Alpha2-macroglobulin as a promising biomarker for cerebral small vessel disease in acute ischemic stroke patients

Alpha2-macroglobulin is a protease inhibitor that enhances procoagulant properties via the neutralization of plasmin, plasminogen activators and metalloproteinases. Additionally, alpha2-macroglobulin is thought to be involved in inflammatory reactions as a carrier protein for interleukin-6 (IL-6). The objective of this study was to evaluate the usefulness of alpha2-macroglobulin as a biomarker for cerebrovascular diseases. Patients with acute ischemic stroke (n = 159; 93 male and 66 female, 71.6 ± 10.3 years) and patients with no previous history of stroke (n = 77; 38 male and 39 female, 70.7 ± 9.5 years) were consecutively enrolled in this study. White matter lesions were assessed via the fluid-attenuated inversion recovery image of magnetic resonance images using the Fazekas classification. The serum alpha2-macroglobulin levels were measured by nephelometry. The serum alpha2-macroglobulin levels at admission in patients with acute ischemic stroke were higher than those in the control patients (230.2 ± 73.7 vs. 205.0 ± 55.8 mg/dl, p = 0.009). The serum alpha2-macroglobulin levels were positively correlated with age and the severity of the white matter lesions (R ² = 0.048, p < 0.001 and R ² = 0.058, p < 0.001, respectively), although there was no significant association between serum alpha2-macroglobulin levels and IL-6 levels. In addition, multivariate analysis showed that increased serum alpha2-macroglobulin levels were independently associated with the severity of white matter lesions [standardized partial regression coefficient (β) 0.102, p = 0.026]. Increased serum alpha2-macroglobulin levels might be involved in the pathophysiology of acute ischemic stroke. Furthermore, serum alpha2-macroglobulin levels, which were associated with high-grade white matter lesions, may reflect the chronic pathophysiological condition of cerebral small vessel disease.     

Potential of a glucagon‐like peptide‐1 receptor/glucose‐dependent insulinotropic polypeptide receptor/glucagon receptor triagonist for the treatment of obesity and type 2 diabetes

Triagonists of GLP‐1R/ GIPR /GCGR, including SAR441255, bind to each receptor and induce specific effects through each receptor signaling pathway, thus result in weight loss and glycemic control in obese T2D animal models.

