Biologic basis for interleukin-1 in disease

To understand the role of the proinflammatory cytokine interleukin-1 (IL-1) in disease, investigators have studied how production of the different members of the IL-1 family is controlled, the various biologic activities of IL-1, the distinct and various functions of the IL-1 receptor (IL-1R) family, and the complexity of intracellular signaling. Mice deficient in IL-1Beta, IL-1Beta converting enzyme, and IL-1R type I have also been studied. Humans have been injected with IL- 1 (either IL-1alpha or IL-1beta) for enhancing bone marrow recovery and for cancer treatment. The IL-1-specific receptor antagonist (IL-1Ra) has also been tested in clinical trials. The topics discussed in this review include production and activities of IL-1 and IL-1Ra molecules, the effects of IL-1 on gene expression, functions of cell-bound and soluble IL-1 receptors, the importance of the IL-1R accessory protein, newly discovered signal transduction pathways, naturally occurring cytokines limiting IL-1 production or activity, the effects of blocking cyclooxygenase and nitric oxide, and the outcomes of IL-1 and IL-1 Ra in human trials. Special attention is paid to IL-1beta converting enzyme and programmed cell death. The roles of IL-1 in hematopoiesis, leukemia, atherosclerosis, and growth of solid tumors are also discussed. This is a lengthy review, with 586 citations chosen to illustrate specific areas of interest rather than a compendium of references. At the end of each section, a short commentary summarizes what the author considers established or controversial topics linking the biology of IL-1 to mechanisms of disease.     

Glucagon-like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: a systematic scoping review

Stroke mortality and morbidity is expected to rise. Despite considerable recent advances within acute ischemic stroke treatment, scope remains for development of widely applicable neuroprotective agents. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally licensed for the management of Type 2 Diabetes Mellitus, have demonstrated pre-clinical neuroprotective efficacy in a range of neurodegenerative conditions. This systematic scoping review reports the pre-clinical basis of GLP-1RAs as neuroprotective agents in acute ischemic stroke and their translation into clinical trials. We included 35 pre-clinical studies, 11 retrospective database studies, 7 cardiovascular outcome trials and 4 prospective clinical studies. Pre-clinical neuroprotection was demonstrated in normoglycemic models when administration was delayed by up to 24 h following stroke induction. Outcomes included reduced infarct volume, apoptosis, oxidative stress and inflammation alongside increased neurogenesis, angiogenesis and cerebral blood flow. Improved neurological function and a trend towards increased survival were also reported. Cardiovascular outcomes trials reported a significant reduction in stroke incidence with semaglutide and dulaglutide. Retrospective database studies show a trend towards neuroprotection. Prospective interventional clinical trials are on-going, but initial indicators of safety and tolerability are favourable. Ultimately, we propose that repurposing GLP-1RAs is potentially advantageous but appropriately designed trials are needed to determine clinical efficacy and cost-effectiveness.     

Persistent reversed end diastolic flow in the fetal middle cerebral artery: an ominous finding

Fetal persistent middle cerebral artery reversed end diastolic flow is a rare and ominous finding. Previous cases have been associated with intracranial hemorrhage, growth restriction, anaemia, and hepatic anomaly. Intrauterine demise or early neonatal death is a common outcome. We report the case of persistent middle cerebral artery reversed end diastolic flow in a well-grown fetus at 32 weeks’ gestation resulting from acute, severe anaemia due to a large feto-maternal hemorrhage. An emergency cesarean section was performed and the neonate required advanced resuscitation and immediate blood transfusion. Postnatal magnetic resonance imaging confirmed a hemorrhagic parietal infarct and bilateral ischaemic changes in the basal ganglia. This provides further evidence that persistent middle cerebral artery reversed end diastolic flow in any fetus is an ominous finding warranting urgent diagnostic evaluation and/or delivery.     

