Partial Fanconi syndrome induced by ifosfamide.

Ifosfamide-induced proximal tubular nephropathy can present as a spectrum of disease, from isolated hyperaminoaciduria to a partial or complete Fanconi syndrome. We report a case of ifosfamide-induced partial Fanconi syndrome in a man with metastatic progressive Ewing sarcoma and put forth a hypothesis on the mechanism.

Functional redundancy of class I phosphoinositide 3-kinase (PI3K) isoforms in signaling growth factor-mediated human neutrophil survival.

We have investigated the contribution of individual phosphoinositide 3-kinase (PI3K) Class I isoforms to the regulation of neutrophil survival using (i) a panel of commercially available small molecule isoform-selective PI3K Class I inhibitors, (ii) novel inhibitors, which target single or multiple Class I isoforms (PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ), and (iii) transgenic mice lacking functional PI3K isoforms (p110δ(KO)γ(KO) or p110γ(KO)). Our data suggest that there is considerable functional redundancy amongst Class I PI3Ks (both Class IA and Class IB) with regard to GM-CSF-mediated suppression of neutrophil apoptosis. Hence pharmacological inhibition of any 3 or more PI3K isoforms was required to block the GM-CSF survival response in human neutrophils, with inhibition of individual or any two isoforms having little or no effect.

Development of isoform selective PI3-kinase inhibitors as pharmacological tools for elucidating the PI3K pathway.

Using a parallel synthesis approach to target a non-conserved region of the PI3K catalytic domain a pan-PI3K inhibitor 1 was elaborated to provide alpha, delta and gamma isoform selective Class I PI3K inhibitors 21, 24, 26 and 27. The compounds had good cellular activity and were selective against protein kinases and other members of the PI3K superfamily including mTOR and DNA-PK.

Automated detection of toxigenic Clostridium difficile in clinical samples: isothermal tcdB amplification coupled to array-based detection.

Clostridium difficile can carry a genetically variable pathogenicity locus (PaLoc), which encodes clostridial toxins A and B. In hospitals and in the community at large, this organism is increasingly identified as a pathogen. To develop a diagnostic test that combines the strengths of immunoassays (cost) and DNA amplification assays (sensitivity/specificity), we targeted a genetically stable PaLoc region, amplifying tcdB sequences and detecting them by hybridization capture.

Design and synthesis of a library of chemokine antagonists.

A library of chemokine antagonists has been synthesized using a combination of solid and solution-phase chemistry. Structures of known chemokine antagonists were used to produce a pharmacophore which served to guide monomer selection. Several combinations of monomers have resulted in providing novel chemokine antagonists which in some cases display dual chemokine receptor antagonism.

Essential role of phosphoinositide 3-kinase gamma in eosinophil chemotaxis within acute pulmonary inflammation.

We and others have established an important role for phosphoinositide-3 kinase gamma (PI3Kgamma) in the chemotactic responses of macrophages and neutrophils. The involvement of this lipid kinase in allergic inflammatory responses is, however, yet to be fully determined. Here we compare wild-type (WT) and PI3Kgamma(-/-) (KO) mice within a model of ovalbumin (OVA) -specific pulmonary inflammation.

Inhibition of PI-3 kinase for treating respiratory disease: good idea or bad idea?

Inhibition of one or more members of the phosphoinositide 3-kinase (PI3K) family for the treatment of respiratory diseases remains the goal of many pharmaceutical companies over the past 20 years. Here we briefly review the PI3K family, then focus on the assessment of each isoform as a drug discovery target. The rationale for PI3Kalpha inhibition in the treatment of lung cancer, and PI3Kbeta inhibitors in pulmonary thrombotic processes, are balanced with a potential side effect profile affecting metabolism and/or foetal development.

Intrinsic frames of reference and egocentric viewpoints in scene recognition.

Three experiments investigated the roles of intrinsic directions of a scene and observer's viewing direction in recognizing the scene. Participants learned the locations of seven objects along an intrinsic direction that was different from their viewing direction and then recognized spatial arrangements of three or six of these objects from different viewpoints. The results showed that triplets with two objects along the intrinsic direction (intrinsic triplets) were easier to recognize than triplets with two objects along the study viewing direction (non-intrinsic triplets), even when the intrinsic triplets were presented at a novel test viewpoint and the non-intrinsic triplets were presented at the familiar test viewpoint.

GERD is associated with shortened telomeres in the squamous epithelium of the distal esophagus.

Telomeres are repetitive DNA sequences located at the ends of chromosomes. Telomeres are shortened by repeated cell divisions and by oxidative DNA damage, and cells with critically shortened telomeres cannot divide. We hypothesized that chronic gastroesophageal reflux disease (GERD)-induced injury of the esophageal squamous epithelium results in progressive telomeric shortening that eventually might interfere with mucosal healing.

