bluuebunny/crossref_metadata_2025 huggingface dataset:
Sickness‐related dysfunction in persons with self‐reported multiple chemical sensitivity at four levels of severity
Authors: Gibson Pamela Reed , Vogel Valerie M
Published: October 2008

Aim.  To examine quality of life outcome for persons who self‐report chemical sensitivity, often referred to as multiple chemical sensitivity.

Background.  Multiple chemical sensitivity is poorly understood with few providers specialising in its treatment. This lack of treatment and the ubiquity of chemicals engender severe life impacts such as job loss, financial loss, social isolation and even homelessness for persons who experience these sensitivities.

Design.  Survey.

Method.  We examined chemical incitants, symptoms and sickness‐related behavioural dysfunction as measured by the Sickness Impact Profile in 254 persons self‐identified with multiple chemical sensitivity.

Results.  Chemicals rated as causing the most symptomatology in respondents were pesticide, formaldehyde, fresh paint, new carpet, diesel exhaust, perfume and air fresheners. The five highest rated symptoms in this sample were tiredness/lethargy, difficulty concentrating, muscle aches, memory difficulties and long‐term fatigue. Overall mean Sickness Impact Profile score was 25·25%, showing serious impairment, with the most serious dysfunction in the categories of work (55·36%), alertness behaviour (53·45%) and recreation and pastimes (45·20%).

Conclusion.  Multiple chemical sensitivity is an important health care issue because it often includes serious dysfunction, is poorly understood by providers and poses extensive financial and treatment obstacles for those who experience it.

Relevance to clinical practice.  Persons with multiple chemical sensitivity seek medical treatment in a variety of contexts and informed providers can both avoid iatrogenic harm due to medical exposures and provide any possible treatment for the chemical sensitivities. Understanding the impact of the health condition is crucial to communicate with and treat persons who experience the sensitivities.
Elimination disorders in people with intellectual disability
Authors: Van Laecke E.
Published: October 2008

Incontinence in children with intellectual and physical disabilities is an underestimated problem in paediatric urology. Literature is scarce, often limited to the incidence and urodynamics, and seldom focused on treatment and prevention. Lack of interest and knowledge of this population are the major reasons why urologists know so little. Very often continence difficulties are accepted and even expected in children with intellectual disabilities.

The published prevalence of urinary incontinence in children with intellectual and physical disabilities varies between 23% and 86%. In our experience the prevalence ranges from 60% to 65%. The vast majority of these children have bladder dysfunction, showing overactive detrusor and sphincter dyssynergia on video‐urodynamic examination. The uroflow pattern is disturbed in over 65% of these children but is not correlated with the degree of urinary incontinence. Over 70% of the children have reduced bladder capacity. This is due to low bladder compliance and restricted fluid intake which effects urinary incontinence and is an important cause of constipation. Constipation is a common problem in intellectual and physical disabled children and there is a correlation between constipation and urinary incontinence.

Children with intellectual disability, particularly those with a greater degree of disability need more time to become continent than typically developing children. Children with mild intellectual disability do not differ significantly from typically developing children with regard to nocturnal enuresis and faecal continence but they are more prone to urinary incontinence during the day. Greater mobility is associated with a higher incidence of continence.

Some factors that influence continence, such as intellectual and motor capacity cannot easily be influenced but others, such as bladder capacity, detrusor overactivity and fluid intake, are treatable. It is importance that children with intellectual and physical disabilities suffering urinary incontinence are referred for assessment and treatment to increase their quality of life.
Sleep problems in developmental disabilities: Trends in research and treatment
Authors: Didden R.
Published: October 2008

An increasing number of studies show that sleep problems are common in individuals with developmental disabilities. Several risk factors have now been identified. In many cases, presence of a genetic disorder is related to sleep problems. Treatment of such problems in target groups has received increased attention during the last two decades. In this presentation, some trends and developments in the research (prevalence, measurement, treatment) on sleep problems will be reviewed. Special attention is given to several genetic disorders (e.g., Angelman, Prader‐Willi, Rett). Measurement issues, studies of behavioural phenotypes and treatment approaches of sleep problems in children with developmental disabilities and/or genetic disorders are discussed. More specifically, our work within the Dutch national policlinic for sleep problems will be highlighted.
Sleep Disordered Breathing in Prader‐Willi patients treated with rh GH
Authors: Nespoli L. , Verri A. , Nosetti L. , Salvatoni A. , Berini J. , Chierici V. , Niespolo A. C. , Cremante A.
Published: October 2008

