bluuebunny/crossref_metadata_2025 huggingface dataset:
Repeated administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) modulates neuroinflammation and amyloid plaque load in mice bearing amyloid precursor protein and presenilin-1 mutant transgenes
Authors: Pugh Perdita L , Vidgeon-Hart Martin P , Ashmeade Tracey , Culbert Ainsley A , Seymour Zoe , Perren Marion J , Joyce Flora , Bate Simon T , Babin Anna , Virley David J , Richardson Jill C , Upton Neil , Sunter David
Published: February 2007

Background

Data indicates anti-oxidant, anti-inflammatory and pro-cognitive properties of noradrenaline and analyses of post-mortem brain of Alzheimer's disease (AD) patients reveal major neuronal loss in the noradrenergic locus coeruleus (LC), the main source of CNS noradrenaline (NA). The LC has projections to brain regions vulnerable to amyloid deposition and lack of LC derived NA could play a role in the progression of neuroinflammation in AD. Previous studies reveal that intraperitoneal (IP) injection of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) can modulate neuroinflammation in amyloid over-expressing mice and in one study, DSP-4 exacerbated existing neurodegeneration.

Methods

TASTPM mice over-express human APP and beta amyloid protein and show age related cognitive decline and neuroinflammation. In the present studies, 5 month old C57/BL6 and TASTPM mice were injected once monthly for 6 months with a low dose of DSP-4 (5 mg kg-1) or vehicle. At 8 and 11 months of age, mice were tested for cognitive ability and brains were examined for amyloid load and neuroinflammation.

Results

At 8 months of age there was no difference in LC tyrosine hydroxylase (TH) across all groups and cortical NA levels of TASTPM/DSP-4, WT/Vehicle and WT/DSP-4 were similar. NA levels were lowest in TASTPM/Vehicle. Messenger ribonucleic acid (mRNA) for various inflammatory markers were significantly increased in TASTPM/Vehicle compared with WT/Vehicle and by 8 months of age DSP-4 treatment modified this by reducing the levels of some of these markers in TASTPM. TASTPM/Vehicle showed increased astrocytosis and a significantly larger area of cortical amyloid plaque compared with TASTPM/DSP-4. However, by 11 months, NA levels were lowest in TASTPM/DSP-4 and there was a significant reduction in LC TH of TASTPM/DSP-4 only. Both TASTPM groups had comparable levels of amyloid, microglial activation and astrocytosis and mRNA for inflammatory markers was similar except for interleukin-1 beta which was increased by DSP-4. TASTPM mice were cognitively impaired at 8 and 11 months but DSP-4 did not modify this.

Conclusion

These data reveal that a low dose of DSP-4 can have varied effects on the modulation of amyloid plaque deposition and neuroinflammation in TASTPM mice dependent on the duration of dosing.
Feline aminopeptidase N is not a functional receptor for avian infectious bronchitis virus
Authors: Chu Victor C , McElroy Lisa J , Aronson Jed M , Oura Trisha J , Harbison Carole E , Bauman Beverley E , Whittaker Gary R
Published: February 2007

Background

Coronaviruses are an important cause of infectious diseases in humans, including severe acute respiratory syndrome (SARS), and have the continued potential for emergence from animal species. A major factor in the host range of a coronavirus is its receptor utilization on host cells. In many cases, coronavirus-receptor interactions are well understood. However, a notable exception is the receptor utilization by group 3 coronaviruses, including avian infectious bronchitis virus (IBV). Feline aminopeptidase N (fAPN) serves as a functional receptor for most group 1 coronaviruses including feline infectious peritonitis virus (FIPV), canine coronavirus, transmissible gastroenteritis virus (TGEV), and human coronavirus 229E (HCoV-229E). A recent report has also suggested a role for fAPN during IBV entry (Miguel B, Pharr GT, Wang C: The role of feline aminopeptidase N as a receptor for infectious bronchitis virus. Brief review. Arch Virol 2002, 147:2047–2056.

Results

Here we show that, whereas both transient transfection and constitutive expression of fAPN on BHK-21 cells can rescue FIPV and TGEV infection in non-permissive BHK cells, fAPN expression does not rescue infection by the prototype IBV strain Mass41. To account for the previous suggestion that fAPN could serve as an IBV receptor, we show that feline cells can be infected with the prototype strain of IBV (Mass 41), but with low susceptibility compared to primary chick kidney cells. We also show that BHK-21 cells are slightly susceptible to certain IBV strains, including Ark99, Ark_DPI, CA99, and Iowa97 (<0.01% efficiency), but this level of infection is not increased by fAPN expression.

Conclusion

We conclude that fAPN is not a functional receptor for IBV, the identity of which is currently under investigation.
Quantitative image analysis of immunohistochemical stains using a CMYK color model
Authors: Pham Nhu-An , Morrison Andrew , Schwock Joerg , Aviel-Ronen Sarit , Iakovlev Vladimir , Tsao Ming-Sound , Ho James , Hedley David W
Published: February 2007

Background

Computer image analysis techniques have decreased effects of observer biases, and increased the sensitivity and the throughput of immunohistochemistry (IHC) as a tissue-based procedure for the evaluation of diseases.

Methods

We adapted a Cyan/Magenta/Yellow/Key (CMYK) model for automated computer image analysis to quantify IHC stains in hematoxylin counterstained histological sections.

