bluuebunny/crossref_metadata_2025 huggingface dataset:
Virchow and his triad: a question of attribution
Authors: Bagot Catherine N. , Arya Roopen
Published: September 2008

Virchow’s triad describes three factors that contribute to the development of venous thrombosis: hypercoagulability, stasis and endothelial injury. Yet, extensive review of the historical literature casts doubt on the existence of a triad described by Virchow in the form it is currently quoted throughout contemporary medical literature. Certainly his work involved extensive study of venous thrombosis and pulmonary embolism, with these two terms being coined by Virchow, but a triad of factors relating to the development of venous thrombosis is elusive. Interestingly, Virchow only began to be routinely credited with this triad one hundred years after publication of his work on venous thrombosis. This acknowledgement coincided with the accumulation of experimental evidence for the role these factors play in thrombogenesis. Controversial as the origins of Virchow’s triad might be, it is apt given his substantial contribution to our knowledge of venous thromboembolism, and the fact that the triad continues to be clinically relevant today that a triad pertaining to Virchow should remain.
History of bloodletting by phlebotomy
Authors: Parapia Liakat Ali
Published: September 2008

Bloodletting by phlebotomy has been an obsession with medical practitioners for thousands of years, causing countless suffering to patients, initially for unproven indications and more recently for diagnoses. The approach to medical evidence‐based phlebotomy has been a triumph for scientifically inclined practitioners. Progress, primarily achieved since the nineteenth century, has been in spite of considerable opposition from the medical establishment. The evaluation of phlebotomy as a useful tool continues and no doubt further myths will be dispelled. The history of bloodletting remains one of the greatest stories of medical progress, not because of new discoveries but mainly by persistent unbiased audit.
High third generation/second generation PTH ratio in a patient with parathyroid carcinoma: clinical utility of third generation/second generation PTH ratio in patients with primary hyperparathyroidism
Authors: Caron Philippe , Maiza Jean Christophe , Renaud Claire , Cormier Catherine , Barres Béatrice Herbault , Souberbielle Jean Claude
Published: September 2008

Background  Primary hyperparathyroidism (PHP) is caused by parathyroid adenomas or hyperplasia, and occasionally by parathyroid carcinoma. Recently a high third generation/second generation PTH ratio has been observed in some patients with parathyroid carcinoma.

Patients and methods  We report the case of a 60‐year old woman who was presented a fourth episode of PTH‐related hypercalcaemia due to a parathyroid carcinoma. Serum PTH levels were measured using a second generation assay and a third generation assay before, 4 and 7 months after the fourth surgery. Then, PTH levels were measured in 294 osteoporotic normocalcaemic patients as well as in 30 consecutive PHP patients.

Results  Before surgery of the patient with parathyroid carcinoma, second generation PTH was 229 pg/ml, third generation PTH was 675 pg/ml and third generation/second generation PTH ratio was 2·95. Four and 7 months after surgery the third generation/second generation PTH ratio was 0·70 and 0·66, respectively. All osteoporotic patients had a normal third generation/second generation PTH ratio (0·585 ± 0·118) whereas only one patient (3·3%) with PHP had a third generation/second generation PTH ratio > 1 (1·54).

Conclusion  A high third generation/second generation PTH ratio could be observed in patients with parathyroid carcinoma, is uncommon in benign PHP and is absent in osteoporotic patients without PHP. Therefore, PTH level can be measured using second and third generation assays in some PHP patients, and a specific surgical protocol for possible parathyroid carcinoma could be discussed in patients with a high third generation/second generation PTH ratio.
Coupling ecosystem and individual‐based models to simulate the influence of environmental variability on potential growth and survival of larval sprat (Sprattus sprattus L.) in the North Sea
Authors: DAEWEL UTE , PECK MYRON A. , KÜHN WILFRIED , ST. JOHN MICHAEL A. , ALEKSEEVA IRINA , SCHRUM CORINNA
Published: September 2008

To investigate the impact of changing environmental conditions in the North Sea on the distribution and survival of early life stages of a marine fish species, we employed a suite of coupled model components: (i) an Eulerian coupled hydrodynamic/ecosystem (Nutrients, Phyto‐, Zooplankton, Detritus) model to provide both 3‐D fields of hydrographical properties, and spatially and temporally variable prey fields; (ii) a Lagrangian transport model to simulate temporal changes in cohort distribution; and (iii) an individual‐based model (IBM) to depict foraging, growth and survival of fish early life stages. In this application, the IBM was parameterized for sprat (Sprattus sprattus L.) and included non‐feeding (egg and yolk‐sac larval) stages as well as foraging and growth subroutines for feeding (post‐yolk sac) larvae. Sensitivity analyses indicated that the angle of visual acuity, assimilation efficiency and the maximum food consumption rate were the most critical intrinsic model parameters. As an example, we applied this model system for 1990 in the North Sea. Results included not only information concerning the interplay of temperature and prey availability on larval fish survival and growth but also information on mechanisms underlying larval fish aggregation within frontal zones. The good agreement between modelled and in situ estimates of sprat distribution and growth rates in the German Bight suggested that interconnecting these different models provided an expedient tool to scrutinize basic processes in fish population dynamics.
Movement and behaviour of large southern bluefin tuna (Thunnus maccoyii) in the Australian region determined using pop‐up satellite archival tags
Authors: PATTERSON TOBY A. , EVANS KAREN , CARTER THOR I. , GUNN JOHN S.
Published: September 2008