Background: Previous reports showed that Growth Hormone (GH) therapy in Prader‐Willi Syndrome (PWS) was associated with an increased risk of sudden death by Obstructive Sleep Apnea (OSA). The aim of this study was to evaluate the effects of GH therapy on OSA in PLWS patients. Method: We selected 12 prepubescent patients with genotype‐confirmed PWS without OSA: 6 boys, aged (mean 3.8 years; SD 1.9 years). ENT video endoscopy of upper airways was performed contemporary to one night 12 channels polysomnography (PSG) before starting GH therapy and after 6 weeks of treatment. The Katz et al. criteria were used for PSG evaluation. The main parameter considered was total apnea hypopnea index (AHI), resulting from central apnea hypopnea index and obstructive apnea hypopnea index (OAI). Results: Before treatment none of the patients showed symptoms of OSA or was receiving systemic steroids. However, PSG revealed that all patients showed signs of central and/or obstructive apnea. After 6 weeks of therapy OAI decreased in 3/12 (25%) patients was unchanged in 4/12 (33%) and increased in 5/12 (42%). In four of these patients OAI exceeded the cut‐off of 1. In these four patients treatment was temporary discontinued. On average during rhGH treatment we did not find any significant change of the polysomnographic index: before rhGH therapy mean OAI was 0.7, RDI (Respiratory Disturbance Index) 5.5, and minSpO2 87.4% while after 6 weeks of therapy mean OAI was 0.8, RDI 6.5, and min SpO2 83.9%. Conclusion: The increased death rate could be an adverse effect of GH therapy. In our patients, GH treatment caused an increase of OAI in one out of three of our patients. It is recommended that a PSG and ENT evaluations are undertaken before and during the therapy for monitoring respiratory function. In those patients with increased OAI, temporary discontinuation of GH treatment is recommended until respiratory function is normal.
Parental perception of sleep behaviour and sleep disorders in children with VCFS and their siblings
Authors: Swillen A. , Berghs I. , Schoeters A. , Fryns J.‐P. , Hellinkcx W. , Devriendt K.
Published: October 2008

Background: Disrupted sleep in children may lead to multiple behavioural problems that affect the individual and the family. The aim of this study was to compare sleep behaviour and sleep disorders in children with VCFS with those of their siblings and to determine the severity and pattern of the sleep problems. Method: Parents completed the Children’s Sleep Habits Questionnaire (CSHQ) (Owens et al., 2000) for 31 children with VCFS (mean age 10 years). This instrument has good psychometric properties and validity. It includes items relating to a number of key sleep domains grouped conceptually into eight subscales reflecting: (1) Bedtime Resistance; (2) Sleep Onset Delay; (3) Sleep Duration; (4) Sleep Anxiety; (5) Night Wakings; (6) Parasomnias; (7) Sleep Disordered Breathing; (8) Daytime Sleepiness. Total Sleep Disturbance Score includes all items of the eight subscales. Higher scores are indicative of more disturbed sleep. Results: The severity of sleep problems in the VCFS group was reported by parents as being significantly higher than in the sibling group (mean score 42.97 and 36.55, respectively; p < 0.001). Values for five of eight sleep subscales including bedtime resistance, sleep anxiety, night waking, parasomnias and daytime sleepiness were significantly (p < 0.001) higher in the VCFS group. Conclusion: Parents report that sleep problems are significantly more severe in children with VCFS compared to their siblings, and that the pattern appears diverse. Sleep problems in children with VCFS require further research and clinical attention.
Abnormal protein glycoforms in Prader‐Willi syndrome
Authors: Bowling F. G. , Munce T. B.
Published: October 2008

Background: Prader‐Willi syndrome (PWS) is a contiguous gene disorder characterized by a range of neurological and endocrine abnormalities. Genetically, PWS arises from a loss of paternal chromosome 15q11‐q13 with associated maternal imprinting of genes in this region. The most common molecular mechanisms are either paternal interstitial deletions or maternal uniparental disomy leading to haploinsufficiency. A number of genes involved in protein processing are present in the PWS region. After synthesis, proteins are frequently glycosylated as a post‐translational modification. Proteins with incorrect processing or other cellular damage are postulated to be cleared by certain putative genes within the common PWS deletion breakpoints. Method: We undertook investigations into protein post‐translational modifications in our PWS cohort (n = 23, age range = 1–18 years) using isoelectric focusing (IEF) of the serum O‐linked glycoprotein, apolipoprotein C‐III (apoC‐III). Through apoC‐III IEF, three isoforms differing in sialic acid content may be resolved. Non affected individuals typically contain relatively equal amounts of the disialylate d and monosialylated isoforms with low levels of the asialylated isoform. The glycans observed in PWS were further characterized by mass spectrometry. Results: Our study revealed nine PWS patients (∼40%) had an abnormal apoC‐III IEF profile with increases in the asialylated isoform (9.1–16.9%; normal range 0–8.0%) and decreases in the disialylated isoform (22–39%; normal range 26–59%). The abnormal apoC‐III IEF patterns observed in our study were independent of genotype. Mass spectrometry confirmed the abnormal structures. Conclusion: Although no genes involved in glycosylation are situated in 15q11–q13, there are two genes that have been given putative roles as ubiquitin E3 enzymes. We propose the increase in asialylated apoC‐III isoforms in PWS is a reflection of an abnormality in the clearance of abnormal proteins rather than from a defect in glycan biosynthesis. Accumulation of other abnormal proteins in PWS is hypothesized.
White matter microstructure in children with Velocardiofacial Syndrome: A Diffusion Tensor Imaging and Voxel Based Morphometry study
Authors: Sundram F. , Murphy D. G. , Murphy K. C.
Published: October 2008

