A noncyclical analog of salmon calcitonin (N alpha-propionyl Di-Ala1,7,des-Leu19 sCT) retains full potency without inducing anorexia in rats

A new analog of salmon calcitonin (N alpha-propionyl Di-Ala1,7,des-Leu19 sCT; RG-12851; here termed CTR), which lacks the ring structure of native calcitonin, was tested for biological activity in several in vitro and in vivo assay systems. The analog (CTR) and salmon calcitonin (sCT) stimulated kidney cell adenylate cyclase activity and inhibited bone resorption in organ cultures of fetal rat long bones with similar potencies and efficacies. Furthermore, CTR and sCT, at similar doses, induced comparable hypocalcemic responses in mice following sc injection or infusions. However, unlike sCT, CTR did not induce anorexia and weight loss in rats following sc injection. These data suggest that the ring structure of sCT may be important for the anorexigenic effect but is not required for effect on bone resorption or calcium homeostasis. Clinical studies appear warranted as, potentially, CTR might induce fewer side effects than does sCT.     

Monoclonal antibodies against receptor for epidermal growth factor induce early and delayed effects of epidermal growth factor.

Mice were immunized with human epidermoid carcinoma cells (A-431 cell line) that possess an unusually high number of membrane receptors for epidermal growth factor (EGF). Spleen cells from these mice were fused with NSI cells, a nonsecreting murine myeloma. The immunoglobulins secreted by the obtained hybridomas were screened for specific binding to A-431 cells and selected according to their ability to inhibit the binding of radiolabeled EGF to the membrane of A-431 cells. Several antibodies secreted by cloned hybrid lines were found to inhibit the binding of radiolabeled EGF to membrane receptors of living A-431 cells, human foreskin fibroblasts, and mouse 3T3 fibroblasts and also to membrane preparations from A-431 cells. These monoclonal antibodies induced the early and delayed biological effects mediated by EGF. Like EGF, the antibodies induced morphological changes in A-431 cells and enhanced the phosphorylation of endogenous membrane proteins in membranes from these cells. They also stimulated DNA synthesis in human foreskin fibroblasts. These observations support the notion that the biological information of the EGF-receptor complex resides in the membrane receptor. Furthermore, the antibodies offer a powerful tool to study the structure, processing, and mode of action of EGF receptors.     

De Novo Mutations in the Motor Domain of KIF1A Cause Cognitive Impairment,Spastic Paraparesis,Axonal Neuropathy,and Cerebellar Atrophy

KIF1A is a neuron‐specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type‐2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.     

Impact of Regular Physical Activity on Adipocytokines and Cardiovascular Characteristics in Spinal Cord–Injured Subjects

Objective

To investigate the relationship of carotid artery intima-media thickness (IMT) and cardiac structure and function with adipocytokines in sedentary (S-SCI) and physically active (PA-SCI) subjects with spinal cord injury (SCI).

Risk-Taking in Disorders of Natural and Drug Rewards: Neural Correlates and Effects of Probability,Valence, and Magnitude

Pathological behaviors toward drugs and food rewards have underlying commonalities. Risk-taking has a fourfold pattern varying as a function of probability and valence leading to the nonlinearity of probability weighting with overweighting of small probabilities and underweighting of large probabilities. Here we assess these influences on risk-taking in patients with pathological behaviors toward drug and food rewards and examine structural neural correlates of nonlinearity of probability weighting in healthy volunteers. In the anticipation of rewards, subjects with binge eating disorder show greater risk-taking, similar to substance-use disorders. Methamphetamine-dependent subjects had greater nonlinearity of probability weighting along with impaired subjective discrimination of probability and reward magnitude. Ex-smokers also had lower risk-taking to rewards compared with non-smokers. In the anticipation of losses, obesity without binge eating had a similar pattern to other substance-use disorders. Obese subjects with binge eating also have impaired discrimination of subjective value similar to that of the methamphetamine-dependent subjects. Nonlinearity of probability weighting was associated with lower gray matter volume in dorsolateral and ventromedial prefrontal cortex and orbitofrontal cortex in healthy volunteers. Our findings support a distinct subtype of binge eating disorder in obesity with similarities in risk-taking in the reward domain to substance use disorders. The results dovetail with the current approach of defining mechanistically based dimensional approaches rather than categorical approaches to psychiatric disorders. The relationship to risk probability and valence may underlie the propensity toward pathological behaviors toward different types of rewards.     

The effect of hydroxychloroquine on platelet activation in model experiments

Journal of Thrombosis and Thrombolysis - Hydroxychloroquine (HCQ) is an antimalarial agent with pleiotropic effects and now represents a cornerstone in the management of patients with autoimmune...     

Modified bypass procedure and apicoaortic conduit. Management of coronary artery disease,aortic valve stenosis and porcelain aorta

BACKGROUND: In case of severely calcified ascending aorta, modified operative strategies are required in order to avoid manipulations of the aorta and minimize subsequent cerebral vascular accidents. CASE REPORT: A 73-year-old woman, with a coronary two-vessel disease and aortic stenosis was scheduled for coronary artery bypass grafting and aortic valve replacement. Due to severed calcification of the ascending aorta including the transverse arch, neither cannulation, clamping nor incision of the aorta or its replacement was feasible. Therefore bypass operation was performed using a modified approach. After 1 month, implantation of a valved conduit between the left ventricular apex and the descending aorta through a lateral thoracotomy followed. CONCLUSION: Only in few cases the surgical treatment of a coronary artery disease in combination with left ventricular outflow tract obstruction and heavily calcified ascending aorta has been described. Undoubtedly, creation of an apicoaortic connection is today only indicated in the adult population in a small collective with multiple previous operations or porcelain aorta.     

Immediate effect of percutaneous myocardial laser revascularization on hemodynamics and left ventricular systolic function in severe angina pectoris

Experimental data suggest that myocardial revascularization with a high-energy laser may cause a significant reduction in left ventricular (LV) function immediately after creation of myocardial channels. We sought to determine if percutaneous myocardial laser revascularization (PMR) causes immediate deterioration in hemodynamic parameters or regional LV systolic function. PMR was performed in 40 patients (mean age 62.9 +/- 10.8 years) using the Eclipse Holmium laser (26 had PMR alone; 14 patients underwent PMR plus percutaneous coronary intervention). Intracardiac pressures and left ventriculograms were recorded before and after PMR. Regional wall motion was assessed using the centerline method. A mean of 18 +/- 5 channels were created per patient. There was no significant change in LV ejection fraction immediately after PMR (56 +/- 9% vs 55 +/- 10%, p = 0.25). No deterioration in regional wall motion was demonstrated in the lased region (mean chord motion for anterior wall PMR: -1.5 +/- 0.8 before vs -1.5 +/- 0.8 after the procedure, p = 0.93; inferior wall PMR: -1.5 +/- 0.9 before vs - 1.6 +/- 0.8 after the procedure, p = 0.43). Similarly, there was no change in the number of hypokinetic chords in the treated region. Systemic blood pressure, LV end-diastolic pressure, heart rate, and right-sided heart pressures were not significantly different after laser revascularization. In patients with refractory angina, PMR did not cause immediate deterioration in hemodynamic status or regional LV function.