Type 2 diabetes, which often accompanies obesity, is one of the major health‐threatening diseases worldwide. Incretin‐based therapies, such as dipeptidyl peptidase‐4 inhibitors and glucagon‐like peptide‐1 receptor (GLP‐1R) agonists, are used for the treatment of type 2 diabetes. The GLP‐1R agonists have been shown to improve glycemic control and reduce bodyweight through its various actions, including glucose‐dependent insulin secretion, suppression of glucagon secretion, and inhibition of gastric emptying and food intake ¹ .Recently, dual agonists of GLP‐1R and glucose‐dependent insulinotropic polypeptide receptor (GIPR), and those of GLP‐1R and glucagon receptor (GCGR) have been developed. One of the dual agonists of GLP‐1R and GIPR, named tirzepatide, has been shown to bind and activate both GLP‐1R and GIPR in vitro and in vivo, its efficacy for the treatment of type 2 diabetes has been proven in a phase III trial, and it has recently been approved by the US Food and Drug Administration ^{2 , 3} . In the phase III trial, once‐weekly injection of trizepatide (5, 10 or 15 mg) for 40 weeks reduced glycated hemoglobin (HbA1c) from baseline by 1.87, 1.89 or 2.07%, respectively, and reduced bodyweight from baseline by 7.0, 7.8 or 9.5 kg, respectively, in type 2 diabetes patients. The most frequent adverse events with trizepatide were gastrointestinal events ³ . In the clinical trial that compared trizepatide (5, 10 or 15 mg) with once‐weekly semaglutide (1 mg) in type 2 diabetes patients, trizepatide showed non‐inferior and superior reductions in HbA1c levels and in bodyweight ⁴ . For both treatments, gastrointestinal events were the most common adverse events ⁴ . The possible additional effects of GIP signaling in type 2 diabetes patients might depend on its augmentation of insulin secretion during hyperglycemic states ⁵ .The dual agonists of GLP‐1R and GCGR specific for mice or monkeys have been developed and were investigated their effects in each species. In obese and diabetic cynomolgus monkeys induced by high‐fat diet feeding, the monkey‐specific dual agonist of GLP‐1R and GCGR reduced total energy intake, decreased bodyweight and improved glucose tolerance ⁶ . However, in another study using obese diabetic monkeys, glycemic control was worse when they were co‐administered with both GLP‐1R and GCGR agonists compared with that treated with an GLP‐1R agonist alone ⁷ . Therefore, the significance of the activation of GCGR signaling has not yet been fully clarified.In 2015, Finan et al. ⁸ created a triagonist that activates GLP‐1R, GIPR and GCGR by selecting amino acids from the three peptide hormones, GLP‐1, GIP and glucagon, and reported that the triagonist reduced bodyweight and improved glucose control in rodent models of obesity and diabetes.More recently, Bossart et al. ⁹ developed a novel GLP‐1R, GIPR and GCGR triagonist, SAR441255. SAR441255 was confirmed to efficiently bind to and stimulate all three receptors in in vitro studies. In a diet‐induced obesity mouse model, subcutaneous injection of SAR441255 (0.3, 1, 3, 10 or 30 μg/kg) showed a dose‐dependent effect on bodyweight (+9.7%, +6.9%, +5.8%, −4.8% and −14.1%, respectively) compared with injection of vehicle (+11.5%). Non‐fasted blood glucose levels were significantly lower in mice treated with SAR441255 at doses of ≥1 μg/kg when compared with vehicle‐treated controls. In obese diabetic cynomolgus monkeys, treatment with SAR441255 (11 μg/kg) or a monkey‐specific GLP‐1R/GCGR dual agonist (4 μg/kg) ⁶ significantly reduced the bodyweight by −12.6% or −8.1%, respectively, and decreased the HbA1c levels by −1.37% or −1.85%, respectively. Fasting plasma glucose and alanine aminotransferase levels were significantly reduced with SAR441255, but not with the dual agonist (Figure 1).Open in a separate windowFigure 1Possible mechanisms of glucagon‐like peptide‐1 receptor (GLP‐1R)/glucose dependent insulinotropic polypeptide receptor (GIPR)/glucagon receptor (GCGR) triagonist in weight loss and glycemic control in obese type 2 diabetes animal models. Triagonists of GLP‐1R/GIPR/GCGR, including SAR441255, bind to each receptor and induce specific effects through each receptor signaling pathway, thus resulting in weight loss and glycemic control in obese type 2 diabetes animal models. Potential effects of each receptor signaling that contribute to weight loss and/or better glycemic control are listed below each receptor.To further understand engagement of the different receptors in vivo, receptor occupancy of SAR441255 at the GLP‐1 and the GCG receptors was studied with the use of positron emission tomography imaging after radiotracer administration in lean cynomolgus monkeys. A subcutaneous injection of 11 μg/kg SAR411255 together with radiotracers specific for GLP‐1R and GCGR showed the significant signals of both receptors in the liver and pancreas of monkeys, suggesting the binding of SAR411255 to both receptors existing in these organs. Cardiovascular safety of SAR411255 was further confirmed in lean cynomolgus monkeys.Finally, a phase I study with SAR411255 in lean to overweight healthy participants was carried out to assess the safety, tolerability, pharmacokinetics and pharmacodynamics. After subcutaneous administration, SAR441255 concentration reached the median maximum serum concentration by 3.0–3.5 h, and was eliminated with a mean elimination terminal half‐life of 3.5–6.1 h. After administration of single doses (80 and 150 mg) of SAR441255 in the fasting state, maximal reduction in blood glucose levels were observed at 1 h post‐dose. At this time point, three of six participants who received the 80 mg dose and all six participants who received the 150 mg dose showed hypoglycemia (<70 mg/dL) without any clinical signs or symptoms. No further low blood glucose values were observed in either dose group. Blood glucose levels subsequently returned to baseline levels within 1–2 h. In contrast, fasting insulin and C‐peptide levels were relatively stable, and showed no correlation with the glucose levels. Therefore, the mechanisms of this early phase hypoglycemia have not yet been clarified. After the mixed‐meal test 3 h after the SAR441255 administration (80 and 150 mg), a dose‐dependent reduction in postprandial plasma glucose was observed. Because insulin and C‐peptide levels were also reduced during mixed‐meal test, postprandial plasma glucose reduction was suggested to be due to inhibition of gastric emptying, as observed with GLP‐1R engagement.Gastrointestinal disorders (nausea, vomiting, dry mouth and mouth ulceration) were the most frequent treatment‐emergent adverse events after treatment with SAR441255. All events were mild in severity, and occurred between 3 and 4 h after SAR441255 administration.To clarify the effects of SAR441255 on GIPR and GCGR in humans, specific biomarkers for each receptor were measured. As expected, a biomarker for GIPR activation, C‐telopeptide of cross‐linked type I collagen, which is a marker of bone turnover, was significantly reduced by >50% in participants who received SAR441255 administration (80 and 150 mg). Likely, plasma amino acids levels, which are sensitive biomarkers of GCGR activation, were reduced after SAR441255 administration in these individuals.As aforementioned, the dual agonists of GLP‐1R and GIPR might have comparable or even more stronger effects in reductions of HbA1c and bodyweight in obese type 2 diabetes patients ⁴ ; the significance of the activation of GCGR signaling should be evaluated to confirm the benefits of the triagonists of GLP‐1R, GIPR and GCGR. In this regard, the effects of glucagon to enhance energy expenditure partly through enhancement of fat and glucose oxidation could cover some of the benefits ⁷ , but further investigations should be necessary. In addition, it has recently been reported that GLP‐1R agonists have clinically significant cardiovascular benefits in type 2 diabetes patients ¹ . Therefore, it should be clarified if the dual or triagonists also have comparable cardiovascular benefits, as observed in GLP‐1R agonists in type 2 diabetes patients.Because triagonists have been shown to have better profiles in weight loss and glycemic control in animal models of obese type 2 diabetes compared with GLP‐1R agonists and dual agonists of GLP‐1R and GIPR or GLP‐1R and GCGR ^{8 , 9} , clinical studies that investigate the efficacy in type 2 diabetes patients should be of great interest.     