Pop‐up satellite archival tags (PSATs) were deployed on 52 large (156–200 cm length to caudal fork) southern bluefin tuna (Thunnus maccoyii) in the western Tasman Sea during the austral winters of 2001–2005. Southern bluefin tuna (SBT) were resident in the Tasman Sea for up to 6 months with movements away from the tagging area occurring at highly variable rates. The data indicated a general tendency for SBT to move south from the tagging area in the Western Tasman Sea. Four individuals migrated west along the southern continental margin of Australia and into the Indian Ocean. Three individuals moved east into the central Tasman Sea, with one individual reaching New Zealand. We also describe the first observed migration of an SBT from the Tasman Sea to the Indian Ocean spawning grounds south of Indonesia. Individuals spent most of their time relatively close to the Australian coast, with an estimated 84% of time spent in the Australian Fishing Zone. SBT favored temperatures between 19 and 21°C, adjusting their depth to the vertical temperature distribution. Distinct diurnal diving patterns were observed and adjustment of depth to maintain constant ambient light levels over a 24‐h period. The findings of this study are a significant advance toward greater understanding of the spatial dynamics of large SBT and understanding the connectivity between distant regions of their distribution.
Establishing climate–growth relationships for yelloweye rockfish (Sebastes ruberrimus) in the northeast Pacific using a dendrochronological approach
Authors: BLACK BRYAN A. , BOEHLERT GEORGE W. , YOKLAVICH MARY M.
Published: September 2008

We applied dendrochronology (tree‐ring) methods to develop multidecadal growth chronologies from the increment widths of yelloweye rockfish (Sebastes ruberrimus) otoliths. Chronologies were developed for the central California coast, a site just north of Vancouver Island, British Columbia, and at Bowie Seamount west of the Queen Charlotte Islands, British Columbia. At each site, synchronous growth patterns were matched among otoliths via the process of cross‐dating, ensuring that the correct calendar year was assigned to all increments. Each time series of growth‐increment measurements was divided by the values predicted by a best‐fit negative exponential function, thereby removing age‐related trends. These detrended time series were averaged into a master chronology for each site, and chronologies were correlated with monthly averages of sea surface temperatures, upwelling, the Northern Oscillation Index, and the Pacific Decadal Oscillation. The two northern growth chronologies positively correlated with indices of warm ocean conditions, especially from the prior summer through the spring of the current year. During the same period, the California chronology positively correlated with indices of cool ocean conditions, indicating an opposing productivity regime for yelloweye rockfish between the California Current and the Gulf of Alaska. Overall, this study demonstrates how tree‐ring techniques can be applied to quickly develop annually resolved chronologies and establish climate–growth relationships across various temporal and spatial scales.
Density‐independent and density‐dependent factors affecting temporal changes in spatial distributions of eastern Bering Sea flatfish
Authors: SPENCER PAUL D.
Published: September 2008

The general warming of the eastern Bering Sea (EBS) and the wide range of abundance exhibited by several eastern Bering Sea flatfish motivated an examination of how density‐dependent and density‐independent factors may influence the spatial distributions of EBS flatfish. In this study, EBS trawl survey data from 1982 to 2006 were used to examine how temporal changes in the distributions of six flatfish species groups [yellowfin sole (Limanda aspera), rock sole (Lepidopsetta sp.), flathead sole (Hippoglossoides sp.), Alaska plaice (Pleuronectes quadrituberculatus), arrowtooth flounder (Atheresthes sp.), and Greenland turbot (Reinhardtius hippoglossoides)] are related to temporal changes in the location of the ‘cold pool’ (bottom water < 2°C), and how the area occupied by flatfish are related to the cold pool and population abundance. Rock sole and flathead sole distributions have generally moved northwest since 1982 and are significantly correlated with the movement of the cold pool, whereas arrowtooth flounder avoid the cold pool and their area occupied is inversely related to the size of the cold pool. The area occupied by arrowtooth flounder and rock sole are also significantly related to stock abundance. Multivariate statistical models indicate that the location of rock sole is more strongly related to stock abundance than to the cold pool, whereas the area occupied by arrowtooth flounder is more strongly related to the area of the cold pool rather than abundance. The temperatures occupied by several flatfish stocks indicate a substantial variability in suitable temperatures. These results suggest that a complex suite of density‐dependent and density‐independent factors may determine the response of EBS flatfish spatial distributions to increasing temperatures.
Japanese sardine (Sardinops melanostictus) mortality in relation to the winter mixed layer depth in the Kuroshio Extension region
Authors: NISHIKAWA HARUKA , YASUDA ICHIRO
Published: September 2008

A drastic population change in Japanese sardine (Sardinops melanostictus) has been noted as being related to winter sea surface temperature (SST) in the Kuroshio Extension region. The former studies suggest two possible explanations. One is that temperature itself affects sardine. The other is that SST represents the environmental change of the Kuroshio Extension region and other causes directly affecting sardine. In this study, we found that sardine mortality from post‐larva to age 1 negatively correlated with the winter mixed layer depth (MLD) in the Kuroshio Extension region from 1979 to 1993. During the period of a deep winter mixed layer (during the early 1980s), sardine mortality was low, whereas mortality was high when the winter mixed layer was shallow (during the late 1980s to early 1990s). By using a lower trophic‐level ecosystem model forced by the observed time series of MLD, SST, light intensity and nutrient data, we found that the estimated spring zooplankton density drastically varies from year to year and has a significant negative correlation with sardine mortality. The inter‐annual variation of spring zooplankton density is caused by the winter MLD variation. During the deep winter mixed layer years, a phytoplankton bloom occurs in spring, whereas during the shallow winter mixed layer years, the bloom occurs in winter. The results of our study suggest that the decline in the Japanese sardine population during the late 1980s to early 1990s was due to an insufficient spring food supply in the Kuroshio Extension region where sardine larvae and juvenile are transported.
Dialysis in the haemophilia patient: a practical approach to care
Authors: LAMBING A. , KURIAKOSE P. , LANZON J. , KACHALSKY E.
Published: September 2008

