Anion-induced conformational changes in 2,7-disubstituted indole-based receptors.

The conformational preorganization and anion-induced conformational changes of indole-based receptors functionalized with an amide group at the 2-position and a variety of amide, urea and thiourea moieties at the 7-position have been studied by the means of NMR spectroscopy. NOE experiments showed that anti-anti orientation across C2-C2alpha and C7-N7alpha bonds is preferred for receptors 1-4 in acetone solution in the absence of anions. Anion-receptor interactions have been evaluated through (1)H and (15)N chemical shift changes.

Expression of the forkhead box transcription factor FOXP1 is associated with oestrogen receptor alpha, oestrogen receptor beta and improved survival in familial breast cancers.

Background: The role of FOXP1 in sporadic breast cancers has been widely studied but its role in familial breast cancers is yet unexplored.

Aims: To investigate FOXP1 expression in different molecular subtypes of familial breast cancers and to correlate its expression with clinicopathological parameters, oestrogen receptors (ER) and survival.

Methods: Immunohistochemical staining for FOXP1 was performed in 126 familial breast carcinomas comprising 35 BRCA1, 34 BRCA2 and 57 BRCAX.

The polyubiquitin Ubc gene modulates histone H2A monoubiquitylation in the R6/2 mouse model of Huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disease caused by the expansion of a polyglutamine tract in the protein huntingtin (htt). HD brains are characterized by the presence of ubiquitin-positive neuronal inclusion bodies, suggesting that disturbances in the distribution of cellular ubiquitin may contribute to disease pathology. The fact that several neurodegenerative diseases are caused by mutations in ubiquitin-processing enzymes and that the polyubiquitin genes are required for resistance to cellular stress led us to investigate the effect of perturbing the ubiquitin system in HD.

Genetic knock-down of HDAC7 does not ameliorate disease pathogenesis in the R6/2 mouse model of Huntington's disease.

Huntington's disease (HD) is an inherited, progressive neurological disorder caused by a CAG/polyglutamine repeat expansion, for which there is no effective disease modifying therapy. In recent years, transcriptional dysregulation has emerged as a pathogenic process that appears early in disease progression. Administration of histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA) have consistently shown therapeutic potential in models of HD, at least partly through increasing the association of acetylated histones with down-regulated genes and by correcting mRNA abnormalities.

Systematic behavioral evaluation of Huntington's disease transgenic and knock-in mouse models.

Huntington's disease (HD) is one of the few neurodegenerative diseases with a known genetic cause, knowledge that has enabled the creation of animal models using genetic manipulations that aim to recapitulate HD pathology. The study of behavioral and neuropathological phenotypes of these HD models, however, has been plagued by inconsistent results across laboratories stemming from the lack of standardized husbandry and testing conditions, in addition to the intrinsic differences between the models. We have compared different HD models using standardized conditions to identify the most robust phenotypic differences, best suited for preclinical therapeutic efficacy studies.

Discussion: 'Novel clomiphene protocol in polycystic ovarian syndrome' by Hurst et al.

In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Hurst BS, Hickman JM, Matthews ML, Usadi RS, Marshburn PB. Novel clomiphene "stair-step" protocol reduces time to ovulation in women with polycystic ovarian syndrome.

The ubiquitin-proteasome reporter GFPu does not accumulate in neurons of the R6/2 transgenic mouse model of Huntington's disease.

Impairment of the ubiquitin-proteasome system (UPS) has long been considered an attractive hypothesis to explain the selective dysfunction and death of neurons in polyglutamine disorders such as Huntington's disease (HD). The fact that inclusion bodies in HD mouse models and patient brains are rich in ubiquitin and proteasome components suggests that the UPS may be hindered directly or indirectly by inclusion bodies or their misfolded monomeric or oligomeric precursors. However, studies into UPS function in various polyglutamine disease models have yielded conflicting results, suggesting mutant polyglutamine tracts may exert different effects on the UPS depending on protein context, expression level, subcellular localisation and cell-type.

Immunomodulation of FOXP3+ regulatory T cells by the aromatase inhibitor letrozole in breast cancer patients.

Purpose: We have shown previously that tumor infiltration by FOXP3+ regulatory T cells (Treg) is associated with increased relapse and shorter survival of patients with both in situ and invasive breast cancer. Because estrogen regulates Treg numbers in mice and promotes the proliferation of human Tregs, we hypothesized that blocking estrogen receptor-alpha signaling would abrogate Tregs and be associated with response to hormonal therapy and increased survival.

Experimental Design: FOXP3+ Tregs were quantified in tumor samples collected at baseline by incisional biopsy and after 6 months at definitive surgery in 83 elderly breast cancer patients (T2-4 N0-1) enrolled in a randomized phase II trial based on 6 months of primary letrozole (2.

A large number of protein expression changes occur early in life and precede phenotype onset in a mouse model for huntington disease.

Huntington disease (HD) is fatal in humans within 15-20 years of symptomatic disease. Although late stage HD has been studied extensively, protein expression changes that occur at the early stages of disease and during disease progression have not been reported. In this study, we used a large two-dimensional gel/mass spectrometry-based proteomics approach to investigate HD-induced protein expression alterations and their kinetics at very early stages and during the course of disease.

Exendin-4 improves glycemic control, ameliorates brain and pancreatic pathologies, and extends survival in a mouse model of Huntington's disease.

