This study examined a new model of paclitaxel-induced neuropathic pain and the effects of systemic paclitaxel on the gap junction protein subunit Cx43 and potassium inwardly-rectifying channel Kir4.1 within the dorsal root ganglia. In the new neuropathic pain model, subplantar injections of paclitaxel resulted in decreased conduction velocities of A-beta fiber compound action potentials in the sciatic (5.9%) and tibial nerves (6.8%) as well as in M (10.6%) and H (10.2%) waves. By using repeated recordings it was found that following paclitaxel injection, conduction velocities in the contralateral plantar nerve increased (9.2%). Systemic injections of paclitaxel resulted in reduced Kir4.1 immunolabeling in the dorsal root ganglia compared to vehicle injections. This reduction was observed in total labeling (32.4%) as well as in areas of intense labeling (28.7%). Reductions in overall Cx43 immunolabeling (25%) and area (25%) following systemic paclitaxel injections were not statistically significant. The results of these studies suggest that subplantar injections of paclitaxel can result in reduced peripheral nerve conduction velocities. The results also show that a unilateral neuropathy can result in contralateral changes in conduction velocities. The effects of paclitaxel on reducing Kir4.1 levels suggest that neuropathic pain caused by paclitaxel may share mechanisms in common with other types of neuropathies which show similar changes in Kir4.1 levels.

Atrial Fibrillation (AF) is rare amongst young people whilst epidemic in the elderly. Whilst much is known about the pathophysiology of AF, the mechanisms underlying the vulnerability to AF amongst older people in incompletely understood. Young (< 18 months, first quintile of life) and old (> 8 years, last quintile of life) Welsh mountain sheep were used to investigate changes in atrial electrophysiology with age. Old sheep were more vulnerable to induced AF than young sheep. On the surface ECG, p-wave duration increased with age suggesting increasing atrial size. The corrected sinus node recovery time increased with age, suggesting deteriorating sinus node function. These findings confirmed the validity of sheep as a model for human ageing. In isolated atrial myocytes, action potentials (APs) were recorded using the perforated patch clamp technique. AP duration increased with age, and an increase in AP amplitude was also seen at the lowest stimulation rates. Right atrial AP durations were prolonged compared to those from left atrial myocytes, and the inter-atrial difference was similar between old and young. However, when right atrial monophasic APs were recorded from anaesthetised sheep in vivo, no difference in AP duration was seen between age groups. Alternans occurred at lower stimulation rates in old compared to young myocytes and was of greater magnitude. These age-related differences were present in isolated myocytes and in vivo. Alternans mechanisms were explored by simultaneously recording APs and intracellular calcium concentration. Atrial alternans was driven by alternans of Ca2+ cycling at low stimulation rates. However, despite disabling Ca2+ cycling using thapsigargin, alternans could still be elicited from myocytes during rapid stimulation. Right atrial conduction velocity (CV) was assessed in vivo and found to increase with age. A key determinant of CV, the Na+ current INa was investigated using the whole cell patch clamp technique. INa increased with age in left atrial myocytes and recovered faster from inactivation. Protein expression was investigated using Western blotting. Expression of the Na+ channel α-subunit did not change with age. The gap junction protein Cx43 was expressed less in older subjects, but Cx40 expression was similar. This work has cast light on several aspects of atrial electrophysiology in which the effects of age have not been thoroughly investigated. The longer cellular APs seen with age decrease the wavelength of potential re-entrant circuits which could be seen as protective against AF. However, AP prolongation is also associated with afterdepolarisations which could serve to trigger AF. The increase in alternans behaviour may set the stage for wavebreak, leading to re-entrant circuit formation. The increase in CV was surprising and might be seen as protective against AF as it increases arrhythmia wavelength, and is likely to be caused by the increased INa.

n-Hexane and its metabolites are neurotoxic to animals and man. Studies have revealed a progressive neuropathy which affects the distal regions of motor and sensory peripheral nerves. This paper describes efforts to determine whether 2-hexanone or 2,5-hexanedione is more neurotoxic to rats when given in drinking water. Our results show that 2,5-hexanedione is more neurotoxic than 2-hexanone and that it first affects the distal axon. Concentrations of 20 mM produced no effects after 3 weeks but 40 mM increased distal latency after 2 weeks.

