Research ArticleNeuroscience Free access | 10.1172/JCI88321 Nigel A. Calcutt,1 Darrell R. Smith,2 Katie Frizzi,1 Mohammad Golam Sabbir,2 Subir K. Roy Chowdhury,2 Teresa Mixcoatl-Zecuatl,1 Ali Saleh,2 Nabeel Muttalib,1 Randy Van der Ploeg,2 Joseline Ochoa,1 Allison Gopaul,1 Lori Tessler,2 Jürgen Wess,3 Corinne G. Jolivalt,1 and Paul Fernyhough2,4 1Department of Pathology, UCSD, La Jolla, California, USA. 2Division of Neurodegenerative Disorders, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada. 3Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA. 4Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada. Address correspondence to: Paul Fernyhough, R4046 – 351 Taché Avenue, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, R2H 2A6, Canada. Phone: 204.235.3692; E-mail: pfernyhough@sbrc.ca. Find articles by Calcutt, N. in: JCI | PubMed | Google Scholar 1Department of Pathology, UCSD, La Jolla, California, USA. 2Division of Neurodegenerative Disorders, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada. 3Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA. 4Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada. Address correspondence to: Paul Fernyhough, R4046 – 351 Taché Avenue, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, R2H 2A6, Canada. Phone: 204.235.3692; E-mail: pfernyhough@sbrc.ca. Find articles by Smith, D. in: JCI | PubMed | Google Scholar 1Department of Pathology, UCSD, La Jolla, California, USA. 2Division of Neurodegenerative Disorders, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada. 3Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA. 4Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada. Address correspondence to: Paul Fernyhough, R4046 – 351 Taché Avenue, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, R2H 2A6, Canada. Phone: 204.235.3692; E-mail: pfernyhough@sbrc.ca. Find articles by Frizzi, K. in: JCI | PubMed | Google Scholar 1Department of Pathology, UCSD, La Jolla, California, USA. 2Division of Neurodegenerative Disorders, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada. 3Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA. 4Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada. Address correspondence to: Paul Fernyhough, R4046 – 351 Taché Avenue, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, R2H 2A6, Canada. Phone:

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Abstract Bladder inflammation frequently causes cystitis pain and lower urinary tract dysfunction (LUTD) such as urinary frequency and urgency. Although mast cells have been identified to play a critical role in bladder inflammation and pain, the role of mast cells in cystitis-associated LUTD has not been demonstrated. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic and debilitating inflammatory condition of the urinary bladder characterized by the hallmark symptoms of pelvic pain and LUTD. In this study we investigated the role of mast cells in LUTD using a transgenic autoimmune cystitis model (URO-OVA) that reproduces many clinical correlates of IC/BPS. URO-OVA mice express the membrane form of the model antigen ovalbumin (OVA) as a self-antigen on the urothelium and develop bladder inflammation upon introduction of OVA-specific T cells. To investigate the role of mast cells, we crossed URO-OVA mice with mast cell-deficient KitW-sh mice to generate URO-OVA/KitW-sh mice that retained urothelial OVA expression but lacked endogenous mast cells. We compared URO-OVA mice with URO-OVA/KitW-sh mice with and without mast cell reconstitution in response to cystitis induction. URO-OVA mice developed profound bladder inflammation with increased mast cell counts and LUTD, including increased total number of voids, decreased mean volume voided per micturition, and decreased maximum volume voided per micturition, after cystitis induction. In contrast, similarly cystitis-induced URO-OVA/KitW-sh mice developed reduced bladder inflammation with no mast cells and LUTD detected. However, after mast cell reconstitution URO-OVA/KitW-sh mice restored the ability to develop bladder inflammation and LUTD following cystitis induction. We further treated URO-OVA mice with cromolyn, a mast cell membrane stabilizer, and found that cromolyn treatment reversed bladder inflammation and LUTD in the animal model. Our results provide direct evidence for the role of mast cells in cystitis-associated LUTD, supporting the use of mast cell inhibitors for treatment of certain forms of IC/BPS. Citation: Wang X, Liu W, O’Donnell M, Lutgendorf S, Bradley C, Schrepf A, et al. (2016) Evidence for the Role of Mast Cells in Cystitis-Associated Lower Urinary Tract Dysfunction: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Animal Model Study. PLoS ONE 11(12): e0168772. https://doi.org/10.1371/journal.pone.0168772 Editor: Jayoung Kim, Cedars-Sinai Medical Center, UNITED STATES Received: October 11, 2016; Accepted: November 16, 2016; Published: December 21, 2016 Copyright: © 2016 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: All relevant data are within the paper and its Supporting Information files. Funding: This work

