bluuebunny/crossref_metadata_2025 huggingface dataset:
Short‐term exposure to constant light promotes strong circadian phase‐resetting responses to nonphotic stimuli in Syrian hamsters
Authors: Knoch Megan E. , Gobes Sharon M. H. , Pavlovska Ivanda , Su Cathy , Mistlberger Ralph E. , Glass J. David
Published: May 2004

Behavioral (nonphotic) stimuli can shift circadian rhythms by serotonin (5‐HT) and/or neuropeptide Y (NPY) inputs to the suprachiasmatic nucleus (SCN) circadian clock. Based on the idea that behavioral phase resetting is modulated by endogenous changes in postsynaptic sensitivity to such transmitters, hamsters were exposed to constant light (LL; ∼ 250 lx) for 1–3 days, which suppresses locomotor activity and eliminates the daily rhythm of SCN 5‐HT release measured by microdialysis. Groups subjected to brief LL or maintained under a light/dark cycle (LD) received phase‐resetting treatments with the 5‐HT1A,7 agonist (±)‐2‐dipropyl‐amino‐8‐hydroxyl‐1,2,3,4‐tetrahydronapthalene (8‐OH‐DPAT) or sleep deprivation (SD). Animals were released to constant darkness at the start of the treatments. Phase advances to 8‐OH‐DPAT and SD during the day were 11 and 3 h for LL vs. 2 and 1 h for LD, respectively. Phase delays during the night were −12 and −5 h for LL vs. no responses for LD, respectively. Phase‐transition curves for both LL treatments had slopes approximating 0, indicative of Type 0 phase resetting. For all treatments, the degree of locomotor suppression by LL was not correlated with the phase shift magnitude. Re‐establishing locomotor activity by overnight food deprivation did not prevent potentiated shifting to SD. However, re‐establishing peak extracellular 5‐HT levels by intra‐SCN 5‐HT reverse microdialysis perfusion in LL did significantly reduce potentiated 8‐OH‐DPAT phase advances. Constant light also enhanced intra‐SCN NPY‐induced phase advances during the day (6 vs. 2 h for LD). These results suggest that LL promotes Type 0 phase resetting by supersensitizing 5‐HT and/or NPY postsynaptic responses and possibly by attenuating the amplitude of the circadian pacemaker, thus enhancing circadian clock resetting nonspecifically.
The cytosolic II–III loop of Cav2.3 provides an essential determinant for the phorbol ester‐mediated stimulation of E–type Ca2+ channel activity
Authors: Klöckner Udo , Pereverzev Alexey , Leroy Jérôme , Krieger Andreas , Vajna Rolf , Pfitzer Gabriele , Hescheler Jürgen , Malécot Claire O. , Schneider Toni
Published: May 2004

There is growing evidence that E‐type voltage dependent Ca2+ channels (Cav2.3) are involved in triggering and controlling pivotal cellular processes like neurosecretion and long‐term potentiation. The mechanism underlying a novel Ca2+ dependent stimulation of E‐type Ca2+ channels was investigated in the context of the recent finding that influx of Ca2+ through other voltage dependent Ca2+ channels is necessary and sufficient to directly activate protein kinase C (PKC). With Ba2+ as charge carrier through Cav2.3 channel α1 subunits expressed in HEK‐293 cells, activation of PKC by low concentrations of phorbol ester augmented peak IBa by approximately 60%. In addition, the non‐inactivating fraction of IBa was increased by more than three‐fold and recovery from short‐term inactivation was accelerated. The effect of phorbol ester on IBa was inhibited by application of the specific PKC inhibitor bisindolylmaleimide I. With Ca2+ as charge carrier, application of phorbol ester did not change the activity of Cav2.3 currents but they were modified by the PKC inhibitor bisindolylmaleimide I. These results suggest that with Ca2+ as charge carrier the incoming Ca2+ can activate PKC, thereby augmenting Ca2+ influx into the cytosol. No modulation of Cav2.3 channels by PKC was observed when an arginine rich region in the II–III loop of Cav2.3 was eliminated. Receptor independent stimulation of PKC and its interaction with Cav2.3 channels therefore represents an important positive feedback mechanism to decode electrical signals into a variety of cellular functions.
Tetrodotoxin administration in the suprachiasmatic nucleus prevents NMDA‐induced reductions in pineal melatonin without influencing Per1 and Per2 mRNA levels
Authors: Paul Ketema N. , Gamble Karen L. , Fukuhara Chiaki , Novak Colleen M. , Tosini Gianluca , Albers H. Elliott
Published: May 2004

The suprachiasmatic nucleus (SCN) of the anterior hypothalamus contains a light‐entrainable circadian pacemaker. Neurons in the SCN are part of a circuit that conveys light information from retinal efferents to the pineal gland. Light presented during the night acutely increases mRNA levels of the circadian clock genes Per1 and Per2 in the SCN, and acutely suppresses melatonin levels in the pineal gland. The present study investigated whether the ability of light to increase Per1 and Per2 mRNA levels and suppress pineal melatonin levels requires sodium‐dependent action potentials in the SCN. Per1 and Per2 mRNA levels in the SCN and pineal melatonin levels were measured in Syrian hamsters injected with tetrodotoxin (TTX) prior to light exposure or injection of N‐methyl‐d‐aspartate (NMDA). TTX inhibited the ability of light to increase Per1 and Per2 mRNA levels and suppress pineal melatonin levels. TTX did not, however, influence the ability of NMDA to increase Per1 and Per2 mRNA levels, though it did inhibit the ability of NMDA to suppress pineal melatonin levels. These results demonstrate that action potentials in the SCN are not necessary for NMDA receptor activation to increase Per1 and Per2 mRNA levels, but are necessary for NMDA receptor activation to decrease pineal melatonin levels. Taken together, these data support the hypothesis that the mechanism through which light information is conveyed to the pacemaker in the SCN is separate from and independent of the mechanism through which light information is conveyed to the SCN cells whose efferents suppress pineal melatonin levels.
Frequency‐dependent requirement for calcium store‐operated mechanisms in induction of homosynaptic long‐term depression at hippocampus CA1 synapses
Authors: Nakano Makoto , Yamada Shin‐ichiro , Udagawa Rie , Kato Nobuo
Published: May 2004

