Fair trade in building digital knowledge repositories: the knowledge economy as if researchers mattered

Medicine, Health Care and Philosophy - Both a significant body of literature and the case study presented here show that digital knowledge repositories struggle to attract the needed level of data...     

Early onset demyelinating Charcot‐Marie‐Tooth disease caused by a novel in‐frame isoleucine deletion in peripheral myelin protein 2

Peripheral myelin protein 2 (PMP2) is a small protein located on the cytoplasmic side of compact myelin, involved in the lipids transport and in the myelination process. In the last years few families affected with demyelinating Charcot‐Marie‐Tooth neuropathy (CMT1), caused by PMP2 mutations, have been identified. In this study we describe the first case of a PMP2 in‐frame deletion. PMP2 was analyzed by direct sequencing after exclusion of the most frequent CMT‐associated genes by using a next generation sequencing (NGS) genes panel. Sanger sequencing was used for family's segregation analysis. Molecular modeling analysis was used to evaluate the mutation impact on the protein structure. A novel PMP2: p.I50del has been identified in a child with early onset CMT1 and in three affected family members. All family members show an early onset demyelinating neuropathy without other distinguish features. Molecular modeling analysis and in silico evaluations do not suggest a strong impact on the overall protein structure, but a most likely altered protein function. This study suggests the importance to add PMP2 in CMT NGS genes panels or, at most, to test it after major CMT1 genes exclusion, due to the lack of diagnostic‐addressing additional features.     

Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) is characterized by epidermal growth factor receptor (EGFR) overexpression, where EGFR levels correlate with survival. To date, EGFR targeting has shown limited antitumor effects in head and neck cancer when administrated as monotherapy. We previously identified a gastrin-releasing peptide/gastrin-releasing peptide receptor (GRP/GRPR) aurocrine regulatory pathway in HNSCC, where GRP stimulates Src-dependent cleavage of EGFR proligands with subsequent EGFR phosphorylation and mitogen-activated protein kinase (MAPK) activation. To determine whether GRPR targeting can enhance the antitumor efficacy of EGFR inhibition, we investigated the effects of a GRPR antagonist (PD176252) in conjunction with an EGFR tyrosine kinase inhibitor (erlotinib). Combined blockade of GRPR and EGFR pathways significantly inhibited HNSCC, but not immortalized mucosal epithelial cell, proliferation, invasion, and colony formation. In addition, the percentage of apoptotic cells increased upon combined inhibition. The enhanced antitumor efficacy was accompanied by increased expression of cleaved poly(ADP-ribose) polymerase (PARP) and decreased phospho-EGFR, phospho-MAPK, and proliferating cell nuclear antigen (PCNA). Using reverse-phase protein microarray (RPPA), we further detected decreased expression of phospho-c-Jun, phospho-p70S6K, and phospho-p38 with combined targeting. Cumulatively, these results suggest that GRPR targeting can enhance the antitumor effects of EGFR inhibitors in head and neck cancer.     

Antimicrobial susceptibility of Campylobacter jejuni with special reference to resistance patterns of Canadian isolates.

Agar dilution antimicrobial susceptibility testing of Camphylobacter jejuni showed that erythromycin, clindamycin, nitrofurantoin, and gentamicin were the most active compounds, inhibiting 90% of the isolates at a concentration of 1 microgram/ml or less. The frequency of high-level erythromycin resistance was 1%. Erythromycin-resistant isolates showed cross-resistance to clindamycin. All strains were inhibited by chloramphenicol at less than or equal to 8 micrograms/ml. About 20% of the isolates were resistant to tetracycline at 4 micrograms/ml. All strains were highly resistant to novobiocin, bacitracin, vancomycin, and trimethoprim and resistant to rifampin. The minimal inhibitory concentrations (MICs) of metronidazole ranged from less than or equal to 0.5 to 128 micrograms/ml. The susceptibility of strains to sulfamethoxazole and polymyxin B sulfate was markedly influenced by inoculum size. The MICs of polymyxin B sulfate were significantly higher at 42 than 36 degrees C. All strains were inhibited by nalidixic acid at 32 micrograms/ml. In the penicillin group, ampicillin was the most active compound, inhibiting only about three-quarters of the strains at 8 micrograms/ml. The cephalosporins as a group showed only moderate to poor activity, the most active cephalosporin being cefotaxime, which inhibited about 90% of the strains at 8 micrograms/ml. The use of antibiotics in selective media is discussed.     

