bluuebunny/crossref_metadata_2025 huggingface dataset:
Drug‐induced liver graft toxicity caused by cytochrome P450 poor metabolism
Authors: Kóbori László , Kõhalmy Krisztina , Porrogi Pálma , Sárváry Enikõ , Gerlei Zsuzsa , Fazakas János , Nagy Péter , Járay Jenõ , Monostory Katalin
Published: February 2008

What is already known about this subject

• The activity of drug‐metabolizing enzymes, primarily cytochrome P450 enzymes, can determine a patient's response to a drug.

• Therapeutic failure or drug toxicity in the postoperative period after liver transplantation is influenced by the drug metabolizing capacity of the graft.

• Dose adjustment or selection of an alternative drug, which is not a substrate for the polymorphic enzyme may prevent the development of side‐effects in recipients of poor metabolizer liver grafts.

What this study adds

• A validated analytical system with metabolomic tools has been developed to estimate the drug‐metabolizing capacity of transplanted liver, which allows the prediction of potential poor metabolizer phenotypes of donors and facilitates the improvement of individual recipient therapy.

• In the test of drug‐metabolizing status, one of the liver grafts was found to be a CYP2C9 poor metabolizer, while the other was a CYP2C19 poor metabolizer.

• Rationalization of the medication resulted in the recovery of both the grafts and the recipients within 1 week.

Aims

The drug‐metabolizing capacity of transplanted liver highly influences drug efficacy or toxicity, particularly in the early postoperative period. The aim of our study was to predict therapeutic failures or severe adverse drug reactions by phenotyping for cytochrome P450 (P450) polymorphism resulting in reduced or no activity of the key drug‐metabolizing enzymes.

Methods

A validated analytical system with metabolomic tools has been developed for estimation of the drug‐metabolizing capacity of transplanted liver, which allows the prediction of potential poor metabolizer phenotypes of donors and facilitates improvement of the individual recipient therapy.

Results

Of the 109 liver donors in Hungary, the frequency of poor metabolizers was found to be 0.92%, 5.5% and 8.3% for CYP2C9, CYP2C19 and CYP2D6, respectively. In the present study, two liver grafts transplanted in paediatric recipients were reported to be poor metabolizer phenotypes. The liver grafts presented normal function in the early postoperative days; 2 weeks after transplantation, however, increasing liver enzymes were detected. Histological investigation of a liver biopsy suggested drug toxicity. The test of drug metabolizing status showed one of the liver grafts to be a CYP2C9 poor metabolizer, and the other was found to be a CYP2C19 poor metabolizer. Rationalization of the medication resulted in the recovery of both the grafts and the recipients within 1 week.

Conclusions

Prospective investigation of the P450 status may lead to the optimization of drug choice and/or dose for a more effective therapy, avoid serious adverse effects, and decrease medical costs. Phenotyping donor livers and tailored medication can contribute to the improvement of graft and recipient survival.
Pyrazinamide blood concentrations in children suffering from tuberculosis: a comparative study at two doses
Authors: Gupta Pooja , Roy Vandana , Sethi Gulshan Rai , Mishra Tarun Kumar
Published: February 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Pyrazinamide is recommended in doses varying from 15 to 40 mg kg−1. The most commonly used average daily dose is 25 mg kg−1. Its use is associated with dose dependent hepatotoxicity.

• Lower doses are not used because of lack of pharmacokinetic data especially in children. There is only one detailed study of pyrazinamide in children at a dose of 35 mg kg−1.

WHAT THIS STUDY ADDS

• This is the first study evaluating serum concentrations of pyrazinamide in children at a dose of 15 mg kg−1 which is on the lower side of the recommended dose. The study also compared the serum concentrations and pharmacokinetics achieved with this dose with the widely used dose of 25 mg kg−1 in children suffering from tuberculosis.

• The pharmacokinetics and pharmacodynamic indices of pyrazinamide were comparable with the 25 and 15 mg kg−1 doses.

AIMS

To evaluate the pharmacokinetics and pharmacodynamic indices of pyrazinamide at doses of 15 and 25 mg kg−1 in children suffering from tuberculosis.

METHODS

Twenty children with tuberculosis received pyrazinamide at a single dose of 25 mg kg−1 (group I) and 15 mg kg−1 (group II). Serial blood samples were collected and the drug concentrations were analyzed spectrophotometrically. The pharmacokinetic parameters were calculated and the duration of time for which pyrazinamide concentrations in serum remained above the pyrazinamide inhibitory concentrations of 20 μg ml−1 and 25 μg ml−1 was studied.

RESULTS

The mean peak serum concentration was 42.4 ± 3.3 μg ml−1 (95% CI ± 6.5) and 38.6 ± 3.9 μg ml−1 (95% CI ± 7.7) in groups I and II, respectively. The elimination half‐life was 9.3 ± 1.3 h and 10.5 ± 2.3 h (P = 0.6) and clearance was 0.06 ± 0.01 l h−1 kg−1 and 0.04 ± 0.01 l h−1 kg−1 (P = 0.08) in groups I and II, respectively. Pharmacokinetic parameters and PKPD indices were comparable with both the doses.