Results

The spectral characteristics of the chromogens AEC, DAB and NovaRed as well as the counterstain hematoxylin were first determined using CMYK, Red/Green/Blue (RGB), normalized RGB and Hue/Saturation/Lightness (HSL) color models. The contrast of chromogen intensities on a 0–255 scale (24-bit image file) as well as compared to the hematoxylin counterstain was greatest using the Yellow channel of a CMYK color model, suggesting an improved sensitivity for IHC evaluation compared to other color models. An increase in activated STAT3 levels due to growth factor stimulation, quantified using the Yellow channel image analysis was associated with an increase detected by Western blotting. Two clinical image data sets were used to compare the Yellow channel automated method with observer-dependent methods. First, a quantification of DAB-labeled carbonic anhydrase IX hypoxia marker in 414 sections obtained from 138 biopsies of cervical carcinoma showed strong association between Yellow channel and positive color selection results. Second, a linear relationship was also demonstrated between Yellow intensity and visual scoring for NovaRed-labeled epidermal growth factor receptor in 256 non-small cell lung cancer biopsies.

Conclusion

The Yellow channel image analysis method based on a CMYK color model is independent of observer biases for threshold and positive color selection, applicable to different chromogens, tolerant of hematoxylin, sensitive to small changes in IHC intensity and is applicable to simple automation procedures. These characteristics are advantageous for both basic as well as clinical research in an unbiased, reproducible and high throughput evaluation of IHC intensity.
Ethnoveterinary medicines used for ruminants in British Columbia, Canada
Authors: Lans Cheryl , Turner Nancy , Khan Tonya , Brauer Gerhard , Boepple Willi
Published: February 2007

Background

The use of medicinal plants is an option for livestock farmers who are not allowed to use allopathic drugs under certified organic programs or cannot afford to use allopathic drugs for minor health problems of livestock.

Methods

In 2003 we conducted semi-structured interviews with 60 participants obtained using a purposive sample. Medicinal plants are used to treat a range of conditions. A draft manual prepared from the data was then evaluated by participants at a participatory workshop.

Results

There are 128 plants used for ruminant health and diets, representing several plant families. The following plants are used for abscesses:Berberis aquifolium/Mahonia aquifolium Echinacea purpurea,Symphytum officinale,Bovista pila,Bovista plumbea,Achillea millefoliumandUsnea longissima.Curcuma longaL.,Salix scoulerianaandSalix lucidaare used for caprine arthritis and caprine arthritis encephalitis.Euphrasia officinalisandMatricaria chamomillaare used for eye problems.

Wounds and injuries are treated withBovistaspp.,Usnea longissima,Calendula officinalis,Arnicasp.,Malvasp.,Prunella vulgaris,Echinaceapurpurea,Berberis aquifolium/Mahonia aquifolium,Achillea millefolium,Capsella bursa-pastoris,Hypericum perforatum,Lavandula officinalis,Symphytum officinaleandCurcuma longa.

Syzygium aromaticumandPseudotsuga menziesiiare used for coccidiosis. The following plants are used for diarrhea and scours:Plantago major,Calendula officinalis,Urtica dioica,Symphytum officinale,Pinus ponderosa,Potentilla pacifica,Althaea officinalis,Anethum graveolens,Salix albaandUlmus fulva.

Mastitis is treated withAchillea millefolium,Arctiumlappa,Salix alba,Teucrium scorodoniaandGalium aparine.Anethum graveolensandRubussp., are given for increased milk production.Taraxacum officinale,Zea mays, andSymphytum officinaleare used for udder edema. Ketosis is treated withGaultheria shallon,Vacciniumsp., andSymphytum officinale.Hedera helixandAlchemilla vulgarisare fed for retained placenta.

Conclusion

Some of the plants showing high levels of validity wereHedera helixfor retained placenta andEuphrasia officinalisfor eye problems. Plants with high validity for wounds and injuries includedHypericum perforatum,Malva parvifloraandPrunella vulgaris. Treatments with high validity against endoparasites included those withJuniperus communisandPinus ponderosa. Anxiety and pain are well treated withMelissa officinalisandNepeta caesarea.
Functional intercomparison of intraoperative radiotherapy equipment – Photon Radiosurgery System
Authors: Armoogum Kris S , Parry John M , Souliman Salam K , Sutton David G , Mackay Colin D
Published: February 2007

Background

Intraoperative Radiotherapy (IORT) is a method by which a critical radiation dose is delivered to the tumour bed immediately after surgical excision. It is being investigated whether a single high dose of radiation will impart the same clinical benefit as a standard course of external beam therapy. Our centre has four Photon Radiosurgery Systems (PRS) currently used to irradiate breast and neurological sites.

Materials and methods

The PRS comprises an x-ray generator, control console, quality assurance tools and a mobile gantry. We investigated the dosimetric characteristics of each source and its performance stability over a period of time. We investigated half value layer, output diminution factor, internal radiation monitor (IRM) reproducibility and depth-doses in water. The half value layer was determined in air by the broad beam method, using high purity aluminium attenuators. To quantify beam hardening at clinical depths, solid water attenuators of 5 and 10 mm were placed between the x-ray probe and attenuators. The ion chamber current was monitored over 30 minutes to deduce an output diminution factor. IRM reproducibility was investigated under various exposures. Depth-dose curves in water were obtained at distances up to 35 mm from the probe.

