Placebo controlled phase II clinical trial: Safety and efficacy of combining intranasal insulin & acute exercise

A growing number of investigations are exploring the utility of intranasal insulin as a means of mitigating cognitive decline. However, as a basic tenant of dementia prevention programs is increasing physical activity, it is essential to obtain a preliminary assessment of the safety profile of combining intranasal insulin with physical activity; to ensure that undue risks are not incurred. Utilizing a randomized double-blind placebo-controlled design, a sample of 116 non-diabetic, fasted college-aged adults were randomly assigned to receive a dose of 0-to-120 IU of NovoLog (Insulin Aspart) before being randomized to 20 min of exercise or sitting control condition. The safety of intranasal insulin was assessed by examining the incidence of potential symptoms of hypoglycemia and changes in peripheral blood glucose. The efficacy of a combination therapeutic approach was assessed using behavioral measures of inhibition and sustained attention alongside neuroelectric indices of attentional engagement. The frequency of symptoms reported following administration of intranasal insulin were not observed to interact with exercise so as to make their occurrence any more or less prominent, nor was the frequency observed to relate to the dose of intranasal insulin. However, doses of intranasal insulin of 100 IU or more were observed to result in a 7-fold increase in the likelihood of a level 1 hypoglycemic event for those individuals in the exercise condition. This study provides preliminary evidence to suggest that exercise is not associated with an increase in risk when combined with lower doses of intranasal insulin.

Clinical trial registration The trial is registered at ClinicalTrials.gov, number NCT04292535.

     

Anatomic relations of the Marshall vein: importance for catheterization of the coronary sinus in ablation procedures.

AIMS: Our objective was to study the anatomic relations of the human left atrial oblique vein (Marshall vein), particularly of its ostium opening into the coronary sinus, in order to guide ablation procedures related to that vein. METHODS AND RESULTS: The study was carried out in 23 heart-specimens (mean weight 446 +/- 204 g) of individuals whose mean ages were 43 +/- 21 years, 20 males. The coronary sinus was opened longitudinally, exposing the ostium of the tributary veins; the Vieussens valve was looked for, as well as its relationship to the left atrial oblique vein. The diameters of the left atrial oblique vein and the coronary sinus ostia were measured and the distance between them was determined. The left atrial oblique vein could be identified in 20 (87%) of the hearts, while the Vieussens valve was present in 17 (74%) of the specimens (in 16 of which the left atrial oblique vein was identified). In such condition, the vein was adjacent to the Vieussens valve and proximally positioned relative to the coronary sinus ostium in most of them (14/16 cases). The mean diameters of the left atrial oblique vein and of the coronary sinus ostia were, respectively, 1.23 +/- 0.38 and 8.22 +/- 1.88 mm. The mean distance between both ostia was 30.9 +/- 10.2 mm. CONCLUSION: When present, the left atrial oblique vein can be easily recognized, adjacent to the Vieussens valve. The mean distance between the coronary sinus opening and left atrial oblique vein ostium was around 30 mm, independently of the heart weight and the presence of cardiomegaly.     

In vivo specific uptake of labeled insulin by liver,adipose tissue,pituitary, and adrenals in the turtle Chrysemys dorbigni

Insulin labeled with ¹²⁵I was injected into turtles (Chrysemys dorbigni) to study its specific uptake by tissues. The maximum specific uptake of radioactivity by turtle tissues was obtained 1 hr after administration of [¹²⁵I]iodoinsulin. Besides liver and adipose tissue, specific uptake of labeled insulin was detected in some endocrine glands, such as pituitary and adrenals. Both glands were as active in concentrating labeled insulin as liver and adipose tissue. A significant reduction of the uptake was observed when unlabeled insulin was injected together with the labeled hormone. This reduction was dose dependent, and the concentration of unlabeled insulin that prevented 50% of the tissue uptake of [¹²⁵I]iodoinsulin was of 1 to 10 μg/kg body weight. These doses were able to induce blood glucose decrease in the turtle. Prolactin, growth hormone, or glucagon were unable to displace labeled insulin uptake. The major proportion of the radioactive material extracted from liver and pituitary 1 hr after [¹²⁵I]iodoinsulin injection into turtle coeluted with [¹²⁵I]iodoinsulin in Sephadex G-50 column. The presence of radioactive degradation products are consistent with the intracellular receptor mediated degradation hypothesis. These findings suggest the presence of specific insulin binding sites in liver, adipose tissue, pituitary, and adrenal glands from turtles.     

Influence of intercellular junctions on endothelin secretion of human umbilical vein endothelial cells in vitro