For induction of long‐term depression (LTD), mechanisms dependent on N‐methyl‐d‐aspartate receptors (NMDARs) and on intracellular calcium stores have been separately known. How these two mechanisms coexist at the same synapses is not clear. Here, induction of LTD at hippocampal Schaffer collateral‐to‐CA1 pyramidal cell synapses was shown to depend on NMDARs throughout the theoretically predicted activation range for LTD induction. With stimulation at 1 Hz, the largest LTD was induced in a store‐independent manner. With stimulation at 0.5 and 2.0 Hz the induced LTD was much smaller, and dependence on calcium stores appeared. Under caffeine application, an enlarged LTD was induced with 0.5 Hz stimulation. Postsynaptic blockade of ryanodine receptors prevented this caffeine‐induced enhancement of LTD. It is therefore suggested that calcium release from calcium stores facilitated by caffeine contributed to the LTD enhancement, and that the caffeine effect was exerted on the postsynaptic side. Induction of this enhanced LTD was resistant to NMDAR blockade. We thus propose that the store‐dependent mechanism for LTD induction is dormant at the centre of the theoretically predicted activation range for LTD induction, but operates at the fringes of this activation range, with its contribution more emphasized when ample calcium release occurs.
Differential regulation of the mitochondrial and death receptor pathways in neural stem cells
Authors: Tamm Christoffer , Robertson John D. , Sleeper Eric , Enoksson Mari , Emgård Mia , Orrenius Sten , Ceccatelli Sandra
Published: May 2004

Despite an increasing interest in neural stem cell (NSC) research, relatively little is known about the biochemical regulation of cell death pathways in these cells. We demonstrate here, using murine‐derived multipotent C17.2 NSCs, that cells undergo mitochondria‐mediated cell death in response to apoptotic stimuli such as oxidative stress induced by 2,3‐dimethoxy‐1,4‐naphthoquinone (DMNQ). In particular, treated cells exhibited apoptotic features, including Bax translocation, cytochrome c release, activation of caspase‐9 and ‐3, chromatin condensation and DNA fragmentation. Although C17.2 cells possess the Fas receptor and express procaspase‐8, agonistic Fas mAb treatment failed to induce apoptosis. Fas treatment activated the extracellular signal‐regulated protein kinase (ERK) pathway, which may have an antiapoptotic as well as a growth stimulating role. Combined, our findings indicate that while NSCs are sensitive to cytotoxic stimuli that involve an engagement of mitochondria, Fas treatment does not induce death and may have an alternative role.
Targeted introduction of V642I mutation in amyloid precursor protein gene causes functional abnormality resembling early stage of Alzheimer's disease in aged mice
Authors: Kawasumi Masaoki , Chiba Tomohiro , Yamada Marina , Miyamae‐Kaneko Makiko , Matsuoka Masaaki , Nakahara Jin , Tomita Taisuke , Iwatsubo Takeshi , Kato Shigeaki , Aiso Sadakazu , Nishimoto Ikuo , Kouyama Keisuke
Published: May 2004

While the exact aetiology of Alzheimer's disease (AD) is unknown, distinct genetic mutations have been identified for the rare cases of familial AD (FAD). V642I mutation in amyloid precursor protein (APP) co‐segregates with FAD with perfect penetration, and the clinicopathological characteristics of patients with this mutation resemble that of sporadic AD. To examine the pathogenic process of this FAD‐linked trait in vivo, we produced a mouse with the corresponding point mutation in the APP gene using homologous recombination and Cre‐loxP site‐specific recombination (‘knock‐in’ technique). Mice with the heterozygous V642I‐APP allele most precisely reflected the genotype of humans bearing this mutation. For the observation period of 2.5 years the mutants stayed apparently indistinguishable from the wild‐type littermates. However, behavioural analysis revealed significantly deteriorated long‐term memory in mutants when examined for the retention of spatial attention. Interestingly, acquisition of spatial memory was slightly affected but short‐term working memory was not deteriorated at all. Histological examination was negative for formation of neuritic plaques or neurofibrillary tangles, whereas the relative amount of longer form of β‐amyloid species Aβ42(43) was significantly increased against that of the shorter form (Aβ40) in the mutant brain homogenates. We conclude that a V642I‐APP mutant allele in aged mice confers functional components, but not organic components, of the AD‐related phenotype that are observed in the early stage of AD. This V642I‐APP knock‐in mutant line may serve as a model to study the early pathogenic processes of AD in vivo and to develop therapeutics for this stage.
A parvalbumin‐containing, axosomatic synaptic network in the rat medial septum: relevance to rhythmogenesis*
Authors: Henderson Z. , Fiddler G. , Saha S. , Boros A. , Halasy K.
Published: May 2004