CONCLUSIONS

The study indicates that comparable serum concentrations of pyrazinamide are attained with 25 mg kg−1 and 15 mg kg−1 doses in children. The elimination half‐life was longer and volume of distribution greater in children than in the adult population.
Strategic use of an adenoviral vector for rapid and efficient ex vivo‐generation of cytomegalovirus pp65‐reactive cytolytic and helper T cells
Authors: Forsberg Ole , Carlsson Björn , Tötterman Thomas H. , Essand Magnus
Published: February 2008

Cytomegalovirus (CMV) reactivation can cause severe complications for transplant patients. Such patients can be protected against CMV‐associated diseases through reconstitution of donor‐derived CMV‐reactive cytolytic and helper T cells. We have developed a strategic protocol for efficient simultaneous generation of CMV‐reactive CD8+ and CD4+ T cells ex vivo. The protocol uses peripheral blood lymphocytes (PBLs), antigen‐modified mature dendritic cells (DCs) generated in only 3 d and an adenoviral vector encoding the CMV pp65 antigen (Adpp65) both as an endogenous and exogenous source of antigen. PBLs stimulated once with Adpp65‐transduced DCs (endogenously expressed pp65) resulted in preferential activation and expansion of pp65‐specific CD8+ T cells while PBLs stimulated with DCs pulsed with cell lysate from Adpp65‐transduced autologous monocytes (exogenously expressed pp65) yielded pp65‐specific CD4+ T cells. Stimulation with double‐modified DCs efficiently activated and expanded cytolytic and helper T cells simultaneously. The frequency of T cells producing interferon‐γ in response to pp65 increased after one stimulation on average 9·6‐fold to 4·3% for CD8+ T cells and 25·8‐fold to 6·5% for CD4+ T cells. This implies that sufficient number of pp65‐specific cytolytic and helper T cells for adoptive transfer may be obtained in only 2 weeks.
Thalidomide in advanced mastocytosis
Authors: Damaj Gandhi , Bernit Emmanuelle , Ghez David , Claisse Jean‐François , Schleinitz Nicolas , Harlé Jean‐Robert , Canioni Danielle , Hermine Olivier
Published: February 2008

Mastocytosis is an acquired orphan disease characterized by the abnormal accumulation of mast cells responsible for organ failure and systemic symptoms. Cytoreductive drugs have been shown to be effective, but have rarely resulted in complete or long‐term remission. We report two patients with advanced systemic mastocytosis (SM) who were treated successfully with thalidomide, given at the maximal tolerated dosage. B and C‐findings as well as clinical symptoms rapidly improved. After a follow‐up of more than 1 year, the patients remained in partial remission. Thalidomide seems to be an active drug in advanced SM. However, clinical trials are warranted to define its efficacy and safety profiles.
Suppression of cytokine expression by roflumilast and dexamethasone in a model of chronic asthma
Authors: Herbert C. , Hettiaratchi A. , Webb D. C. , Thomas P. S. , Foster P. S. , Kumar R. K.
Published: February 2008

BackgroundIn a mouse model of mild chronic asthma, both inflammation and remodelling can be suppressed by dexamethasone (a glucocorticoid) and roflumilast (a selective phosphodiesterase‐4 inhibitor).

ObjectiveTo better understand the underlying molecular mechanisms, we investigated the effects of treatment on airway expression of inflammation‐related cytokines, as well as on epithelial expression of growth factors.

MethodsBALB/c mice systemically sensitized to ovalbumin were challenged with aerosolized antigen for 6 weeks and treated with roflumilast or dexamethasone during the final 2 weeks. Expression of mRNA, for a variety of cytokines and growth factors, was assessed in selectively dissected proximal airways or in airway epithelium obtained by laser capture microdissection.

ResultsIn the airway wall of vehicle‐treated challenged animals, there was significantly elevated expression of mRNA for a variety of pro‐inflammatory and T helper type 2 cytokines, as well as for IFN‐γ. All these cytokines were suppressed by dexamethasone. Treatment with roflumilast reduced expression of IL‐17A, TNF‐α, granulocyte‐macrophage colony‐stimulating factor and IL‐6, but did not inhibit other cytokines. Both drugs suppressed the enhanced expression of mRNA for growth factors such as TGF‐β1 and FGF‐2 in airway epithelium.

ConclusionsWhereas dexamethasone non‐specifically inhibits numerous mediators involved in inflammation and the immune response, roflumilast selectively inhibits a subset of pro‐inflammatory cytokines and growth factors. These mediators and/or the cells that produce them may have critical roles in the pathogenesis of the lesions of chronic asthma.
Role of epidermal growth factor receptor in maintaining airway goblet cell hyperplasia in rats sensitized to allergen
Authors: Takeyama K. , Tamaoki J. , Kondo M. , Isono K. , Nagai A.
Published: February 2008

Background
Stimulation of epidermal growth factor receptor (EGFR) induces airway goblet cell hyperplasia, but the role of this molecule in the maintenance of this pathologic change remains uncertain.

Objective
To determine the mechanisms by which goblet cell hyperplasia is maintained in airway epithelium, we investigated EGFR‐induced signalling pathways that lead to both mucin production and antiapoptosis in vitro. We also tested whether the inhibition of EGFR tyrosine kinase speeds reversal of established goblet cell hyperplasia to normal epithelial phenotype in vivo.

Methods
MUC5AC production was measured by immunoassay, and antiapoptotic responses were determined by Bcl‐2 expression and terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin Nick End Labelling staining using NCI‐H292 cells. The effect of an inhibitor of EGFR tyrosine kinase (AG1478) on goblet cell hyperplasia was also determined in rats sensitized with ovalbumin (OVA).