The endothelium plays a pivotal role in the theological regulation of blood flow by the secretion of vasoactive factors. The interaction between shear forces and the endothelium is determined by the mechanical properties of the endothelial cell layer which are associated with intercellular junctions. Cell-cell contacts could therefore modulate the secretion of vasocative factors in response to theological stimuli. We investigated the relationship between intercellular junctions and the secretion of the vasoconstrictor peptide endothelin and the coagulation co-factor von Willebrand factor (vWF). Human umbilical vein endothelial cells (HUVECs) were used as in vitro endothelial model system. Intercellular junctions were reversibly disrupted by calcium chelation or hypertonic stress; alternatively, the formation of intercellular junctions was inhibited by culturing the cells in suspension or by plating them in the presence of an inhibitory anti-VE-cadherin antibody. The opening of intercellular junctions was verified by assessing transmonolayer electrical resistance (TMR) and immunofluorescence morphology. The concentration of endothelin and vWF was measured in the cell culture supernatants using specific ELISAs. The secretion of endothelin was inhibited by EGTA (5 mM) and stimulated by incubation with tumor necrosis factor α (TNFα, 40 ng/ml). Treatment with hypertonic medium (glycerol, 1200 mosmol/l) for 10 minutes opened intercellular junctions and markedly reduced the secretion of endothelin. HUVECs in suspension culture did not secrete endothelin and failed to respond to TNFα, but readily resumed these functions upon forming a new monolayer on plastic. The reconstitution of intercellular junctions after suspension culture could be inhibited using a specific anti-VE-cadherin antibody. This antibody, but not a non-specific anti-humanIgG antibody reduced endothelin secretion. The secretion of von Willebrand Factor was less dependent on intercellular junctions. The opening of intercellular junctions did not induce cell death, since the cells continued to exclude trypan blue. The results of this study suggest a novel and potentially pathophysiologically/clinically relevant correlation between intercellular junctions and the secretion of endothelin in endothelial cells. Received: 17 December 1999, Returned for revision: 20 January 2000, Revision received: 14 February 2000, Accepted: 2 March 2000     

Smooth muscle-like cells in pulmonary lymphangioleiomyomatosis

Proliferation, migration, and differentiation of smooth muscle (SM)-like lymphangioleiomyomatosis (LAM) cells in the lungs are pathologic manifestations of pulmonary LAM, a rare lung disease predominantly afflicting women and exacerbated by pregnancy. LAM cells form nodules throughout the lung without any predominant localization, but can also form small cell clusters dispersed within lung parenchyma. LAM cells have the appearance of "immature" SM-like cells, irregularly distributed within the nodule in contrast to organized SM cell layers in airways and vasculature. Progressive growth of LAM cells leads to the cystic destruction of the lung parenchyma, obstruction of airways and lymphatics, and loss of pulmonary function. Pathogenetically, LAM occurs from somatic or genetic mutations of tumor suppressor genes tuberous sclerosis complex 1 (TSC1) or TSC2. The TSC1/TSC2 protein complex is an integrator of signaling networks regulated by growth factors, insulin, nutrients, and energy. The observation that the TSC1/TSC2 functions as a negative regulator of the mammalian target of rapamycin (mTOR)/p70 S6 kinase (S6K1) signaling pathway yielded the first rapamycin clinical trial for LAM. Although LAM is a rare lung disease, the elucidation of disease-relevant mechanisms of LAM will provide a better understanding of not only SM-like cell growth, migration, and differentiation in LAM but may also offer insights into other metabolic diseases such as cardiovascular diseases, diabetes, and cancer. In this article, we will summarize the progress made in our understanding of LAM, and we will focus on how dysregulation of TSC1/TSC2 signaling results in abnormal proliferation and migration of SM-like LAM cells.     

Intravascular large B-cell lymphoma as a cause of hypopituitarism: gradual and late reversal of hypopituitarism after long-term remission of lymphoma with immunochemotherapy

Intravascular large B-cell lymphoma (IVL) is a rare generally fatal disease characterized by massive proliferation of lymphoid cells within the small and medium blood vessels. Hypopituitarism has been reported only in a few fatal cases. We describe the clinical course of hypopituitarism as a complication of IVL, successfully treated with immunochemotherapy (cyclophosphamide/doxorubicin/vincristine/prednisone-CHOP) plus Rituximab anti-CD20 humanized antibody). Before immunochemotherapy, basal hormonal analysis and dynamic test for pituitary function were performed in a 67-year-old female with IVL. Endocrinological evaluation of the pituitary function was repeated after complete hematological remission and during the 2 years of follow-up. Multiple pituitary hormone deficiencies were diagnosed before therapy for IVL. Magnetic resonance imaging (MRI) of the pituitary gland showed partially empty sella. The patient was replaced with thyroxine 50 microg/day and prednisone 5 mg/day between the cycles of chemotherapy. After complete hematological remission (6 months after initial diagnosis) reversal of cortisol and gonadotropin deficiency occurred. After 18 months of hematological remission there was further improvement in growth hormone (GH) response to provocative testings (partial GH deficiency), with normalization of somatotropic and thyreotropic axis after 2 years of follow-up. This is the first case of IVL complicated with hypopituitarism, treated with immunochemotherapy which resulted in complete hematological remission and gradual and late reversal of hypopituitarism.     

Splenic infarction secondary to acute pancreatitis

BACKGROUND AND OBJECTIVE: the close anatomic relationship of the pancreas with the splenic vessels and the spleen is responsible for splenic complications in the course of acute pancreatitis. Our objective was to report two cases of severe acute pancreatitis complicated by splenic infarction. PATIENTS: in a three-month period of time two patients were diagnosed with splenic infarction secondary to acute pancreatitis. In both cases splenic infarction diagnosis and follow-up were carried out using computed tomography. RESULTS: in the first case images clearly showed a narrowing of the splenic artery due to the inflammatory pancreatic condition. In the second case no involvement of the splenic vessels could be demonstrated, hence the only possible etiological explanation was a hypercoagulability state generated by pancreatitis. CONCLUSIONS: it would be advisable that splenic complications were added to the list of relevant extrapancreatic manifestations. CT is very useful for the diagnosis and follow-up of splenic complications arising in acute pancreatitis.