The medial septal diagonal band complex (MS/DB), made up of cholinergic and GABAergic neurons, plays an important role in the generation of the hippocampal theta rhythm. A GABAergic neuron type in the MS/DB that has fast spiking properties was shown previously to contain parvalbumin immunoreactivity and to form axosomatic connections with unidentified somata. The aim in the current study was to determine the neurochemical identities of these target neurons. In slices and in perfused‐fixed brain, staining for parvalbumin immunoreactivity first of all revealed the presence of two types of parvalbumin‐positive somata in the MS/DB: medially located neurons with parvalbumin‐positive basket‐like terminals on them, and more laterally located neurons with fewer parvalbumin‐positive contacts on them. In MS/DB slices, the terminals of fast spiking neurons filled with biocytin correspondingly made either numerous contacts that surrounded the parvalbumin‐positive cell body in basket‐like formation, or 1–5 contacts on a localized patch of the soma. These contacts were shown by electron microscopy to form synaptic junctions. No terminals of biocytin‐filled fast spiking neurons were observed on cholinergic neurons, and dual staining in perfused‐fixed brain did not reveal the presence of parvalbumin‐containing terminals on cholinergic somata. Our results suggest therefore that there are two subtypes of parvalbumin‐containing neuron in the MS/DB, and that these are interconnected via axosomatic synapses. The contrasting topographical organization of the two types of parvalbumin‐containing neuron suggests that they may receive different types of afferent input, but this will require substantiation in future studies. We propose that generation of rhythmic activity in the MS/DB is controlled by contrasting contributions from two types of parvalbumin‐positive neuron, and that the role of the cholinergic neuron is modulatory.
Plexin‐B family members demonstrate non‐redundant expression patterns in the developing mouse nervous system: an anatomical basis for morphogenetic effects of Sema4D during development
Authors: Worzfeld Thomas , Püschel Andreas W. , Offermanns Stefan , Kuner Rohini
Published: May 2004

Semaphorins and their receptors play important roles in patterning the connectivity of the developing nervous system and recent data suggest that members of the plexin‐B family of semaphorin receptors may be involved in axonal guidance. Here we show that the mRNAs of the three plexin‐B genes, plxnb1, plxnb2 and plxnb3 (plexin‐B1, plexin‐B2 and plexin‐B3), respectively, are expressed in highly specific and non‐redundant patterns in peripheral and central components of the nervous system over defined periods during murine development. Whereas plexin‐B1 and plexin‐B2 are strongly expressed in the neuroepithelium and developing neurons, plexin‐B3 mRNA is selectively localized to the white matter. Moreover, plexin‐B1 and its ligand Sema4D are expressed in complementary patterns in several regions such as the developing neopallial cortex, the dorsal root ganglia and the spinal cord over embryonic stages. The Sema4d gene demonstrates a dramatic switch from prenatal expression in neuronal populations to a postnatal expression in oligodendrocytes. In contrast to its collapsing activity on growth cones of embryonic retinal ganglion cells and hippocampal neurons, soluble Sema4D enhances axonal outgrowth in embryonic cortical explants cultured in collagen matrices. Thus, plexin‐B family members and Sema4D are likely to play complex and non‐redundant roles during the development of the nervous system.
Implicit Forward Rents as Predictors of Future Rents
Authors: Englund Peter , Gunnelin Åke , Hoesli Martin , Söderberg Bo
Published: May 2004

This paper investigates the relation between the term structure of rents and future spot rents. A rich database of office rental agreements for various maturities is used to estimate the term structure of rents, and from this structure implicit forward rents are extracted. The data pertain to commercial properties in the three largest Swedish cities for the period 1998–2002. A positive relation between forward and spot rents is found in some regions, but forward rents underestimate future rent levels. Another contribution of the paper lies in the area of rental index construction. We provide evidence that rental indices should not only be quality constant (i.e., control for characteristics), but should also be maturity constant.
Transaction‐Based Office Price Indexes: A Spatiotemporal Modeling Approach
Authors: Tu Yong , Yu Shi‐Ming , Sun Hua
Published: May 2004

This study examines the potential of a two‐order spatiotemporal autoregressive model with a Bayesian heteroskedasticity robust procedure in modeling strata‐titled Singapore office unit transaction prices and in constructing transaction‐based disaggregate office price indexes. The model reduces the problems caused by the infrequent trading of individual commercial properties. However, for those office properties that are located outside the CBD and also for those less frequently transacted, the power of the model in capturing these particular office buildings' price dynamics is limited. The significant differences of the office prices across the various office buildings and submarkets show that the model can capture the variation in office prices and track the timing of capital gains and losses that investors may accrue on spatially distributed office properties more accurately than hedonic or weighted least squares estimates.
Sale before Completion of Development: Pricing and Strategy
Authors: Lai Rose Neng , Wang Ko , Zhou Yuqing
Published: May 2004

The paper examines the risk‐and‐return characteristics of a popular development strategy, the presale system (or sale before completion), used in many Asian cities. We model a presale decision in a real‐options framework and suggest that the use of presale is primarily for a risk‐sharing purpose. That is, developers can reduce bankruptcy and marketing risks by selling (or leasing) their projects before their completion dates. Our model also indicates that, because of the presale system, there is a barrier for new developers to enter into a market, which helps explain the anecdotal observation that most real estate markets in Asian cities are oligopolistic in nature and dominated by large developers.
Effects of single or combined histamine H1‐receptor and leukotriene CysLT1‐receptor antagonism on nasal adenosine monophosphate challenge in persistent allergic rhinitis
Authors: Lee Daniel K. C. , Jackson Catherine M. , Soutar Patricia C. , Fardon Thomas C. , Lipworth Brian J.
Published: May 2004

Background

The effects of single or combined histamine H1‐receptor and leukotriene CysLT1‐receptor antagonism on nasal adenosine monophosphate (AMP) challenge in allergic rhinitis are unknown.