Results
MUC5AC was constitutively expressed and few apoptotic cells were observed in NCI‐H292 cells under non‐stimulated condition. TGF‐α increased MUC5AC and Bcl‐2 expression, an effect that was prevented by inhibitors of EGFR tyrosine kinase (AG1478), MEK (PD98059), and NF‐κB (CAPE). After the addition of TGF‐α, AG1478 and an inhibitor of phosphatidylinositol 3 kinase/Akt (LY294002), but not PD98059, induced a marked apoptotic response, which was prevented by the caspase inhibitor Z‐VAD fmk. Goblet cell hyperplasia and EGFR expression in airway epithelium were noted in the OVA‐sensitized rats. Intratracheal instillation of AG1478 induced apoptosis of goblet cells, reverting the airway epithelium to normal epithelial phenotype.

Conclusion
These findings indicate that EGFR plays an important role in the maintenance of goblet cell hyperplasia. We speculate that inhibitors of the EGFR cascade might be an effective therapy of airway remodelling.
Assessment of the immunoglobulin E‐mediated immune response to milk‐specific proteins in allergic patients using microarrays
Authors: Gaudin J.‐C. , Rabesona H. , Choiset Y. , Yeretssian G. , Chobert J.‐M. , Sakanyan V. , Drouet M. , Haertlé T.
Published: February 2008

Background
Cow's milk allergy (CMA) is one of the most widespread human allergies, especially in young children. Although CMA is intensively studied, little is known about the recognition patterns of milk allergens in allergic patients, and the determination these patterns is a prerequisite for the development of efficient diagnostic and prognostic tools. Several factors present difficulties for such a determination, because (i) milk contains a large number of potential allergens; (ii) the majority of these allergens consist of complex suspensions rather than solutions; (iii) the major allergens, such as caseins, cannot be highly purified in large amounts; and (iv) most of the time, very small amount of young patients' sera are readily available.

Methods
To overcome these difficulties, we developed a sensitive microarray assay that, in combination with near‐infrared fluorescence detection, was used to study the immune response to milk and purified native milk proteins.

Results
This new assay allowed us to assess the binding ability of IgE to milk allergens from a large number of young patients using reduced amounts of clinical material. The data show that bovine lactoferrin can be classed as a strong milk allergen. We confirmed that bovine caseins are the main allergens in milk and that αS1‐casein is more allergenic than αS2‐, β‐ and κ‐caseins, which were recognized with almost a similar frequency by the sera of patients.

Conclusion
Microarray methods, in combination with near‐infrared fluorescence detection, can be useful for the in vitro diagnosis of food allergies.
Allergic rhinitis in children with asthma: a questionnaire‐based study
Authors: Hamouda S. , Karila C. , Connault T. , Scheinmann P. , De Blic J.
Published: February 2008

Background
Allergic rhinitis (AR) and asthma frequently coexist but has rarely been evaluated in children.

Objective
This prospective study aimed to estimate the prevalence of AR in asthmatic children, and ascertain whether AR is a risk factor for the severity of asthma.

Methods
The questionnaire, modified from the adult form of the score for allergic rhinitis (SFAR), was completed by 404 asthmatic children aged 3–18 years seen in the outpatient clinic between June 2005 and July 2007. Each item was assigned a number of points with a final score ranging from 0 to 17. AR and asthma were classified according to ARIA and GINA 2004 recommendations, respectively.

Results
AR was diagnosed in 237 patients (58.7%). It was intermittent in 57.8% of the patients and persistent in 42.2%. A total score 9 was discriminant for AR (sensitivity=91.1%, specificity=95.2%, positive predictive value=96.4%, negative predictive value=88.3%, Youden's Index=0.86). The proportion of children having mild or moderate‐to‐severe asthma was independent of the presence of AR, 61.6% of moderate‐to‐severe asthmatic children and 55.4% of intermittent and mild asthmatic children having AR.

Conclusion
AR and asthma are frequently associated (58.7%). The SFAR adapted for children seems to be a simple and a reliable tool to detect AR in asthmatic children.
Inhibition of airway eosinophilia and pulmonary pathology in a mouse model of allergic asthma by the live vaccine strain of Francisella tularensis
Authors: KuoLee R. , Zhou H. , Harris G. , Zhao X. , Qiu H. , Patel G. B. , Chen W.
Published: February 2008

Background
It has been suggested that exposure to certain microbes and their products, particularly during neonatal and early childhood periods, may shift the immune response towards a T‐helper cell (Th) 1 phenotype and thereby prevent the development of and/or alleviate the clinical symptoms of allergic airway diseases.

Objective
We evaluated the ability of the live vaccine strain (LVS) of Francisella tularensis to suppress airway eosinophilia and pulmonary pathology in a murine model of allergic airway disease.

Methods
C57BL/6 mice were sensitized by intraperitoneal injection of ovalbumin (OVA) on days 1 and 14, and challenged intranasally (i.n.) with OVA on day 21 or thereafter. Some sensitized mice were i.n. treated with live LVS or its cell‐free sonicate extract (CFSE) before i.n. OVA challenge. Bronchoalveolar lavage fluid, regional lymph node cells, lung tissues and serum samples were collected 3–7 days after the i.n. challenge.

Results
Intranasal and, to a lesser degree, intradermal immunization of OVA‐sensitized mice with LVS suppressed the development of airway eosinophilia and associated pulmonary pathology induced by i.n. OVA challenge. Moreover, CFSE prepared from LVS showed a similar inhibitory effect whereas neither LPS nor DNA purified from F. tularensis LVS had such an effect. The inhibition was associated with the reduction in mRNA expression and protein levels of Th2 cytokines IL‐5 and IL‐13 in the lungs and the enhanced production of OVA‐induced IFN‐γ by local draining lymph node cells, but not with the serum levels of OVA‐specific IgG1 or IgE.