Nitrergic Neurons in the Spinal Cord of the Bottlenose Dolphin (Tursiops truncatus)

Nitric oxide (NO) is a freely diffusible gaseous neurotransmitter generated by a selected population of neurons and acts as a paracrine molecule in the nervous system. NO is synthesized from l ‐arginine by means of the neuronal nitric oxide synthase (nNOS), an enzyme requiring nicotine adenine dinucleotide phosphate (NADPH) as cofactor. In this study, we used histochemical and immunohistochemical techniques to investigate the distribution of NADPH‐diaphorase (NADPH‐d) and nNOS in the spinal cord of the bottlenose dolphin (Tursiops truncatus). Cells with a fusiform‐shaped somata were numerous in the laminae I and II. The intermediolateral horn showed darkly‐stained cells with a multipolar morphology. Neurons with a multipolar or fusiform morphology were observed in the ventral horn. Multipolar and fusiform neurons were the most common cell types in lamina X. Nitrergic fibers were numerous especially in the dorsal and intermediolateral horns. The presence of nitrergic cells and fibers in different laminae of the spinal cord suggests that NO may be involved in spinal sensory and visceral circuitries, and potentially contribute to the regulation of the complex retia mirabilia. Anat Rec, 296:1603–1614, 2013. © 2013 Wiley Periodicals, Inc.     

Clinical features and molecular modelling of novel MPZ mutations in demyelinating and axonal neuropathies

Mutations in the myelin protein zero (MPZ) gene have been associated with different Charcot–Marie–Tooth disease (CMT) phenotypes, including classical demyelinating CMT1B and the axonal form of the disease (CMT2). The MPZ role in the pathogenesis of both demyelinating and axonal inherited neuropathies was evaluated in the Italian population by screening a cohort of 214 patients with CMT1 or CMT2. A MPZ mutation frequency of 7.9% in demyelinating cases and of 4.8% in axonal cases was observed. In the total cohort (264 patients), including those with mutations in other genes, a mutation frequency of 5.8% (7/121) in demyelinating cases and 4.2% (6/143) in axonal cases was found. Three novel MPZ mutations, two missense (p.Ser111Cys, p.Thr124Ala) and one frameshift (p.Tyr145fs) were found, and a molecular modelling approach was used to test the effects of these mutations on the protein structure. Electrostatic distribution changes within the protein, caused by the amino acid substitution, fit in with phenotypes presented by patients herein described. Our findings suggest that the clinical features associated with MPZ mutations depend partly on the nature of amino acid change and that molecular modelling may provide useful support, based on effects on secondary and tertiary protein structure, to predict the phenotype associated with MPZ mutations.     

Targeting secondary immune responses to cetuximab: CD137 and the outside story

Cetuximab is a murine-human chimeric IgG1 mAb directed against the EGFR that is approved for use in patients with colorectal and head and neck carcinomas. While some patients benefit greatly from cetuximab, many do not; therefore, strategies to increase the efficacy of this drug are of great clinical interest. In this issue of the JCI, Kohrt and colleagues report a strategy for enhancing the secondary immune response to cetuximab that involves sequential targeting with an agonist mAb against CD137 expressed on NK and T cells.     

Stimulation of ovine placental lactogen secretion by arachidonic acid

To determine whether arachidonic acid stimulates the secretion of ovine placental lactogen (oPL), arachidonic acid was infused as an intravenous bolus into pregnant ewes and fetuses. Plasma oPL concentrations were determined in mothers and fetuses before and for 5 h after infusion. The administration of 12.5 mg arachidonic acid (0.15-0.2 mg/kg, n = 11 experiments) to the pregnant ewes caused an increase in maternal plasma oPL concentrations of 73.9 +/- 15.6% (S.E.M.) and 60.8 +/- 18.1% above the pretreatment concentrations at 4 and 5 h respectively (P less than 0.01 in each instance). The infusion of 25 mg arachidonic acid (n = 8) caused increases of 96.0 +/- 19.1% and 100.3 +/- 26.4% (P less than 0.005), and the stimulation was not inhibited by the cyclo-oxygenase inhibitors indomethacin and ibuprofen. In contrast to arachidonic acid, vehicle alone or palmitic acid had no effects on plasma oPL concentrations. Despite the increase in maternal plasma oPL concentrations, plasma oPL concentrations in the fetus remained unchanged after the maternal infusions. The infusion of arachidonic acid (0.5-1.5 mg/kg) directly into six fetuses had no effects on either fetal or maternal oPL concentrations. These studies indicate that arachidonic acid stimulates maternal plasma oPL concentrations but has no effect on fetal oPL concentrations and the stimulation of oPL secretion is not due to the conversion of arachidonic acid to prostaglandins or other cyclo-oxygenase products.