Objective

We elected to study the effects of usual clinically recommended doses of fexofenadine (FEX), montelukast (ML) and FEX + ML combination, compared with placebo (PL), on nasal AMP challenge in patients with persistent allergic rhinitis.

Methods

Twelve patients with persistent allergic rhinitis (all skin prick positive to house dust mite) were randomized in a double‐blind cross‐over fashion to receive for 1 week either FEX 180 mg, ML 10 mg, FEX 180 mg + ML 10 mg combination, or PL, with nasal AMP challenge performed 12 h after dosing. There was a 1‐week washout period between each randomized treatment. The primary outcome measure was the maximum percentage peak nasal inspiratory flow (PNIF) fall from baseline over a 60‐min period after nasal challenge with a single 400 mg ml−1 dose of AMP. The area under the 60‐min time–response curve (AUC) and nasal symptoms were measured as secondary outcomes.

Results

There was significant attenuation (P < 0.05) of the mean maximum percentage PNIF fall from baseline after nasal AMP challenge vs. PL, 48; with FEX, 37; 95% confidence interval for difference 2, 20; ML, 35 (4, 22); and FEX + ML, 32 (7, 24). The AUC (%.min) was also significantly attenuated (P < 0.05) vs. PL, 1893; with FEX, 1306 (30, 1143); ML, 1246 (214, 1078); and FEX + ML, 1153 (251, 1227). There were no significant differences for FEX vs. ML vs. FEX + ML comparing either the maximum or AUC response. The total nasal symptom score (out of 12) was also significantly improved (P < 0.05) vs. PL, 3.3; with FEX, 2.1 (0.3, 2.0); ML, 2.0 (0.5, 1.9); and FEX + ML, 2.5 (0.1, 1.4).

Conclusion

FEX and ML as monotherapy significantly attenuated the response to nasal AMP challenge and improved nasal symptoms compared with PL, while combination therapy conferred no additional benefit.
Population pharmacokinetics of (R)‐, (S)‐ and rac‐methadone in methadone maintenance patients
Authors: Foster David J. R. , Somogyi Andrew A. , White Jason M. , Bochner Felix
Published: May 2004

Aim

To construct a population pharmacokinetic model for methadone enantiomers in the setting of methadone maintenance treatment for opioid dependence.

Methods

A population pharmacokinetic model was developed using P‐Pharm software for rac‐, (R)‐ and (S)‐methadone using data (8–13 plasma samples per subject) obtained from 59 methadone maintenance patients during one interdosing interval at steady state. The patients were randomly assigned to either a development (n = 38) or a validation dataset (n = 21). The model was refined by inclusion of all subjects to construct a final basic model, which was used to construct a covariate model.

Results

A population‐based two‐compartment open model with first‐order absorption and lag time was developed and validated for all analytes. The population geometric mean (coefficient of variation) of maximum a posteriori probability Bayesian estimated values for clearance, terminal half‐life and volume of distribution at steady‐state of the active (R)‐enantiomer were 8.7 (42%) l h−1, 51 (45%) h and 597 (45%) l, respectively. For all analytes, the volume of the central compartment was decreased with increasing plasma α1‐acid glycoprotein concentration and was lower in females, while the delay in absorption was longer at higher doses. No covariates were identified for apparent oral clearance. The apparent oral clearance of (R)‐methadone (geometric mean ratio; 95% confidence interval) was 105% (99, 110), that of (S)‐methadone (P = 0.19), while (R)‐methadone Vc/F (154%; 151, 157), Vdss /F  (173%; 164, 183), t1/2β (162%; 153, 172) and mean residence time (166%; 156, 176) were significantly greater (P < 0.0001) than for (S)‐methadone. The population pharmacokinetic models were able to predict accurately oral clearance values from limited (one or two samples) blood sampling protocols.

Conclusions

The substantial stereoselectivity in methadone disposition reinforces the potential for misinterpretation of racemic methadone disposition data. The marked interindividual variability in (R)‐methadone clearance, with no covariates identified, highlights the need for alternative methods to determine an individual's metabolic clearance. The ability to predict (R)‐methadone clearance from one to two blood samples at steady state may prove clinically useful if a drug–drug interaction or poor adherence are suspected and guide the prescriber in deciding if a client's request for a dose increase is warranted or whether an alternative opioid would be more appropriate.
Maximum a posteriori Bayesian estimation of epirubicin clearance by limited sampling
Authors: Ralph Lorraine D. , Thomson Alison H. , Dobbs Nicola A. , Twelves Chris
Published: May 2004

Aims  To develop a limited sampling strategy for estimation of epirubicin clearance.

Methods  The data set comprised 1051 concentrations measured in 105 patients with advanced or metastatic breast cancer treated with epirubicin alone. Ten limited sampling designs comprising two or three blood samples were proposed, taken at times identified by D‐optimality from population pharmacokinetic parameter estimates. The data set was then truncated to include the sampling times for each of the designs. MAP Bayesian estimates of clearance were generated for each design and compared with clearance estimates obtained using all the data. The limited sampling designs were also validated using a separate data set obtained from 18 patients with either breast cancer or hepatocellular carcinoma. The sensitivity of the best limited sampling designs to sample time recording errors of 0–10% or 10–20% was then assessed using a simulated data set including 200 patients.

