individuals from different pools were performed in the lab. The results suggest high costs to dispersing.

Delayed diagnosis of red-back spider envenomation: a timely reminder.

A case of the delayed diagnosis of envenomation by the redback spider (Latrodectus mactans hasselti) is reported. The common and more unusual presentations then are discussed, together with treatment guide-lines, and comparison is made with the management of latrodectism in the United States as a result of envenomation by the black-widow spider.