No description available.

Introduktion: Vid perifera nervundersökningar med elektroneurografi spelar temperaturen i vävnaden som undersöks stor roll. Kall vävnad leder till försämrad funktion i nervernas jonkanaler, vilket leder till att aktionspotentialer utlöses långsammare och nervledningshastigheten minskar vilket därmed kan ge falskt patologiska undersökningsresultat. För att minska den risken mäts och korrigeras alltid hudtemperaturen. Vid registrering från övre extremiteter mäts hudtemperaturen standardmässigt på handryggen. Trots att stimulering sker från handflatan och från fingrar så mäts inte temperaturen där. Syftet med studien är därför att undersöka om kalla fingrar på en i övrigt varm hand påverkar conduction velocity och peaklatenstiden, jämfört med när hand och fingrar har samma varma temperatur. Metod: 30 unga, friska personer deltog i studien. Ortodrom elektroneurografiundersökning utfördes på nervus medianus sensoriska del. Handryggstemperaturen var konstant 32° Celsius (C) och fingertoppstemperaturerna var 32° C, 27° C respektive 22° C. Vid varje fingertoppstemperatur registrerades conduction velocity och peaklatenstiden vid stimuleringar från handflatan, fingerbasen och fingertoppen på digitorum III. Resultat: En statistiskt signifikant skillnad fanns i både nervledningshastigheten och peaklatenstiden vid registrering från fingerbasen vid fingertoppstemperaturen 32° C jämfört med såväl 27° C som 22° C. Slutsats: Kalla fingrar på en varm hand ger en statistiskt signifikant påverkan på både nervledningshastigheten och peaklatenstiden. / Background: In peripheral nerve examinations with electroneurography, temperatures in the tissue that is being examined is important. Cold tissue leads to impaired function of the ion channels of the nerves, which causes action potentials to be triggered more slowly and the nerve conduction velocity to decrease, which can cause false pathological examination results. To reduce this risk, the skin temperature is always measured and corrected. When registering from the upper extremities, the skin temperature is measured by default on the back of the hand. Despite stimulating in the palm and on the fingers, the temperature is not measured there. The purpose of the study is to investigate whether cold fingers on a warm hand affects the conduction velocity and peak latency time, compared with the hand and the fingers having the same warm temperature. Methods: 30 young, healthy persons participated in the study. An orthodrome electroneurography examination was performed on the sensory part of the median nerve. The backhand temperature was constant 32° Celsius (C) and the fingertip temperatures were 32 ° C, 27 ° C and 22 ° C. Results: A statistically significant difference was found in both nerve conduction velocity and peak latency time when registering from the finger base with fingertip temperature 32 ° C compared with both 27 ° C and 22 ° C Conclusions: Cold fingers on a warm hand give a statistically significant effect on both the nerve conduction velocity and the peak latency time.

Electrical restitution has been shown to inaccurately predict the occurrence of alternans of action potential duration. A new method using the spatial gradient of alternans (SGA) is proposed to predict alternans and cardiac electrical stability. A simulated 1-D strand of tissue was used to compare indexes computed from restitution methods and the SGA method to changes in the amplitude of alternans using different electro-physiological alterations. The SGA method correlated better with changes in the amplitude of alternans than restitution methods for a decrease in the transient outward current (Ito) and conduction velocity. Restitution methods correlated better with changes in the amplitude of alternans than the SGA method when the inward rectifier potassium current (Ik1) and the delayed rectifier potassium current (Ikr) were decreased. Restitution methods and the SGA method correlated well with changes in the amplitude of alternans when the L-type calcium channel current (ICaL) was altered and when Ikr, Ik1, and the sodium/calcium exchange current (INaCa) were increased. The SGA method includes the effect of conduction in tissue and reveals other features that provide advantages in predicting stability over currently used restitution methods.