Results  The optimum sampling times were: end of the injection and 18 min, 40 min, 3 h, 10 h and 48 h after the start of the injection. The best three‐sample design included samples at 40 min, 3 h and 48 h and gave unbiased estimates of clearance with an imprecision of 9.1% (95% CI 7.3, 10.5). The best two sample design included samples at 3 and 48 h and gave unbiased estimates of clearance with an imprecision of 12.4% (95% CI 9.6, 14.6). Using the validation data set, these two and three sample designs gave unbiased estimates of clearance with an imprecision of 5.6% (95% CI 3.7, 7.0) and 4.2% (95% CI 2.6, 5.3), respectively. Simulations that included 0–10% or 10–20% errors in the recording of the blood sampling times had negligible effects on the bias and imprecision of clearance estimates.

Conclusions  Limited sampling designs have been identified and validated that estimate epirubicin clearance with adequate precision and without bias from two or three blood samples. These designs also allow flexibility in blood sample collection and are robust with regard to sample time recording errors.
Stroke prevention and atrial fibrillation: reasons leading to an inappropriate management. Main results of the SAFE II study
Authors: Deplanque Dominique , Leys Didier , Parnetti Lucilla , Schmidt Reinhold , Ferro Jose , De Reuck Jacques , Mas Jean‐Louis , Gallai Virgilio ,   the SAFE ll Investigators
Published: May 2004

Aims  The aim of the Stroke and Atrial Fibrillation Ensemble (SAFE) II study was to identify the reasons underlying the under‐utilization of oral anticoagulation (OAC) in patients with nonvalvular atrial fibrillation (NVAF).

Methods  We investigated from all available sources the reasons why patients hospitalized for a stroke, who had a previously known NVAF, were not receiving OAC beforehand. We interviewed general practitioners (GPs) and cardiologists with a structured questionnaire, to identify the reasons for their therapeutic choice.

Results  Of 370 patients, 257 were theoretically eligible for OAC according to guidelines and the presence of contra‐indications, but only 82 (22.2%) of them had actually received OAC before. We found that factors independently associated with the prescription of OAC were being followed‐up by a cardiologist and having a younger GP. The leading reason evoked by GPs or cardiologists to explain why patients were not treated with OAC was the presence of a ‘potential contra‐indication’, which was often inappropriate, followed by ‘there was no indication’, ‘low compliance’ and ‘fear of bleeding’.

Conclusions  An important reason for not prescribing OAC was the lack of knowledge about trials and guidelines. Medical education about OAC in NVAF should therefore be improved.
The calcimimetic agent KRN 1493 lowers plasma parathyroid hormone and ionized calcium concentrations in patients with chronic renal failure on haemodialysis both on the day of haemodialysis and on the day without haemodialysis
Authors: Ohashi Naro , Uematsu Toshihiko , Nagashima Satoru , Kanamaru Mitsutaka , Togawa Akashi , Hishida Akira , Uchida Eiji , Akizawa Tadao , Koshikawa Shozo
Published: May 2004

Aims  Treatment with vitamin D sterols can lower plasma parathyroid hormone (PTH) in patients with secondary hyperparathyroidism; however, hypercalcaemia, hyperphosphataemia, or both, often develop. Calcimimetic agents, employed in alternative therapeutic approaches, directly inhibit PTH secretion by activating the calcium‐sensing receptor in the parathyroid glands.

Methods  In this study, patients were given orally 25, 50, and 100 mg doses of the calcimimetic agent KRN 1493 each on two occasions, on the day of haemodialysis and on the day without haemodialysis.

Results  In the pharmacokinetic results, because the clearance of KRN 1493 by haemodialysis was much smaller than the systemic clearance, the influence of haemodialysis was not remarkable. In the pharmacodynamic study, on both the days with or without haemodialysis, plasma PTH concentrations decreased in a dose‐dependent manner. Serum calcium concentrations decreased in association with the decrease in plasma PTH concentrations. Mild dose‐dependent adverse effects (mainly nausea) were seen after the administration of KRN 1493 on both the day of haemodialysis and the day without haemodialysis.

Conclusions  We conclude that the pharmacokinetics of KRN 1493 after a single administration were similar on the day of haemodialysis and the day without haemodialysis. KRN 1493 is safe and effective in suppressing PTH secretion and serum calcium concentrations on the day of haemodialysis and on the day without haemodialysis in patients with secondary hyperparathyroidism.
Treatment of advanced Ewing tumors by combined radiochemotherapy and engineered cellular transplants
Authors: Burdach Stefan
Published: May 2004

Abstract:  The use of HDT in Ewing tumors has been reviewed recently (Crit Rev Oncol Hematol 2002: 41: 169). This review will focus primarily on own recent work on the treatment of advanced Ewing tumors (AETs) and will attempt, in addition, to give a comprehensive overview of novel developments. The field under review has been shaped by investigators from both Europe and the United States of America in a scientific debate evolving over more than a decade at the meetings of the International Society of Pediatric Oncology and other scientific meetings. In the light of this debate, most oncologists will agree that patients with AETs are facing the worst prognosis of all patients with this disease and include both: (i) patients with primary metastatic disease with the worst prognosis as well as (ii) patients with relapse with the worst prognosis. The contributions of various investigators have lead to the identification of specific risk stratification criteria to overcome the heterogeneity of patients within the conventionally defined clinical stages of localized metastatic and relapsed disease. This review will address the following issues of treatment of AETs: (i) a definition of AET; (ii) risks and benefits of allogeneic vs. autologous stem cell transplantation; (iii) the role of total body irradiation; (iv) the number of involved bones as a risk factor in multifocal bone disease in AET; (v) the development of immunogene therapy in AET; (vi) the matching of radiochemo‐ and immunotherapy in AET; (vii) the future perspective of functional genomics and targeted therapy.
History of pediatric stem cell transplantation
Authors: Storb Rainer
Published: May 2004