Conclusion
F. tularensis LVS is capable of suppressing allergic airway inflammation probably through a Th1‐mediated suppression of an ongoing Th2 response mechanism, and raises the possibility of exploring LVS and its components as potential therapeutic modalities for human allergic asthma.
Simulations of tip‐enhanced optical microscopy reveal atomic resolution
Authors: DOWNES ANDREW , SALTER DONALD , ELFICK ALISTAIR
Published: February 2008

We have performed finite element electromagnetic analysis of ‘apertureless’ scanning near‐field optical microscope tips. A variety of radii was considered, from 40 nm down to 1 nm, and the enhancement of optical scattering from the region beneath the probe apex was modelled in air and water. We observed sizeable spectral shifts when the radius decreases, together with a surprising increase in the amount of scattering from small tips. The lateral resolution is considered, which is shown to be always smaller than the tip radius, and for 1‐nm‐radius tips can allow atomic resolution imaging with sufficient optical enhancement. Gold, silver, copper and aluminium were modelled as tip materials.
Single molecules probe local density of modes (LDOS) around photonic nanostructures
Authors: COLAS DES FRANCS G. , SANCHEZ‐MOSTEIRO G. , UJUE‐GONZALEZ M. , MARKEY L. , VAN HULST N. , DEREUX A.
Published: February 2008

According to Fermi's golden rule, the fluorescence decay rate is directly proportional to the projected local density of photonic modes (LDOS) at the molecule location. The relevant LDOS depends on the molecule orientation. In this paper, the direct measurement of the fluorescence lifetime near gold dot photonic structures is investigated and compared to calculated LDOS. Detailed analysis of the decay channels is presented on the basis of numerical simulations.
Near‐ and far‐field verification of electro‐optic effect enhancement on a tunable lithium niobate photonic crystal
Authors: BERNAL M.‐P. , ROUSSEY M. , BAIDA F. I.
Published: February 2008

In this paper, we present the optical response of a tunable lithium niobate photonic crystal (PC) using the electro‐optic effect of the material. The band gap tunability is 300 times higher than what one could expect for a bulk lithium niobate device of the same characteristics. Theoretical calculations based on the finite‐difference time domain technique have allowed us to determine the physical origin of this enhanced electro‐optic coefficient. Indeed, the effective second‐order susceptibility in the LN nanostructure increases, giving rise to an ultra‐compact low‐voltage photonic crystal modulator when it operates at its band edge. In addition, the theoretical and far‐field transmission results are confirmed by near‐field optical microscopy images of the structure at different excitation voltages.
Detection in near‐field domain of biomolecules adsorbed on a single metallic nanoparticle
Authors: BARBILLON G. , BIJEON J.‐L. , BOUILLARD J.‐S. , PLAIN J. , LAMY De La CHAPELLE M. , ADAM P.‐M. , ROYER P.
Published: February 2008

In this paper, we study the performances of nanosensors based on Localized Surface Plasmon Resonance in the context of biological sensing. We demonstrate the sensitivity and the selectivity of our designed nanosensors by studying the influence of the concentration of Streptavidin on the shift of Localized Surface Plasmon Resonance wavelength. In addition, to study the detection of biomolecules on a single Au nanoparticle, we used a Scanning Near‐field Optical Microscope. These results represent new steps for applications in biological research and medical diagnostics.
Biomolecular sensors utilizing waveguide modes excited by evanescent fields
Authors: FUJIMAKI M. , ROCKSTUHL C. , WANG X. , AWAZU K. , TOMINAGA J. , IKEDA T. , KOGANEZAWA Y. , OHKI Y.
Published: February 2008

Properties of evanescent‐field‐coupled waveguide‐mode sensors consisting of a multi‐layer structure made of a SiO2 waveguide, a thin metal layer (Au, Cu, W or Ti), and a high refractive index glass substrate illuminated under the Kretschmann configuration have been theoretically and experimentally investigated. In all cases, reflectivity changes attributed to streptavidin combining to biotinyl groups were observed in close spectral vicinity of the waveguide resonances. The sensors with the Au and the Cu layers show superior sensitivity as compared to those with the W and the Ti layers, whereas the W and Ti layers show better thermal and chemical stability. The results indicate that the materials of thin metal layers should be chosen in accordance with the purpose of sensors and/or environment in which the sensors are used.
A novel approach to detect and characterize the scattering patterns of single Au nanoparticles using confocal microscopy
Authors: ZÜCHNER T. , FAILLA A. V. , HARTSCHUH A. , MEIXNER A. J.
Published: February 2008

We demonstrate a novel optical method for characterizing single Au nanoparticles by acquiring their scattering patterns. This technique combines confocal microscopy and higher‐order laser modes for detecting the light scattered by sub‐wavelength–sized nanoobjects. The optical patterns are generated by the coherent superposition of the field scattered by individual metallic particles and the excitation field reflected at the cover slide–air interface and provide information about the particles' position, orientation, size and shape. Detectable changes in the full width at half maximum (FWHM) of the signal intensity permit to distinguish between 20‐ and 60‐nm diameter Au spheres. The confocal images are also very sensitive to the particle's geometry and polarizability, that is, Au nanospheres, Au nanorods and triangular Au nanoplates give different characteristic patterns if the excitation wavelength is varied.
Near‐field–induced tunability of surface plasmon polaritons in composite metallic nanostructures
Authors: CHRIST A. , LÉVÊQUE G. , MARTIN O. J. F. , ZENTGRAF T. , KUHL J. , BAUER C. , GIESSEN H. , TIKHODEEV S. G.
Published: February 2008