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Making beta cells from people with type 1 diabetes Research Update Dec. 27, 2016 Scientists generated functional β (beta) cells from the skin cells of people with type 1 diabetes. In type 1 diabetes, a misguided attack by the immune system leads to destruction of insulin-producing β cells found in clusters called islets in the pancreas. Although administration of insulin via injections or a pump is life-saving, it does not mimic the exquisite blood glucose (sugar) control of the pancreas. Therefore, scientists are pursuing strategies to replace the destroyed β cells. One way to do that is through islet transplantation-an experimental procedure using islets from a cadaveric donor. The procedure has shown promise for people with difficult-to-control diabetes, but has significant challenges: donor islet tissue is limited, and immunosuppressive medications, which have toxic side effects, are required to prevent rejection of tissue transplanted from another individual. Toward overcoming the first barrier, scientists recently developed a new laboratory production method to make large quantities of β cells-called stem-cell derived β (SC-β) cells-from human stem cells. This method could, with further development, be used to make β cells from a sample of cells from a person with type 1 diabetes in the quantities needed for transplantation back into that same person. These cells would likely require protection from the autoimmune attack, but might not require toxic immunosuppressive medications to prevent rejection of the tissue. To investigate this possibility, in new research, scientists used skin cells from three people with type 1 diabetes (T1D cells) and three people without diabetes (ND cells). By introducing specific factors into these cells and using the new large-scale production method they developed, they made the skin cells become stem cells-cells that could subsequently become any cell type. They then, by introducing other factors, coaxed these stem cells to become SC-β cells (T1D SC-β cells and ND SC-β cells). Cells from the two different origins showed no differences in the ability to become SC-β cells, indicating for the first time that cells from a person with type 1 diabetes could be used to make SC-β cells. Next, the scientists demonstrated that the T1D SC-β cells functioned like healthy β cells. For example, in laboratory culture, T1D SC-β cells secreted insulin in response to glucose; they also released insulin in response to diabetes drugs that are known to stimulate insulin secretion, demonstrating their potential for use in screening for new diabetes drugs. The T1D SC-β also functioned in live animals: when T1D SC-β cells were transplanted into male mice, they produced insulin in response to glucose and controlled the animals’ blood glucose levels. Many research questions remain before an SC-β cell transplant procedure will be ready for testing in humans. First, it remains possible that differences between T1D

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Gastric band Surgery In France Being overweight may be more harmful than you thought Sign in Log in with your Medical News Today account to create or edit your custom homepage, catch-up on your opinions notifications and set your newsletter preferences. Sign in Register for a free account For FREE No Obligation Information about the cost of Gastric Band Surgery in France Click here Or Click the Image Below to visit our Special offer Page to see if you Qualify for any Discounts Read more……>click Here< Read more... Read more…

Genome-Wide Association Study of Primary Sclerosing Cholangitis Identifies New Risk Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn’s disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC. Read more......>click Here< Read more... Read more…