Summary.  The major focus of care for patients with haemophilia is to ensure health with minimal joint dysfunction. As this population ages, additional coexisting conditions can develop including rare instances of nephrotic syndrome in haemophilia B inhibitor patients undergoing immune tolerance, hypertension, diabetes, and coronary artery disease, all of which can adversely affect the renal system over time. In haemophilia patients, co‐infected with HIV and hepatitis C, these conditions can also increase the risk of renal problems resulting in the need for dialysis. This article provides a practical approach for the haemophilia patient who requires dialysis and outlines the decision making process to ensure a positive outcome. The goal of care is to optimize dialysis treatment without increasing the bleeding risk.
Haemophilia A: patients’ knowledge level of treatment and sources of treatment‐related information
Authors: MILLER K. L. , GUELCHER C. , TAYLOR A.
Published: September 2008

Summary.  There are minimal or no data regarding the extent of patient and/or parent/legal guardian/caregiver knowledge about haemophilia A and its treatment, their sources for this information, or their preferred methods of communication. A pilot study using a survey instrument developed by haemophilia nurse coordinators was conducted at a national meeting to obtain information on these topics. A total of 187 surveys were completed. More than 80% of respondents reported high and high‐medium knowledge levels about how haemophilia A is inherited, types of bleeding, identifying and treating bleeding emergencies, prophylaxis and on‐demand treatment, travel and vacation planning and guidelines for exercise and sports activities. However, a lower proportion of respondents (<65%) reported high and high‐medium knowledge levels for drug‐related topics. The majority of respondents (>55%) consistently ranked healthcare providers as the most useful source of information for most topics related to haemophilia A. This pilot survey of well‐informed respondents identified deficits in knowledge regarding factor concentrates for the treatment of haemophilia A and highlights the need for healthcare providers to provide more information about factor concentrates, insurance coverage for treatments, and community and educational resources. Additional study is necessary to determine the extent of knowledge deficits and how best to address them in the haemophilia A population as a whole. Other areas of study needed are whether information deficits and delivery of information vary by age or by other factors.
Subepithelial apoptosis in normal caecal biopsy specimens is primarily an age‐related phenomenon
Authors: Wong N A C S , Jenkins R , Reid G J
Published: September 2008

Aims:  To determine whether prominent subepithelial apoptosis in otherwise normal caecal endoscopic biopsy specimens has any clinical significance.

Methods and results:  Calculating the average number of subepithelial apoptotic bodies per intercrypt space [i.e. a subepithelial apoptotic index (SAI)] was found to reflect accurately and reproducibly the density of subepithelial apoptosis in a colonic biopsy specimen. The SAIs of 124 histologically normal caecal biopsy specimens from adult patients showed a positively skewed normal distribution without bimodality. The clinical details of patients with specimens in the top quartile of this distribution were compared with those of patients in the bottom quartile. Patients in the top quartile were found to be older and more likely to suffer with ulcerative colitis than those in the bottom quartile. However, controlling for age removed the association between SAI and ulcerative colitis. The SAIs of 144 caecal biopsy specimens (including 20 paediatric cases) showed a positive correlation with patient age.

Conclusions:  Subepithelial apoptosis in normal caecal biopsy specimens appears to be an age‐related phenomenon with no demonstrable clinical significance.
High frequency of RASSF1A and RARb2 gene promoter methylation in morphologically normal endometrium adjacent to endometrioid adenocarcinoma
Authors: Arafa M , Kridelka F , Mathias V , Vanbellinghen J‐F , Renard I , Foidart J‐M , Boniver J , Delvenne P
Published: September 2008

Aims:  To identify a DNA methylation signature of endometrioid carcinoma of the endometrium (EEC) in the early stages of endometrial carcinogenesis.

Methods and results:  Archival biopsy specimens of 39 EECs, 14 cases of atypical hyperplasia (AH), 11 histologically normal endometrial tissues adjacent to EECs and 24 normal control endometrial samples were retrieved. The cases were tested by quantitative methylation‐specific polymerase chain reaction with primers hybridizing in the promoter regions of five genes frequently methylated in human cancer (RASSF1A, RARb2, P16, MGMT and GSTPi). Twenty‐nine of 39 (74%) EECs and 7/14 (50%) AHs were methylated for the RASSF1A gene, whereas 17/39 (44%) EECs and 6/14 (43%) AHs were positive for the methylation of the RARb2 gene. No significant results were obtained for the other genes (P16, MGMT and GSTPi). Interestingly, 4/11 (36%) and 6/11 (55%) histologically normal endometrial tissues adjacent to EEC showed, respectively, RASSF1A and RARb2 gene methylation. Furthermore, these 11 specimens were microsatellite stable and showed similar proliferative, cell cycle and apoptotic mean labelling indices as the normal endometrial control tissues.