Congenital heart defects are the number one cause of birth defect-related deaths. Cardiovascular diseases are the most common cause of death worldwide. Layered cellular sheet constructs offer one very valuable option for cardiac patch implantation during surgical treatment of both pediatric and adult patients with cardiac defects or damage. A very exciting, relatively unexplored, autologous, available cell source for making patches are placenta-derived mesenchymal stem cells (pMSCs). In this study, pMSCs were assessed as a potential cell source for cardiac repair and regeneration by evaluating their differentiation capacity into cardiomyocytes, their effects on cardiac cell migration and proliferation, and their ability to be grown into cell sheets. It was found that pMSC cardiac protein content was enhanced by differentiation media treatment, but no beating cells were produced. Undifferentiated pMSCs improved migration and proliferation of a cardiac cell population and formed intact, aligned cell sheets. However, like many new cell sources for cardiac repair, pMSCs should still be functionally characterized to understand how compatible they will be with resident heart tissue. Implanting non-autologous, potentially pluripotent, non-myocyte (non-beating) cells presents concerns regarding electromechanical mismatch and implant rejection. The characterization of non-traditional cell sources such as pMSCs motivated the design of a bio-MEMS device that assesses contractile force and conduction velocity in response to electrical and mechanical stimulation of a cell source as it is grown and once it forms a cellular sheet. This ideally creates the ability for patient specific cell sheets to be cultured, characterized, and conditioned to be compatible with the patient’s cardiac environment in vitro, prior to implantation. In this work, the device was designed to achieve the following: cellular alignment, electrical stimulation, mechanical stimulation, conduction velocity readout, contraction force readout, and upon characterization, cell sheet release. The platform is based on a set of comb electrical contacts which are three dimensional wall contacts made of polydimethylsiloxane and coated with electrically conductive metals. Device fabrication and initial validation experiments were completed as part of this study; ultimately the device will allow for the complete functional characterization and conditioning of variable cell source cell sheet implants for myocardial implantation. / 2019-07-02T00:00:00Z

No description available.

Gain of function of cardiac voltage-gated sodium channel (Nav1.5) leads to Long QT Syndrome Type 3 (LQT3). LQT3 phenotype can be exacerbated by expanding the perinexus, which is an intercellular nanodomain with high density of Nav1.5 in the intercalated disc. Following this finding, we found that elevating extracellular sodium and widening the perinexus synergistically exacerbated LQT3 phenotype, Importantly, we also found that perinexal expansion increases the susceptibility to cardiac arrest in aged LQT3, which demonstrated that perinexal expansion is an arrhythmogenic risk especially in aged LQT3 patients. Furthermore, we observed that the perinexus narrows with aging and conceals LQT3 phenotype, which suggests that perinexal narrowing may have a cardio-protective role during aging in LQT3. Surprisingly, following the finding of the synergistic effect of extracellular sodium elevation and perinexal widening on LQT3 phenotype in drug-induced LQT3 guinea pig hearts, we found that this synergistic effect was not observed in genetically-modified LQT3 mouse hearts, which is due to high sodium also increasing transient outward potassium current (Ito). In summary, the whole project investigated the role of the perinexus in LQT3 from different conditions including sodium, aging and species. The findings in this project discovered the importance of perinexal expansion in LQT3 and also the involvement of Ito in sodium regulating LQT3 phenotype in hearts which functionally express Ito channels. Therefore, a LQT3 animal model which has similar electrophysiology close to human may be a great option for translational purpose. / Doctor of Philosophy / Long QT Syndrome Type 3 (LQT3) is an inherited heart disease with the phenotype of long QT interval in ECG. It has been found that LQT3 phenotype gets worse when a very tiny space in the heart, termed as the perinexus, is wide due to cardiac edema. Following this finding, we also found that increasing sodium concentration together with wide perinexus can further exacerbate LQT3 phenotype in guinea pig hearts. Furthermore, we found that widening the perinexus in aged LQT3 hearts causes cardiac death but not in adult, which suggests that perinexal widening worsens LQT3 phenotype and even leads to cardiac death in aged hearts. Besides, we found that the perinexus narrows with aging and there is no difference in LQT3 phenotype between adult and aged hearts, which suggests that the narrow perinexus during aging may protect the hearts from cardiac death in LQT3. Surprisingly, we discovered that increasing sodium and widening the perinexus together fails to exacerbate LQT3 phenotype when compared with widening the perinexus alone in LQT3 mouse hearts, which is due to high sodium increasing transient outward potassium current (Ito). Notably, Ito channels are not functionally expressed in guinea pig hearts. In summary, the whole project investigated the role of the perinexus in LQT3 from different conditions including sodium, aging and species. The findings in this project discovered the importance of perinexal expansion in LQT3 and also the involvement of Ito in sodium regulating LQT3 phenotype in hearts. Therefore, a LQT3 animal model which has similar electrophysiology close to human may be a great option for translational purpose.