Background: Velocardiofacial Syndrome (VCFS) is the most common human genetic deletion syndrome and young people with VCFS are at substantial risk for developing psychosis in later life. It has been reported that people with VCFS have significant differences in white matter volume. However, there are few in vivo studies of white matter microstructural integrity (as measured using Diffusion Tensor (DT)‐MRI), and nobody has related differences in white matter anatomy to schizotypy in VCFS children or adolescents. Method: We used (respectively) DT‐MRI and voxel based morphometry (VBM) to measure the fractional anisotropy (FA) and proportion of white matter in 11 VCFS children and adolescents and 12 controls (7 of whom were siblings). Also, within people with VCFS we carried out a preliminary analysis in which we related differences in white matter to severity of schizotypy. Results: VCFS, compared to controls, had a significantly lower FA in frontal, parietal and temporal lobe regions as measured using DT‐MRI. In contrast, FA was significantly higher than controls in the internal capsule, anterior/superior corona radiata and corpus callosum. Using VBM we found a significantly smaller proportion of white matter in the cerebellum, occipital lobes and hippocampus but a significantly higher amount in the internal capsule, basal ganglia, cingulum and corpus callosum in VCFS. Also, within people with VCFS, FA of the internal capsule was significantly positively correlated with severity of schizotypy. Conclusion: Young people with VCFS have significant differences in white matter microstructure and volume. Some, but not all of these, overlap with each other. Also, within VCFS, regional differences in FA are associated with schizotypal behaviour.
Physical and mental health of adults with Williams syndrome
Authors: Stinton C. , Elison S. , Udwin O. , Howlin P.
Published: October 2008

Background: Individuals with Williams syndrome (WS) are reported to experience a range of physical and mental health problems. However, much of this information is derived from children and young adults. Little is known about these issues in older adults. The aims of this study were to (1) examine these issues in adults with WS of a wide age range and (2) examine the long term pattern of these problems. Method: Two groups of adults with WS and their parents/carers were interviewed to examine physical and mental health problems. Study 1 comprised 92 adults with WS (19 years 11 month–55 years 4 months). Study 2 consisted of 47 adults with WS (25 years 7 months–49 years 7 months) who had taken part in a previous study of adults with WS 10 years previously. Results: The studies indicated that high numbers of adults with WS (75%–81%) had physical health problems that impacted upon their everyday life. These included heart, bowel and blood pressure problems (18%–33%). Eating, sleeping and toileting problems were reported in 7%–16% of the sample. Mental health problems were common (25%–33%). There were increases over time in the number of individuals with health problems relating to the heart, bowel and blood pressure and a small decrease in the numbers with joint problems, hernias and dental problems. Overall, there was a decrease in the number of participants with emotional/behavioural problems. Specifically, rates of problems such as anxiety and compulsions decreased, but rates of depression and overactivity increased. Conclusions: Adults with WS have a range of physical and mental problems. While the overall number of individuals with physical health problems remained high over time, the rates of different types of problems changed. Emotional/behavioural problems generally decreased with age.
Pathogenetic mechanisms in Down Syndrome
Authors: Einfeld S. , Götz J. , Holsinger R. M. D.
Published: October 2008

Background: Although it has been known for some time that there are 200–400 genes on Chromosome 21, there has been a paucity of information as to which of these is responsible for causing the Down syndrome phenotype. Recently, new data have focussed attention on several key genes. Method: Review of relevant literature identified through Medline and Google Scholar. Results: Two genes in the Down syndrome critical region, DYRK1A and DSCR1 have been shown to contribute to Down syndrome features in mouse models. A mutation of DYRK1A has been identified in a human family with a mild Down syndrome phenotype. A function of DYRK1A is to phosphorylate tau protein, a key step in the pathogenesis of Alzheimer dementia. Conclusion: Recent research has substantially advanced our knowledge of possible pathogenic pathways in Down syndrome. Ultimately, gene therapy for Down syndrome may no longer be fanciful.
Trial of fenobam, an mGluR5 antagonist, in adults with Fragile X Syndrome
Authors: Hagerman R. , Berry‐Kravis E. , Hessl D. , Coffey S. , Schneider A. , Nguyen D. , Hervey C. , Hutchison J. , Snape M.
Published: October 2008

Background: Recent advances in the study of the Fragile X knockout mouse model have demonstrated enhanced activity of the metabolic glutamate receptor 5 (mGluR5) pathway. The use of mGluR5 antagonists has rescued behavioural, cognitive and dendritic structural abnormalities in the knockout mouse. An initial phase II trial in adults with FXS was approved by the FDA. Method: We have completed this initial trial of fenobam (50 mg to 150 mg/dose) in twelve adults with FXS (mean age 23.9 (SD 5.4; range 18.7–30.7 years) seen either at UC Davis MIND Institute or at RUSH, University in Chicago, to assess safety, side‐effects, and metabolism after a single dose. Results: Outcome measures included prepulse inhibition (PPI) and a continuous performance task (CPT). All patients tolerated this single dose without significant side‐effects. The metabolism of fenobam in patients with FXS is similar to controls and peaks at approximately 180 minutes after oral dose. Fifty percent of the patients had a 20% or more improvement in PPI that is significantly different from test‐retest changes in PPI previously reported in individuals with FXS (p = 0.03). This effect was more pronounced in males. The majority of patients scored at ceiling on the CPT so it was not a helpful measure to assess medication benefits. Conclusion: This work documents the safety and aspects of the metabolism of fenobam in patients with FXS and will facilitate further expansion of fenobam trials in patients with FXS. Although fenobam is a targeted treatment for FXS, subgroups of autism may also benefit from fenobam treatment.
Identifying effective interventions for young children with autism spectrum disorders
Authors: Howlin P.
Published: October 2008

