Effects of localized intraspinal injections of a noradrenergic blocker on locomotion of high decerebrate cats

Previous studies demonstrated that neuronal networks located in midlumbar segments (L3-L4) are critical for the expression of locomotion in cats following complete spinalization. In the present study the importance of several thoracolumbar segments (T8-L7) for the generation of spontaneous hindlimb locomotion in decerebrate cats was evaluated. Experiments were performed in high decerebrate cats (n = 18) walking spontaneously. Yohimbine, an alpha2-noradrenergic antagonist, was microinjected intraspinally in various thoracolumbar segments. Locomotor performance was evaluated with kinematics and electromyographic (EMG) recordings before and after each injection. When and if spontaneous locomotion (SL) was abolished, skin or perineal stimuli (exteroceptive stimuli) were used to trigger locomotion (exteroceptive-induced locomotion [EL]). Yohimbine injections at L3 or L4 completely inhibited SL and EL. In contrast, injections at T8 did not interfere with SL or EL. Injections at T10, T11, T12, L5, L6, and L7 inhibited SL but EL could still be evoked. Injections at T13, L1, and L2 had similar effects except that the quality of locomotion evoked by exteroceptive stimulation declined. Combined injections at T13, L1, and L2 abolished SL and EL, in contrast to injections restricted to the same individual segments. Simultaneous injections at L5, L6, and L7 also abolished SL but EL could still be induced. These results suggest that noradrenergic mechanisms in L3-L4 segments are involved in the expression of locomotion in decerebrate cats, whereas antagonizing noradrenergic inputs in individual rostral or caudal segments may alter the expression and overall quality of the locomotor pattern without abolishing locomotion.     

An unusual case of hemochromatosis due to a new compound heterozygosity in HFE (p.[Gly43Asp;His63Asp]+[Cys282Tyr]): structural implications with respect to binding with transferrin receptor 1

Most adults affected with HFE hereditary hemochromatosis (HH type 1, MIMmusical sharp 235200) are homozygous for the p.Cys282Tyr mutation in HFE (NC_000006.10, region 26195427 to 26205038). The aim of this study was to investigate the molecular basis of iron overload in a patient presenting with severe clinical HH with one c.845G>A (p.Cys282Tyr) allele only. Molecular and pedigree studies demonstrated the presence of the c.845G>A (p.Cys282Tyr) mutation in one allele whereas the other carried the c.187C>G (p.His63Asp) mutation plus a new c.128G>A (p.Gly43Asp) substitution in cis. A molecular modeling study of the p.[Gly43Asp;His63Asp] and p.His63Asp variants versus the wild type was carried out using molecular dynamics (MD) simulation in presence of implicit solvent. We found that the c.187C>G (p.His63Asp) mutation does not introduce any major change in the 1- domains of HFE whereas the c.128G>A (p.Gly43Asp) substitution is responsible for a modification of the dynamics and the structure of the Gln40-Ser45 loop, a critical region for HFE-TfR1 interaction thus impairing HFE-TfR1 normal contact. We conclude that the occurrence of complex alleles may be an alternative explanation for the variability of the phenotype in individuals who are compound heterozygous for c.[187C>G]+[845G>A] (p.[His63Asp]+[Cys282Tyr]).     

Targeting renal glucose reabsorption for the treatment of type 2 diabetes mellitus using the SGLT2 inhibitor dapagliflozin

Sodium-glucose co-transporter 2 (SGLT2) plays a key role in glucose homeostasis as the key transporter responsible for most renal glucose reabsorption in the proximal tubules of the kidney. Dapagliflozin is a potent, selective, and reversible inhibitor of SGLT2 that lowers blood glucose levels in an insulin-independent fashion. This novel agent has been studied extensively in patients with type 2 diabetes mellitus (T2DM). In these clinical trials, dapagliflozin significantly decreased glycated hemoglobin and fasting plasma glucose levels when administered alone or as add-on treatment in patients who were already receiving metformin, a sulfonylurea (glimepiride), pioglitazone, or insulin. Moreover, dapagliflozin decreased body weight when taken as monotherapy or in combination with metformin, a sulfonylurea, or insulin, and mitigated weight gain in patients receiving pioglitazone. Consistent with preclinical toxicology studies, dapagliflozin has a manageable adverse event profile that is largely predictable from its mechanism of action. While there are no clinically significant negative effects on renal function or electrolytes, dapagliflozin treatment is associated with increased frequencies of urinary tract infections and vulvovaginitis/balanitis. With a mechanism of action that is distinct from and complementary to that of existing antihyperglycemic therapies, dapagliflozin is an effective antihyperglycemic agent that is well tolerated and may enhance weight loss. As such, dapagliflozin promises to become an important adjunctive therapy for comprehensive treatment of T2DM.     

