Exendin-4, a glucagon-like peptide-1 receptor agonist, provides neuroprotection in mice transient focal cerebral ischemia

Glucagon-like peptide-1 (GLP-1) is an incretin hormone known to stimulate glucose-dependent insulin secretion. The GLP-1 receptor agonist, exendin-4, has similar properties to GLP-1 and is currently in clinical use for type 2 diabetes mellitus. As GLP-1 and exendin-4 confer cardioprotection after myocardial infarction, this study was designed to assess the neuroprotective effects of exendin-4 against cerebral ischemia–reperfusion injury. Mice received a transvenous injection of exendin-4, after a 60-minute focal cerebral ischemia. Exendin-4-treated vehicle and sham groups were evaluated for infarct volume, neurologic deficit score, various physiologic parameters, and immunohistochemical analyses at several time points after ischemia. Exendin-4 treatment significantly reduced infarct volume and improved functional deficit. It also significantly suppressed oxidative stress, inflammatory response, and cell death after reperfusion. Furthermore, intracellular cyclic AMP (cAMP) levels were slightly higher in the exendin-4 group than in the vehicle group. No serial changes were noted in insulin and glucose levels in both groups. This study suggested that exendin-4 provides neuroprotection against ischemic injury and that this action is probably mediated through increased intracellular cAMP levels. Exendin-4 is potentially useful in the treatment of acute ischemic stroke

Effects of daily aspirin on cancer incidence and mortality in the elderly Japanese

BackgroundLong‐term follow‐up of studies to investigate preventive effects of aspirin on arterial thrombosis indicate that aspirin reduces the incidence and mortality of some cancers in Western populations.ObjectivesTo explore the effects of aspirin on cancer incidence and mortality in the elderly Japanese.Patients/MethodsPatients aged 60 to 85 years, presenting with hypertension, dyslipidemia, or diabetes mellitus (n = 14 601, 7297 in the aspirin group and 7304 in the no‐aspirin group) participated the Japanese Primary Prevention Project (JPPP), a multicenter, open‐label, randomized, parallel‐group trial. A subanalysis of JPPP was performed to analyze the incidence of newly diagnosed cancer and death related to cancer.ResultsThe cumulative incidence of newly diagnosed cancer was 5.60% (4.65‐6.64%) in the aspirin group and 4.14% (3.67‐4.66%) in the no‐aspirin group. The hazard ratio for newly diagnosed cancer was 1.24 (1.06‐1.46), and the cancer incidence was significantly higher in the aspirin group. The cumulative cancer mortality was 1.96% (1.65‐2.31%) in the aspirin group and 1.87% (1.56‐2.22%) in the no‐aspirin group, with no statistically significant difference. The Fine and Gray model suggested that the difference in the incidence of newly diagnosed cancer between the two groups decreased year by year.ConclusionsLow‐dose aspirin use did not reduce the cancer incidence or cancer mortality during a 5‐year‐average study period in the elderly Japanese. The cancer incidence in the aspirin group might decrease, however, to less than that in the no‐aspirin group after the study period. Aspirin use might have led to earlier cancer diagnosis in our study

An Overview of Pituitary Incidentalomas: Diagnosis, Clinical Features, and Management

Pituitary incidentalomas are tumors or mass lesions of the pituitary gland. These are incidentally discovered during imaging studies for symptoms that are not causally related to pituitary diseases. The most common symptom that triggers an examination is headache, and the most common type of pituitary incidentalomas are pituitary neuroendocrine tumors (PitNETs) and Rathke cleft cysts. The existing treatment strategy is controversial; however, surgical resection is recommended in cases of clinically non-functioning PitNETs with optic chiasm compression. In contrast, cystic lesions, such as Rathke cleft cysts, should be followed if the patients are asymptomatic. In this case, MRI and pituitary function tests are recommended every six months to one year; if there is no change, the follow-up period should be extended. The natural history of PitNET is partially known, and the management of pituitary incidentalomas is determined by this history. However, the pathogenesis of PitNET has significantly changed with the new World Health Organization classification, and follow-up is important based on this new classification. Therefore, a high level of evidence-based research is needed to consider treatment guidelines for pituitary incidentalomas in the future

Minimizing the risk of injury to the popliteal artery during pullout repair of medial meniscus posterior root tears: A cadaveric study

Background: The purpose of this study was to investigate the positional effect of guide pins used in the transtibial pullout repair of medial meniscus posterior root tears on the popliteal artery. Methods: We used eight cadaveric knees. Two 2.4-mm guide pins were inserted into the posterior root of the medial meniscus at 50° to the articular surface from the medial edge of the tibial tuberosity (anteromedial group) and the anterior edge of the medial collateral ligament (posteromedial group) using an aiming guide placed at the posterior root attachment of the medial meniscus from the anteromedial portal. The posterior capsule was dissected, and the popliteal artery was identified. The positional effect of the guide pins on the popliteal artery was photographed arthroscopically at 0°, 30°, 60°, and 90° knee flexion angles. The popliteal artery diameter and the minimum distance between the popliteal artery center and the guide pin tip were measured. Results: At 90° knee flexion, most of the guide pins in the anteromedial (6 knees; 75 %) and posteromedial groups (7 knees; 87.5 %) collided with the femoral intercondylar wall. The rate of collision was significantly higher at the 90° knee flexion position than that at other angles (p = 0.02). The average shortest distance between the popliteal artery center and the guide pin tip at 0° knee flexion in the posteromedial group (5.4 mm ± 3.4 mm) was significantly greater than that at other knee flexion angles, although the mean distance in the posteromedial group was so negligible that the guide pin could penetrate the popliteal artery. Conclusions: Knee flexion at 90° causes less damage to the popliteal artery during the transtibial pullout repair of medial meniscus posterior root tears