Results

The mean energies for the beam attenuated by 5 and 10 mm of solid water were derived from ICRU Report 17 and found to be 18 and 24 keV. The average output level over a period of 30 minutes was found to be 99.12%. The average difference between the preset IRM limit and the total IRM count was less than 0.5%. For three x-ray sources, the average difference between the calculated and actual treatment times was found to be 0.62% (n = 30). The beam attenuation in water varied by approximately 1/r3.

Conclusion

The x-ray sources are stable over time. Most measurements were found to lie within the manufacturer's tolerances and an intercomparison of these checks suggests that the four x-ray sources have similar performance characteristics.
Gene promoter hypermethylation in ductal lavage fluid from healthy BRCAgene mutation carriers and mutation-negative controls
Authors: Locke Imogen , Kote-Jarai Zsofia , Jo Fackler Mary , Bancroft Elizabeth , Osin Peter , Nerurkar Ashutosh , Izatt Louise , Pichert Gabriella , Gui Gerald PH , Eeles Rosalind A
Published: February 2007

Introduction

Female germline BRCA gene mutation carriers are at increased risk for developing breast cancer. The purpose of our study was to establish whether healthy BRCA mutation carriers demonstrate an increased frequency of aberrant gene promoter hypermethylation in ductal lavage (DL) fluid, compared with predictive genetic test negative controls, that might serve as a surrogate marker of BRCA1/2 mutation status and/or breast cancer risk.

Methods

The pattern of CpG island hypermethylation within the promoter region of a panel of four genes (RAR-β, HIN-1, Twist and Cyclin D2) was assessed by methylation-specific polymerase chain reaction using free DNA extracted from DL fluid.

Results

Fifty-one DL samples from 24 healthy women of known BRCA mutation status (7 BRCA1 mutation carriers, 12 BRCA2 mutation carriers and 5 controls) were available for methylation analysis. Eight of 19 (42.1%) BRCA mutation carriers were found to have at least one hypermethylated gene in the four-gene panel. Two BRCA mutation carriers, in whom aberrant methylation was found, also had duct epithelial cell atypia identified. No hypermethylation was found in DL samples from 5 negative controls(p = 0.13).

Conclusion

We found substantial levels of aberrant methylation, with the use of a four-gene panel, in the fluid from the breasts of healthy BRCA mutation carriers compared with controls. Methylation analysis of free DNA in DL fluid may offer a useful surrogate marker for BRCA1/2 mutation status and/or breast cancer risk. Further studies are required for the evaluation of the specificity and predictive value of aberrant methylation in DL fluid for future breast cancer development in BRCA1/2 mutation carriers.
DNA variation and brain region-specific expression profiles exhibit different relationships between inbred mouse strains: implications for eQTL mapping studies
Authors: Hovatta Iiris , Zapala Matthew A , Broide Ron S , Schadt Eric E , Libiger Ondrej , Schork Nicholas J , Lockhart David J , Barlow Carrolee
Published: February 2007

Background

Expression quantitative trait locus (eQTL) mapping is used to find loci that are responsible for the transcriptional activity of a particular gene. In recent eQTL studies, expression profiles were derived from either homogenized whole brain or collections of large brain regions. However, the brain is a very heterogeneous organ, and expression profiles of different brain regions vary significantly. Because of the importance and potential power of eQTL studies in identifying regulatory networks, we analyzed gene expression patterns in different brain regions from multiple inbred mouse strains and investigated the implications for the design and analysis of eQTL studies.

Results

Gene expression profiles of five brain regions in six inbred mouse strains were studied. Few genes exhibited a significant strain-specific expression pattern, whereas a large number of genes exhibited brain region-specific patterns. We constructed phylogenetic trees based on the expression relationships between the strains and compared them with a DNA-level relationship tree. The trees based on the expression of strain-specific genes were constant across brain regions and mirrored DNA-level variation. However, the trees based on region-specific genes exhibited a different set of strain relationships, depending on the brain region. An eQTL analysis showed enrichment of cis-acting regulators among strain-specific genes, whereas brain region-specific genes appear to be mainly regulated by trans-acting elements.

Conclusion

Our results suggest that many regulatory networks are highly brain region specific and indicate the importance of conducting eQTL mapping studies using data from brain regions or tissues that are physiologically and phenotypically relevant to the trait of interest.
When a patient dies by suicide: incidence, implications and
coping strategies
Authors: Foley Sharon R. , Kelly Brendan D.
Published: March 2007

Patient suicide is a relatively common event: 50–70% of consultant
psychiatrists and 40–50% of psychiatric trainees have experienced at least
one patient suicide. Patient suicide can have significant personal and
professional effects on psychiatrists, including increased stress, social
withdrawal, disruption to relationships, symptoms of post-traumatic stress
disorder and consideration of early retirement. Following patient suicide,
psychiatrists derive most support from informal contacts with team members,
family and friends; additional support may be available through formal
support structures or local team initiatives. It is important to place
appropriate emphasis on the effects of patient suicide in psychiatry
training programmes; to maintain awareness of the importance of informal
supports following patient suicide; to strengthen formal systems of support;
to identify other potential forms of assistance (e.g. spiritual support);
and to develop local team initiatives in this area.
Cognitive rehabilitation: assessment and treatment of persistent memory impairments following ECT
Authors: Mangaoang Maeve A. , Lucey Jim V.
Published: March 2007