Conclusions:  Promoter region methylation of RASSF1A and RARb2 genes is an early event in endometrial carcinogenesis.
New insights into intra‐ and intermolecular interactions of immunoglobulins: crystal structure of mouse IgG2b‐Fc at 2·1‐Å resolution
Authors: Kolenko Petr , Dohnálek Jan , Dušková Jarmila , Skálová Tereza , Collard Renata , Hašek Jindřich
Published: September 2008

The structure of the Fc fragment of monoclonal antibody IgG2b from hybridom M75 of Mus musculus has been determined by single crystal X‐ray diffraction. This is the first report of the structure of the murine immunoglobulin isotype IgG2b. The structure refined at 2·1 Å resolution provides more detailed structural information about native oligosaccharides than was previously available. High‐quality Fourier maps provide a clear identification of α‐l‐fucose with partial occupancy in the first branch of the antennary oligosaccharides. A unique Fc:Fc interaction was observed at the CH2‐CH3 interface.
IL‐12 p80‐dependent macrophage recruitment primes the host for increased survival following a lethal respiratory viral infection
Authors: Gunsten Sean , Mikols Cassandra L. , Grayson Mitchell H. , Schwendener Reto A. , Agapov Eugene , Tidwell Rose M. , Cannon Carolyn L. , Brody Steven L. , Walter Michael J.
Published: September 2008

A protective immune response to a respiratory viral infection requires a series of coordinated cellular and molecular responses. We have previously demonstrated that increased expression of airway epithelial cell interleukin (IL)‐12 p80, a macrophage chemoattractant, is associated with human respiratory viral infection and mediates post‐viral mortality in the mouse. To better understand the role of IL‐12 p80‐dependent macrophage chemotaxis in mediating viral immunity, we generated a transgenic mouse strain utilizing a promoter to drive IL‐12 p40 gene expression in the airway epithelium. This transgenic strain secreted biologically active IL‐12 p80 in a lung‐specific manner, and demonstrated a selective increase in the number of resident, unactivated airway macrophages at baseline. Following infection with a sublethal dose of mouse parainfluenza virus type 1 (Sendai virus), the transgenic mice demonstrated an earlier peak and decline in the number of airway inflammatory cells. The transgenic mice were resistant to a lethal dose of virus and this viral resistance was dependent on the increased number of airway macrophages at baseline as partial depletion prior to infection abrogated this phenotype. The survival advantage in the transgenic mice was independent of viral load but was associated with a more rapid decline in the number of airway inflammatory cells and concentrations of multiple chemokines including the CC chemokine ligand 2 (CCL2)/JE, CCL3/macrophage inflammatory protein (MIP)‐1α, CCL4/MIP‐1β, and CCL5/RANTES. Collectively, these results suggest that IL‐12 p80‐driven increases in the number of resident airway macrophages prime the host for a protective immune response that can confer increased survival following a lethal respiratory viral infection.
The impact of androgen receptor polymorphism and parental ethnicity on semen quality in young men from Latvia
Authors: Erenpreiss J. , Tsarev I. , Giwercman A. , Giwercman Y.
Published: September 2008

Recent studies on young men from the general population have demonstrated geographic and ethnic differences in semen quality. The aim of this study was to investigate whether reported ethnic differences in semen quality might be associated with the maternally derived CAG and GGN polymorphisms in the androgen receptor gene or paternal ethnicity. In total 114 military conscripts from Latvia were included in the study. Information on maternal and parental ethnicity was collected by questionnaires. CAG and GGN repeats were analysed by direct sequencing of leukocyte DNA. Men with Latvian mothers (n = 83) had marginally shorter CAG repeat length (21.6 ± 2.9) as compared with those with non‐Latvian mothers (22.9 ± 3.2,n = 31), not reaching statistical significance (p = 0.053). Sperm concentration did not differ significantly between these two groups (76 ± 59 and 70 ± 52,p = 0.9 respectively). In contrast, significantly higher sperm concentration and total sperm count were found in men with Latvian fathers (n = 77) as compared with men with non‐Latvian fathers (n = 37) (80 ± 61 vs. 62 ± 48,p = 0.035, for sperm concentration and 225.7 ± 209 vs. 158.4 ± 134.4,p = 0.002, for total sperm count respectively). CAG repeat length did not correlate with any semen parameters in the whole population. However, GGN repeat length correlated with semen volume: men with GGN > 23 presented with higher semen volume (3.2 ± 2.1) as compared with men with GGN = 23 (2.6 ± 1.3,p = 0.04) or GGN < 23 (2.0 ± 1.2,p = 0.006). We conclude that GGN repeat length has an impact on semen volume, whereas differences in sperm numbers are associated with the paternal ethnicity.
Development of parent–nurse relationships in neonatal intensive care units – from closeness to detachment
Authors: Fegran Liv , Fagermoen May Solveig , Helseth Sølvi
Published: September 2008

Title.  Development of parent–nurse relationships in neonatal intensive care units – from closeness to detachment

Aim.  This paper is a report of a study to explore the development of relationships between parents and nurses in a neonatal intensive care unit.

Background.  As increasingly smaller premature babies survive, the prolonged hospitalization that follows makes relationships between parents and nurses crucial. A collaborative partnership in which all the family members’ needs are acknowledged is suggested as the best approach.

Method.  A hermeneutic approach was adopted, using overt participant observation (160 hours) and in‐depth interviews to study interactions between parents and nurses. The participants were six mothers, six fathers, and six nurses from a 13‐bed Norwegian neonatal intensive care unit. Data were obtained over 27 weeks from 2003 until 2004.

Findings.  A partnership between parents and nurses developed in three phases: the acute critical phase, the stabilizing phase, and the discharge phase. The stabilizing phase seemed the most challenging. As exhausted parents expressed the importance of maintaining the trusting relationship with their primary nurses to become confident when assuming more responsibility and adjusting to the new situation, nurses purposely withdrew and reduced their contact with parents, facilitating their independence and confidence as caretakers. Parents and nurses rarely seemed to discuss with each other the discrepancy in their understanding of the detachment process.