Immunoglobulin E: role in asthma and allergic disease: lessons from the clinic.

The role of immunoglobulin E (IgE) in allergic asthmatic disease is well established. Allergen-specific IgE binds to its cognate receptors, thus triggering a series of cellular events. These events include presentation of antigen by dendritic cells and the degranulation of mast cells and basophils to release numerous factors that play an integral part in potentiating the disease symptoms.

Evaluating rehabilitation using cost-consequences analysis: an example in Parkinson's disease.

Objective: To use cost-consequences analysis to evaluate rehabilitation, and to discuss some practical limitations.

Design: Case study of a cost-consequences analysis.

Setting: Day hospital.

Gain of allelic gene expression for IGF-II occurs frequently in Barrett's esophagus.

The IGF-II gene normally exhibits genomic imprinting, a DNA modification that allows the expression of only one of the two inherited alleles. With loss of imprinting, there is a gain of allelic gene expression (GOAGE) due to IGF-II being expressed by both alleles. GOAGE for IGF-II has been demonstrated in a number of malignancies and in normal epithelia surrounding malignancies, but not in epithelia without associated neoplasia.

Acute Acalculous Cholecystitis.

Acute acalculous cholecystitis is defined as acute inflammation of the gallbladder in the absence of gallstones. Patients are usually critically ill with atherosclerotic heart disease, recent trauma, burn injury, surgery, or hemodynamic instability. The presentation of acute acalculous cholecystitis may be insidious, characterized by unexplained fever, leukocytosis, hyperamylasemia, or abnormal aminotransferases, and patients often lack right upper quadrant tenderness.

Frames of reference in mobile augmented reality displays.

In 3 experiments, the authors investigated spatial updating in augmented reality environments. Participants learned locations of virtual objects on the physical floor. They were turned to appropriate facing directions while blindfolded before making pointing judgments (e.

Activation of phosphoinositide 3-kinases by the CCR4 ligand macrophage-derived chemokine is a dispensable signal for T lymphocyte chemotaxis.

Macrophage-derived chemokine (MDC/CC chemokine ligand 22 (CCL22)) mediates its cellular effects principally by binding to its receptor CCR4, and together they constitute a multifunctional chemokine/receptor system with homeostatic and inflammatory roles in the body. We report the CCL22-induced accumulation of phosphatidylinositol-(3,4,5)-trisphosphate (PI(3,4,5)P(3)) in the leukemic T cell line CEM. CCL22 also had the ability to chemoattract human Th2 cells and CEM cells in a pertussis toxin-sensitive manner.

Gallbladder polyps, cholesterolosis, adenomyomatosis, and acute acalculous cholecystitis.

Acute acalculous cholecystitis is characterized by acute inflammation of the gallbladder in the absence of stones, usually occurring in elderly and critically ill patients with atherosclerosis, recent surgery or trauma, or hemodynamic instability. Patients may present with only unexplained fever, leukocytosis, and hyperamylasemia without right upper quadrant tenderness. If untreated, rapid progression to gangrene and perforation occurs.

Regulation of intracellular pH in human melanoma: potential therapeutic implications.

Melanoma cells in vivo maintain intracellular pH (pHi) in a viable range despite an extracellular tumor pH (pHe) that is typically below 7.0. In general, three families of transporters are capable of removing metabolic protons, but the specific transporters responsible for the maintenance of pHi at low pHe in melanomas have not been identified.

Short-term effectiveness of intensive multidisciplinary rehabilitation for people with Parkinson's disease and their carers.

Objective: To evaluate the short-term effectiveness of an intensive multidisciplinary rehabilitation programme for people with Parkinson's disease and their carers.

Design: Observational, with assessments before and after intervention.

Setting: An elderly care day unit in a district general hospital in south-east England.

Anti-immunoglobulin E therapy for asthma.

The role of immunoglobulin E (IgE) in allergic asthmatic disease is well established. Allergen-specific IgE binds to its cognate receptors, thus triggering a series of cellular events. These events include presentation of antigen by dendritic cells and the degranulation of mast cells and basophils to release numerous factors that play an integral part in potentiating the disease symptoms.

Angiostatin induces intracellular acidosis and anoikis in endothelial cells at a tumor-like low pH.

Angiostatin inhibits angiogenesis by binding to endothelial cells (ECs) lining the vasculature of growing tumors. These cells are in a dynamic state during angiogenesis and are thus not firmly attached to the extracellular matrix. This makes them more vulnerable to anoikis, a process resulting in cell death initiated by or promoted by loss of attachment.