Until recently, intervention research for young children with autism has been strongly criticized because of the paucity of well controlled comparative studies and particularly the lack of randomized control trials (RCT’s). Over the last decade, however, there has been a steady improvement of the quality of research in this area. RCT’s, although still relatively rare, have increased in number, and have been used to examine the effectiveness of a range of different treatment approaches, including parent management style; early, intensive behavioural interventions; social communication, joint attention and play programmes, and augmentative communication systems. Well controlled trials, involving closely matched groups of children have also added to our knowledge of treatment effects. The present paper will focus on a series of recent studies, utilizing both randomized and matched case‐control comparison designs. Overall, group results indicate moderate, but encouraging improvements for children involved in each of these interventions. However, at an individual child level, outcome is much more variable, with some children in each programme showing considerable change, others only minor improvements and some showing no improvement, or even deterioration over time. Identification of the children who respond most to specific types of intervention remains a major challenge for research in this field in the future.
Commonalities in the neurobiology between autism and fragile X
Authors: Hagerman R.
Published: October 2008

There is a close association between autism and fragile X syndrome (FXS) with 30% of males with FXS having autism and 2 to 7% of children with autism having the fragile X mutation. The protein that is missing or deficient in FXS, FMRP, is an RNA binding and transport protein which regulates the translation of many messages important for synaptic plasticity. Typically FMRP inhibits the translation of these messages, such that protein production increases when FMRP is absent. Some of these proteins are known to also cause autism when they are mutated including neuroligin 3 and 4 and the SHANK protein. Therefore, when FMRP is missing there is dysregulation of other proteins that are known to cause autism. FMRP is an important inhibitor of protein production in the metabotropic glutamate receptor 5 pathway (mGluR5) which leads to long term depression (LTD) or the weakening of synaptic connections. Therefore, when FMRP is missing there is enhanced mGluR5 activity leading to enhanced LTD and weak or immature synaptic connections. The use of mGluR5 antagonists to reverse the LTD in the animal models of FXS has led to reversal of the learning, behaviour and dendritic spine abnormalities in these animals. There are now initial studies taking place in humans regarding the use of mGluR5 antagonists to improve behaviour and cognition in FXS. It is likely that these mGluR5 antagonists will also be helpful in a subgroup of patients with non fragile X autism who have similar problems with hyperactivity, hyperarousal and anxiety to those seen in FXS. A second cause of autism is the fragile X premutation but this mechanism of involvement is related to RNA toxicity which perhaps stimulates neuroimmune problems and may mimic other causes of autism. Neurons with the premutation are more vulnerable to environmental toxicity and oxidative stress leading to early cell death.
What can we learn from tuberous sclerosis complex (TSC) about autism?
Authors: De Vries P. J.
Published: October 2008

Tuberous Sclerosis Complex (TSC) is now recognized as one of the medical conditions most commonly associated with autism. Between 1–5% of those with autism have TSC and up to 50% of people with TSC meet criteria for an autism spectrum disorder. The clinical characteristics of autism in TSC are qualitatively indistinguishable from those of idiopathic autism. So, what can TSC teach us about autism? We will present an overview of the neuropsychiatric features of TSC and will proceed with an examination of aetiological models of autism in TSC. Structural models (suggesting that autism is caused by brain lesions in specific neuroanatomical locations) and seizure models (suggesting that the age, type and control of seizures may predict autism) have both received some support, but with limited replication. More recently, molecular approaches have suggested that dysregulation of intracellular signalling through the TSC1/2‐mTOR pathway may be sufficient to lead to socialization deficits and autism, and that drugs that act as mTOR inhibitors may reverse some aspects of the learning and social deficits in TSC.
Tibolone Rapidly Attenuates the GABAB Response in Hypothalamic Neurones
Authors: Qiu J. , Bosch M. A. , Rønnekleiv O. K. , Kloosterboer H. J. , Kelly M. J.
Published: October 2008

Tibolone is primarily used for the treatment of climacteric symptoms. Tibolone is rapidly converted into three major metabolites: 3α‐ and 3β‐hydroxy (OH)‐tibolone, which have oestrogenic effects, and the Δ4‐isomer (Δ4‐tibolone), which has progestogenic and androgenic effects. Because tibolone is effective in treating climacteric symptoms, the effects on the brain may be explained by the oestrogenic activity of tibolone. Using whole‐cell patch clamp recording, we found previously that 17β‐oestradiol (E2) rapidly altered γ‐aminobutyric acid (GABA) neurotransmission in hypothalamic neurones through a membrane oestrogen receptor (mER). E2 reduced the potency of the GABAB receptor agonist baclofen to activate G‐protein‐coupled, inwardly rectifying K+ (GIRK) channels in hypothalamic neurones. Therefore, we hypothesised that tibolone may have some rapid effects through the mER and sought to elucidate the signalling pathway of tibolone’s action using selective inhibitors and whole cell recording in ovariectomised female guinea pigs and mice. A sub‐population of neurones was identified post hoc as pro‐opiomelanocortin (POMC) neurones by immunocytochemical staining. Similar to E2, we have found that tibolone and its active metabolite 3βOH‐tibolone rapidly reduced the potency of the GABAB receptor agonist baclofen to activate GIRK channels in POMC neurones. The effects were blocked by the ER antagonist ICI 182 780. Other metabolites of tibolone (3αOH‐tibolone and Δ4‐tibolone) had no effect. Furthermore, tibolone (and 3βOH‐tibolone) was fully efficacious in ERα knockout (KO) and ERβKO mice to attenuate GABAB responses. The effects of tibolone were blocked by phospholipase C inhibitor U73122. However, in contrast to E2, the effects of tibolone were not blocked by protein kinase C inhibitors or protein kinase A inhibitors. It appears that tibolone (and 3βOH‐tibolone) activates phospholipase C leading to phosphatidylinositol bisphosphate metabolism and direct alteration of GIRK channel function. Therefore, tibolone may enhance synaptic efficacy through the Gq signalling pathways of mER in brain circuits that are critical for maintaining homeostatic functions.
Evaluation of Endocrine Profile, Hypothalamic–Pituitary–Testis Axis and Semen Quality in Multiple Sclerosis
Authors: Safarinejad M. R.
Published: October 2008