Conclusion.  Acknowledging the need for parents and nurses to discuss the processes of involvement and detachment may contribute positively to the development of family‐centred care in neonatal intensive care units.
Low PAI‐1 activity in relation to inflammatory parameters, insulin profile and body mass index
Authors: Ågren A. , Wiman B. , Schulman S.
Published: September 2008

Background and objective.  High plasminogen activator inhibitor type 1 (PAI‐1) activity is associated with inflammatory reactions and insulin resistance, but it is unclear what regulates PAI‐1 activity at the low end. The purpose of this study was to investigate if patients with low PAI‐1 activity have a lack of inflammatory response or a low insulin level.

Design.  Retrospective cohort study with internal controls.

Subjects.  Sixty‐three patients referred for investigation of bleeding tendency and with low PAI‐1 activity were compared with 118 patients with normal or high PAI‐1 activity.

Outcome.  Levels of C‐peptide, proinsulin, high‐sensitivity C‐reactive protein (hs‐CRP) and interleukin‐6 (IL‐6). Adjustments were made for body mass index (BMI), oral oestrogens and age. Low PAI‐1 activity was defined as less than 1 U mL−1.

Results.  Body mass index in the low normal range, oral oestrogens, young age and low C‐peptide were significantly associated with low PAI‐1 activity and there was a trend for association with IL‐6 in univariable analysis. The effect of age disappeared after correction for oral oestrogens and the effect of C‐peptide and IL‐6 disappeared after further adjustments. Low BMI remained as the strongest predictor of low PAI‐1 activity.

Conclusion.  Patients with bleeding tendency and low PAI‐1 activity have inflammatory and insulin profiles similar to those with normal or high PAI‐1, whereas BMI seems to be the most important determinant.
Specific IgE serum concentration is associated with symptom severity in children with seasonal allergic rhinitis
Authors: Rolinck‐Werninghaus C. , Keil T. , Kopp M. , Zielen S. , Schauer U. , Von Berg A. , Wahn U. , Hamelmann E. ,   the Omalizumab Rhinitis Study Group
Published: September 2008

Background:  The impact of allergen‐specific and total IgE serum levels before and during the pollen season on symptom severity as well as efficacy of treatment with anti‐IgE requires further delineation.

Methods:  Birch and grass pollen allergic patients aged 6–17 years with seasonal allergic rhinitis (SAR) were analyzed for the association of IgE serum concentration with symptom severity and rescue medication use (combination: symptom load, SL) during the grass pollen season. Reference group A (n = 53) received placebo, while group B (n = 54) received Omalizumab (anti‐IgE) monotherapy before and during the grass pollen season.

Results:  Patients on placebo with high baseline specific grass pollen IgE (>50 kU/l) had a significantly higher SL compared with those with low IgE levels (≤50 kU/l): SL 1.28 vs 0.61, P = 0.015. This association was nonexistent in patients treated with anti‐IgE. In contrast, baseline total IgE levels did not correlate with SL in any group. Patients with anti‐IgE treatment and high free total IgE levels (>16.7 ng/ml) had a significantly higher SL compared with those with low free total IgE levels (≤16.7 ng/ml): SL 0.63 vs 0.23, P = 0.031.

Conclusions:  Baseline specific IgE, but not total IgE, is associated with symptom severity during the pollen season in children with SAR. Likewise, the symptom load in SAR patients with anti‐IgE correlates with free total IgE levels. Although further research in larger populations is needed to confirm our findings, our data suggest that specific IgE can be used as a parameter for patient selection for this kind of treatment.
Indices of lower airway inflammation in children monosensitized to house dust mite after nasal allergen challenge
Authors: Inal A. , Kendirli S. G. , Yilmaz M. , Altintas D. U. , Karakoc G. B. , Erdogan S.
Published: September 2008

Background:  There are few available data assessing the united airway disease and its systemic aspects in children. With this study, we aimed to investigate the inflammation markers of upper and lower airways before and after nasal allergen challenge in mite sensitive children with different clinical expression of the allergic disease.

Methods:  Four study groups were formed: rhinitis only, without bronchial hyper‐responsiveness (R, n = 10), rhinitis with asthma (R + A, n = 22), atopic asymptomatics (AA, n = 8) and nonallergic healthy controls (C, n = 10). Blood eosinophils, nasal and sputum eosinophils, sputum eosinophil cationic protein (ECP) and cys‐LTs, and serum ECP levels were measured before and 24 h after nasal allergen challenge.

Results:  The groups were comparable in terms of age and gender. Cumulative symptom scores recorded during and 1 h after nasal challenge were not significantly different between patients with R, R + A and AA groups. At T24, the children belonging to R, R + A and AA showed significant increases in nasal eosinophils (P < 0.01, P < 0.001, and P = 0.01, respectively), sputum eosinophils (P = 0.01, P < 0.001, and P < 0.05, respectively) and blood eosinophils (P < 0.01, P < 0.001, and P < 0.05, respectively). Similarly, increases in sputum ECP (P < 0.01, P < 0.001, and P = 0.07, respectively) and sputum cys‐LT levels (P = 0.07, P < 0.001, and P < 0.05, respectively) were detected in children belonging to these three groups at T24. Sputum eosinophils significantly correlated with blood eosinophils (r = 0.54, P < 0.001) and sputum ECP (r = 0.58, P < 0.001) at T24.