Autologous bone marrow transplantation for acute myeloid leukemia using busulfan plus etoposide as a preparative regimen

We have studied the use of a new preparative regimen for the treatment of patients in remission of acute myeloid leukemia (AML) with autologous bone marrow transplantation. Chemotherapy consisted of busulfan 1 mg/kg every 6 hours for 4 days (total dose, 16 mg/kg) on days -7 through -4 followed by an intravenous infusion over 6 to 10 hours of etoposide 60 mg/kg on day -3. Autologous bone marrow, treated in vitro with 100 micrograms/mL of 4-hydroperoxycyclophosphamide, was infused on day 0. We have treated 58 patients up to the age of 60 years, 32 in first remission, 21 in second or third remission, and 5 with primary refractory AML unresponsive to high-dose Ara-C, but achieving remission with aggressive salvage regimens. Of the first remission patients, there has been 1 treatment related death and 5 relapses. With median follow-up of 22 months, the actuarial relapse rate is 22% +/- 9% and disease-free survival is 76% +/- 9% at 3 years. Patients with favorable French-American-British (FAB) subtypes (M3 or M4 EO) did especially well, with no relapses seen in 15 patients observed for a median of 30 months. Actuarial relapse rate at 3 years was 48% for first remission patients with less favorable FAB subtypes. Of patients in second or third remission, there were 5 treatment related deaths and 4 relapses. With median follow-up of 22 months, the actuarial relapse rate is 25% +/- 11% and disease-free survival is 56% +/- 11% at 3 years. Four of five primary refractory patients died during treatment and 1 remains in remission with short follow-up. These preliminary data are very encouraging and, if confirmed, support the use of autologous purged bone marrow transplantation using aggressive preparative regimens as one approach to improve the outcome of adults with AML.     

Active tuberculosis in inflammatory bowel disease patients under treatment from an endemic area in Latin America

BACKGROUNDThere has been an increase in cases of inflammatory bowel disease (IBD) in recent years. There is also greater access and availability of immunosuppressive and biological agents, which increase the risk of opportunistic infection despite improving the quality of life and promoting mucosal healing. Tuberculosis (TB) remains a public health problem, and it has a high incidence in several countries. Therefore, knowledge of the risk of developing TB in patients with IBD is important.AIMTo evaluate the risk of active TB in patients with IBD under treatment from an endemic area in Latin America.METHODSA standard questionnaire included demographic variables, clinical aspects of IBD disease, history of active TB during treatment, active TB characteristics and evolution, initial screening and results and time from the start of anti-tumor necrosis factor alpha (TNFα) to TB development.RESULTSAzathioprine, anti-TNFα and the combination of these two drugs were associated with a higher risk of active TB incidence. The TNFα blockers increased the relative risk of developing active TB compared to other treatments. All four multivariable models showed that the use of TNFα blockers alone or in combination with azathioprine was an important risk factor for the incidence of active TB. After adjustment for sex, age, type of IBD and latent TB, anti-TNFα with azathioprine increased the relative risk to 17.8 times more than conventional treatment. Late TB, which was diagnosed 3 mo after the start of anti-TNFα, was the most frequent.CONCLUSIONTreatment with anti-TNFα increased the risk of active TB in IBD patients from an endemic area in Latin America. This risk was increased when anti-TNFα was combined with azathioprine. The time from the beginning of the treatment to the active TB diagnosis suggests a new TB infection.     

Direct Effects of Exendin-(9,39) and GLP-1-(9,36)amide on Insulin Action, β-Cell Function,and Glucose Metabolism in Nondiabetic Subjects