Several endocrine and sexual disturbances have been demonstrated in multiple sclerosis (MS) patients of both sexes. The endocrine profile, hypothalamic–pituitary–testis (HPT) axis and semen quality were evaluated in male patients with MS. A total of 68 male MS patients aged 18 years or older were recruited. Forty‐eight age‐matched healthy male volunteers served as controls. All subjects underwent complete physical examination and routine semen analysis. Two blood samples were drawn from each participant at 15‐min intervals for the determination of the resting levels of: luteinising‐hormone (LH), follicle‐stimulating hormone (FSH), prolactin, testosterone, oestradiol and sex hormone binding globulin. The HPT axis was assessed using gonadotrophin‐releasing hormone (GnRH) and human chorionic gonadotrophin tests. The mean basal serum levels for LH, FSH and testosterone in MS patients were significantly lower than the mean for normal controls (P = 0.01). The injection of GnRH analogue did not yield a significant increase in FSH and LH levels in the MS patients compared to normal controls (P = 0.001). Total sperm count, sperm motility and percent normal sperm morphology were lower in MS patients compared to controls. MS subjects with progressive disease had higher and more severe HPT axis abnormalities than that for patients with relapsing remitting MS. Most subjects with MS have hypogonadotrophic hypogonadism state and fertility impairment. It appears that the damage to HPT axis is both in pituitary and testicular levels. Further studies are needed to better elucidate the underlying pathophysiology of HPT axis dysregulation.
Evaluation of two scopolamine and physostigmine pretreatment regimens against nerve agent poisoning in the dog
Authors: BONHAGE M. R. , CHILCOAT C. D. , LI Q. , MELENDEZ V. , FLOURNOY W. S.
Published: October 2008

Currently, there is no viable protection against chemical warfare agents for the working dog. Physostigmine (PHY) and scopolamine (SCO) have been shown to protect dogs against nerve agents with minimal side effects. The goal of this study was to investigate whether reported protective SCO/PHY plasma concentrations of 0.2 and 0.7 ng/mL, respectively, could be reached and maintained with minimal side‐effects thereby identifying possible pretreatment regimens. Two continuous regimens of SCO/PHY were administered to beagle dogs. The first regimen consisted of administering transdermal SCO and intraocular PHY, the second consisted of transdermal SCO and rectal PHY. SCO/PHY plasma concentrations for each regimen were determined, individual protective times were calculated and a computerized pharmacokinetic analysis was performed. The results showed transdermal SCO and intraocular PHY routes of delivery achieved sustained protective drug concentrations with minimal side‐effects and the rectal route of delivery did not. Group median protective times for the first regimen were 54.45 h for SCO and 64.35 h for PHY, and for the second regimen 63.75 h for SCO and 0 h for PHY. The combined transdermal patch and intraocular regimen may provide a safe and effective regimen against nerve agent poisoning in dogs.
Regulation of platelet activating factor‐induced equine platelet activation by intracellular kinases
Authors: BROOKS A. C. , MENZIES‐GOW N. J. , WHEELER‐JONES C. P. D. , BAILEY S. R. , ELLIOTT J. , CUNNINGHAM F. M.
Published: October 2008

Lipopolysaccharide (LPS) can activate equine platelets directly or indirectly, via leukocyte‐derived platelet activating factor (PAF). Thromboxane (Tx) production by LPS‐stimulated equine platelets requires p38 MAPK and this kinase has been suggested as a therapeutic target in endotoxaemia. The present study has utilised selective inhibitors to investigate the role of p38 MAPK and two other kinases, phosphatidylinositol‐3 kinase (PI3K) and protein kinase C (PKC), in regulating PAF‐induced Tx production, aggregation and 5‐HT release in equine platelets, and the modification of these responses by LPS. LPS enhanced PAF‐induced 5‐HT release, an effect that was reduced by the p38 MAPK inhibitor, SB203580 (60 ± 8% reduction;n = 6). SB203580 did not affect responses to PAF alone; whereas inhibition of PKC reduced PAF‐induced 5‐HT release, Tx production and aggregation (maximal inhibition by the PKCδ inhibitor, rottlerin: 69 ± 13%, 63 ± 14% and 97 ± 1%, respectively;n = 6). Wortmannin and LY249002, which inhibit PI3K, also caused significant inhibition of PAF‐induced aggregation (maximal inhibition 78 ± 3% and 88 ± 2%, respectively;n = 6). These data suggest that inhibition of platelet p38 MAPK may be of benefit in equine endotoxaemia by counteracting some of the effects of LPS. However, detrimental effects of platelet activation mediated by PAF and not enhanced by LPS are unlikely to be markedly affected.
Detection and pharmacokinetics of tetrahydrogestrinone in horses
Authors: MACHNIK M. , GERLACH M. , KIETZMANN M. , NIEDORF F. , THEVIS M. , SCHENK I. , GUDDAT S. , DÜE M. , SCHÄNZER W.
Published: October 2008