Few tests address the types of memory problem commonly reported after electroconvulsive therapy (ECT). Here, we focus on the importance of neuropsychological assessment in ECT-treated patients and describe a number of tasks that may be useful in measuring the everyday memory problems of such patients with ongoing memory difficulties. At the time of writing, no attempts have been made to rehabilitate patients who experience persistent adverse cognitive effects, but clinicians should be aware of the potential beneficial role of cognitive rehabilitation in the treatment and management of these effects.
Mindfulness in psychotherapy: an introduction
Authors: Mace Chris
Published: March 2007

‘Mindfulness' has become a popular topic among psychological therapists. This introductory article explains what mindfulness is and how it can be developed, before exploring how it has been incorporated within psychoanalytic and cognitive–behavioural psychotherapies. These reflect general as well as specific presumed therapeutic actions. At present, variations in the way mindfulness is understood, taught and applied mean that it is too early to fully assess its potential. They demonstrate how the use of attention and awareness in therapy cuts across traditional divisions and where mindfulness in therapy is most in need of further investigation.
PMS: diagnosis, aetiology, assessment and management
Authors: Henshaw Carol A.
Published: March 2007

This article reviews our understanding of the epidemiology and aetiology of premenstrual syndrome and premenstrual dysphoric disorder, and its assessment and management. It also addresses the concerns of the feminist community and the views of women themselves about this condition and its management. Service provision in the UK for women with these problems is unfocused and greatly varying, and they might be better assessed and treated by psychiatrists.
Interleukin-4 Promoter Polymorphisms: A Genetic Prognostic Factor for Survival in Metastatic Renal Cell Carcinoma
Authors: Kleinrath Thomas , Gassner Christoph , Lackner Peter , Thurnher Martin , Ramoner Reinhold
Published: February 2007

Purpose

Renal cell carcinoma (RCC) is considered a cytokine-responsive tumor. The clinical course of a patient may thus be influenced by the patient's capacity to produce distinct cytokines. Therefore, cytokine gene polymorphisms in RCC patients were analyzed to determine haplotype combinations with prognostic significance.

Patients and Methods

A selection of 21 single nucleotide polymorphisms within the promoter regions of 13 cytokine genes were analyzed in a cross-sectional single-center study of 80 metastatic RCC patients. Univariate and multivariate analyses and the Cox forward-stepwise regression model were chosen to assess genetic risk factors.

Results

Multivariate Cox regression analysis confirmed by a bootstrap technique identified the heterozygous IL4 genotype −589T−33T/−589C−33C as an independent prognostic risk factor (risk ratio, 3.1; P < .01; 95% CI, 1.4 to 6.9; adjusted for age, sex, and nuclear grading) in metastatic RCC patients. IL4 haplotype −589T−33T and −589C−33C were found with a frequency of 0.069 and 0.925, respectively, which represents a two-fold decrease of IL4 haplotype −589T−33T (P < .01) and an increase of IL4 haplotype −589C−33C frequency (P < .05) in metastatic RCC compared with other white reference study populations. The median overall survival was decreased 3.5-fold (P < .05) in heterozygote patients carrying IL4 haplotype −589T−33T and −589C−33C (3.78 months) compared with patients homozygote for IL4 haplotype −589C−33C (13.44 months). In addition, a linkage disequilibrium between the IL4 gene and the KIF3A gene was detected.

Conclusion

Our findings indicate that IL4 promoter variants influence prognosis in patients with metastatic RCC and suggest that genetically determined interleukin-4 (IL-4) production affects the clinical course of the disease possibly through regulation of immune surveillance.
Clinical Activity and Immune Modulation in Cancer Patients Treated With CP-870,893, a Novel CD40 Agonist Monoclonal Antibody
Authors: Vonderheide Robert H. , Flaherty Keith T. , Khalil Magi , Stumacher Molly S. , Bajor David L. , Hutnick Natalie A. , Sullivan Patricia , Mahany J. Joseph , Gallagher Maryann , Kramer Amy , Green Stephanie J. , O'Dwyer Peter J. , Running Kelli L. , Huhn Richard D. , Antonia Scott J.
Published: February 2007

Purpose

The cell-surface molecule CD40 activates antigen-presenting cells and enhances immune responses. CD40 is also expressed by solid tumors, but its engagement results in apoptosis. CP-870,893, a fully human and selective CD40 agonist monoclonal antibody (mAb), was tested for safety in a phase I dose-escalation study.

Patients and Methods

Patients with advanced solid tumors received single doses of CP-870,893 intravenously. The primary objective was to determine safety and the maximum-tolerated dose (MTD). Secondary objectives included assessment of immune modulation and tumor response.

Results

Twenty-nine patients received CP-870,893 in doses from 0.01 to 0.3 mg/kg. Dose-limiting toxicity was observed in two of seven patients at the 0.3 mg/kg dose level (venous thromboembolism and grade 3 headache). MTD was estimated as 0.2 mg/kg. The most common adverse event was cytokine release syndrome (grade 1 to 2) which included chills, rigors, and fever. Transient laboratory abnormalities affecting lymphocytes, monocytes, platelets, D-dimer and liver function tests were observed 24 to 48 hours after infusion. Four patients with melanoma (14% of all patients and 27% of melanoma patients) had objective partial responses at restaging (day 43). CP-870,893 infusion resulted in transient depletion of CD19+ B cells in blood (93% depletion at the MTD for < 1 week). Among B cells remaining in blood, we found a dose-related upregulation of costimulatory molecules after treatment.