Figure 1 Functional characterization of Atxn1, Ebf1, Rreb1 and Ube2e2 (a,b,e) Data is displayed as box/whisker plots where the center line represents the median, box limits contain the 25th-75th percentiles, and whiskers span max/min values.(a) Gene expression measured by qPCR in murine subcutaneous (SAT), perigonadal visceral (VAT), and pericardial (PAT) adipose tissues (n=6 mice). Statistical significance was assessed using ANOVA and Sidak’s correction for multiple comparisons.(b) Gene expression measured by qPCR in murine adipose tissues after 8 weeks of high fat feeding compared to normal chow fed controls (n=5 mice per group). Statistical significance was assigned using a two-sided T-test.(c) Gene expression measured by qPCR in cultured adipocyte progenitors isolated from the subcutaneous (SAT) or perigonadal visceral (VAT) depots (n=4 replicates). Cells were expanded to confluence and then collected at intervals after induction of adipogenic differentiation. Data displayed as mean, error bar=s.e.m. Statistical significance was assessed using ANOVA and Sidak’s correction for multiple comparisons to time 0.(d) Oil-red-o staining of progenitors isolated from subcutaneous adipose and exposed to retroviral delivery of shRNA constructs during ex vivo expansion and induction of adipogenesis. Relative to control vector carrying a scramble sequence, shRNA constructs specific for Atxn1 and Ube2e2 impaired adipogenic differentiation. Scale=1mm.(e) Oil-red-o stain was alcohol extracted and quantified at OD520 (n=9 technical replicates). Statistical significance was assessed using ANOVA and Sidak’s correction for multiple comparisons to control (Scramble). Data representative of 3 independent experiments. Read more……>click Here< Read more... Read more…

Gastric band Surgery In France Does living next to a gym lower obesity risk? Sign in Log in with your Medical News Today account to create or edit your custom homepage, catch-up on your opinions notifications and set your newsletter preferences. Sign in Register for a free account For FREE No Obligation Information about the cost of Gastric Band Surgery in France Click here Or Click the Image Below to visit our Special offer Page to see if you Qualify for any Discounts Read more……>click Here< Read more... Read more…

Gastric band Surgery In France Could this device help to prevent the harms of sitting? Sign in Log in with your Medical News Today account to create or edit your custom homepage, catch-up on your opinions notifications and set your newsletter preferences. Sign in Register for a free account For FREE No Obligation Information about the cost of Gastric Band Surgery in France Click here Or Click the Image Below to visit our Special offer Page to see if you Qualify for any Discounts Read more……>click Here< Read more... Read more…

Gastric band Surgery In France Diabetes: New pathway to treatment suggested by protein culprit What is the link between anxiety and diabetes? New research shows that a protein related to the development of anxiety and depression may also play a role in triggering diabetes. Scientists from the Max Planck Institutes hypothesize that an antagonist compound could be used to block its effect. Scientists investigate a new lead in the search for better diabetes treatments. The main known causes for type 2 diabetes so far include obesity and lack of physical exercise – both of which can lead to insulin resistance – as well as a family history of the condition. Insulin resistance occurs when muscles, liver, and fat cells become unable to use insulin appropriately, which ultimately leads to a dangerous rise in blood glucose levels. Now, researchers from the Max Planck Institute of Psychiatry in Munich, Germany, have found that a protein called FKBP51 may also play a role in triggering type 2 diabetes. The protein has so far been associated with anxiety and depression; it contributes to the regulation of the stress system. When the gene that controls the production of FKBP51 suffers a mutation, this can lead to dysregulation of the stress system, which, in turn, can cause mental health disorders. Mathias Schmidt – lead researcher of the current study – and colleagues have recently noted that the FKBP51 protein also contributes to forming a molecular link between the stress system and the regulation of various metabolic functions. This may make FKBP51 responsible for the onset of metabolic diseases such as obesity and diabetes. The team’s findings have now been published in the journal Nature Communications. Protein reacts to metabolic stress Schmidt and team looked at a mouse model to understand the potential role played by FKBP51 in metabolic processes. They studied the effect of a high-fat diet on mice in which the FKBP51 gene was expressed, as well as on knockout mice, in which that gene was inactivated artificially. They found that the knockout mice did not gain weight after exposure to the diet, had better glucose, or blood sugar, tolerance, and had more effective insulin signaling. This allowed the researchers to understand that the FKBP51 protein – regulated by the gene with the same name – affects signaling pathways in skeletal muscles. Since the protein is sensitive to metabolic stress factors, such as high fat intake, it can ultimately lead to blood sugar buildup and insulin resistance. These are the main factors to blame in the development of type 2 diabetes and obesity. “FKBP51 influences a signaling cascade in muscle tissue, which with excessive calorie intake leads to the development of glucose intolerance, i.e., the key indicator of diabetes type 2.” Mathias Schmidt The cause may lead to the treatment Fortunately, this mechanism has also offered the scientists an insight into how they might be able to prevent FKBP51’s response to the

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