Conclusions:  This study showed that nasal allergen challenge increased markers of eosinophilic inflammation in both upper and lower airways of children monosensitized to mites, even before the onset of clinical symptoms.
Seasonal idiopathic rhinitis with local inflammatory response and specific IgE in absence of systemic response
Authors: Rondón C. , Doña I. , López S. , Campo P. , Romero J. J. , Torres M. J. , Mayorga C. , Blanca M.
Published: September 2008

Background:  Patients with idiopathic rhinitis (IR) are considered to be nonallergic because they have a negative skin prick test (SPT) and allergen specific‐IgE in serum. The concept of localized mucosal allergy in the absence of atopy has recently been proposed. The immunological mechanisms involved in seasonal IR have not been sufficiently studied. We examined nasal mucosa inflammation, the presence of nasal specific‐IgE and the response to nasal allergen provocation test (NAPT) in patients with seasonal IR who presented symptoms only in spring.

Methods:  We evaluated 32 patients with seasonal IR and 35 with persistent allergic rhinitis to pollen (PAR‐P) and compared these with healthy controls and persons with PAR to house dust mite during the pollen season, as well as by NAPT out‐of‐season with grass and Olea europea. We measured the nasal leukocyte–lymphocyte phenotype (CD45, CD33, CD16, CD3, CD4 and CD8), eosinophil‐cationic‐protein, and total and specific‐IgE to grass and olive pollen in serum and nasal lavage and performed NAPT.

Results:  In the IR group, 62.5% had a positive NAPT (IR‐PosNAPT), 20/32 to grass, with four of these having a positive NAPT to olive pollen as well. IR‐PosNAPT patients showed a similar nasal leukocyte–lymphocyte profile to the PAR‐P patients and different to controls. We detected nasal specific‐IgE in 35% of IR‐PosNAPT patients.

Conclusions:  These results support the hypothesis that a subgroup of patients with IR have seasonal symptoms with evidence of a nasal allergic immune reaction in the absence of a positive SPT or serum specific IgE.
Histamine H4receptors modulate dendritic cell migration through skin – immunomodulatory role of histamine
Authors: Bäumer W. , Wendorff S. , Gutzmer R. , Werfel T. , Dijkstra D. , Chazot P. , Stark H. , Kietzmann M.
Published: September 2008

Background: Dendritic cells (DC) are the major antigen‐presenting cells and play a key role in adaptive immunity as they are able to activate naive T cells. It was recently described, that the histamine H4receptor (H4R) is present on human monocyte‐derived DC and that chemotaxis and T‐helper (Th)1–Th2 polarization is mediated by this receptor. However, the distribution of histamine receptors on murine DC has not been studied yet.

Methods: The histamine receptor expression on murine bone marrow (BM)‐derived DC and effects of histamine and H4R agonism on DC migration through skin were studied. As it was demonstrated in scratching experiments that NMRI mice are more susceptible to H4R‐mediated itch than BALB/c mice, DC function of NMRI and BALB/c mice was compared.

Results: The mRNA of the H1R, H2R and H4R could be detected in murine BM‐derived DC, while mRNA of the H3R was found to be low or undetectable. There were no distinct differences in mRNA expression and in H4R protein level (flow cytometry) between NMRI compared with BALB/c mice indicating, that a higher susceptibility is not associated with a generally higher H4R expression in all cell types. Histamine as well as the H4R agonist clobenpropit induced an enhanced chemotaxis in the skin DC migration assay. The enhanced chemotaxis was blocked by the H4R antagonist JNJ7777120. This finding was confirmed byin vitromigration experiments with BM‐derived DC.

Conclusion: Referring to DC migration, blocking the H4R on inflammatory cells might be a promising anti‐inflammatory, immunomodulatory strategy.
Mediterranean diet is associated with reduced asthma and rhinitis in Mexican children
Authors: De Batlle J. , Garcia‐Aymerich J. , Barraza‐Villarreal A. , Antó J. M. , Romieu I.
Published: September 2008

Background:  Diet during pregnancy and childhood has been suggested to play an important role in children’s asthma risk. We assessed whether the adherence to a Mediterranean dietary pattern, for children in the last 12 months and their mothers during pregnancy, was associated with both childhood asthma and allergic rhinitis.

Methods:  A cross‐sectional study was conducted in 2004 using a random sample of 1476 children (6‐ to 7‐year old) from the Mexicali region, Mexico. Dietary data of children’s intake in the last 12 months and their mothers’ intake during pregnancy was collected, through a parental food frequency questionnaire. A Mediterranean diet score was computed [Trichopoulou et al., N Engl J Med 348 (2003), 2599]. Data on seven asthma and rhinitis‐related outcomes were obtained from the International Study of Asthma and Allergies in Childhood questionnaire.

Results:  Adherence to a Mediterranean dietary pattern was inversely associated with asthma ever (OR = 0.60, 95% CI = 0.40–0.91), wheezing ever (0.64, 0.47–0.87), rhinitis ever (0.41, 0.22–0.77), sneezing ever (0.79, 0.59–1.07), current sneezing (0.71, 0.52–0.96) and current itchy‐watery eyes (0.63, 0.42–0.95). No associations were found using the mothers’ pregnancy diet score, except for current sneezing (0.71, 0.53–0.97).

Conclusions:  Our findings suggest a protective effect of following a healthy dietary pattern on asthma and allergic rhinitis in Mexican children.
Soluble HLA‐G and HLA‐A,‐B,‐C serum levels in patients with allergic rhinitis
Authors: Ciprandi G. , Colombo B. M. , Contini P. , Cagnati P. , Pistorio A. , Puppo F. , Murdaca G.
Published: September 2008

Background:  Allergic rhinitis (AR) is characterized by Th2‐polarized immune response. Soluble HLA (sHLA) molecules play an immunomodulatory activity. So far, however, no study investigated them in AR.