Conclusion

The CD40 agonist mAb CP-870,893 was well tolerated and biologically active, and was associated with antitumor activity. Further studies of repeated doses of CP-870,893 alone and in combination with other antineoplastic agents are warranted.
Tumor-Infiltrating Lymphocytes Predict Sentinel Lymph Node Positivity in Patients With Cutaneous Melanoma
Authors: Taylor Rebecca C. , Patel Ami , Panageas Katherine S. , Busam Klaus J. , Brady Mary S.
Published: February 2007

Purpose

Tumor-infiltrating lymphocytes (TILs) are considered a manifestation of the host immune response to tumor, but the influence of TILs on outcome remains controversial. Studies evaluating the prognostic significance of TILs were published before routine examination of draining lymph nodes by sentinel lymph node (SLN) biopsy, the most important predictor of survival in patients with melanoma. The prognostic implications of TILs were re-evaluated in a large group of patients undergoing SLN biopsy at our institution.

Patients and Methods

All patients who underwent SLN mapping for primary cutaneous melanoma between January 1996 and July 2005 were evaluated. Univariate and multivariate analyses were performed to assess factors that predict SLN positivity and survival. Factors analyzed included Breslow thickness, ulceration, anatomic site, sex, Clark level, age, mitotic rate, and the presence (brisk or nonbrisk) or absence of TIL.

Results

Eight hundred eighty-seven patients underwent SLN mapping, and a SLN was identified in 875 patients (98.8%). The SLN was positive for tumor in 156 patients (17.6%). Multivariate analysis revealed that only Breslow thickness (P < .0001), ulceration (P = .0004), male sex (P = .03), and absent TILs (P = .0003) were independently predictive of the presence of SLN metastases. In melanomas with a brisk TIL infiltrate, the probability of a positive SLN was 3.9% as compared with 26.2% for melanomas in which TILs were absent. TILs were not an independent predictive factor for survival.

Conclusion

The absence of TILs, together with increasing Breslow thickness, presence of ulceration and male sex, predicts SLN metastasis in patients undergoing SLN biopsy for primary cutaneous melanoma.
P2X receptor signaling inhibits BDNF-mediated spiral ganglion neuron development in the neonatal rat cochlea
Authors: Greenwood Denise , Jagger Daniel J. , Huang Lin-Chien , Hoya Noriyuki , Thorne Peter R. , Wildman Scott S. , King Brian F. , Pak Kwang , Ryan Allen F. , Housley Gary D.
Published: March 2007

Type I and type II spiral ganglion neurons (SGN) innervate the inner and outer hair cells of the cochlea, respectively. This neural system is established by reorganization of promiscuous innervation of the hair cells,immediately before hearing is established. The mechanism for this synaptic reorganization is unresolved but probably includes regulation of trophic support between the hair cells and the neurons. We provide evidence that P2X receptors (ATP-gated ion channels) contribute such a mechanism in the neonatal rat cochlea. Single-cell quantitative RT-PCR identified the differential expression of two P2X receptor subunits, splice variant P2X2-3 and P2X3, in a 1:2 transcript ratio. Downregulation of this P2X2-3/3 receptor coincided with maturation of the SGN innervation of the hair cells. When the P2X2-3 and P2X3 subunits were co-expressed in Xenopus oocytes, the resultant P2X receptor properties corresponded to the SGN phenotype. This included enhanced sensitivity to ATP and extended agonist action. In P4 spiral ganglion explants, activation of the P2X receptor signaling pathway by ATPγS or α,βMeATP inhibited BDNF-induced neurite outgrowth and branching. These findings indicate that P2X receptor signaling provides a mechanism for inhibiting neurotrophin support of SGN neurites when synaptic reorganization is occurring in the cochlea.
The Zic family member,odd-paired, regulates theDrosophilaBMP,decapentaplegic, during adult head development
Authors: Lee Heuijung , Stultz Brian G. , Hursh Deborah A.
Published: March 2007

The eye/antennal discs of Drosophila form most of the adult head capsule. We are analyzing the role of the BMP family member decapentaplegic (dpp) in the process of head formation, as we have identified a class of cis-regulatory dpp mutations(dpps-hc) that specifically disrupts expression in the lateral peripodial epithelium of eye/antennal discs and is required for ventral head formation. Here we describe the recovery of mutations in odd-paired (opa), a zinc finger transcription factor related to the vertebrate Zic family, as dominant enhancers of this dpp head mutation. A single loss-of-function opa allele in combination with a single copy of a dpps-hc produces defects in the ventral adult head. Furthermore, postembryonic loss of opa expression alone causes head defects identical to loss of dpps-hc/dpps-hc, and dpphc/+;opa/+ mutant combinations. opais required for dpp expression in the lateral peripodial epithelium,but not other areas of the eye/antennal disc. Thus a pathway that includes opa and dpp expression in the peripodial epithelium is crucial to the formation of the ventral adult head. Zic proteins and members of the BMP pathway are crucial for vertebrate head development, as mutations in them are associated with midline defects of the head. The interaction of these genes in the morphogenesis of the fruitfly head suggests that the regulation of head formation may be conserved across metazoans.
Timing of the onset of a developmental cell death is controlled by transcriptional induction of theC. elegans ced-3caspase-encoding gene
Authors: Maurer Carine W. , Chiorazzi Michael , Shaham Shai
Published: March 2007

