Metabolic and Renal Effects of Mammalian Target of Rapamycin Inhibitors Treatment After Liver Transplantation: Real-Life Single-Center Experience.

BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors following liver transplantation (LT) are used to minimize calcineurin inhibitor (CNI)-related nephrotoxicity. Data about metabolic effects of mTOR inhibitors are still limited. AIM: This study aims to determine the renal and metabolic effects of different mTOR inhibitor-based protocols in real-life LT patients. METHODS: This is a retrospective cohort study of patients treated with mTOR inhibitors after LT. Demographics, treatment protocols, glomerular filtration rate (GFR), and metabolic parameters were collected over a period of 4 years. Initiation of blood pressure (BP), diabetes mellitus, and lipid medications was also noted. RESULTS: Fifty-two LT recipients received mTOR inhibitors. GFR improved significantly (by 1.96 mL/min/year), with greater improvement in patients with baseline renal dysfunction (+13.3 mL/min vs +4.5 mL/min at 3 years). Conversion to an mTOR inhibitor during the first post-transplant year resulted in a more durable improvement in GFR (for 4 years vs only 1 year for later conversion).No significant weight gain or new-onset diabetes mellitus was observed. However, there was some increase in total cholesterol (+7 mg/dL) and blood pressure (+2 mm Hg during the third year and +8 mm Hg in the fourth years), followed by initiation of lipid-lowering and BP medications in 25% and 13% of patients, respectively. CONCLUSIONS: Treatment with an mTOR inhibitor following LT resulted in improved kidney functions without significant negative metabolic effects such as weight gain or new-onset diabetes mellitus. This makes mTOR inhibitors a valuable immunosuppressive option in the face of the growing incidence of nonalcoholic steatohepatitis as a leading cause for LT.

Action Observation of Motor Skills Followed by Immediate Sleep Enhances the Motor Rehabilitation of Older Adults With Stroke.

BACKGROUND AND PURPOSE: Motor rehabilitation following stroke is a demanding challenge in search for new strategies to improve outcome. Rehabilitation through action observation has been reported beneficial for older adults recovering from stroke. Early sleep session following motor learning enhanced the performance of the acquired motor skills. The purpose of this study was to examine whether an early sleep session following action observation has benefit over action observation alone in the rehabilitation of older adults after stroke. METHODS: Twenty patients with paresis of dominant upper limb in first ischemic stroke were assigned to 2 study groups (10 subjects each). The participants were presented a 5-minute video film of phone operation. Participants of the intervention group had a sleep session of 90 to 120 minutes immediately following the film while control participants did not sleep. Identical procedure was repeated for 4 consecutive sessions (4 weeks). A single item of the Chedoke Arm and Hand Activity Inventory was used as rehabilitation's outcome measure. RESULTS: During the 4 weeks of the study, the performances of both groups improved but the intervention group had higher Chedoke Arm and Hand Activity Inventory scores, as indicated by a significant session by group interaction (P < .001). CONCLUSIONS: An early sleep session added to action observation therapy may significantly improve motor performances of patients with stroke. Further studies are required to support this method for inclusion in rehabilitation arsenal.

Empirical validation of statistical parametric mapping for group imaging of fast neural activity using electrical impedance tomography.

Electrical impedance tomography (EIT) allows for the reconstruction of internal conductivity from surface measurements. A change in conductivity occurs as ion channels open during neural activity, making EIT a potential tool for functional brain imaging. EIT images can have >10 000 voxels, which means statistical analysis of such images presents a substantial multiple testing problem. One way to optimally correct for these issues and still maintain the flexibility of complicated experimental designs is to use random field theory. This parametric method estimates the distribution of peaks one would expect by chance in a smooth random field of a given size. Random field theory has been used in several other neuroimaging techniques but never validated for EIT images of fast neural activity, such validation can be achieved using non-parametric techniques. Both parametric and non-parametric techniques were used to analyze a set of 22 images collected from 8 rats. Significant group activations were detected using both techniques (corrected p < 0.05). Both parametric and non-parametric analyses yielded similar results, although the latter was less conservative. These results demonstrate the first statistical analysis of such an image set and indicate that such an analysis is an approach for EIT images of neural activity.