Tannin-phytobezoars with Gastric Outlet Obstruction Treated by Dissolution with Administration and Endoscopic Injection of Coca-ColaⓇ, Endoscopic Crushing,and Removal (with Video)

A 77-year-old man complained of postmeal vomiting and sustained general fatigue. An abdominal computed tomography scan showed massive gastric expansion and fluid storage. Gastroscopy revealed four gastric bezoars that were considered to have caused pyloric ring obstruction. The patient was asked to drink 500 mL per day of Coca-Cola^Ⓡ for 4 days. On the fourth day, we performed endoscopic crushing and removal by injecting Coca-Cola^Ⓡ, cutting the softened bezoar with endoscopic snares, and collecting the pieces with endoscopic nets. We herein report (with a video presentation) a rare case of tannin-phytobezoars endoscopically removed with the administration and injection of Coca-Cola^Ⓡ.     

Über die Epidermolysis bullosa hereditaria Köbner

Ohne ZusammenfassungHiezu Taf. XI–XVII.     

A sporadic case of CTLA4 haploinsufficiency manifesting as Epstein–Barr virus-positive diffuse large B-cell lymphoma

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) is a coinhibitory receptor that plays an essential role in maintaining immune system homeostasis by suppressing T-cell activation. We report a sporadic case of CTLA4 haploinsufficiency in a patient with Epstein–Barr virus-positive diffuse large B-cell lymphoma and subsequent benign lymphadenopathy. A missense mutation in exon 2 of the CTLA4 gene (c.251T>C, p.V84A) was found in the patient’s peripheral blood and buccal cell DNA, but not in her parents’ DNA. CTLA4 expression decreased in the peripheral regulatory T cells upon stimulation, whereas CTLA4 and PD-1-positive T cell subsets increased, possibly to compensate for the defective CTLA4 function. This case suggests that some adult lymphoma patients with no remarkable medical history have primary immune disorder. As immune-targeted therapies are now widely used for the treatment of malignancies, it is increasingly important to recognize the underlying primary immune disorders to properly manage the disease and avoid unexpected complications of immunotherapies.