Exploring endocrinological pitfalls in pituitary surgery in the elderly

Background: Endoscopic transsphenoidal surgery (ETSS) is performed more frequently in elderly patients. We investigated endocrinological pitfalls in pituitary surgery in the elderly by a comparative study focusing only on elderly patients. Methods: Ninety-nine elderly patients aged 65 years and over with non-functioning pituitary adenoma (NFPA) who underwent ETSS were retrospectively examined and classified into the early (aged 65–74 years) and late (aged 75 years and over) elderly groups. The baseline characteristics and anterior pituitary function were compared between the groups. Results: Seventy patients were assigned to the early elderly group and 29 to the late elderly group. Thyroid-stimulating hormone (TSH) response in preoperative and postoperative thyrotropin-releasing hormone (TRH) tests revealed a significant difference between the groups. Preoperative and postoperative TSH responses were significantly correlated in both groups. Residual analysis of the correlation between preoperative free triiodothyronine (T3) secretion quantity and preoperative TSH response in both groups, which was significant, indicated that preoperative TSH response was significantly normal when preoperative free T3 secretion quantity was normal in the early elderly group, but preoperative free T3 secretion quantity was significantly lower regardless of preoperative TSH response in the late elderly group. Conculsions: The present study suggested that preoperative and postoperative TSH secretory capacity was presumed to be normal when preoperative free T3 levels were normal in the early elderly patients with NFPA. On the other hand, TSH secretory capacity in the late elderly patients could only be assessed by the TRH test, which should be taken into account

Human-derived physiological heat shock protein 27 complex protects brain after focal cerebral ischemia in mice.

Although challenging, neuroprotective therapies for ischemic stroke remain an interesting strategy for countering ischemic injury and suppressing brain tissue damage. Among potential neuroprotective molecules, heat shock protein 27 (HSP27) is a strong cell death suppressor. To assess the neuroprotective effects of HSP27 in a mouse model of transient middle cerebral artery occlusion, we purified a "physiological" HSP27 (hHSP27) from normal human lymphocytes. hHSP27 differed from recombinant HSP27 in that it formed dimeric, tetrameric, and multimeric complexes, was phosphorylated, and contained small amounts of αβ-crystallin and HSP20. Mice received intravenous injections of hHSP27 following focal cerebral ischemia. Infarct volume, neurological deficit scores, physiological parameters, and immunohistochemical analyses were evaluated 24 h after reperfusion. Intravenous injections of hHSP27 1 h after reperfusion significantly reduced infarct size and improved neurological deficits. Injected hHSP27 was localized in neurons on the ischemic side of the brain. hHSP27 suppressed neuronal cell death resulting from cytochrome c-mediated caspase activation, oxidative stress, and inflammatory responses. Recombinant HSP27 (rHSP27), which was artificially expressed and purified from Escherichia coli, and dephosphorylated hHSP27 did not have brain protective effects, suggesting that the phosphorylation of hHSP27 may be important for neuroprotection after ischemic insults. The present study suggests that hHSP27 with posttranslational modifications provided neuroprotection against ischemia/reperfusion injury and that the protection was mediated through the inhibition of apoptosis, oxidative stress, and inflammation. Intravenously injected human HSP27 should be explored for the treatment of acute ischemic strokes

Characterization of hHSP27.

<p><b><i>A–B,</i></b> Isolated human heat shock protein 27 (hHSP27) or recombinant HSP27 (rHSP27) proteins (1 µg or 10 µg) were separated by SDS-PAGE (<b><i>A</i></b>) and native-PAGE (<b><i>B</i></b>) and stained with Coomassie brilliant blue. <b><i>C,</i></b> hHSP27 proteins were immunoblotted with antibodies against HSP27, phosphorylated S15 HSP27, S78 HSP27, and S82 HSP27. <b><i>D,</i></b> hHSP27 proteins were separated by native-PAGE and immunoblotted with antibodies against αβ-crystallin and HSP20. <b><i>E,</i></b> rHSP27 (10 ng), hHSP27 (10 ng), αβ-crystallin (5 ng), and HSP20 (5 ng) were separated by SDS-PAGE followed by immunoblotting with antibodies against HSP27, αβ-crystallin, and HSP20.</p

Neuroprotective effects of hHSP27 against ischemic/reperfusion injury 72 h after reperfusion.

<p><b><i>A,</i></b> Photomicrographs of infarct areas stained with cresyl violet in control and hHSP27 groups 72 h after reperfusion. Infarct areas are circumscribed with dotted lines. Scale bar = 1 mm. <b><i>B,</i></b> Infarct volumes in control and hHSP27 groups. <b><i>C,</i></b> Neurological deficit scores in control and hHSP27 groups. Data are presented as mean±SEM of 3 mice (<b><i>B</i></b>) and 5 mice (<b><i>C</i></b>) in each group. *<i>P</i><0.05, **<i>P</i><0.001 vs. controls.</p

Effects of hHSP27 on oxidative stress and inflammatory response.

<p><b><i>A,</i></b> Photomicrographs of 8-OHdG-, HHE-, Iba-1-, and GFAP-immunostaining in the infarct boundary zones in the control and hHSP27 groups 24 h after reperfusion. Bars = 50 µm. <b><i>B,</i></b> Numbers of 8-OHdG-, HHE–, Iba-1-, and GFAP-positive cells in control and hHSP27-treated mice. Data are means±SEM (<b><i>B</i></b>). **<i>P</i><0.001 vs. controls. 8-OHdG, 8-hydroxydeoxyguanosine; HHE, 4-hydroxy-2-hexenal; Iba-1, ionized calcium-binding adapter molecule-1; GFAP, glial fibrillary acidic protein; hHSP27, human heat shock protein.</p