Functional hyposplenism is an important and underdiagnosed immunodeficiency condition in children.

AIM: Few studies have focused on paediatric hyposplenism/asplenism, in which splenic phagocytic activity is diminished or absent in an anatomically present spleen. This study aimed to evaluate clinical findings, laboratory tests and prognosis of children with functional hyposplenism/asplenism. METHODS: The study group comprised 74 children who had liver/spleen technetium-99m sulphur colloid scintigraphy from 2002 to 2008. Information collected included demographic features, background diseases, blood smear findings, indications for scintigraphy and outcome. Children with functional hyposplenism were followed until 2012. RESULTS: We found that 34 patients had functional hyposplenism/asplenism. The main indications for scintigraphy in the hyposplenic patients were persistent thrombocytosis and recurrent infections. Associated conditions included immunodeficiencies, autoimmune diseases, malignancies and genetic disorders. Main infections were sinopulmonary infections, bacteraemia and sepsis. The major pathogens were Streptococcus pneumoniae and Haemophilus influenza group A. There was no correlation between the presence of Howell-Jolly bodies in blood smear with clinical disease severity or scintigraphic findings. Repeated scintigraphy showed spontaneous normalisation in 40% of patients. CONCLUSION: Functional hyposplenism is an important and underdiagnosed immunodeficiency condition in children, associated with various clinical conditions including prolonged unexplained thrombocytosis, immune deficiency and autoimmunity. Technetium-99m sulphur colloid scintigraphy is the method of choice for evaluating splenic function.

A novel method for recording neuronal depolarization with recording at 125-825 Hz: implications for imaging fast neural activity in the brain with electrical impedance tomography.

Electrical impedance tomography (EIT) is a recently developed medical imaging method which has the potential to produce images of fast neuronal depolarization in the brain. Previous modelling suggested that applied current needed to be below 100 Hz but the signal-to-noise ratio (SNR) recorded with scalp electrodes during evoked responses was too low to permit imaging. A novel method in which contemporaneous evoked potentials are subtracted is presented with current applied at 225 Hz to cerebral cortex during evoked activity; although the signal is smaller than at DC by about 10×, the principal noise from the EEG is reduced by about 1000×, resulting in an improved SNR. It was validated with recording of compound action potentials in crab walking leg nerve where peak changes of -0.2% at 125 and 175 Hz tallied with biophysical modelling. In recording from rat cerebral cortex during somatosensory evoked responses, peak impedance decreases of -0.07 ± 0.006% (mean ± SE) with a SNR of >50 could be recorded at 225 Hz. This method provides a reproducible and artefact free means for recording resistance changes during neuronal activity which could form the basis for imaging fast neural activity in the brain.

A method for removing artefacts from continuous EEG recordings during functional electrical impedance tomography for the detection of epileptic seizures.

Electrical impedance tomography (EIT) is a portable, non-invasive medical imaging method, which could be employed to image the seizure onset in subjects undergoing assessment prior to epilepsy surgery. Each image is obtained from impedance measurements conducted with imperceptible current at tens of kHz. For concurrent imaging with video electroencephalogram (EEG), the EIT introduces a substantial artefact into the EEG due to current switching at frequencies in the EEG band. We present here a method for its removal, so that EIT and the EEG could be acquired simultaneously. A low-pass analogue filter for EEG channels (-6 dB at 48 Hz) and a high-pass filter (-3 dB at 72 Hz) for EIT channels reduced the artefact from 2-3 mV to 50-300 microV, but still left a periodic artefact at about 3 Hz. This was reduced to less than 10 microV with a software filter, which subtracted an artefact template from the EEG raw traces. The EEG was made clinically acceptable at four times its acquisition speed. This method could enable EIT to become a technique for imaging on telemetry units alongside EEG, without interfering with routine EEG reporting.

Non-invasive baroreflex sensitivity assessment using wavelet transfer function-based time-frequency analysis.