The anti‐doping rules of national and international sport federations ban any use of tetrahydrogestrinone (THG) in human as well as in horse sports. Initiated by the THG doping scandals in human sports a method for the detection of 3‐keto‐4,9,11‐triene steroids in horse blood and urine was developed. The method comprises the isolation of the analytes by a combination of solid phase and liquid–liquid extraction after hydrolysis and solvolysis of the steroid conjugates. The concentrations of THG in blood and urine samples were measured by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS).

A THG excretion study on horses was conducted to verify the method capability for the analysis of postadministration urine samples. In addition, blood samples were collected to allow for determination of the pharmacokinetics of THG in horses. Following the administration of a single oral dose of 25 μg THG per kg bodyweight to 10 horses, samples were collected at appropriate intervals. The plasma levels of THG reached maximal concentrations of 1.5–4.8 ng/mL. Twenty‐four hours after the administration plasma levels returned to baseline. In urine, THG was detectable for 36 h. Urinary peak concentrations of total THG ranged from 16 to 206 ng/mL. For the 10 horses tested, the mean plasma clearance of THG was 2250 mL/h/kg and the plasma elimination half‐life was 1.9 h.
Pharmacokinetics of cimetidine in dogs after oral administration of cimetidine tablets
Authors: LE TRAON G. , BURGAUD S. , HORSPOOL L. J. I.
Published: October 2008

Long‐term oral treatment with cimetidine is recommended to reduce vomiting in dogs with chronic gastritis. Despite this, few studies have specifically examined the plasma disposition and pharmacokinetics of cimetidine in dogs, particularly following repeated oral administration. The pharmacokinetics of cimetidine following oral administration as tablets was investigated in healthy dogs. Cimetidine was absorbed rapidly post‐treatment (tmax = 0.5 h). A mean absolute bioavailability of 75% was calculated following a single oral administration of 5 mg cimetidine/kg body weight. After intravenous administration, a plasma half‐life of 1.6 h was calculated. Repeated oral administration at the recommended dose rate and regime (5 mg/kg body weight three times daily) for 30 consecutive days did not lead to any accumulation of cimetidine in plasma. Food intake concomitant with oral administration of cimetidine delayed (tmax = 2.25 h) and decreased the rate and extent of absorption (AUC) by about 40%. Cimetidine was well absorbed in fasted dogs. Administration of food decreased the bioavailability of cimetidine by 40%. Cimetidine does not accumulate over time in plasma when administered long term to dogs.
Entry of pseudotyped hepatitis C virus into primary human hepatocytes depends on the scavenger class B type I receptor
Authors: Régeard M. , Trotard M. , Lepère C. , Gripon P. , Le Seyec J.
Published: October 2008

Summary.  Entry of the hepatitis C virus (HCV) into the cell seems to be a complex multi‐step process involving several cellular factors such as the scavenger class B type I receptor (SRBI). Until now, all investigations conducted to assess the involvement of SRBI have been based on in vitro infection models which use human hepatoma‐derived cell lines. However, the HCV entry pathway may be altered in these types of cells because of the impairment of some hepatic characteristics. In this study, we showed that SRBI also plays an essential role in HCV entry into primary human hepatocytes with two distinct approaches: gene extinction and antibodies neutralization assays.
Opening a can of worms: unprecedented sympatric cryptic diversity within British lumbricid earthworms
Authors: KING R. ANDREW , TIBBLE AMY L. , SYMONDSON WILLIAM O. C.
Published: October 2008

Earthworms play a major role in many aspects of soil fertility, food web ecology and ecosystem functioning, and hence are frequently the subjects of, for example, ecological and toxicological research. Our aim was to examine the genetic structure of common earthworm species, to identify cryptic lineages or species that may be distinct ecotypes or biotypes (and hence confound current research based upon morphotypes) and to try to explain the massive cryptic diversity that eventually emerged. We demonstrated that species such as Allolobophora chlorotica, Aporrectodea longa, Aporrectodea rosea and Lumbricus rubellus all comprise highly divergent lineages with species‐level divergence at the mitochondrial cytochrome oxidase I (COI) gene. In Allo. chlorotica alone, we found 55 haplotypes for COI, with 35 of these being found in pink and 20 in green morph worms. There were no cases of the two colour morphs sharing COI haplotypes. Phylogenetic analyses of mitochondrial COI and 16S genes showed the presence of five highly divergent lineages, suggesting the presence of multiple cryptic species within Allo. chlorotica. There was no clear geographical pattern to lineage distribution and many populations were polymorphic for both mitochondrial DNA lineage and colour morph. Amplified fragment length polymorphism results, based on two primer combinations, were broadly congruent with mitochondrial DNA results with one significant exception. Despite showing over 14% divergence at COI, amplified fragment length polymorphism markers showed that the two green morph lineages may be interbreeding and therefore represent a single taxon. The cryptic diversity revealed by these results has profound consequences for all areas of earthworm research.
Toilet reading habits in Israeli adults
Authors: Goldstein O. , Shaham Y. , Naftali T. , Konikoff F. , Lavy A. , Shaoul R.
Published: October 2008