Abstract:  During the past 50 yr, intensive studies into the use of hematopoietic cell transplantation (HCT) for therapy of cancer and non‐malignant hematologic diseases have changed this treatment modality from one that was thought to be plagued by insurmountable complications to one that is now standard therapy for some diseases. Continued research by transplant teams worldwide is likely to allow continued progress toward developing novel and improved treatment modalities and even wider application of the use of pluripotent hematopoietic stem cells in the treatment of human diseases.
Study of the WFS1 gene and mitochondrial DNA in Spanish Wolfram syndrome families
Authors: Domènech E , Gómez‐Zaera M , Nunes V
Published: May 2004

Wolfram syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by early onset diabetes mellitus and progressive optic atrophy. Patients with WS frequently develop deafness, diabetes insipidus, renal tract abnormalities, and diverse psychiatric illnesses, among others. A gene responsible for WS was identified on 4p16.1 (WFS1). It encodes a putative 890 amino acid transmembrane protein present in a wide spectrum of tissues. A new locus for WS has been located on 4q22–24, providing evidence for the genetic heterogeneity of this syndrome. Six Spanish families with a total of seven WS patients were screened for mutations in the WFS1‐coding region by direct sequencing. We found three previously undescribed mutations c.873C > A, c.1949_50delAT, and c.2206G > C, as well as the duplication c.409_424dup16, formerly published as 425ins16. Several groups had detected deletions in the mitochondrial DNA (mtDNA) of WS patients. For this reason, we also studied the presence of mtDNA rearrangements as well as Leber's hereditary optic neuropathy, mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes, and A1555G point mutations in the WS families. No mtDNA abnormalities were detected.
Tolerance of interferon‐alpha therapy in children with chronic hepatitis B
Authors: Liberek A , Łuczak G , Korzon M , Szlagatys‐Sidorkiewicz A , Bako W , Góra‐Gębka M , Rytlewska M , Sikorska‐Wiśniewska G
Published: May 2004

Objective:  To assess the side‐effects of interferon‐α (IFN‐α) therapy in children with chronic hepatitis B.

Methods:  This prospective study was performed on one hundred children by interviewing the patients and their parents; clinical examinations and laboratory investigations were performed during and after therapy.

Results:  The most frequent side‐effects of IFN‐α therapy were fever, flu‐like symptoms, and headaches. Lowering of the mean haemoglobin level, leukocyte and platelet count was significant, but transient during INF‐α treatment. No increase in autoantibody titres or significant alterations in thyroid function was observed. Twelve months after treatment, hepatitis Be antigen (HBeAg) elimination and alanine aminotransferase (ALT) normalization was achieved in 46% of the children; HBeAg and hepatatis B surface antigen (HBsAg) elimination, together with ALT normalization, was achieved in 14% of the cases.

Conclusion:  The side‐effects of the IFN‐α therapy in children such as fever, flu‐like symptoms and bone marrow suppression are common, but transient and mild.
Skin exposure during conventional phototherapy in preterm infants: A randomized controlled trial
Authors: Pritchard MA , Beller EM , Norton B
Published: May 2004

Objective:  To assess the effect of reduced skin exposure in preterm infants receiving overhead phototherapy treatment on total serum bilirubin (TSB).

Methods:  Randomized controlled trial. Preterm infants (>1500 g birthweight and ≤ 36 weeks gestation) were randomized to being nursed either partially clothed with only disposable nappies and in posturally supported positions (n = 30) or naked without postural support (n = 29). Primary outcome was mean TSB percentage change at 24 h of completed conventional overhead phototherapy treatment (irradiance of 6 µWcm−2/nm at a wavelength of 425−475 nm). The incidence of rebound jaundice, number of infants continuing to receive phototherapy treatment at 24 h periods, parental stress, mother−infant interaction and mean TSB percentage change at 24 h of completed conventional overhead phototherapy treatment were examined.

Results:  Mean TSB percentage change at 24 h of completed treatment for the partially clothed group was 15.4% (±18) and for the naked group 19% (±15) (mean difference 3.6% 95% CI −5.1, 12.3). No other outcomes were significantly affected by reduced skin exposure to overhead phototherapy treatment.

Conclusion:  Our results show no statistically significant difference in TSB level change using either nursing practice.
Behavioural and physiological reactivity to noise in the newborn
Authors: Trapanotto M , Benini F , Farina M , Gobber D , Magnavita V , Zacchello F
Published: May 2004

Objective:  To assess the electromyographic (EMG) and behavioural reactivity of a group of newborn infants exposed to noisy stimulation of various intensity recorded in the Paediatric intensive care Unit (PICU).

Methods:  The study was performed at the nursery of the Paediatrics Department (University of Padova) on a group of 21 healthy newborns (mean 39 weeks of gestation), assessed between 24 and 72 h after birth. The study involved taking EMG recordings of the corrugator supercilii muscle and assessing the infant's behaviour at the baseline (15 seconds before stimulation), during noisy stimulation (for 1−2 seconds) and during recovery (15 seconds in three subphases). The noises, previously recorded in PICU, had four different intensities and were administered in random order to all infants. Descriptive analysis and repeated‐measures analysis of variance (anova) were performed on the EMG and behavioural data.