Exendin-(9,39) is a competitive antagonist of glucagon-like peptide-1 (GLP-1) at its receptor. However, it is unclear if it has direct and unique effects of its own. We tested the hypothesis that exendin-(9,39) and GLP-1-(9,36)amide have direct effects on hormone secretion and β-cell function as well as glucose metabolism in healthy subjects. Glucose containing [3-³H]glucose was infused to mimic the systemic appearance of glucose after a meal. Saline, GLP-1-(9,36)amide, or exendin-(9,39) at 30 pmol/kg/min (Ex 30) or 300 pmol/kg/min (Ex 300) were infused in random order on separate days. Integrated glucose concentrations were slightly but significantly increased by exendin-(9,39) (365 ± 43 vs. 383 ± 35 vs. 492 ± 49 vs. 337 ± 50 mmol per 6 h, saline, Ex 30, Ex 300, and GLP-1-[9,36]amide, respectively; P = 0.05). Insulin secretion did not differ among groups. However, insulin action was lowered by exendin-(9,39) (25 ± 4 vs. 20 ± 4 vs. 18 ± 3 vs. 21 ± 4 10⁻⁴ dL/kg[min per μU/mL]; P = 0.02), resulting in a lower disposition index (DI) during exendin-(9,39) infusion (1,118 ± 118 vs. 816 ± 83 vs. 725 ± 127 vs. 955 ± 166 10⁻¹⁴ dL/kg/min² per pmol/L; P = 0.003). Endogenous glucose production and glucose disappearance did not differ significantly among groups. We conclude that exendin-(9,39), but not GLP-1-(9,36)amide, decreases insulin action and DI in healthy humans.The incretin hormone glucagon-like peptide-1 (GLP-1) arises by posttranslational processing of preproglucagon in the enteroendocrine L cells distributed throughout the intestine. GLP-1 secretion occurs within minutes of food ingestion, is a potent insulin secretagogue, and suppresses glucagon (1). However, the active form(s) of GLP-1 are rapidly deactivated by a serine protease dipeptidyl peptidase-4, which cleaves the two NH₂-terminal amino acids necessary for activation of the GLP-1 receptor (GLP-1R). This enzyme is widely distributed so that the half-life of active GLP-1 in the circulation is ∼1 min (2). The resulting metabolite GLP-1-(9,36) has been proposed as a potential antagonist of GLP-1R, although at present there is no evidence of an effect of this peptide on insulin secretion (3).Exendin-(7,39) is a naturally occurring analog of GLP-1-(7,36) and is an agonist of the GLP-1R. This compound binds to GLP-1R with greater affinity than the natural ligand due to a nine–amino acid COOH-terminal sequence absent in native GLP-1 (4). On the other hand, exendin-(9,39), which arises from the removal of the two NH₂-terminal amino acids, is a competitive antagonist of GLP-1 at the GLP-1R (5). It has been used to examine the effects of endogenous GLP-1 secretion on glucose homeostasis (6). Although it is presumed that exendin-(9,39) has no direct effects on glucose metabolism, it alters gastric emptying and capacitance through vagal mechanisms, thereby altering glucose tolerance independent of its ability to inhibit GLP-1-(7,36) effects on insulin and glucagon secretion (7,8). A direct effect of GLP-1-(9,36) signaling on glucose metabolism has been reported (9).The present studies were undertaken to determine whether exendin-(9,39) and GLP-1-(9,36)amide have direct effects on β-cell function, insulin action, glucagon secretion, and glucose metabolism. We did so by infusing glucose in a manner that mimicked the systemic appearance of glucose after ingestion of carbohydrate. Since glucose was infused intravenously, this created a model that resulted in the stimulation of insulin and suppression of glucagon in the absence of a change in endogenous GLP-1 concentrations. Subjects were studied on four occasions: receiving, in random order, saline, exendin-(9,39) infused at 30 pmol/kg/min (Ex 30) and at 300 pmol/kg/min (Ex 300), and GLP-1-(9,36)amide. Glucose turnover was measured on each occasion using [3-³H]glucose; insulin secretion and action were measured using the minimal model.     

Does self-motivation improve success rates of pelvic floor muscle training in women with urinary incontinence in a secondary care setting?

Introduction and hypothesis

Pelvic floor muscle training (PFMT) is the recommended first-line treatment for women with urinary incontinence (UI). Success rates are variable and dependent on a number of factors. The development of an incontinence treatment motivation questionnaire (ITMQ) provides us with a tool to assess patient self-motivation with respect to PFMT and UI. The aim of this study was to determine the effect of women’s self-motivation to perform PFMT on outcome.

Methods

Women with stress predominant UI completed an ITMQ and a 24-h pad test and then underwent a 12-week course of supervised PFMT. At the end of their treatment they completed a patient global impression of improvement questionnaire (PGI-I) and a second 24-h pad test. The PGI-I scores and the difference in pad test weight correlated with the ITMQ according to Spearman’s correlation coefficient.

Results

Sixty-five women were recruited. Thirty-two (49 %) patients perceived themselves as having improved, 28 women (43 %) did not experience any change in symptoms and 5 women (8 %) felt that their symptoms deteriorated following treatment. When correlating the PGI-I with the ITMQ, 3 of the 5 domains: MQS1 (positive attitude for treatment; p?=?0.003), MQS3 (frustration of living with incontinence; p?=?0.002) and MQS4 (desire for treatment; p?=?0.002) correlated significantly with outcome. Desire for treatment was the only domain to correlate with change in pad weight (p?=?0.001).

Conclusion

Self-motivation is essential in order to determine improved success rates with PFMT.