Abstract  Although toilet reading (TR) is a common habit, the effect of TR on bowel movements is neglected in the medical literature. Our hypothesis was that TR provides a distraction and acts as an unconscious relaxation technique and allows an easier defecation process. The aim of this study was to assess how common is TR and to map the reading/playing toilet habits in the Israeli adult population. In addition, we aimed to explore a possible connection between TR and the nature of bowel habits in general and constipation and haemorrhoids in particular. Five hundred adults who represent the diverse demographic backgrounds have been asked to fill an anonymous short questionnaire. The subjects were questioned regarding their demographic details, their TR and playing habits, their bowel habits, whether they suffer from haemorrhoids and whether they use some sort of faecal softener. We found that TR is common and involves 52.7% of the population. Males, younger age, secular population, higher education level and white collar workers compose the TR profile. Although toilet readers spent significantly more time in the toilets, no differences were noted for the type or frequency of stools. Nevertheless, the TR group considered themselves to be less constipated (8.0%vs 13.7%) and had more haemorrhoids (23.6%vs 18.2%). These differences, however, were not significant. Toilet reading is a common and benign habit. It is involved with a longer time spent in the toilet. It seems to be more for fun and not necessarily to solve or due to medical problems.
Real time RT‐PCR assay for quantitative detection of Citrus viroid III in plant tissues
Authors: Rizza S. , Nobile G. , Tessitori M. , Catara A. , Conte E.
Published: October 2008

A rapid and sensitive real time reverse transcription‐PCR (RT‐PCR) assay based on SYBR Green I chemistry was developed for the quantitative detection of Citrus viroid III (CVd‐III) in citrus samples. CVd‐III titre was determined at different times in green bark of sour orange, Troyer citrange, trifoliate orange and alemow seedlings inoculated with a CVd‐IIIb source. Ten weeks after inoculation the viroid was detected in the four species, without substantial differences in viroid titre among them. Nine weeks later an overall increase of viroid titre was observed. The copy number of CVd‐III in sour orange and Troyer citrange was monitored up to 52 weeks after inoculation and a further increase of viroid titre was observed at 35 weeks. For validation purposes, field samples were tested from 58 citrus trees with mixed infections of CVd‐III, Citrus exocortis viroid (CEVd) and Hop stunt viroid (HSVd), as well as from healthy controls. Based on the sensitivity (100%), specificity (96·7%), accuracy (99·2%) and repeatability (Cohen's kappa index 0·98) of the assay, it is suggested that its employment in breeding programmes would be helpful in the evaluation of host resistance and viroid accumulation in plants.
Development of Oculimacula yallundae and O. acuformis (eyespot) lesions on stems of winter wheat in relation to thermal time in the UK
Authors: Bock C. H. , Wan A. M. , Fitt B. D. L.
Published: October 2008

Relationships between development of eyespot, caused by Oculimacula yallundae (OY) or O. acuformis (OA) on stems of winter wheat (cv. Avalon), and thermal time (°C days after sowing) were investigated in field experiments in 1985/86, 1986/87 and 1987/88 (two experiments). In all experiments, the incidence and severity of stem eyespot (uninoculated plots, OY‐ and OA‐inoculated plots) were linearly related to accumulated thermal time after sowing. There were ca. 600–800°C days from the time of the first sample when eyespot lesions were recorded on stems to the time when maximum eyespot incidence or severity was recorded. Relationships between stem eyespot incidence or severity and thermal time differed between seasons, with more severe eyespot in 1986/87 and 1987/88 than 1985/86. Both the severity and volume of stem lesions were initially greater in OY‐inoculated plots than OA‐inoculated plots in spring but differences were less by harvest in all seasons. The percentage of plants with stems colonized by OY or OA over all plots (including uninoculated) showed a consistent pattern in 1986/87 and 1987/88 (two experiments), with the percentage colonized by OY greater initially and the percentage colonized by OA gradually increasing with time towards harvest.
Detection and quantification of airborne inoculum of Sclerotinia sclerotiorum using quantitative PCR
Authors: Rogers S. L. , Atkins S. D. , West J. S.
Published: October 2008

This paper reports the development of a new specific diagnostic technique to accurately quantify airborne inoculum of Sclerotinia sclerotiorum and discusses its potential use in disease‐forecasting schemes, using examples of three contrasting epidemic seasons: 2007, when there was a severe epidemic of sclerotinia stem rot (SSR) in England and high numbers of airborne ascospores were trapped at Rothamsted, and, in contrast, 2003 and 2004, when the incidence of SSR in England was low and low numbers of airborne ascospores were trapped at Rothamsted. DNA was extracted from wax‐coated plastic tapes, such as those used in Burkard (Hirst‐type) spore traps and rotating‐arm traps. A SYBR‐green quantitative PCR (qPCR) method produced a linear relationship between ascospore numbers and S. sclerotiorum DNA (mean 0·35 pg DNA per spore) and was able to detect DNA representing as few as two ascospores. The technique was insensitive to DNA of the host plant, Brassica napus, and other plant pathogens, including Sclerotinia minor, S. trifoliorum and Botrytis cinerea, and common airborne fungal genera such as Cladosporium and Penicillium. There was no relationship between rainfall and numbers of airborne ascospores of S. sclerotiorum present at Rothamsted during the period of infection in the severe SSR season (2007).
Dothistromin toxin is not required for dothistroma needle blight in Pinus radiata
Authors: Schwelm A. , Barron N. J. , Baker J. , Dick M. , Long P. G. , Zhang S. , Bradshaw R. E.
Published: October 2008