Results:  The infants demonstrated a significant reaction to the noises both in the EMG recordings and in behavioural changes, especially during intense noisy stimulation. The reaction lasted longer than the stimulation period, preventing the infants from returning to the baseline condition.

Conclusions:  Exposure to high‐intensity noise produced in PICU causes evident behavioural and physiological effects (EMG). This is a field of study that could have important repercussions, given the medium‐ and long‐term effects of repeated noise stimulation.
Predictors of chronic lung disease in the ‘CPAP era’
Authors: Groves AM , Briggs KA , Kuschel CA , Harding JE
Published: May 2004

Objective:  To assess predictors of chronic lung disease (CLD), in infants requiring nasal continuous positive airway pressure (CPAP) support in the first 4 weeks of life.

Methods:  A retrospective case note audit of infants of birthweight 1250 g or less was undertaken.

Results:  Of 290 infants identified, 50% were initially treated with ventilation, 41% with CPAP, 4% required no support, and 5% had care withdrawn. Of infants initially treated with CPAP, 23% subsequently required ventilation. Overall mortality was 19%, with a further 21% of infants developing CLD. For infants requiring CPAP support, requirement for supplementary oxygen at between 10 and 21 days predicted increased risk of CLD, and receiver operating characteristic curves suggest requirement for supplementary oxygen at 14 days to be the most reliable cut‐off (area under curve = 0.72). Positive predictive values for future CLD or death for FiO2 .25, .30 and .40 while on CPAP at 14 days were 0.56, 0.61 and 0.76, respectively.

Conclusions:  CLD remains prevalent in very low birthweight infants in the CPAP era. Oxygen requirement at 14 days is the strongest predictor of CLD. Infants requiring 30% oxygen or more while on CPAP at 14 days have a 60% risk of subsequent CLD or death.
Outcomes of a nutrition audit in a tertiary paediatric hospital: Implications for service improvement
Authors: O'Connor J , Youde LS , Allen JR , Hanson RM , Baur LA
Published: May 2004

Objective:  To examine the process of anthropometric assessment of nutritional status in a tertiary paediatric hospital, to identify the barriers and to make recommendations for service improvement.

Methods:  The accuracy of height and weight scales in wards was checked. Dietitians measured height and weight of a representative sample of 245 inpatients and checked whether these measurements had been recorded on bed charts. Patients were classified as overweight, obese or under‐nourished. Diagnoses and procedures were obtained for each patient. Funding implications were modelled for inappropriate coding of nutritional status.

Results:  The barriers to nutritional assessment and management of nutritional comorbidities were: (i) inaccurate height scales in seven out of 12 wards; (ii) under‐recording of height and weight on patient bed charts (73% height missing, 12% both height and weight missing); (iii) under‐reporting of obesity and under‐nutrition in medical notes (one of eight obese patients, and none of 28 undernourished patients, reported); and (iv) low referral rate of obese or under‐nourished children to dietetic services (two of 42 overweight/obese patients referred, five of 28 undernourished patients referred). Funding simulation showed that if under‐nourished patients were correctly diagnosed then the potential facility reimbursement would have increased by $A52 326.

Conclusions:  Barriers to nutritional assessment can lead to failure to diagnose and treat both over‐ and under‐nutrition, thereby affecting quality of patient care, and may have financial implications for hospitals. Suggestions for service improvement include provision of accurate equipment, adequate training of staff undertaking nutritional assessments and clear definitions of staff responsibilities in all aspects of the process.
Osteomyelitis and pyogenic sacroiliitis: A difficult diagnosis
Authors: Ford LS , Ellis AM , Allen HW , Campbell DE
Published: May 2004

Abstract:  Pyogenic sacroiliitis is an uncommon infection often diagnosed late because of poor localization of symptoms and inadequate physical examination. We describe a 12‐year‐old girl whose osteomyelitis and pyogenic sacroiliitis was initially misdiagnosed and discuss examination, investigation and management of the condition. This case highlights the importance of thorough physical examination and the consideration of septic arthritis in an unusual joint.
Infant bath seats, drowning and near‐drowning
Authors: Byard RW , Donald T
Published: May 2004

Objective:  To investigate the possible role of infant bathtub seats in drowning and near‐drowning episodes in infants.

Methods:  A review was conducted of the files of the Forensic Science Centre and Child Protection Unit, Women's and Children's Hospital, Adelaide, South Australia, for significant immersion incidents in infants involving bathtub seats from January 1998 to December 2003.

Results:  A total of six cases of drowning occurred over the 6‐year period of the study in children under 2 years of age, including two infants. One of these cases, a 7‐month‐old boy, had been left unattended for some time in an adult bath in a bathtub seat. He was found drowned, having submerged after slipping down and becoming trapped in the seat. Three near‐drowning episodes occurred in children under the age of 2 years, including two boys aged 7 and 8 months, both of whom had been left for some time in adult baths in bath seats. Both were successfully resuscitated and treated in hospital.

