Regulation of ER molecular chaperone prevents bone loss in a murine model for osteoporosis

Endoplasmic reticulum (ER) stress response is important for protein maturation in the ER. Some murine models for bone diseases have provided significant insight into the possibility that pathogenesis of osteoporosis is related to ER stress response of osteoblasts. We examined a possible correlation between osteoporosis and ER stress response. Bone specimens from 8 osteoporosis patients and 8 disease-controls were used for immunohistochemical analysis. We found that ER molecular chaperones, such as BiP (immunoglobulin heavy-chain binding protein) and PDI (protein-disulfide isomerase) are down-regulated in osteoblasts from osteoporosis patients. Based on this result, we hypothesized that up-regulation of ER molecular chaperones in osteoblasts could restore decreased bone formation in osteoporosis. Therefore, we investigated whether treatment of murine model for osteoporosis with BIX (BiP inducer X), selective inducer BiP, could prevent bone loss. We found that oral administration of BIX effectively improves decline in bone formation through the activation of folding and secretion of bone matrix proteins. Considering these results together, BIX may be a potential therapeutic agent for the prevention of bone loss in osteoporosis patients.     

Randomized, placebo-controlled, double-blind clinical trial evaluating the treatment of plantar fasciitis with an extracoporeal shockwave therapy (ESWT) device: a North American confirmatory study.

Despite numerous publications and clinical trials, the results of treatment of recalcitrant chronic plantar fasciitis with extracorporeal shockwave therapy (ESWT) still remain equivocal as to whether or not this treatment provides relief from the pain associated with this condition. The objective of this study was to determine whether extracorporeal shock wave therapy can safely and effectively relieve the pain associated with chronic plantar fasciitis compared to placebo treatment, as demonstrated by pain with walking in the morning. This was set in a multicenter, randomized, placebo-controlled, double-blind, confirmatory clinical study undertaken in four outpatient orthopedic clinics. The patients, 114 adult subjects with chronic plantar fasciitis, recalcitrant to conservative therapies for at least 6 months, were randomized to two groups. Treatment consisted of approximately 3,800 total shock waves (+/-10) reaching an approximated total energy delivery of 1,300 mJ/mm(2) (ED+) in a single session versus placebo treatment. This study demonstrated a statistically significant difference between treatment groups in the change from baseline to 3 months in the primary efficacy outcome of pain during the first few minutes of walking measured by a visual analog scale. There was also a statistically significant difference between treatments in the number of participants whose changes in Visual Analog Scale scores met the study definition of success at both 6 weeks and 3 months posttreatment; and between treatment groups in the change from baseline to 3 months posttreatment in the Roles and Maudsley Score. The results of this study confirm that ESWT administered with the Dornier Epos Ultra is a safe and effective treatment for recalcitrant plantar fasciitis.     

Novel mutation p.Gly59Arg in GJB6 encoding connexin 30 underlies palmoplantar keratoderma with pseudoainhum, knuckle pads and hearing loss

Background  Connexins, components of the gap junction, are expressed in several organs including the skin and the cochlea. Mutations in connexin genes including GJB2 (Cx26), GJB3 (Cx31), GJB4 (Cx30.3), GJB6 (Cx30) and GJA1 (Cx43) are responsible for various dermatological syndromes and/or inherited hearing loss, frequently showing overlapping phenotypes.
Objectives  To clarify the spectrum of clinical phenotypes caused by connexin mutations.
Methods  We report a 32-year-old Japanese woman with mild palmoplantar keratoderma (PPK) with severe sensorineural hearing loss, knuckle pads and pseudoainhum of her toes.
Results  Direct sequencing revealed no mutation in GJB2 , but a novel heterozygous missense mutation p.Gly59Arg in GJB6 . Electron microscopy revealed no apparent morphological abnormality of gap junctions in the patient's lesional epidermis.
Conclusions  The patient harboured the novel GJB6 missense mutation p.Gly59Arg in the first extracellular loop of Cx30. Mutations in glycine 59 of Cx26 are associated with PPK–deafness syndrome, and the similar phenotype here supports the observed heteromeric channel formation; the dominant nature of the mutation suggests an effect on gap junctions similar to that of the comparable mutation in Cx26.     

Total replacement of the urinary bladder using an ileal pouch bladder

We have used the continent ileal bladder as a bladder replacement after radical cystectomy. The ileal bladder is an ileal pouch which is anastomosed to the urethral stumps. The ureters are implanted by a free end ureteroileostomy. The long term results with 26 patients who underwent this procedure are reported. In the early postoperative period, urodynamic and radiographic studies revealed small capacity and high intravesical pressure of the ileal bladder. However, it became a low pressure reservoir with increased capacity gradually. The average bladder capacity was about 250 ml and average residual urine was 30 ml. Most of the patients were continent in the daytime if the voiding intervals were less than 3 hours at night, some patients were incontinent. Urinary leakage was the most frequent complication. VUR and hydronephrosis were still the problems to be solved. The ileal pouch bladder is a valuable procedure in properly selected cases.     

Transport of amino acids by the human placenta: Predicted effects thereon of maternal hyperphenylalaninaemia

Summary Brush border and basal plasma membrane vesicles prepared from normal term human placental syncytiotrophoblast have been used to study amino acid transport. Such studies are reviewed and novel results presented which confirm that saturation of placental transport by phenylalanine is unlikely to limit delivery of this amino acid to the fetus even with grossly raised maternal concentrations. Such raised maternal levels of phenylalanine are, however, likely to severely embarrass the delivery to the fetus across the placental brush border membrane ofl-tyrosine and, to a lesser extent, ofl-tryptophan. Reasons for thinking that this may be relevant to the fetal damage found in maternal PKU are discussed.     

Molecular mechanisms of portal vein tolerance

The liver has been considered as a tolerogenic organ in the sense that favors the induction of peripheral tolerance. The administration of antigens (Ags) via the portal vein causes tolerance, which is termed portal vein tolerance and can explain the occurrence of tolerogenic responses in the liver. Here we discuss the fundamental mechanisms accounting for portal vein tolerance. Antigen-presenting cells (APCs) in the liver, especially dendritic cells and sinusoidal endothelial cells, have limited the ability to produce pro-inflammatory cytokines upon stimulation with endotoxin, an effect that could be due to the continuous exposure to bacterial Ags derived from intestinal microflora. Ag presentation by liver APCs results in T cell tolerance through clonal deletion and selection of regulatory T cells. Thus, APCs with immunosuppressive functions are associated with the achievement of portal vein tolerance via the induction of clonal deletion and generation of regulatory T cells.     

Fully automated diagnostic system with artificial intelligence using endocytoscopy to identify the presence of histologic inflammation associated with ulcerative colitis (with video)

1. Download high-res image (358KB)
2. Download full-size image