Significance of missing telemetered markers in implanted cardioverter-defibrillators

Background: We report three patients with St Jude ICDs (St. Jude Medical, Sylmar, CA, USA) where some aspect of the marker channel was missing. Methods and Results: Two cases were caused by the simultaneous occurrence of two distinct cardiac or device events that affected the proper delivery of markers by the telemetry system. Inability of the devices to sequentially process these events resulted in incomplete transmission of telemetry data to the programmers and caused missing markers in the telemetry recordings. In the third case, sensed atrial interference resulted in a short period of atrial asynchronous pacing, which prevented the delivery of a sensed atrial marker coincident with an atrial electrogram. This atrial electrogram by virtue of its timing would have otherwise been sensed outside the atrial refractory period. Conclusion: The perplexing recordings of the three patients should not be interpreted as representing true pacemaker malfunction. PACE 2012; 35:409–415)     

Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disorder caused by genetic and environmental factors that results in degeneration of the nigrostriatal dopaminergic pathway in the brain. We analyzed neural cells generated from induced pluripotent stem cells (iPSCs) derived from PD patients and presymptomatic individuals carrying mutations in the PINK1 (PTEN-induced putative kinase 1) and LRRK2 (leucine-rich repeat kinase 2) genes, and compared them to those of healthy control subjects. We measured several aspects of mitochondrial responses in the iPSC-derived neural cells including production of reactive oxygen species, mitochondrial respiration, proton leakage, and intraneuronal movement of mitochondria. Cellular vulnerability associated with mitochondrial dysfunction in iPSC-derived neural cells from familial PD patients and at-risk individuals could be rescued with coenzyme Q(10), rapamycin, or the LRRK2 kinase inhibitor GW5074. Analysis of mitochondrial responses in iPSC-derived neural cells from PD patients carrying different mutations provides insight into convergence of cellular disease mechanisms between different familial forms of PD and highlights the importance of oxidative stress and mitochondrial dysfunction in this neurodegenerative disease.     

Rise in ICD Shock Impedance: Lead Fracture or Death?

Background: Remote monitoring allows for interrogation and extensive data retrieval of implantable cardioverter-defibrillators (ICDs). Data on ICD parameters at the time of death and afterwards are limited. The purpose of this retrospective study was to examine the changes in lead impedances of ICDs at the time of death and afterwards. Methods: A total of 37 Biotronik (SE & CO. KG, Berlin, Germany) ICDs (20 ICD-cardiac resynchronization therapy, 16 dual-chamber ICDs, and one single-chamber ICD), retrieved after death, were interrogated. Stored intracardiac electrograms were analyzed to determine the cause of death. Impedance trend curves of shock and pacing lead impedances were analyzed and correlated retrospectively with the reported time of death. The influence of cold exposure on lead impedances was tested in three other single-chamber Biotronik ICDs. Results: Of 37 patients, the cause of death was due to ventricular tachyarrhythmias in 21 patients. In 12 patients, death was not arrhythmia-related. In four patients, the cause of death could not be determined due to overwriting of the episodes at the time of death. A significant increase of shock and pacing lead impedances was observed in the postmortem days (P < 0.001 for all lead impedances). All lead impedance values increased significantly within the first postmortem day (P < 0.001 for all lead impedances). Cold exposure decreased shock lead impedance but did not affect pacing lead impedance. Conclusion: Postmortem analysis of ICDs allows tracking of lead impedance changes, which correlate with the day of death. The rise in postmortem impedances should not be interpreted as contributing to the mode of death. (PACE 2012; 35:1103-1110).     

Histological analysis of clipped human intracranial aneurysms and parent arteries with short-term follow-up

BackgroundSurgical clipping of intracranial aneurysms is the gold standard for the prevention of rupture. However, the biological processes that occur following clipping are poorly understood. To better understand these effects, retrieved and clipped human intracranial aneurysms were examined histologically.MethodsAt autopsy, 17 aneurysms from 10 patients were retrieved 3–21 days after clipping. The tissues were embedded in paraffin, and microtome sections were stained using hematoxylin–eosin and Movat pentachrome. Using light microscopy, clip placement relative to the internal elastic lamina of the parent artery, endothelialization of the aneurysm neck, thrombus organization inside the aneurysm sac, inflammation in the sac, wall, and parent artery, and atherosclerotic changes were determined.ResultsDespite complete reconstruction of the artery with the clip, diseased vessel wall was frequently observed outside the clip. By 10 days postsurgery, the beginnings of endothelialization and neointima formation were observed at the neck. However, the neck coverage was variable and incomplete at these early time points. Thrombus organization inside the aneurysm sac was rarely observed, and inflammatory cells were not present inside the aneurysm sac. Inflammatory cells were commonly observed in the aneurysm wall, and atherosclerotic change was present in each sample.ConclusionsComplete aneurysm exclusion and apposition of healthy arterial wall occurred infrequently in our series. Endothelialization and neointima formation at the aneurysm neck take some time to complete and are often incomplete. The effectiveness of aneurysm clipping is related to the mechanics of aneurysm exclusion rather than the processes of endothelialization and neointima formation.SummaryComplete aneurysm exclusion and apposition of healthy arterial wall occurred infrequently in our series. Endothelialization and neointima formation at the aneurysm neck take some time to complete and are often incomplete. The effectiveness of aneurysm clipping is related to the mechanics of aneurysm exclusion rather than the processes of endothelialization and neointima formation.     

Experimental spectro-angular mapping of light distribution in turbid media

We present a new approach to the analysis of radiance in turbid media. The approach combines data from spectral, angular and spatial domains in a form of spectro-angular maps. Mapping provides a unique way to visualize details of light distribution in turbid media and allows tracking changes with distance. Information content of experimental spectro-angular maps is verified by a direct comparison with simulated data when an analytical solution of the radiative transfer equation is used. The findings deepen our understanding of the light distribution in a homogenous turbid medium and provide a first step toward applying the spectro-angular mapping as a diagnostic tool for tissue characterization.