Temporal control of programmed cell death is necessary to ensure that cells die at only the right time during animal development. How such temporal regulation is achieved remains poorly understood. In some Caenorhabditis elegans somatic cells, transcription of the egl-1/BH3-only gene promotes cell-specific death. The EGL-1 protein inhibits the CED-9/Bcl-2 protein, resulting in the release of the caspase activator CED-4/Apaf-1. Subsequent activation of the CED-3 caspase by CED-4 leads to cell death. Despite the important role of egl-1 transcription in promoting CED-3 activity in cells destined to die, it remains unclear whether the temporal control of cell death is mediated by egl-1 expression. Here, we show that egl-1 and ced-9 play only minor roles in the death of the C. elegans tail-spike cell, demonstrating that temporal control of tail-spike cell death can be achieved in the absence of egl-1. We go on to show that the timing of the onset of tail-spike cell death is controlled by transcriptional induction of the ced-3 caspase. We characterized the developmental expression pattern of ced-3, and show that, in the tail-spike cell, ced-3 expression is induced shortly before the cell dies, and this induction is sufficient to promote the demise of the cell. Both ced-3 expression and cell death are dependent on the transcription factor PAL-1, the C. elegans homolog of the mammalian tumor suppressor gene Cdx2. PAL-1 can bind to the ced-3promoter sites that are crucial for tail-spike cell death, suggesting that it promotes cell death by directly activating ced-3 transcription. Our results highlight a role that has not been described previously for the transcriptional regulation of caspases in controlling the timing of cell death onset during animal development.
Antagonistic and cooperative actions of the EGFR and Dpp pathways on theiroquoisgenes regulateDrosophilamesothorax specification and patterning
Authors: Letizia Annalisa , Barrio Rosa , Campuzano Sonsoles
Published: March 2007

In Drosophila, restricted expression of the Iroquois complex(Iro-C) genes in the proximal region of the wing imaginal disc contributes to its territorial subdivision, specifying first the development of the notum versus the wing hinge, and subsequently, that of the lateral versus medial notum. Iro-C expression is under the control of the EGFR and Dpp signalling pathways. To analyze how both pathways cooperate in the regulation of Iro-C,we isolated several wing disc-specific cis-regulatory elements of the complex. One of these (IroRE2) integrates competing inputs of the EGFR and Dpp pathways, mediated by the transcription factors Pointed (downstream of EGFR pathway) and Pannier/U-shaped and Mothers against Dpp (Mad), in the case of Dpp. By contrast, a second element (IroRE1) mediates activation by both the EGFR and Dpp pathways, thus promoting expression of Iro-C in a region of elevated levels of Dpp signalling, the prospective lateral notum near the anterior-posterior compartment boundary. These results help define the molecular mechanisms of the interplay between the EGFR and Dpp pathways in the specification and patterning of the notum.
Shroom family proteins regulate γ-tubulin distribution and microtubule architecture during epithelial cell shape change
Authors: Lee Chanjae , Scherr Heather M. , Wallingford John B.
Published: March 2007

Cell shape changes require the coordination of actin and microtubule cytoskeletons. The molecular mechanisms by which such coordination is achieved remain obscure, particularly in the context of epithelial cells within developing vertebrate embryos. We have identified a novel role for the actin-binding protein Shroom3 as a regulator of the microtubule cytoskeleton during epithelial morphogenesis. We show that Shroom3 is sufficient and also necessary to induce a redistribution of the microtubule regulatorγ-tubulin. Moreover, this change in γ-tubulin distribution underlies the assembly of aligned arrays of microtubules that drive apicobasal cell elongation. Finally, experiments with the related protein, Shroom1,demonstrate that γ-tubulin regulation is a conserved feature of this protein family. Together, the data demonstrate that Shroom family proteins govern epithelial cell behaviors by coordinating the assembly of both microtubule and actin cytoskeletons.
Are doctors working the EWTD night shift pattern less tired?
Authors: Levy B , Dowson C , Clark J
Published: February 2007

The introduction of the European Working Time Directive (EWTD) has resulted in shift pattern rotas that include a week of night shifts. The EWTD was introduced to reduce the number of hours worked per week and consequently ensure that tired doctors were not treating patients. A week of night shifts allows rotas to meet the EWTD requirements while providing night-time cover with regular interspersed rest periods, which seems an advantage over the now largely redundant on-call system.
International Comparison of C-Peptide Measurements
Authors: Wiedmeyer Hsiao-Mei , Polonsky Kenneth S , Myers Gary L , Little Randie R , Greenbaum Carla J , Goldstein David E , Palmer Jerry P
Published: March 2007

Background: C-peptide measurement has been widely used as a marker of insulin secretion in patients with diabetes. We assessed the comparability of C-peptide results obtained with different methods and by different laboratories and determined whether C-peptide results could be harmonized by normalization with a WHO reference reagent or with plasma.

Methods: We sent 16 different heparin plasma samples to 15 laboratories in 7 countries. The samples were analyzed with 10 different assay methods. A WHO C-peptide standard was also sent to each laboratory and used to determine the feasibility of normalizing results. To assess the impact of calibrator matrix on the comparability of results, we also used the mean results of all laboratories for 4 of the samples to normalize the remaining sample results.

Results: Between-laboratory variability increased with increasing C-peptide concentrations. Normalization of results with WHO reference reagents did not improve comparability, but normalization with samples significantly improved comparability among laboratories and methods. The 95% confidence interval estimate for the SD for the lab/method effect (0.0–0.061) using sample-normalized values did not overlap with the 95% CI estimate with the raw data (0.090–0.225).

