Combination therapy with glucagon-like peptide-1 and gastrin restores normoglycemia in diabetic NOD mice

OBJECTIVE—Glucagon-like peptide-1 (GLP-1) and gastrin promote pancreatic β-cell function, survival, and growth. Here, we investigated whether GLP-1 and gastrin can restore the β-cell mass and reverse hyperglycemia in NOD mice with autoimmune diabetes.RESEARCH DESIGN AND METHODS—Acutely diabetic NOD mice were treated with GLP-1 and gastrin, separately or together, twice daily for 3 weeks. Blood glucose was measured weekly and for a further 5 weeks after treatments, after which pancreatic insulin content and β-cell mass, proliferation, neogenesis, and apoptosis were measured. Insulin autoantibodies were measured, and adoptive transfer of diabetes and syngeneic islet transplant studies were done to evaluate the effects of GLP-1 and gastrin treatment on autoimmunity.RESULTS—Combination therapy with GLP-1 and gastrin, but not with GLP-1 or gastrin alone, restored normoglycemia in diabetic NOD mice. The GLP-1 and gastrin combination increased pancreatic insulin content, β-cell mass, and insulin-positive cells in pancreatic ducts, and β-cell apoptosis was decreased. Insulin autoantibodies were reduced in GLP-1–and gastrin-treated NOD mice, and splenocytes from these mice delayed adoptive transfer of diabetes in NOD-scid mice. Syngeneic islet grafts in GLP-1–and gastrin-treated NOD mice were infiltrated by leukocytes with a shift in cytokine expression from interferon-γ to transforming growth factor-β1, and β-cells were protected from apoptosis.CONCLUSIONS—Combination therapy with GLP-1 and gastrin restores normoglycemia in diabetic NOD mice by increasing the pancreatic β-cell mass and downregulating the autoimmune response.Pancreatic β-cells can regenerate in response to experimental injury in adult animals (1–3) and can increase in humans in response to conditions such as pregnancy (4) and obesity (5). In addition, there is histological evidence of attempts at β-cell regeneration in humans with type 1 diabetes (6,7). Similarly, β-cell proliferation is increased before diabetes onset in NOD mice, an animal model for human type 1 diabetes, but not sufficiently to keep up with the ongoing autoimmune response that decreases the β-cell mass (8). Therefore, therapies directed at stimulating β-cell regeneration in addition to arresting autoimmunity may restore the β-cell mass and reverse type 1 diabetes.Many putative β-cell growth factors have been identified, one of the most promising being glucagon-like peptide-1 (GLP-1), a peptide secreted from intestinal L-cells in response to nutrient ingestion (9). The actions of GLP-1 to stimulate glucose-dependent insulin secretion and inhibit glucagon release, gastric emptying, and food intake (10) have led to its application as a therapy for type 2 diabetes (11). GLP-1 has additional actions that suggest a therapeutic role in conditions with a deficit in β-cell mass. GLP-1 and long-acting GLP-1 receptor agonists, such as exendin-4, increase the β-cell mass in rodents with surgically or chemically induced diabetes through stimulation of β-cell proliferation and islet neogenesis and inhibition of β-cell apoptosis (12–15). Also, GLP-1 (16) and exendin-4 (17) reduce insulitis and protect β-cells in NOD mice when given before diabetes onset. Exendin-4 has also been reported to reverse diabetes in NOD mice; however, this required combination of exendin-4 with immunosuppressive therapy using antilymphocyte serum (18).Gastrin is a gastrointestinal peptide reported to induce β-cell neogenesis from pancreatic exocrine duct cells in rodents (19,20). Combined gastrin and epidermal growth factor (EGF) treatment induces islet regeneration and restores normoglycemia in alloxan-treated mice (21) and ameliorates hyperglycemia after diabetes onset in NOD mice (22). Here, we report that addition of gastrin to GLP-1 treatment restored normoglycemia in acutely diabetic NOD mice by increasing the pancreatic β-cell mass and downregulating the autoimmune response.     

The Hong Kong Society of Rheumatology consensus recommendations for the management of gout

Clinical Rheumatology - Gout is one of the most common noncommunicable diseases in Hong Kong. Although effective treatment options are readily available, the management of gout in Hong Kong remains...     

Prolonged islet allograft survival by alpha-1 antitrypsin: the role of humoral immunity

Immunomodulatory properties have been recognized for human alpha-1 antitrypsin (hAAT). However, production of anti-hAAT antibodies in mice may inactivate the protein. In this study, we evaluated the effects of chronic hAAT administration on allogeneic islet graft survival. Chemically diabetic mice lacking an efficient humoral response due to the targeted disruption of the Ig mu-chain (muMT mice) or wild-type (WT) C57BL/6 mice received DBA/2 mouse islets under the kidney capsule. hAAT (Prolastin or Aralast) was given intraperitoneally on day 0 and every 3 days thereafter. Control animals received no treatment. hAAT administration in WT mice resulted in prolongation of islet allograft survival in a dose-dependent fashion in both hAAT-treated groups. Lack of Ig response (muMT mice) per se conferred a beneficial effect on graft survival that worsened in the Prolastin-treated groups but improved in the Aralast-treated group. Our data indicate that systemic administration of hAAT results in prolongation of islet allograft survival. Absence of mature B cells and Ig mu-chain resulted in improved graft survival, pointing to a role for B cells in the rejection process in this model. Treatment with Prolastin worsened graft survival in muMT mice, whereas Aralast did improve it, suggesting a different efficacy and possible actions of the two drug formulations.     