Objective: The aim of this study was to find an effective treatment for the genetic form of diabetes that is present in some Huntington's disease patients and in Huntington's disease mouse models. Huntington's disease is a neurodegenerative disorder caused by a polyglutamine expansion within the huntingtin protein. Huntington's disease patients exhibit neuronal dysfunction/degeneration, chorea, and progressive weight loss.

Intercellular Ca2+ wave propagation involving positive feedback between CRAC channels and cysteinyl leukotrienes.

Mast cells are key components of the immune system, where they help orchestrate the inflammatory response. Aberrant mast cell activation is linked to a variety of allergic diseases, including asthma, eczema, rhinitis, and nasal polyposis, which in combination affect up to 20% of the population in industrialized countries. On activation, mast cells release a variety of signals that target the bronchi and vasculature and recruit other immune cells to the inflammatory site.

Optimisation of region-specific reference gene selection and relative gene expression analysis methods for pre-clinical trials of Huntington's disease.

Background: Transcriptional dysregulation is an early, key pathogenic mechanism in Huntington's disease (HD). Therefore, gene expression analyses have biomarker potential for measuring therapeutic efficacy in pre-clinical trials, particularly those aimed at correcting gene expression abnormalities. Housekeeping genes are commonly used as endogenous references in gene expression studies.

Pseudonarcolepsy in an 11-year-old boy.

Narcolepsy is a common disorder with a prevalence of 0.56/1000. Patients present with a classic tetrad of excessive daytime sleepiness, cataplexy, sleep paralysis and hypnagogic hallucinations, which is seen only rarely in children.

Hydration status and physiological workload of UAE construction workers: A prospective longitudinal observational study.

Background: The objective of the study was to investigate the physiological responses of construction workers labouring in thermally stressful environments in the UAE using Thermal Work Limit (TWL) as a method of environmental risk assessment.

Methods: The study was undertaken in May 2006. Aural temperature, fluid intake, and urine specific gravity were recorded and continuous heart rate monitoring was used to assess fatigue.

Effects of dexmedetomidine on intraoperative motor and somatosensory evoked potential monitoring during spinal surgery in adolescents.

Background: Dexmedetomidine may be a useful agent as an adjunct to an opioid-propofol total intravenous anesthesia (TIVA) technique during posterior spinal fusion (PSF) surgery. There are limited data regarding its effects on somatosensory (SSEPs) and motor evoked potentials (MEPs).

Methods: The data presented represent a retrospective review of prospectively collected quality assurance data.

Structural diversity in the first metal complexes of 2,5-dicarboxamidopyrroles and 2,5-dicarbothioamidopyrroles.

Metal complexes of 2,5-dicarboxamidopyrroles and 2,5-dicarbothioamidopyrroles have been structurally characterised for the first time, complementing the significant amount of work that has been reported for the analogous pyridine ligands. N,N'-Bis(3,5-dinitrophenyl)-3,4-diphenyl-1H-pyrrole-2,5-dicarboxamide forms octahedral bis(tridentate) complexes with cobalt(III) and nickel(II), where the ligands are bound to the metal centres through deprotonated pyrrole and amide N atoms. N,N'-Dibutyl-3,4-diphenyl-1H-pyrrole-2,5-dicarboxthioamide and N,N'-diphenyl-3,4-diphenyl-1H-pyrrole-2,5-dicarboxthioamide also form bis(tridentate) cobalt complexes but are only deprotonated at the pyrrole N atom, the remainder of the coordination sphere comprising the thioamide S atoms.

A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. We examined the peripheral immune system and found widespread evidence of innate immune activation detectable in plasma throughout the course of HD. Interleukin 6 levels were increased in HD gene carriers with a mean of 16 years before the predicted onset of clinical symptoms.

The presence of tumor-infiltrating FOXP3+ lymphocytes correlates with intratumoral angiogenesis in endometrial cancer.

Objectives: CD4(+)CD25(+) regulatory T-cells (Tregs), that express the transcription factor FOXP3, suppress effector T-cell populations and can enable tumour cells to evade the host immune response. In this study, we investigated the numbers of FOXP3(+) Tregs in the normal and malignat endometrium and examined potential links with tumor angiogenesis.

Methods: Paraffin-embedded tissues from 79 patients with stage I endometrial adenocarcinoma and 12 samples from normal endometrium were analyzed using immunohistochemistry for the detection of FOXP3(+) lymphocytes.

Resistance of the Soybean Cultivar Archer to Pythium Damping-Off and Root Rot Caused by Several Pythium spp.

Archer, a maturity group I soybean cultivar with demonstrated flood tolerance and resistance to Pythium ultimum, was compared with Hutcheson, a widely planted maturity group V cultivar in Arkansas, for resistance to P. ultimum, P. irregulare, P.

Anion binding vs. sulfonamide deprotonation in functionalised ureas.

Sulfonamide groups, commonly used as neutral hydrogen bond donors in a wide variety of anion receptors, deprotonate upon addition of certain basic anionic guests in two simple functionalised ureas.

DNA instability in postmitotic neurons.

Huntington's disease (HD) is caused by a CAG repeat expansion that is unstable upon germ-line transmission and exhibits mosaicism in somatic tissues. We show that region-specific CAG repeat mosaicism profiles are conserved between several mouse models of HD and therefore develop in a predetermined manner. Furthermore, we demonstrate that these synchronous, radical changes in CAG repeat size occur in terminally differentiated neurons.

Sweat rate and sodium loss during work in the heat.

Objective: Significant and poorly documented electrolyte losses result from prolonged sweating. This study aimed to quantify likely sodium losses during work in heat.

Methods: Male subjects exercised in an environmental chamber on two consecutive days in both winter and summer.