Conclusions: C-peptide results generated by different methods and different laboratories do not always agree, especially at higher concentrations of C-peptide. These data support the concept of using a single laboratory for multisite studies and support efforts to harmonize C-peptide measurements by use of calibrators prepared in the sample matrix.
Longitudinal Analyses of Affect, Temperament, and Childhood Psychopathology
Authors: Goldsmith H. Hill , Lemery-Chalfant Kathryn , Schmidt Nicole L. , Arneson Carrie L. , Schmidt Cory K.
Published: February 2007

The Wisconsin Twin Panel utilizes the resources of state birth records to study the etiology and developmental course of early emotions, temperament, childhood anxiety and impulsivity, the autism spectrum, and related psychobiological and behavioral phenotypes. The panel currently supports 5 active research studies which involve twins from birth to early adolescence. A range of research methods are employed, including questionnaires and structured interviews with caregivers, home and laboratory-based behavioral batteries, observer ratings, child self-report, psychophysiology, neuroendocrine measures, birth records, genotyping, and cognitive testing. The panel is in the early stages of generating longitudinal findings.
Stability of Genetic and Environmental Effects from Adolescence to Young Adulthood: Results of Croatian Longitudinal Twin Study of Personality
Authors: Bratko Denis , Butkovic Ana
Published: February 2007

The primary aim of this study was to conduct a bivariate genetic analysis investigating the extent to which genetic and environmental factors contribute to stability and change in personality factors in the period from adolescence to young adulthood on a sample of Croatian twins. The sample used in this research was formed in 1992 based on a register of citizens of Zagreb and data was collected for 160 twin pairs (75 monozygotic and 85 dizygotic twin pairs). Twins were tested twice, 4 years apart with the Eysenck Personality Questionnaire (mean age at first time point was 17 years). Univariate analyses indicate that the best fitting model for extraversion, neuroticism, psychoticism and lie scale at both time points includes additive genetic (A) and nonshared environmental (E) influences, with heritability estimates in the .40 to .50 range. Longitudinal analyses using AE correlated factors model indicate that genetic factors contribute mainly to stability, while environmental factors contribute mainly to change in personality during that 4-year period of transition from adolescence to young adulthood.
Statistical Power to Detect Genetic and Environmental Influences in the Presence of Data Missing at Random
Authors: Derks Eske M. , Dolan Conor V. , Boomsma Dorret I.
Published: February 2007

We study the situation in which a cheap measure (X) is observed in a large, representative twin sample, and a more expensive measure (Y) is observed in a selected subsample. The aim of this study is to investigate the optimal selection design in terms of the statistical power to detect genetic and environmental influences on the variance of Y and on the covariance of X and Y. Data were simulated for 4000 dizygotic and 2000 monozygotic twins. Missingness (87% vs. 97%) was then introduced in accordance with 7 selection designs: (i) concordant low + individual high design; (ii) extreme concordant design; (iii) extreme concordant and discordant design (EDAC); (iv) extreme discordant design; (v) individual score selection design; (vi) selection of an optimal number of MZ and DZ twins; and (vii) missing completely at random. The statistical power to detect the influence of additive and dominant genetic and shared environmental effects on the variance of Y and on the covariance between X and Y was investigated. The best selection design is the individual score selection design. The power to detect additive genetic effects is high irrespective of the percentage of missingness or selection design. The power to detect shared environmental effects is acceptable when the percentage of missingness is 87%, but is low when the percentage of missingness is 97%, except for the individual score selection design, in which the power remains acceptable. The power to detect D is low, irrespective of selection design or percentage of missingness. The individual score selection design is therefore the best design for detecting genetic and environmental influences on the variance of Y and on the covariance of X and Y. However, the EDAC design may be preferred when an additional purpose of a study is to detect quantitative trait loci effects.
Genetic and Environmental Contributions to Pathological Gambling Symptoms in a 10-Year Follow-Up
Authors: Xian Hong , Scherrer Jeffrey F. , Slutske Wendy S. , Shah Kamini R. , Volberg Rachel , Eisen Seth A.
Published: February 2007

Problem (P) and pathological gambling (PG) symptoms wax and wane. Past symptoms are a risk for future symptoms even after controlling for familial influences. To address the genetic architecture of lifetime PG and current PG symptoms, we tested for common and unique genetic factors to lifetime PG symptoms at baseline and past year PG symptoms at 10-year follow-up. Diagnostic and Statistical Manual of Mental Disorders (3rd ed., Rev.; DSM-III-R; American Psychiatric Association, 1987) lifetime criteria of one or more PG symptoms were derived in 1992 and past year PG symptoms in 2002 from 1675 individual twins from the Vietnam Era Twin Registry. Cholesky decomposition models were fit to baseline and past year PG symptoms. Under the best fitting model we observed that 49% of the risk for one or more baseline PG symptoms in 1992 was due to a genetic factor and 51% of the risk was due to a unique environmental factor. All of the genetic variance (57.5%) in risk to past year PG symptoms in 2002 was common with baseline PG symptoms. Unique environment accounted for the remaining variance in past year PG symptoms with 13% common to baseline and 30% specific to past year PG symptoms. The genetic contributions to lifetime and past year gambling symptoms 10 years later are similar. There is no evidence for genetic contributions unique to past year PG symptoms. However, most of the unique environmental influences to past year PG are not shared with lifetime PG. This may reflect the changed social–cultural environment between 1992 and 2002, characterized by increasing access to legalized gambling.
Covariance of Isometric and Dynamic Arm Contractions: Multivariate Genetic Analysis
Authors: Mars Gunther De , Thomis Martine A. I. , Windelinckx An , Leemputte Marc Van , Maes Hermine H. , Blimkie Cameron J. , Claessens Albrecht L. , Vlietinck Robert , Beunen Gaston
Published: February 2007