We numerically study near‐field–induced coupling effects in metal nanowire‐based composite nanostructures. Our multi‐layer system is composed of individual gold nanowires supporting localized particle plasmons at optical wavelengths, and a spatially separated homogeneous silver slab supporting delocalized surface plasmons. We show that the localized plasmon modes of the composite structure, forming so‐called magnetic atoms, can be controlled over a large spectral range by changing the thickness of the nearby metal slab. The optical response of single‐wire and array‐based metallic structures are compared. Spectral shifts due to wire–mirror interaction as well as the coupling between localized and delocalized surface plasmon modes in a magnetic photonic crystal are demonstrated. The presented effects are important for the optimization of metal‐based nanodevices and may lead to the realization of metamaterials with novel plasmonic functionalities.
Beyond lock‐in analysis for volumetric imaging in apertureless scanning near‐field optical microscopy
Authors: VOGELGESANG R. , ESTEBAN R. , KERN K.
Published: February 2008

Conventional apertureless scanning near‐field optical microscopy uses lock‐in demodulation techniques to filter higher harmonics from the periodically modulated optical signal. On the one hand, this signal notoriously may contain contaminating mechanical contributions; on the other, it reduces the available data to one number per pixel. Realizing that the vertically oscillating near‐field probe actually traverses a whole volume above the sample surface, we discuss a model to extend the data analysis in an attempt to better extract the optical information and to recover its three‐dimensional spatial distribution.
Characterization of Trypanosoma brucei dihydroorotate dehydrogenase as a possible drug target; structural, kinetic and RNAi studies
Authors: Arakaki Tracy L. , Buckner Frederick S. , Gillespie J. Robert , Malmquist Nicholas A. , Phillips Margaret A. , Kalyuzhniy Oleksandr , Luft Joseph R. , DeTitta George T. , Verlinde Christophe L. M. J. , Van Voorhis Wesley C. , Hol Wim G. J. , Merritt Ethan A.
Published: February 2008

Nucleotide biosynthesis pathways have been reported to be essential in some protozoan pathogens. Hence, we evaluated the essentiality of one enzyme in the pyrimidine biosynthetic pathway, dihydroorotate dehydrogenase (DHODH) from the eukaryotic parasite Trypanosoma brucei through gene knockdown studies. RNAi knockdown of DHODH expression in bloodstream form T. brucei did not inhibit growth in normal medium, but profoundly retarded growth in pyrimidine‐depleted media or in the presence of the known pyrimidine uptake antagonist 5‐fluorouracil (5‐FU). These results have significant implications for the development of therapeutics to combat T. brucei infection. Specifically, a combination therapy including a T. brucei‐specific DHODH inhibitor plus 5‐FU may prove to be an effective therapeutic strategy. We also show that this trypanosomal enzyme is inhibited by known inhibitors of bacterial Class 1A DHODH, in distinction to the sensitivity of DHODH from human and other higher eukaryotes. This selectivity is supported by the crystal structure of the T. brucei enzyme, which is reported here at a resolution of 1.95 Å. Additional research, guided by the crystal structure described herein, is needed to identify potent inhibitors of T. brucei DHODH.
Allergy: a systemic disease? The HUNT and Young–HUNT study, Norway.
Authors: Tollefsen Elin , Langhammer Arnulf , Bjermer Leif , Romundstad Pål , Holmen Turid Lingaas
Published: February 2008

A systemic nature of allergic diseases has been hypothesized. As part of this discussion, we studied if adolescent allergic wheeze and increasing combinations of allergic organ involvements (lung, nose and skin) would also increase the reporting of other health problems (headache, muscle pain and abdominal pain). In addition, we studied if parental asthma was associated with adolescent clustering of allergic expressions and if parental asthma with additional health problems (headache or muscle pain) was associated with adolescent reporting allergy in combination with headache, muscle pain and abdominal pain. Adolescents 13–19 yr (n = 8817, 89%) participated in the Young–HUNT study, Norway, 1995–97. Parental data on asthma were eligible in n = 5620. Health and lifestyle were measured by questionnaires and interviews. Associations with additional health problems were significantly strengthened with combinations of wheeze and other allergic expressions. Odds Ratio for associations ‘wheeze only’, ‘wheeze and rhinitis’ and ‘wheeze, rhinitis and eczema’ were for headache 2.1, 3.4 and 3.7; for muscle pain 2.8, 3.2 and 4.9; for abdominal pain 3.6, 4.0 and 4.9. All p for trend were <0.010. Similar results were obtained when studying allergic wheeze; p for trend <0.001. Parental asthma was associated with clustering of adolescent allergic expressions, and parental asthma with headache or muscle pain was significantly associated with reported allergy combined with similar health problems in their offspring. The results indicate that allergy may be expressed beyond organs commonly viewed as part of an allergic disease, and hence may support a hypothesis of a systemic nature of allergic diseases.
Variability in the Italian population of Gnomonia leptostyla, homothallism and resistance of Juglans species to anthracnose
Authors: Belisario A. , Scotton M. , Santori A. , Onofri S.
Published: February 2008