A novel approach for the estimation of baroreflex sensitivity (BRS) is introduced based on time-frequency analysis of the transfer function (TF). The TF method (TF-BRS) is a well-established non-invasive technique which assumes stationarity. This condition is difficult to meet, especially in cardiac patients. In this study, the classical TF was replaced with a wavelet transfer function (WTF) and the classical coherence was replaced with wavelet transform coherence (WTC), adding the time domain as an additional degree of freedom with dynamic error estimation. Error analysis and comparison between WTF-BRS and TF-BRS were performed using simulated signals with known transfer function and added noise. Similar comparisons were performed for ECG and blood pressure signals, in the supine position, of 19 normal subjects, 44 patients with a history of previous myocardial infarction (MI) and 45 patients with chronic heart failure. This yielded an excellent linear association (R > 0.94, p < 0.001) for time-averaged WTF-BRS, validating the new method as consistent with a known method. The additional advantage of dynamic analysis of coherence and TF estimates was illustrated in two physiological examples of supine rest and change of posture showing the evolution of BRS synchronized with its error estimations and sympathovagal balance.

A modelling study to inform specification and optimal electrode placement for imaging of neuronal depolarization during visual evoked responses by electrical and magnetic detection impedance tomography.

Electrical impedance tomography (EIT) has the potential to achieve non-invasive functional imaging of fast neuronal activity in the human brain due to opening of ion channels during neuronal depolarization. Local changes of resistance in the cerebral cortex are about 1%, but the size and location of changes recorded on the scalp are unknown. The purpose of this work was to develop an anatomically realistic finite element model of the adult human head and use it to predict the amplitude and topography of changes on the scalp, and so inform specification for an in vivo measuring system. A detailed anatomically realistic finite element (FE) model of the head was produced from high resolution MRI. Simulations were performed for impedance changes in the visual cortex during evoked activity with recording of scalp potentials by electrodes or magnetic flux density by magnetoencephalography (MEG) in response to current injected with electrodes. The predicted changes were validated by recordings in saline filled tanks and with boundary voltages measured on the human scalp. Peak changes were 1.03 +/- 0.75 microV (0.0039 +/- 0.0034%) and 27 +/- 13 fT (0.2 +/- 0.5%) respectively, which yielded an estimated peak signal-to-noise ratio of about 4 for in vivo averaging over 10 min and 1 mA current injection. The largest scalp changes were over the occipital cortex. This modelling suggests, for the first time, that reproducible changes could be recorded on the scalp in vivo in single channels, although a higher SNR would be desirable for accurate image production. The findings suggest that an in vivo study is warranted in order to determine signal size but methods to improve SNR, such as prolonged averaging or other signal processing may be needed for accurate image production.

Impedance changes recorded with scalp electrodes during visual evoked responses: implications for Electrical Impedance Tomography of fast neural activity.

Electrical Impedance Tomography (EIT) is a recently developed medical imaging method which could enable fast neural imaging in the brain by recording the resistance changes which occur as ion channels open during neuronal depolarization. In published studies in animal models with intracranial electrodes, changes of 0.005 to 3% have been reported but the amplitude of changes in the human is not known. The purpose of this work was to determine if resistance changes could be recorded non-invasively in humans during evoked activity which could form the basis for EIT of fast neural activity. Resistance was recorded with scalp electrodes during 2 Hz pattern visual evoked responses over 10 min using an insensible 1 Hz square wave constant current of 0.1-1 mA. Significant resistance decreases of 0.0010+/-0.0005% (0.30+/-0.15 microV, signal-to-noise ratio (SNR) of 2:1, n=16 recordings over 6 subjects) (mean+/-SE) were recorded. These are in broad agreement with modelling which estimated changes of 0.0039+/-0.0034% (1.03+/-0.75 microV) using an anatomically realistic finite element model. This is the first demonstration of such changes in humans and so encourages the belief that EIT could be used for neural imaging. Unfortunately, the signal-to-noise ratio was not sufficient to permit imaging at present because recording over multiple injection sites needed for imaging would require impractically long recording times. However, in the future, invasive imaging with intracranial electrodes in animal models or humans and improved signal processing or recording may still enable imaging; this would constitute a significant advance in neuroscience technology.

