Retinitis pigmentosa (RP) is an inherited blinding disease characterized by progressive loss of retinal photoreceptors. There are numerous rodent models of retinal degeneration, but most are poor platforms for interventions that will translate into clinical practice. The rabbit possesses a number of desirable qualities for a model of retinal disease including a large eye and an existing and substantial knowledge base in retinal circuitry, anatomy, and ophthalmology. We have analyzed degeneration, remodeling, and reprogramming in a rabbit model of retinal degeneration, expressing a rhodopsin proline 347 to leucine transgene in a TgP347L rabbit as a powerful model to study the pathophysiology and treatment of retinal degeneration. We show that disease progression in the TgP347L rabbit closely tracks human cone-sparing RP, including the cone-associated preservation of bipolar cell signaling and triggering of reprogramming. The relatively fast disease progression makes the TgP347L rabbit an excellent model for gene therapy, cell biological intervention, progenitor cell transplantation, surgical interventions, and bionic prosthetic studies.

Superoxide generation in aqueous solutions of cigarette smoke was determined as a function of the age of smoke using spin trapping. As a spin trap, 5,5-dimethylpyrroline-N-oxide (DMPO) was used. The superoxide adduct of DMPO was detected in a solution of fresh main-stream smoke for over 1 h. The superoxide-generating potential of smoke was rapidly lost as the smoke was kept in a plastic syringe. The smoke that was aged for 3 min did not generate superoxide. Additional evidence of superoxide generation in aqueous solutions of cigarette smoke was obtained by the chemiluminescence method.

In most protocols of peptide-based vaccination, no consideration has been paid to whether or not peptide-specific cytotoxic T-lymphocyte (CTL) precursors are pre-existent in cancer patients. Initiation of immune boosting through vaccination is better than that of immune priming to induce prompt and strong immunity. In this study, 10 human histocompatibility leukocyte antigen-A24(+) patients with advanced colorectal carcinomas were treated with up to four peptides that had been positive for pre-vaccination measurement of peptide-specific CTL precursors in the circulation (CTL precursor-oriented peptide vaccine). No severe adverse effect was observed, although local pain and fever of grade I or II were observed. Post-vaccination peripheral blood mononuclear cells (PBMCs) from five patients demonstrated an increased peptide-specific immune response to the peptides. Increased CTL response to cancer cells was detected in post-vaccination PBMCs of five patients. Antipeptide immunoglobulin G became detectable in post-vaccination sera of seven patients. Three patients developed a positive delayed-type hypersensitivity response to at least one of the peptides administrated. One patient was found to have a partial response; another had a stable disease, sustained through 6 months. These results encourage further development of CTL precursor-oriented vaccine for colorectal cancer patients.

Quality of life (QoL) is a key component in decision-making for surgical palliation, but QoL data in association with surgical palliation in advanced gastric cancer are scarce. The aim of this multicentre observational study was to examine the impact of surgical palliation on QoL in advanced gastric cancer.

The existence of a common lymphoid progenitor that can only give rise to T cells, B cells, and natural killer (NK) cells remains controversial and constitutes an important gap in the hematopoietic lineage maps. Here, we report that the Lin(-)IL-7R(+)Thy-1(-)Sca-1loc-Kit(lo) population from adult mouse bone marrow possessed a rapid lymphoid-restricted (T, B, and NK) reconstitution capacity in vivo but completely lacked myeloid differentiation potential either in vivo or in vitro. A single Lin(-)IL-7R(+)Thy-1(-)Sca-1loc-Kit(lo) cell could generate at least both T and B cells. These data provide direct evidence for the existence of common lymphoid progenitors in sites of early hematopoiesis.

Mice lacking functional IL-7 or IL-7R alpha genes are severely deficient in developing thymocytes, T cells, and B cells. IL-7 and IL-7 receptor functions are believed to result in lymphoid cell proliferation and cell maturation, implying signal transduction pathways directly involved in mitogenesis and elaboration of developmentally specific new gene programs. Here, we show that enforced expression of the bcl-2 gene in T-lymphoid cells (by crossing in the Emu-bcl-2 transgene) in IL-7R alpha-deficient mice results in a significant restoration of thymic positive selection and T cell numbers and function. We propose cell survival signals to be the principal function of IL-7R engagement in thymic and T cell development.

Nitric oxide (NO) modulation of ischemia-reperfusion injury was investigated by measuring lipid peroxide and neutrophil accumulation in rat stomachs treated with NG-nitro-L-arginine (L-NNA), a specific NO synthase inhibitor. Ischemia-reperfusion injury was induced in the rat stomach. Treatment with L-NNA for 3 days at a dose of 3 mg/kg/day significantly enhanced this injury. This enhancement was reversed by the simultaneous administration of L-arginine at a dose of 30 mg/kg/day. Both thiobarbituric acid (TBA)-reactive substances, an index of lipid peroxidation, and myeloperoxidase (MPO) activity, an index of tissue-associated neutrophil accumulation, were increased in the gastric mucosa after ischemia-reperfusion. L-NNA treatment enhanced these increases in TBA-reactive substances and MPO activity. The increase in the area of gastric erosions correlated closely with accumulation of TBA-reactive substances as well as the increase in MPO activity. Enhancement of ischemia-reperfusion injury by L-NNA treatment was inhibited by injection with anti-neutrophil antibody, anti-platelet activating factor (PAF) antagonist, and anti-leukotriene B4 (LTB4) receptor antagonist. In addition, the increase in TBA-reactive substances and MPO activity was decreased by these antibodies or antagonists. Enhancement of reperfusion-induced gastric mucosal injury associated with inhibition of NO synthesis may involve neutrophil infiltration and lipid peroxide accumulation in the gastric mucosa, mediated by PAF and LTB4.