Isolations of Gnomonia leptostyla were carried out in 13 plantations of Juglans regia distributed throughout Italy, including Sardinia and Sicily. Mean diameter of colonies grown in vitro at 22°C and sporulation of 191 isolates, grouped by site of collection, were compared. Four groups of isolates, from environmentally diverse sites, were more thoroughly investigated for the effect of temperature (from 10 to 30°C, 5°C increment) on growth and sporulation. Colony growth of isolates within groups correlated with temperature and environmental parameters at the site of collection, such as temperature, rainfall, number of rain days per month and per year, and altitude. Altitude and mean temperature in April correlated with colony growth. In general, the isolates that grew significantly more slowly were from sites with colder early springs and higher altitudes. More significant data were obtained comparing isolates from different sites obtained from the same walnut cultivar or population. The host source was more significantly correlated with colony growth within the same site of collection. Acervular conidiomata were abundantly produced by all isolates at 22°C in darkness after 21 days, while protoperithecia were produced within 2 months by most isolates, under the same conditions. Similarly, the four groups of isolates tested at different temperatures produced conidiomata at 20 and 25°C, but not at 10, 15 and 30°C. After 2 months, protoperithecia were present in most isolates at 20°C, very few at 25 and 15°C, and no production was recorded at 10 and 30°C. Fertile perithecia with asci and ascospores were produced, after 3 months at 10°C in darkness, by six homothallic isolates out of 38 tested. In general, perithecia were larger than protoperithecia both in ascocarp diameter and in neck length. Ascocarp diameter, width of asci and length of ascopores of in vitro‐produced perithecia were larger than those of perithecia produced in nature. The latter showed a neck length longer than in vitro‐produced perithecia. Virulence of isolates when inoculated on J. regia was correlated with colony growth rate, but rated independently for homothallic or heterothallic isolates. A preliminary screening for sources of resistance to anthracnose in the genus Juglans showed J. sieboldiana and J. cinerea to be highly resistant and both J. nigra and J. hindsii to be highly susceptible to the disease. Juglans regia showed an intermediate response of susceptibility to anthracnose.
Apoptotic Changes in the Epithelium Germinativum of the Cat (Felis catus s. domestica, L. 1758) at Different Ages and Breeding Seasons
Authors: Siemieniuch MJ
Published: February 2008

Contents

Apoptosis (programmed cell death) could be considered as a physiological process that takes part in a healthy organism, which helps to maintain organism homeostasis. The visible deterioration of semen quality and the number of germ cells is accompanied by a seasonal decrease of the reproductive activity in some species. This post‐effect cascade is caused by apoptosis, which is the primary mechanism responsible for the elimination of germ cells during spermatogenesis. The aim of our study was to assess apoptotic changes in the epithelium germinativum in cat testes at different ages. One hundred and two pairs of testes were obtained from domestic cats aged between 4 months and 10 years. The paraffin‐embedded tissue sections were labelled using the Oncogene and Calbiochem Research Products DNA Fragmentation Detection Kit (Cat# QIA21; Darmstadt, Germany), which allows the recognition of apoptotic nuclei in tissue sections with Fragment End Labelling (FragELTM) of DNA. The activity of apoptotic processes in cat testes collected from the spring‐summer period compared with the autumn‐winter season revealed that, 59.42% and 51.51%, respectively, males testes were characterized by insignificant changes. The obtained data revealed a distinctive apoptotic changes in the young animal testes before spermatogenesis onset. An intensification of programmed death cells in the epithelium germinativum in the elder cats (between 3–6 and 6–10 years) was not observed. Apoptotic changes slightly intensified in cats aged between 12 and 36 months.
GABA Control of GnRH Release from the Ewe Hypothalamus In Vitro: Sensitivity to Oestradiol
Authors: Ghuman SPS , Jones DN , Prabhakar S , Smith RF , Dobson H
Published: February 2008

Contents

The present study examines the involvement of GABAA or B receptors in gonadotrophin‐releasing hormone (GnRH) release in vitro and determines whether oestradiol modulates γ‐aminobutyric acid (GABA)–GnRH interaction. Within 10 min after ewe killing, hypothalamic slices were dissected and placed in oxygenated Minimum Essential Media (MEM)‐α at 4°C; within 2 h, slices were singly perifused at 37°C with oxygenated MEM‐α (0.15 ml/min), with or without oestradiol (24 pg/ml). After 4 h equilibration, fractions were collected for 4 h interposed with a 10 min exposure to specific GABAA or B receptor ligands (0.1–10 mm). The GABAA or B agonists (muscimol or baclofen) did not greatly influence GnRH release. However, GnRH increased (p < 0.05) after exposure to 10 mm GABAA or B antagonists (bicuculline or CGP52432, respectively). The GABAA antagonist stimulated greater sustained GnRH release (p < 0.05) in the absence of oestradiol than in its presence. The bioactivity of the released GnRH was studied using a hypothalamus‐pituitary sequential double‐chamber perifusion. Only after exposure of hypothalamic slices to the GABAA antagonist, did the hypothalamic eluate stimulate luteinizing hormone release from pituitary fragments (p < 0.05) confirming that the GABAA antagonist stimulated release of biologically active GnRH. In summary, GnRH release from the hypothalamus is predominantly under GABAA receptor inhibitory control and this is attenuated in the presence of oestradiol.
Spontaneous bilateral fracture of patella
Authors: Moretti Biagio , Speciale Domenico , Garofalo Raffaele , Moretti Lorenzo , Patella Silvio , Patella Vittorio
Published: February 2008