Objective:  The aim of this study was to evaluate sHLA‐G and sHLA‐A,‐B,‐C serum levels in AR patients with pollen allergy and in a group of healthy controls.

Methods:  Forty‐nine AR patients were enrolled. A group of healthy nonallergic subjects was considered as control. sHLA‐G and sHLA‐A,‐B,‐C serum levels were determined by immunoenzymatic method. The study was conducted during the winter, such as outside the pollen season.

Results:  Allergic patients had significantly higher levels of both sHLA‐G (P < 0.0001) and sHLA‐A,‐B,‐C (P = 0.011) molecules than normal controls. Moreover, there was a significant relationship between these two soluble molecules (r = 0.69) in allergic patients.

Conclusion:  The present study provides the first evidence that both sHLA‐G and sHLA‐A,‐B,‐C serum levels are significantly increased in AR patients with pollen allergy.
New oral H1 antihistamines in children: facts and unmeet needs
Authors: De Benedictis F. M. , De Benedictis D. , Canonica G. W.
Published: September 2008

Background:  Second‐generation antihistamines differ from first‐generation ones because of their elevated specificity and affinity for peripheral H1‐receptors and because of their lower penetration to the central nervous system, having fewer sedative effects as a result. Over the last few years, new compounds with different pharmacokinetic properties have been synthesized. More recent improvements of the molecules, generally in the form of active metabolites, led to the synthesis of new‐generation antihistamines.

Methods:  Recommendations on the minimum criteria that would have to be met for compounds to be classified as new‐generation antihistamines have been recently established by a consensus statement. In the past, the pharmacokinetics and pharmacodynamics of H1 antihistamines have not been optimally investigated in the pediatric population, especially in infants and young children.

Results:  The pharmacology of second‐generation H1 antihistamines has been investigated relatively deeper than old antihistamines in children. In the pediatric population, clinical studies with new‐generation antihistamines are still limited in number and, with rare exceptions, of brief duration. Comparative trials on the efficacy and safety between different compounds are also lacking.

Conclusions:  Properly designed, long‐term trials with new‐generation H1 antihistamines need to be performed in single age groups, in order to better define the effects of these drugs in all pediatric population.
Alterations of the ocular surface epithelial MUC16 and goblet cell MUC5AC in patients with atopic keratoconjunctivitis
Authors: Dogru M. , Matsumoto Y. , Okada N. , Igarashi A. , Fukagawa K. , Shimazaki J. , Tsubota K. , Fujishima H.
Published: September 2008

Background:  An increased understanding of the ocular surface at cellular level in the conjunctiva and the cornea may help explain the pathogenesis and the subsequent clinical appearance of atopic ocular allergies, which may be potentially blinding.

Purpose:  To investigate the MUC16 and MUC5AC alterations, tear function and the ocular surface disorder in patients with atopic keratoconjunctivitis (AKC).

Methods:  Thirty‐six eyes of 18 AKC patients as well as 28 eyes of 14 age‐ and sex‐matched normal subjects were studied. The subjects underwent corneal sensitivity measurements, Schirmer test, tear film break‐up time (BUT), fluorescein and Rose‐Bengal staining of the ocular surface, conjunctival impression cytology and brush cytology. Impression cytology samples underwent periodic acid schiff and immunohistochemical staining with MUC16 and MUC5AC antibodies. Brush cytology specimens underwent evaluation for inflammatory cell numbers and quantitative real‐time polymerase chain reaction (PCR) for MUC16 and MUC5AC mRNA expression.

Results:  The mean corneal sensitivity and BUT values were significantly lower in patients with AKC, compared with controls (P < 0.001). Brush cytology specimens from AKC patients revealed significantly higher numbers of inflammatory cells (P < 0.001). Specimens from patient eyes showed positive staining for MUC5AC and MUC16. MUC16 mRNA expression was significantly upregulated with significant downregulation of MUC5AC mRNA expression in eyes with AKC compared with the eyes of control subjects.

Conclusion:  Ocular surface inflammation, decline in corneal sensitivity, tear film instability, changes in conjunctival epithelial MUC5AC and MUC16 mRNA expressions were thought to be important in the pathogenesis of atopic ocular surface disease.
n‐Nonanoyl‐CCL14 (NNY‐CCL14), a novel inhibitor of allergic airway inflammation is a partial agonist of human CCR2
Authors: Gupta S. , Erdmann G. , Schulz‐Maronde S. , Escher S. E. , Richter R. , Forssmann W. G. , Elsner J. , Forssmann U.
Published: September 2008

Background: Modulation of leukocyte recruitment through blocking of chemokine receptors has been proposed as an attractive therapeutic strategy. We have previously demonstrated thatn‐Nonanoyl‐CC chemokine ligand 14 (NNY‐CCL14), a modified analog of the naturally occurring chemokine CCL14(9‐74) internalizes and desensitizes human CCR3 resulting in the inactivation of eosinophils. However, inhibitory effects of NNY‐CCL14 in murine models of allergic airway inflammation are assigned to its interaction with CCR1 and CCR5.

Aim of the study: As CCL2 and its receptor CCR2 have been shown to play important roles in the development of Th2 inflammation, we further evaluated the effects of NNY‐CCL14 treatment on CCL2‐mediated activation of CCR2.

Methods: Effects of NNY‐CCL14 treatment were studied on cell lines transfected with human CCR2 and primary leukocytes. Functional effects were assessed by calcium efflux assays, flow cytometry and chemotaxis.