The purpose of the present study was to examine genetic and environmental contributions to individual differences in maximal isometric, concentric and eccentric muscle strength and muscle cross-sectional area (MCSA) of the elbow flexors. A generality versus specificity hypothesis was explored to test whether the 4 strength variables share a genetic component or common factors in the environment or whether the genetic/environmental factors are specific for each strength variable. The 4 variables under study were measured in 25 monozygotic and 16 dizygotic male Caucasian twin pairs (22.4 ± 3.7 years). The multivariate genetic analyses showed that all 4 variables shared a genetic and environmental component, which accounted for 43% and 6% in MCSA (h2= 81%), 47% and 20% in eccentric (h2= 65%), 58% and 4% in isometric (h2= 70%) and 32% and 1% in concentric strength (h2= 32%) respectively. The remaining variation was accounted for by contraction type specific and muscle cross-sectional area specific genetic and environmental effects, which accounted for 38% and 14% in MCSA, 18% and 15% in eccentric, 12% and 26% in isometric and 0% and 67% in concentric strength respectively. This exploratory multivariate study suggests shared pleiotropic gene action for MCSA, eccentric, isometric and concentric strength, with a moderate to high genetic contribution to the variability of these characteristics.
Vanishing Twin: A Possible Cause of Cerebral Impairment
Authors: Anand Dhullipala , Platt Mary Jane , Pharoah Peter O. D.
Published: February 2007

Fetal death in a twin conception during second and third trimester is associated with increased risk of cerebral injury in the surviving twin. The aim of this study is to test the hypothesis that even early fetal losses as a ‘vanishing’ twin may be associated with an increased risk of cerebral impairment in the surviving twin. The study population comprised 362 pregnant women attending Liverpool Women's Hospital recruited between 1999 and 2001. Women were classified according to the first ultrasound scan into 3 groups: vanishing twin, twin and singleton. The vanishing twin group was further subdivided into ‘definite’ and ‘probable’. Children from these pregnancies were assessed at 1 year of age for their development and neurological function using the Griffiths Mental and Developmental Scales and Optimality score. Children from 229 pregnancies (63.2%) attended the assessment. Information on children from a further 21 (5.8%) pregnancies was obtained through a review of hospital records. Cerebral impairment was found in 2 children from the vanishing twin group, 2 from the twin group and none from the singleton group. When cases with definite vanishing twin are considered there is a significant difference between the vanishing twin and singleton group (relative risk 6.1; 95% confidence interval 1.5–8.3; p = .03). An additional study with an increased sample size would enable a more robust conclusion.
Ultrasound to Identify Cord Knotting in Monoamniotic Monochorionic Twins
Authors: Deutsch Aaron B. , Miller Evan , Spellacy William N. , Mabry Rhonda
Published: February 2007

This case report demonstrates the use of ultrasound and doppler flow in the management of mono-amniotic monochorionic (M/M) twins. M/M twinning is a rare but significant event. It is associated with high rates of fetal mortality, most commonly cited at anywhere from between 30% and 70%. A common cause of death is cord entanglement. The case presented is that of a 19-year-old gravida 1 at 30 weeks with M/M twins in which multiple cord knots were found by ultrasound color doppler flow after variable fetal heart rate decelerations occurred. This prompted a decision for immediate cesarean delivery with normal fetal outcomes. Improvements in perinatal imaging systems are therefore beneficial in the management of M/M twins.
Pattern of Twin Placentation in Ghana
Authors: Nkyekyer Kobinah , Boafor Theodore
Published: February 2007

A 2-year study involving macroscopic examination of twin placentae was conducted at the Korle Bu Teaching Hospital in Accra, Ghana to determine the proportions of the various types of twin placentation, cord insertions and number of cord vessels and their relationships. Of 765 twin-pair placentae examined, 398 (52%, 95% confidence interval [CI] 48.4%–55.6%) had fused dichorionic, 247 (32.3%, 95% CI 29.0%–35.7%) had separate dichorionic, and 119 (15.6%, 95% CI 13.1%–18.4%) had monochorionic diamniotic placentae; only one (0.1%, 95% CI 0.0%–0.8%) had monochorionic monoamniotic placentation. Of 1529 cords whose insertion could be determined, 1285 (84%) had disc, 172 (11.2%) marginal and 72 (4.7%) velamentous insertions. Only 10 (0.65%) cords had two vessels (i.e., single umbilical artery). Abnormal cord insertions (marginal and velamentous) were significantly more likely to occur in monochorionic than in dichorionic placentation (odds ratio [OR] 3.56, 95% CI 2.62–4.84), and in two-vessel than in three-vessel cords (OR 5.79, 95% CI 1.44–24.5). The prevalence of two-vessel cord in monochorionic was not significantly different from that in dichorionic placentation (OR = 0.60, 95% CI 0.10–2.67). Zygosity could be determined in 53.3% of twins from placental examination and babies' sex-pair combinations. In conclusion the most common twin placentation in Ghana is fused dichorionic. Abnormal cord insertion is more common in monochorionic than dichorionic placentation. Monoamniotic twins and single umbilical artery are less common than have been reported in other centers. Modern methods of DNA analysis are needed to establish zygosity in almost half of twin pairs.