Smelter workers who were exposed to air-borne arsenic for a mean of 23 years, and age-matched referents, were examined with clinical, physiological, and neurophysiological methods. Exposure to arsenic in workroom air was estimated to have been around the Swedish occupational limits, which were 500 yg/m before 1975 and 50 yg/ra thereafter. An increased preval ence of Raynaud's phenomenon and a reduced finger systolic blood pressure (FSP) during local and general cooling were found in the smelter workers. Slight, but significant sub-clinical neuropathy, in the form of slightly reduced nerve conduction velocity (NCV) in two or more peripheral nerves, was more common among the arsenic workers than among the referents. There were positive correlations between cumulative exposure to arsenic, reduced NCV in three peripheral motor nerves, and decrease in FSP during cooling. Arsenic levels in urine were 1 ymole/1 (75 yg/1) in the arsenic workers and 0.1 ymole/1 in the referents. In 21 arsenic workers with no or very low exposure to vibra ting hand tools, the FSP during cooling had increased significantly after 3 years wit h the lower arsenic exposure. There was no change in FSP during the summer vacation, whereas urinary levels of arsenic decreased to normal values. Thus there seems to be a slow improvement of finger blood circ ulation which is independent of short-term fluctuations in the exposure to arsenic. No seasonal variation was found in FSP during cooling with the standardized method used. When the NCV-measurements were repeated five years later the difference between arsenic workers and referents had increased, despite the fact that 14 of the 47 arsenic workers had had no exposure to arsenic during the last 1-5 years. These observations indicate, that in subjects with long term exposure to arsenic, sub-clinical neuropathy is not reversible. Ten milligrams of Ketanserin, a serotonin receptor antagonist, was given intravenously to five arsenic workers with cold-induced vasospasm. Skin temperature and FSP during cooling increased significantly with Ketanserin as compared wit h saline solution. After oral treatment, 2 x 40 mg /day for four weeks, no significant increase of FSP during cooling or rise in skin temperature was found in six arsenic workers and eleven patients with Raynaud's phenomenon. The decrease of vasospastic tendency after intravenous injection of Ketanserin indicated that similar mechanisms might operate in arsenic-induced and other types of Raynaud's phenomenon. A general co nclusion from the five studies in this dissertation is that long-term occupational exposure to arsenic has had adverse effects on the peripheral circulation and nerve conduction. The tendency to vasospasm, but not the sub-clinical neuropathy, seemed to be reversible with decreasing exposure. / <p>S. 1-54: sammanfattning, s. 55-112: 5 uppsatser</p> / digitalisering@umu