Bilateral patellae fractures represent a rare entity, accounting for approximately 2.9% of all lesions interesting in this anatomical district. In most cases found in the published work, they are described as stress fractures or as complications of chronic diseases such as osteoporosis, renal failure and secondary hyperparathyroidism. Although many pathogenetic mechanisms have been supposed, none have been proved for certain. Insufficiency fractures of the patellae are rare events and no data has been published on their incidence. We present a case of bilateral fracture of the patellae due to an indirect trauma occurring in an 85‐year‐old patient affected by Parkinson's disease, osteoporosis and diffuse degenerative osteoarthritis. X‐ray of the knees (anteroposterior and lateral) and magnetic resonance imaging evaluation confirmed the fractures. The patient was treated conservatively. She had a good result, returning to her previous autonomous ambulation. This case is unusual because there was no direct trauma to the knees because of bilaterality, but confirmed previous observations about insufficiency fractures of patellae in the presence of comorbidity. Insufficiency fractures of patellae can be an insidious condition in elderly people. Prepatellar pain, a common symptom in the relapse phase of degenerative arthritis of the knee, should not be underestimated, particularly in patients with diseases influencing metabolism of bone and with an elevated risk of fall. A periodical clinical and instrumental follow up should be done in these patient. Moreover, we underline the necessity of a multidisciplinary approach.
SAMPLING ERRORS OF GENETIC CORRELATION COEFFICIENTS CALCULATED FROM ANALYSES OF VARIANCE AND COVARIANCE
Authors: Tallis G. M.
Published: February 2008

Summary. In this paper a formula is developed for estimating the sampling variance of a genetic correlation estimated from analyses of variance and covariance. The formula holds provided the heritability estimate of neither character is zero. However, the development assumes a constant number of offspring per sire, k, and the effect of varying values of k is discussed briefly. The efficiency of experiments from which genetic parameters are to be estimated has also been investigated and optimum values of k are given for various combinations of phenotypic and genetic parameters.
THE “ CAUTION‐LEVEL ” IN MULTIPLE TESTS OF SIGNIFICANCE
Authors: Verhagen A. M. W.
Published: February 2008

The paper produces a measure for the reliability of multiple assertions arrived at with multile tests of significance. it is called the caution level and in the case of single tests it reduces to the well know significance level.

The caution level is introduced and discussed in relation to n independent test statistics for n different null hypotheses. Its value c is given by c = l ‐(l ‐α)n‐(r‐1) where α is the level of significance of the individual tests and r is the observed number of significant test statistics. The caution level is applied to some experimental data and worked out in detail for the case n=2. The caution level depends on the observed number of significant test‐statistics and is therefore closely geared to the actual outcome of the experiment. This gives it an advantage over the “experimentwise error rate” proposed by Tukey (1953), since the latter becomes more unrealistic as the number r of significant test‐statistics increases.

The caution level turns out to be well suited for designing multiple tests in which the caution level is the same irrespective of the possible multiple assertion to which the test may lead. The construction of tests with the caution level equalized over all possible assertions involves only the distribution of the largest of ν independent rectangular variates in the range (0, 1). Such a test is illustrated graphically for thc case n=2.

Just as the significance level in the case of a single test, so the caution level provides a, starting point for the study of errors of the second kind, both in the absence and in the presence of prior distribuions, for the more general multiple‐test situation and thus opens up a wide field of investigation. At a later stage the author proposes to extend the use of the caution level to more complicated situations involving studentized test‐statistics dependent through a common denominator and to correlated test statistics consisting of differences between means.
NOTE ON THE NON‐EXISTENCE OF A MAXIMUM LIKELIHOOD ESTIMATE1
Authors: Konijn H. S.
Published: February 2008

It is shown that in a regression model with intraclass correlation ρ, maximum likelihood estimates and minimum variance unbiased linear estimates of the regression coefficients are unaffected by the value of ρ when ρ is given, and that the former do not exist when ρ is not specified. The usual confidence intervals for the regression slopes remain valid, but there are difficulties in giving a confidence interval for the intercept.
SERIES EXPANSIONS FOR THE DOUBLY NON‐CENTRAL F‐DISTRIBUTION1
Authors: Tiku M. L.
Published: February 2008

Series expansions which can provide accurate approximations for the probability integral of the doubly non‐central F‐distribution are presented and some results tabulated. A three‐moment central‐F approximation to the distribution is derived.
SOME CONTRIBUTIONS TO TWO‐PHASE SAMPLING
Authors: Singh D. , Singh B. D.
Published: February 2008

A new two‐phase sampling procedure is suggested in this paper. The information on the ancillary variate in the preliminary sample is used for selecting the units for sub‐sample with unequal probabilities. Unbiased estimators for the population mean and their variance expressions are obtained for sub‐sampling procedures, both with and without replacement.
QUASI‐STATIONARY BEHAVIOUR IN THE RANDOM WALK WITH CONTINUOUS TIME
Authors: Seneta E.
Published: February 2008

The long‐term behaviour of the random walk on the positive integers is discussed. In particular, one distribution describing this behaviour when there is a non‐zero drift in one direction, is shown to be of discrete gamma‐type. Under the same condition, the effectively ultimate time to absorption is exponential.
AN INVENTORY PROBLEM APPLIED TO A RENTAL SITUATION
Authors: Jain H. C.
Published: February 2008

An inventory problem, applied to a rental situation business, has been considered. If no item is in stock when a demand occurs, the company borrows the units from other concerns in the same line of business. The profit function has been calculated and it has been shown how the inventory level increases with penalty cost.

A review of the literature on inventory control reveals that not much work has been done in holding inventories of rental items. In a recent paper, Tainiter (1964) considered the situation in which a company rents out items such as cars, trucks, farm equipment, books, furniture, etc., and obtained the profit function by taking “rental‐out” time as a negative exponential and demand as a general random variable. The model is equally applicable to companies which rent out “service personnel”, repair men, taxi cabs, etc.