The pine needle blight pathogen Dothistroma septosporum produces a polyketide toxin, dothistromin. This paper reports that loss of the ability to produce dothistromin did not affect the pathogenicity of D. septosporum to Pinus radiata in a laboratory‐based pathogenicity test. However, dothistromin synthesis provided an advantage to the D. septosporum wild‐type, compared to dothistromin‐deficient mutants, in growth competition with other fungi in vitro. Other pine‐needle inhabitants, such as the latent pathogen Cyclaneusma minus and the endophyte Lophodermium conigenum, were inhibited by dothistromin‐producing D. septosporum. Therefore, it was concluded that dothistromin is not a pathogenicity factor, but that it may play a role in competition of D. septosporum with other fungi in its ecological niche.
Trichothecene mycotoxin genotypes ofFusarium graminearum sensu strictoandFusarium meridionalein wheat from southern Brazil
Authors: Scoz L. B. , Astolfi P. , Reartes D. S. , Schmale III D. G. , Moraes M. G. , Del Ponte E. M.
Published: October 2008

A total of 82 fungal isolates was obtained from wheat kernel samples affected by fusarium head blight collected from 20 locations in southern Brazil. Polymerase chain reaction (PCR) assays were used to characterize trichothecene mycotoxin genotypes [deoxynivalenol (DON), nivalenol (NIV) and two acetylated derivatives of DON]. To identify isolates that producing DON and NIV, portions of theTri13gene were amplified. To identify 3‐acetyl‐deoxynivalenol (3‐ADON) and 15‐acetyl‐deoxynivalenol (15‐ADON) genotypes, portions ofTri3andTri12were amplified. Nearly all of the isolates studied (76/82) were of the DON/15‐ADON genotype. Six of the isolates were of the NIV genotype. The DON/3‐ADON genotype was not observed. Portions of three genes were sequenced from representative isolates of the NIV and DON/15‐ADON genotypes and compared with sequences from curated reference isolates ofFusariumin GenBank.blastqueries for individual gene sequences and pairwise comparisons of percentage identity and percentage divergence based on 1676 bp of concatenated DNA sequence suggested that the isolates representing the DON/15‐ADON genotype wereFusarium graminearum sensu strictoand the isolates representing the NIV genotype wereFusarium meridionale. This is the first detailed report of trichothecene mycotoxin genotypes ofF. graminearumandF. meridionalein Brazil.
Tryptophan deficiency affects organ growth by retarding cell expansion in Arabidopsis
Authors: Jing Yanjun , Cui Dayong , Bao Fang , Hu Zhubing , Qin Zhixiang , Hu Yuxin
Published: October 2008

Tryptophan (Trp) is an essential amino acid required not only for protein synthesis but also for the production of many plant metabolites, including the hormone auxin. Mutations that disrupt Trp biosynthesis result in various developmental defects in plant organs, but how Trp affects organ growth and development remains unclear. Here, we identify an Arabidopsis mutant, small organ1 (smo1/trp2‐301), which exhibits a reduction in the size of its aerial organs as a result of the retardation of growth by cell expansion, rather than by the retardation of growth by cell proliferation. smo1/trp2‐301 contains a lesion in TSB1 that encodes a predominantly expressed Trp synthase β‐subunit, and is allelic with trp2 mutants. Further analyses show that in trp2 leaf cells, the nuclear endoreduplication is impaired and chloroplast development is delayed. Furthermore, cell expansion and leaf growth in trp2 can be restored by the exogenous application of Trp, but not by auxin, and the general protein synthesis is not apparently affected in trp2 mutants. Our findings suggest that the deficiency in Trp or its derivatives is a growth‐limiting factor for cell expansion during plant organogenesis.
Repression of the floral transition via histone H2B monoubiquitination
Authors: Gu Xiaofeng , Jiang Danhua , Wang Yuqi , Bachmair Andreas , He Yuehui
Published: October 2008

The Rad6‐Bre1 complex monoubiquitinates histone H2B in target gene chromatin, and plays an important role in positively regulating gene expression in yeast. Here, we show that the Arabidopsis relatives of the yeast Rad6, ubiquitin‐conjugating enzyme 1 (UBC1) and UBC2, redundantly mediate histone H2B monoubiquitination, and upregulate the expression of FLOWERING LOCUS C (FLC; a central flowering repressor in Arabidopsis) and FLC relatives, and also redundantly repress flowering, the developmental transition from a vegetative to a reproductive phase that is critical in the plant life cycle. Moreover, we have found that Arabidopsis relatives of the yeast Bre1, including HISTONE MONOUBIQUITINATION 1 (HUB1) and HUB2, also upregulate the expression of FLC and FLC relatives, and that HUB1 genetically interacts with UBC1 and UBC2 to repress the floral transition. These findings are consistent with a model in which HUB1 and HUB2 specifically interact with and direct UBC1 and UBC2 to monoubiquitinate H2B in developmental genes, and thus regulate developmental processes in plants.