Conclusions:  These cases demonstrate the vulnerability of infants to immersion incidents when left unattended in bathtubs. Bathtubs are particularly dangerous for infants as the slippery and smooth surfaces predispose to loss of balance and make escape from water difficult. Infant bathtub seats may give parents and child carers a false sense of security leading to infants being left unattended. Unfortunately, however, infants may fall out of, or slip and become trapped in, such seats. Infants and young children cannot be left unsupervized in water, and devices used as bathing aids such as bathtub seats may contribute to immersion incidents.
Genetic relations between outbreaks of the Queensland fruit fly, Bactrocera tryoni (Froggatt) (Diptera: Tephritidae), in Adelaide in 2000 and 2002
Authors: Gilchrist A Stuart , Sved John A , Meats Alan
Published: May 2004

Abstract  The Queensland fruit fly (Q‐fly), Bactrocera tryoni, is a serious horticultural pest throughout eastern Australia, and apart from isolated outbreaks, is absent from Adelaide and South Australia. Considerable resources are put into preventing the entry of Q‐fly into South Australia and the eradication of any outbreaks. Nevertheless, some flies are still trapped in Adelaide and, because known permanent populations are too distant for unaided dispersal, these flies must arrive as larvae in infested fruit. To provide authorities with more information on the nature of and the extent of outbreaks, the authors used 26 microsatellite markers to test the relationships between outbreak flies caught in Adelaide in 2000 and 2002. Groupings between individuals were tested using both a model‐based clustering method (implemented in the Structure program) and relatedness testing, using both simple exclusion tests and relatedness coefficients. While many flies appeared unrelated, one group of at least six full sibs was detected, all of which were trapped in the same month. Unexpectedly, these six flies were trapped at sites separated by distances greater than the unaided dispersal distance of Q‐fly, implicating human‐aided dispersal of infested fruit within Adelaide. Thus simultaneous trappings of flies separated by kilometres are not necessarily separate outbreaks as has been assumed. The implications for current outbreak control strategies are discussed.
Day‐degree development and phenology modelling of the immature stages of Chrysophtharta agricola (Chapuis) (Coleoptera: Chrysomelidae), a pest of eucalypt plantations
Authors: Nahrung Helen F , Allen Geoff R , Patel Vinu S
Published: May 2004

Abstract  Day‐degree developmental requirements and lower temperature thresholds were determined in the laboratory for the immature lifestages and preoviposition periods of Chrysophtharta agricola, a pest of eucalypt plantations in Tasmania and Victoria. These data were used to provide a predictive model for C. agricola's spring‐summer phenology under field conditions. The model was validated using field data from two Tasmanian field sites over three seasons. Lower temperature thresholds for immature development ranged from 2.8°C (Liv) to 10.3°C (Li), while the lower temperature threshold for oviposition was 7.4°C for teneral and overwintered adults. Total immature development time (egg‐adult) was approximately 400 ± 16 DD above 8 ± 0.41°C. Development time did not differ between males and females, or between offspring of different females. Beetles reared at 25°C were significantly larger than those reared at low temperatures. Day‐degree models were usually a good predictor of the appearance of developmental stages in the field.
Natural history and description ofOncothrips kinchega, a new species of gall‐inducing thrips with soldiers (Thysanoptera: Phlaeothripidae)
Authors: Wills Taryn E , Chapman Thomas W , Mound Laurence A , Kranz Brenda D , Schwarz Michael P
Published: May 2004

Abstract A new species of gall‐inducing thrips,Oncothrips kinchegasp. n., is described and its biology on the host plantAcacia carneorumwas investigated. Our study showed that a single foundress initiates a gall. Her first‐laid eggs develop into soldiers (mean number of soldiers ± SE = 28 ± 15, 40% males, with no evidence for protogyny or protandry). The soldiers, along with the foundress, produce the (subsequent) dispersing generation (mean number of dispersers ± SE = 187 ± 10, 37% males with no evidence for protogyny or protandry). The brood development‐pattern ofO. kinchegais similar to that found in the complex of forms currently referred to asOncothrips habrusMound andOncothrips waterhouseiMound & Crespi and is different from that ofOncothrips morrisiMound, Crespi & Kranz, a species with soldiers but a non‐social development pattern. However,O. kinchegashares several life history characteristics withO. morrisi, and appears intermediate in brood size betweenO. morrisiand the remainder of the gall‐inducers. The possible evolutionary significance of these observations is discussed.
Recruitment and loss of juvenile stages of Helicoverpa spp. (Lepidoptera: Noctuidae) on contaminant plants in chickpea crops
Authors: Sequeira Richard V
Published: May 2004

Abstract  The hypothesis that contaminant plants growing amongst chickpea serve as Helicoverpa sinks by diverting oviposition pressure away from the main crop was tested under field conditions. Gain (recruitment) and loss (presumed mortality) of juvenile stages of Helicoverpa spp. on contaminant faba bean and wheat plants growing in chickpea plots were quantified on a daily basis over a 12‐d period. The possibility of posteclosion movement of larvae from the contaminants to the surrounding chickpea crop was examined. Estimated total loss of the census population varied from 80 to 84% across plots and rows. The loss of brown eggs (40–47%) contributed most to the overall loss estimate, followed by loss of white eggs (27–35%) and larvae (6–9%). The cumulative number of individuals entering the white and brown egg and larval stages over the census period ranged from 15 to 58, 10–48 and 1–6 per m row, respectively. The corresponding estimates of mean stage‐specific loss, expressed as a percentage of individuals entering the stage, ranged from 52 to 57% for white eggs, 87–108% for brown eggs and 71–87% for first‐instar larvae. Mean larval density on chickpea plants in close proximity to the contaminant plants did not exceed the baseline larval density on chickpea further away from the contaminants across rows and plots. The results support the hypothesis that contaminant plants in chickpea plots serve as Helicoverpa sinks by diverting egg pressure from the main crop and elevating mortality of juvenile stages. Deliberate contamination of chickpea crops with other plant species merits further investigation as a cultural pest management strategy for Helicoverpa spp.