Design of electrodes and current limits for low frequency electrical impedance tomography of the brain.

For the novel application of recording of resistivity changes related to neuronal depolarization in the brain with electrical impedance tomography, optimal recording is with applied currents below 100 Hz, which might cause neural stimulation of skin or underlying brain. The purpose of this work was to develop a method for application of low frequency currents to the scalp, which delivered the maximum current without significant stimulation of skin or underlying brain. We propose a recessed electrode design which enabled current injection with an acceptable skin sensation to be increased from 100 muA using EEG electrodes, to 1 mA in 16 normal volunteers. The effect of current delivered to the brain was assessed with an anatomically realistic finite element model of the adult head. The modelled peak cerebral current density was 0.3 A/m(2), which was 5 to 25-fold less than the threshold for stimulation of the brain estimated from literature review.

Phase-averaged characterization of respiratory sinus arrhythmia pattern.

A method for the accurate time-domain characterization of respiratory sinus arrhythmia (RSA) pattern is presented and applied to two groups of healthy subjects to lay the baseline of RSA patterns and to underlay their features: response to standing, stability in successive recordings, and individuality of the shape of RSA pattern. RSA pattern is evaluated by selective averaging of heart rate (HR) changes from multiple respiratory cycles over the respiratory phase and represents the complete modulating function of HR by respiration. The RSA pattern is evaluated with free respiration and even in cases of severe arrhythmia. Estimation error is 6-8% in magnitude, phase resolution is 0.2 rad, and sensitivity margin for respiratory-related HR variability (HRV) components is 1%. RSA magnitude, phase lag, and expiration-to-inspiration time ratio are derived in addition to the entire pattern. In a group of 10 healthy young adults, a phase lag difference of 11.4 +/- 8.5% (mean +/- SD, P < 0.004) was observed between supine and standing postures, possibly ascribed to breathing mechanics. A second group of 15 healthy young adults at supine rest showed stability of the RSA pattern in successive recordings (several weeks apart) as well as individuality among subjects. This may suggest a nonscalar individual long-term index for cardiorespiratory coupling. The method is complementary to the existing statistical and spectral methods. It allows the complete characterization of the primary RSA components and may provide new insight into the effects of vagal activity and changes in clinical conditions.

A Herpesvirus Associated with Mass Mortality of Juvenile and Adult Koi, a Strain of Common Carp.

A herpesvirus was isolated from adult koi, a strain of common carp Cyprinus carpio, suffering mass mortality in two outbreaks-one in the mid-Atlantic region of the United States and the second in Israel. The principal external signs of dying fish were pale and irregularly colored gills. There were few consistent internal signs in either outbreak. The most prominent microscopic lesions were in the gills, where hyperplasia and necrosis of the epithelium were severe. Other lesions included interstitial nephritis, splenitis, and enteritis. Affected cells often contained nuclei with marginated chromatin and faint intranuclear inclusions. Typical herpesvirus particles were present in branchial epithelial cells, hepatocytes, and among circulating leukocytes. Inoculations of the koi fin (KF-1) cell line with tissue extracts from the gill and kidney-spleen resulted in cytopathic effects characterized by severe vacuolation first detected after 7 d incubation at 20°C. Exposures of adult koi to the herpesvirus as propagated in KF-1 cells by bath or intraperitoneal injections resulted in 80-100% mortality during a 26-d period, and the virus was reisolated from the gill, kidney, liver, spleen, intestine, and brain of dead fish. The viral agents from koi in Israel and the United States appear to be similar if not identical; both could be distinguished from Herpesvirus cyprini by indirect fluorescent antibody tests with rabbit anti-H. cyprini serum. Other factors should be examined but we strongly suspect that this newly recognized koi herpesvirus (KHV) has the potential to be a significant cause of mortality among koi and presumably common carp.

Presbycusis: the aging ear. Part I.

The aging ear is a particularly vexing problem. This review of the literature covers much of the pertinent information and leads to some suggested research which we hope to pursue. It seems to us that research directed toward increased knowledge of the auditory blood supply and a better understanding of the function of the stria vascularis will add much to our understanding of the aging ear.