On the development of the European S3 guidelines on the systemic treatment of psoriasis vulgaris: structure and challenges

Background The development of evidence based guidelines is a demanding and time consuming process. Therefore it is important to share the knowledge and discuss the structure of these guidelines in detail. Objectives To present a method report on the development process of the European evidence based guidelines on the systemic treatment of psoriasis vulgaris with the aim to offer guidance to other guidelines groups with lesser experience and to critically appraise the methodology of the guidelines development process. Methods The guidelines are based on the previously evaluated literature from three European national evidence based guidelines and an additional systematic search and evaluation of new literature. Further steps included a structured consensus conference and a DELPHI procedure to develop the recommendations, as well as several internal and external reviews. All steps were coordinated by the Division of evidence based medicine in cooperation with a group of methodologists. Results A total of 114 studies were included, serving as base for the efficacy chapters of the intervention. The recommendations, based on the efficacy and the level of evidence of the included studies were discussed and finally consented by the guidelines group. After subsequent reviews the guidelines were presented to the European Dermatology Forum, European Academy of Dermatology and Venereology and Union Européenne des Médicins Spécialistes for approval and published in October 2009. Conclusion The development of European evidence based guidelines requires a coordinated structure which can be achieved by the integration of an experienced group of methodologists. Nevertheless further improvements are imaginable and might be considered for an update or other European evidence based guidelines.     

Comparison of measurements obtained with hand files or the Canal Leader attached to electronic apex locators: an in vitro study

AIM: The aim of the present in-vitro study was to combine directly the Canal Leader handpiece (SET, Olching, Germany) with the electronic apex locators ROOT ZX (Morita, Kyoto, Japan) and JUSTY (Yoshida, Tokyo, Japan) to find out whether the working length values thus obtained were identical to those resulting from the combination of the same electronic devices with hand files. METHODOLOGY: A total of 50 natural extracted teeth with single canals and mature apices were used. A radiograph was used as a control and the distance from the radiographic apex to the tip of the file was measured and compared with the results of the electronic length determination. RESULTS: For both electronic devices the differences amongst the distribution of the measurements were not statistically significant under the specified conditions (P > 0.05), indicating that the measurements with hand files and with the Canal Leader were identical for the majority of the cases. CONCLUSIONS: Under the conditions of this study the working length of canals obtained with electronically assisted hand files were similar to those obtained with the electronically assisted mechanical handpiece Canal Leader.     

A case of unfulfilled expectations. Cytokines in idiopathic minimal lesion nephrotic syndrome

Idiopathic minimal lesion nephrotic syndrome (IMLNS) was proposed to be a disorder of T-cell dysfunction by Shalhoub in 1974. The mechanisms by which T-cells increase glomerular permeability have remained elusive (and unproven). There is evidence that IMLNS may be due to a circulating factor released from activated T-cells. In recent years, efforts have been made to identify this pathogenetic cytokine as well as to understand the mechanism(s) for the increased release of this factor. This review attempts to critically analyze the available published data. Using different methodologies, investigators have focused on the production of cytokines in patients with IMLNS during relapse and remission. This has resulted in a plethora of data without definitive conclusions. The pathogenetic cytokine has not been identified, and it is questionable whether there is a Th2 dominance in IMLNS. The review of the available data illustrates the difficulties encountered when one is studying the cytokine secretory pattern in patients with IMLNS. Differences in patient population, type of cells studies, sample preservation, and methodology used to measure cytokines are some of the factors that could account for the disparity of observed results.     

Erythromycin treatment for gastrointestinal dysmotility in preterm infants

To report our clinical experience on the use of oral erythromycin for the treatment of severe gastrointestinal dysmotility in preterm infants.

Methodology:

A case series study of seven preterm infants (six were very low birthweight) with severe intestinal dysmotility in a tertiary neonatal centre.

Results:

All responded favourably without adverse effects and tolerated full enteral feeding within 1–2 weeks of the commencement of the drug.

Conclusions:

As prolonged total parenteral nutrition carries significant risk of complications, this therapy could be considered in selected preterm infants who fail to establish enteral feeding after an extended period, and in whom an anatomically obstructive lesion of the gastrointestinal tract has been excluded. Meanwhile, we would caution against the widespread implementation of this therapeutic approach until formal evaluation by randomized controlled trials have established the exact role of erythromycin, or its analogues, in the treatment of intestinal dysmotility in preterm infants.     

Immunoglobulins in cerebrospinal fluid in central nervous system disorders

Immunoglobulins were estimated in the cerebrospinal fluid from 70 cases of nervous system diseases. Thirty childern with evidence of C.N.S. irritation without infection served as controls. The immunoglobulins were higher in cases with C.N. S infections. Within this group meningeal involvement (tubercular and pyogenic) resulted in a significant rise in IgG compared to viral encephalitis. The proportion of immunoglobulin in the CSF protein can be helpful in distinguishing TBM from PM.     

Infection of human T-cell leukemia virus type I and development of human T-cell leukemia lymphoma in patients with hematologic neoplasms: a possible linkage to blood transfusion

Among 354 adult patients with either hematological malignancy or aplastic anemia, eight were positive for anti-HTLV-I antibodies; six of eight had received multiple transfusions. There was an approximately 3.5-fold increase (P less than .001) of HTLV-I seropositivity in the patients with hematologic disease (8 of 354, 2.23%) compared to the healthy adults older than 20 years (34 of 5252, .65%). Two hematological patients, one with Hodgkin's disease and one with acute promyelocytic leukemia, were found to be positive for HTLV-I, and developed and died of adult T-cell leukemia/lymphoma (ATL) subsequently. Both were long-term survivors of the primary disease and had received multiple transfusions. The latent period from blood transfusion to onset of ATL was 6 months and 11 years, respectively. Immunocompromised patients, who were seropositive for HTLV-I, may be at increased risk for ATL compared to healthy carriers of HTLV-I, and the latent period may be shorter.