We previously isolated an Arabidopsis: peroxisome-deficient ped2 mutant by its resistance to 2,4-dichlorophenoxybutyric acid. Here, we describe the isolation of a gene responsible for this deficiency, called the PED2 gene, by positional cloning and confirmed its identity by complementation analysis. The amino acid sequence of the predicted protein product is similar to that of human Pex14p, which is a key component of the peroxisomal protein import machinery. Therefore, we decided to call it AT:Pex14p. Analyses of the ped2 mutant revealed that AT:Pex14p controls intracellular transport of both peroxisome targeting signal (PTS)1- and PTS2-containing proteins into three different types of peroxisomes, namely glyoxysomes, leaf peroxisomes and unspecialized peroxisomes. Mutation in the PED2 gene results in reduction of enzymes in all of these functionally differentiated peroxisomes. The reduction in these enzymes induces pleiotropic defects, such as fatty acid degradation, photorespiration and the morphology of peroxisomes. These data suggest that the AT:Pex14p has a common role in maintaining physiological functions of each of these three kinds of plant peroxisomes by determining peroxisomal protein targeting.

The ether-à-go-go (EAG) family of voltage-gated K(+) channels contains three subfamilies, EAG, ether-à-go-go related (ERG) and ether-à-go-go like (ELK). The human ether-à-go-go related gene (hERG) K(+) channel has been of significant interest because loss of function in the hERG channel is associated with a markedly increased risk of cardiac arrhythmias. The hERG channel has unusual kinetics with slow activation and deactivation but very rapid and voltage-dependent inactivation. The outer pore region of the hERG K(+) channel is predicted to be different from that of other members of the voltage-gated K(+) channel family. HERG has a much longer linker between the fifth transmembrane domain (SS) and the pore helix (S5P linker) compared to other families of voltage-gated K(+) channels (43 amino acids compared to 14-23 amino acids). Further, the S5P linker contains an amphipathic alpha-helix that in hERG channels probably interacts with the mouth of the pore to modulate inactivation. The human EAG and rat ELK2 channels (hEAG and rELK2) show reduced or no inactivation in comparison to hERG channels, yet both channels are predicted to contain a similarly long S5P linker to that of hERG. In this study, we have constructed a series of chimaeric channels consisting of the S1-S6 of hERG but with the S5P alpha-helical region of either hEAG or rELK2, and one consisting of the S1-S6 of rELK2 but with the S5P alpha-helical region of hERG to investigate the role of the S5P linker in inactivation. Our studies show that charged residues on the alpha-helix of the S5P linker contribute significantly to the differences in inactivation characteristics of the EAG family channels. Further, individually mutating each of the hydrophilic residues on the S5P alpha-helix of hERG to a charged residue had significant effects on the voltage dependence of inactivation and the two residues with the greatest affect when mutated to a lysine, N588 and Q592, both lie on the same face of the S5P alpha -helix. We suggest that inactivation of hERG involves the interaction of this face of the S5P alpha-helix with a charged residue on the remainder of the outer pore domain of the channel.

Systemic sclerosis (SSc) is a connective tissue disorder with excessive fibrosis of the skin and various internal organs. Although SSc is a heterogeneous disease, it has been reported that the particular antinuclear antibodies (ANA) are often indicative of clinical features, disease course and overall severity.

The activation of melanocortin 1 receptor (MC1R) on melanocytes stimulates the production of eumelanin. A tridecapeptide α melanocyte-stimulating hormone (αMSH) is known to induce skin pigmentation.

Tumour stromal cells differ from its normal counterpart. We have shown that tumour endothelial cells (TECs) isolated from tumour tissues are also abnormal. Furthermore, we found that mRNAs of vascular endothelial growth factor-A (VEGF-A) and cyclooxygenase-2 (COX-2) were upregulated in TECs. Vascular endothelial growth factor-A and COX-2 are angiogenic factors and their mRNAs contain an AU-rich element (ARE). AU-rich element-containing mRNAs are reportedly stabilised by Hu antigen R (HuR), which is exported to the cytoplasm.

This study has used multiple-labelling immunohistochemistry and quantitative analysis to examine the projections of subpopulations of parasympathetic and sympathetic neurons to different vascular and secretory structures in five cranial exocrine glands of guinea-pigs. Multiple subpopulations of parasympathetic axons, identified by immunoreactivity (IR) for various combinations of peptides, innervated arteries, arterioles, ducts and acini in sublingual, submandibular, parotid, lacrimal and zygomatic glands, although axons were absent from ducts in the parotid gland. Most parasympathetic axons contained IR for vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY), with or without enkephalin (Enk). The proportion of parasympathetic axons that contained Enk-IR varied greatly between target tissues and glands: Enk-IR was more common in axons supplying secretory ducts, acini and arterioles than in axons innervating more proximal arteries; Enk-IR was less common in axons supplying the lacrimal gland than axons supplying the submandibular, lacrimal and zygomatic glands. Sympathetic axons with IR for tyrosine hydroxylase (TH) innervated arterial vessels in all glands, but innervated secretory structures only in the salivary glands. Sympathetic axons supplying proximal arterial segments often contained NPY-IR and sometimes also contained IR for dynorphin. Dynorphin-IR was more common in axons in the parotid, lacrimal and zygomatic glands than in the sublingual and submandibular glands. In contrast, axons supplying arterioles, ducts and acini lacked peptide IR. These results indicate that neuronal pathways regulating proximal arteries in cranial exocrine glands are different from the neuronal pathways regulating arterioles and acini, and may be different from neurons projecting to proximal secretory ducts. Furthermore, the peptides enkephalin, NPY and dynorphin are likely to make variable contributions to autonomic neurotransmission in different arterial segments and in different cranial exocrine glands.