Results: Prestimulation with NNY‐CCL14 desensitized CCR2‐mediated responses to further stimulation with its selective ligand CCL2. No significant internalization of CCR2 was observed when the cells were stimulated with NNY‐CCL14, even at concentrations eliciting maximal [Ca2+]i mobilization. Above all, NNY‐CCL14 pretreatment blocked CCL2‐induced chemotaxis of monocytes.

Conclusions: This study demonstrates that NNY‐CCL14 is a partial agonist of CCR2, inhibiting responses of monocytes to the CCR2‐selective ligand CCL2. NNY‐CCL14 attenuates CCR2‐mediated responses by rapidly desensitizing the receptor and preventing chemotaxis, although it is able to induce calcium mobilization but does not lead to CCR2 internalization. Hence this study provides further insights into the possible mechanisms of action of NNY‐CCL14, which interacts with multiple chemokine receptors inhibiting the migration and activation of different cell populations involved, thus acting as a potential therapeutic compound to alleviate allergic inflammation.
Staphylococcus aureus in nasal lavage and biopsy of patients with chronic rhinosinusitis
Authors: Niederfuhr A. , Kirsche H. , Deutschle T. , Poppert S. , Riechelmann H. , Wellinghausen N.
Published: September 2008

Background:  Staphylococcus aureus may play a relevant etiologic role in chronic rhinosinusitis (CRS) and may explain the TH2 shift observed in CRS with nasal polyps (CRSNP+). Naturally occurring S. aureus small colony variants (SASCV) escape immune surveillance, antibiotic treatment and microbiologic routine diagnostic techniques. The frequency of S. aureus and SASCV in CRS patients and S. aureus‐related effects on the local immune response should be prospectively investigated.

Methods:  Nasal lavages and mucosal biopsies of CRS patients were examined with bacterial culture suitable for detecting SASCV, real time PCR and fluorescence in situ hybridization. To assess the effects of S. aureus positivity, interleukin‐5 (IL‐5), interferon‐γ, total immunoglobulin E (IgE), eotaxin, granulocyte‐colony stimulating factor, and eosinophil cationic protein in nasal lavages were determined and gene transcription analysis of nasal biopsies from S. aureus positive and negative CRSNP+ patients was performed.

Results:  Thirty‐one CRSNP+ patients, 13 CRS patients without polyps, and 21 control patients were evaluated. Staphylococcus aureus was detected by any method in 25 patients (39%). Staphylococcus aureus detection rates did not differ between the three disease groups (P = 0.3). Staphylococcus aureus small colony variants were not found. In nasal lavages, IL‐5 and total IgE levels were higher in CRSNP+ patients than in CRSNP− patients or controls (P < 0.05). Staphylococcus aureus positivity did not influence biomarker concentrations in nasal lavages. Genes for TH2 cytokines were not differentially transcribed.

Conclusions:  We could not observe a higher prevalence of S. aureus in CRS patients with or without nasal polyps than in controls. We could not substantiate that S. aureus intensifies the TH2 shift in CRSNP+ patients. Staphylococcus aureus small colony variants were not detected in any sample.
Chronic rhinosinusitis and nasal polyps: the role of generic and specific questionnaires on assessing its impact on patient’s quality of life
Authors: Alobid I. , Bernal‐Sprekelsen M. , Mullol J.
Published: September 2008

Chronic rhinosinusitis (CRS) including nasal polyps is a chronic inflammatory disease of the nasal and paranasal sinus mucosa that, despite differing hypotheses of its cause, remains poorly understood. Primary symptoms are nasal blockage, loss of smell, rhinorrhea, and facial pain or pressure. Chronic rhinosinusitis causes significant physical symptoms, has a negative impact on quality of life (QoL), and can substantially impair daily functioning. A global evaluation of patients must include, together with nasal symptoms, nasal endoscopy, and CT scan, the measurement of QoL. To assess QoL in CRS, specific and generic questionnaires may be used. Chronic rhinosinusitis has a considerable impact on a patient’s QoL but comorbidities, such as asthma and atopy, have an accumulative negative effect. Both medical and surgical treatments lead to a similar improvement on the QoL of CRS and nasal polyp patients.
Adenovirus infection and treatment with cidofovir in children after liver transplantation
Authors: Engelmann Guido , Heim Albert , Greil Johann , Schmitt Claus Peter , Flechtenmacher Christa , Daum Edith , Küsters Uta , Schmidt Jan , Meyburg Jochen , Schnitzler Paul
Published: September 2008

Abstract:  In a retrospective study, serum samples from 21 pediatric liver transplant recipients were analysed by quantitative real‐time PCR for ADV infection up to 24 wk after Tx. ADV DNA was detected in serum of eight children after Tx, one of whom developed life‐threatening fulminant hepatitis and sepsis. None of these children were symptomatic at the time of first detection of ADV DNA in serum after Tx. Seven children with positive ADV PCR had low adenoviral loads, showed no increase in viral load and remained clinically asymptomatic in the follow‐up period of 24 wk. After 10 wk under immunosuppression one child presented clinically with adenoviral sepsis and severe necrotizing hepatitis. This patient revealed a dramatic increase of ADV from baseline titers up to 1.3 × 109 copies/mL serum within 10 wk after Tx. ADV was also detected in a liver biopsy of this child at 1.2 × 104 copies/cell and typed by sequence analysis as human ADV species C, type 6, a rarely detected ADV type and first described in a liver transplant patient. Immunosuppression was reduced in this patient immediately and the antiviral drug cidofovir administered intravenously followed by viral suppression and clinical improvement of the child.