“We consider a company renting out items to customers. The company starts its business by purchasing a total number of M items in the inventory. The term inventory, defined by Arrow, Earlin and Scarf (1958) as the stock of goods which is kept for future sale or production, is applicable here. Whenever a demand occurs the item is rented out immediately, if it is available in the stock. But if the inventory is zero, i.e. all the items are rented out, the demand will be satisfied by borrowing items from other companies which are dealing in the same line of business. For example, a manufacturer of refrigerators maintains and repairs his product at the customer's house after sale. If a complaint arrives when no repairmen are available, the company will “borrow” repairmen from elsewhere and will attend to the complaint immediately. The borrowing cost may be negative or positive, representing a penalty or a profit. On the other hand if the company does not borrow and the customer has to wait (and such situations occur very often) the loss of the customer's goodwill may occur. It is also not possible to keep large numbers of items because of the storage costs and tied up capital. The problem is then to devise an optimal policy such that the profits of the company are maximized.
A NOTE ON CONFIDENCE BOUNDS FOR CERTAIN RATIOS OF CHARACTERISTIC ROOTS OF COVARIANCE MATRICES
Authors: Krishnaiah P. R. , Pathak P. K.
Published: February 2008

Let σ1, …, σk be the covariance matrices of k p‐variate normal populations. Let Λij be the jth largest characteristic root of σi (j=1, …, p; i=1, …, k). In this note we obtain simultaneous confidence intervals on (i)Λi+1, p/Λipand by using methods similar to those of Khatri (1965).
THE THEORY OF UNIVARIATE SAMPLING ON SUCCESSIVE OCCASIONS UNDER THE GENERAL CORRELATION PATTERN1,2
Authors: Prabhu‐Ajgaonkar S. G.
Published: February 2008

The present paper is concerned with the various results developed for the theory of successive sampling. The different correlation patterns and the different sampling procedures assumed in the theory are described and further an attempt has been made to derive results for the general correlation pattern. Accordingly, an expression for the best (minimum variance linear unbiased) estimator is presented for the general correlation pattern where the sampling procedure adopted is a restricted one. When the special correlation pattern assumed in the derivation of results breaks down on a particular occasion, its effect on the estimator employed for that occasion is examined. Furthermore, an expression for the variance of the estimator, which is best under a special correlation pattern, is derived when that correlation pattern does not hold good. The expression so obtained is comparable with that furnished by Patterson (1950).
A LIMIT THEOREM FOR THE GALTON‐WATSON PROCESS WITH IMMIGRATION
Authors: Quine M. P. , Seneta E.
Published: February 2008

It is difficult, in general, to optain an explicit expression for the limiting‐stationary distribution, when such a distribution exists, of the process in which teh individuals reproduce as in a Galton‐Wastson process, but are also subject to an independent immigration component at each generation. The main result of this paper is a limit theorem which suggests a means of approximating this distribution by a gamma density, when the mean of the offspring distribution is less than, but close to, unity. Following along the same lines, it is easy to show that a similar limit theorem holds for the asymptotic conditional limit distribution of an ordinary subcritical Galton‐Watson process, whereby this distribution approaches the exponential as the offspring mean approaches unity.
TESTING THE EQUALITY OF PARAMETERS IN THE DISTRIBUTIONS WHEN THE RANGE DEPENDS UPON THE PARAMETER
Authors: Khatri C.G. , Jaiswal M. C.
Published: February 2008

The authors derive the null and non‐null distributions of the test statistic v=ymin/ymax (where ymin= min xij, ymax= max xij, J=1,2, …, k) connected with testing the equality of scale parameters θ1, θ2, …θk in certain, class of density functions given by
The Multiplicative Definition of Interaction
Authors: Lancaster H. O.
Published: February 2008

The theory of the multiplicative definition of second order interaction is considered. Necessary and sufficient conditions in terms of the correlations in the marginal two‐dimensional distributions are found for the existence of a “perfect” set of probabilities. Some progress is reported on the proof of the uniqueness of the multiplicative set of probabilities for a given set of two‐dimensional distributions. The multiplicative property of such sets is preserved under pooling of marginal sets only in trivial cases, and so the multiplicative definition cannot be said to be a straightforward generalization from the definition of no interaction in two‐dimensional distributions.
Further Studies on Two Queues in Parallel
Authors: Hunter Jeffrey J.
Published: February 2008

This paper presents some further results related to a queueing model originally suggested by the author: “Two queues in parallel” (J. Boy. Statist. Soc, Ser. B, 31, 432–445, 1969).

A detailed study of the model under the imposition of finite waiting rooms when each queue can accommodate at most two customers illustrates the complexity of the problems involved. However, this study leads to some results concerning the nature of the equilibrium probabilities in the more general finite waiting room cases.

A study of the correlation between the input distributions and the correlation of the queue size distributions gives rise to some general conjectures concerning these relationships.
Maximum Likelihood Estimation in the Bivariate Binomial (0,1) Distribution:Application TO 2×2 Tables
Authors: Hamdan M. A. , Martinson E. O.
Published: February 2008

We consider a 2×2 contingency table, with dichotomized qualitative characters (A,A) and (B,B), as a sample of size n drawn from a bivariate binomial (0,1) distribution. Maximum likelihood estimates p̂1p̂2 and p̂ are derived for the parameters of the two marginals p1p2 and the coefficient of correlation. It is found that p̂ is identical to Pearson's (1904)ϕ=(χ2/n)½, where ϕ2 is Pearson's usual chi‐square for the 2×2 table. The asymptotic variance‐covariance matrix of p̂lp̂2and p is also derived.