Directional Deep Brain Stimulation for Parkinson's Disease: Results of an International Crossover Study With Randomized,Double-Blind Primary Endpoint

ObjectivePublished reports on directional deep brain stimulation (DBS) have been limited to small, single-center investigations. Therapeutic window (TW) is used to describe the range of stimulation amplitudes achieving symptom relief without side effects. This crossover study performed a randomized double-blind assessment of TW for directional and omnidirectional DBS in a large cohort of patients implanted with a DBS system in the subthalamic nucleus for Parkinson's disease.Materials and MethodsParticipants received omnidirectional stimulation for the first three months after initial study programming, followed by directional DBS for the following three months. The primary endpoint was a double-blind, randomized evaluation of TW for directional vs omnidirectional stimulation at three months after initial study programming. Additional data recorded at three- and six-month follow-ups included stimulation preference, therapeutic current strength, Unified Parkinson's Disease Rating Scale (UPDRS) part III motor score, and quality of life.ResultsThe study enrolled 234 subjects (62 ± 8 years, 33% female). TW was wider using directional stimulation in 183 of 202 subjects (90.6%). The mean increase in TW with directional stimulation was 41% (2.98 ± 1.38 mA, compared to 2.11 ± 1.33 mA for omnidirectional). UPDRS part III motor score on medication improved 42.4% at three months (after three months of omnidirectional stimulation) and 43.3% at six months (after three months of directional stimulation) with stimulation on, compared to stimulation off. After six months, 52.8% of subjects blinded to stimulation type (102/193) preferred the period with directional stimulation, and 25.9% (50/193) preferred the omnidirectional period. The directional period was preferred by 58.5% of clinicians (113/193) vs 21.2% (41/193) who preferred the omnidirectional period.ConclusionDirectional stimulation yielded a wider TW compared to omnidirectional stimulation and was preferred by blinded subjects and clinicians.     

Differential risks for adverse outcomes 3 years after kidney transplantation based on initial immunosuppression regimen: a national study

We examined integrated national transplant registry, pharmacy fill, and medical claims data for Medicare‐insured kidney transplant recipients in 2000–2011 (n = 45 164) from the United States Renal Data System to assess the efficacy and safety endpoints associated with seven early (first 90 days) immunosuppression (ISx) regimens. Risks of clinical complications over 3 years according to IS regimens were assessed with multivariate regression analysis, including the adjustment for covariates and propensity for receipt of a nonreference ISx regimen. Compared with the reference ISx (thymoglobulin induction with tacrolimus, mycophenolate, and prednisone maintenance), sirolimus‐based ISx was associated with significantly higher three‐year risks of pneumonia (adjusted hazard ratio, aHR 1.45; P < 0.0001), sepsis (aHR 1.40; P < 0.0001), diabetes (aHR 1.21; P < 0.0001), acute rejection (AR; adjusted odds ratio, aOR 1.33; P < 0.0001), graft failure (aHR 1.78; P < 0.0001), and patient death (aHR 1.40; P < 0.0001), but reduced skin cancer risk (aHR 0.71; P < 0.001). Cyclosporine‐based IS was associated with increased risks of pneumonia (aHR 1.17; P < 0.001), sepsis (aHR 1.16; P < 0.001), AR (aOR 1.43; P < 0.001), and graft failure (aHR 1.39; P < 0.001), but less diabetes (aHR 0.83; P < 0.001). Steroid‐free ISx was associated with the reduced risk of pneumonia (aHR 0.89; P = 0.002), sepsis (aHR 0.80; P < 0.001), and diabetes (aHR 0.77; P < 0.001), but higher graft failure (aHR 1.35; P < 0.001). Impacts of ISx over time warrant further study to better guide ISx tailoring to balance the efficacy and morbidity.     

Podocyte Purinergic P2X4 Channels Are Mechanotransducers That Mediate Cytoskeletal Disorganization

Podocytes are specialized, highly differentiated epithelial cells in the kidney glomerulus that are exposed to glomerular capillary pressure and possible increases in mechanical load. The proteins sensing mechanical forces in podocytes are unconfirmed, but the classic transient receptor potential channel 6 (TRPC6) interacting with the MEC-2 homolog podocin may form a mechanosensitive ion channel complex in podocytes. Here, we observed that podocytes respond to mechanical stimulation with increased intracellular calcium concentrations and increased inward cation currents. However, TRPC6-deficient podocytes responded in a manner similar to that of control podocytes, and mechanically induced currents were unaffected by genetic inactivation of TRPC1/3/6 or administration of the broad-range TRPC blocker SKF-96365. Instead, mechanically induced currents were significantly decreased by the specific P2X purinoceptor 4 (P2X₄) blocker 5-BDBD. Moreover, mechanical P2X₄ channel activation depended on cholesterol and podocin and was inhibited by stabilization of the actin cytoskeleton. Because P2X₄ channels are not intrinsically mechanosensitive, we investigated whether podocytes release ATP upon mechanical stimulation using a fluorometric approach. Indeed, mechanically induced ATP release from podocytes was observed. Furthermore, 5-BDBD attenuated mechanically induced reorganization of the actin cytoskeleton. Altogether, our findings reveal a TRPC channel-independent role of P2X₄ channels as mechanotransducers in podocytes.     

Perioperative Complications After Living Kidney Donation: A National Study

We integrated the US transplant registry with administrative records from an academic hospital consortium (97 centers, 2008–2012) to identify predonation comorbidity and perioperative complications captured in diagnostic, procedure, and registry sources. Correlates (adjusted odds ratio, aOR) of perioperative complications were examined with multivariate logistic regression. Among 14 964 living kidney donors, 11.6% were African American. Nephrectomies were predominantly laparoscopic (93.8%); 2.4% were robotic and 3.7% were planned open procedures. Overall, 16.8% of donors experienced a perioperative complication, most commonly gastrointestinal (4.4%), bleeding (3.0%), respiratory (2.5%), surgical/anesthesia‐related injuries (2.4%), and “other” complications (6.6%). Major Clavien Classification of Surgical Complications grade IV or higher affected 2.5% of donors. After adjustment for demographic, clinical (including comorbidities), procedure, and center factors, African Americans had increased risk of any complication (aOR 1.26, p = 0.001) and of Clavien grade II or higher (aOR 1.39, p = 0.0002), grade III or higher (aOR 1.56, p < 0.0001), and grade IV or higher (aOR 1.56, p = 0.004) events. Other significant correlates of Clavien grade IV or higher events included obesity (aOR 1.55, p = 0.0005), predonation hematologic (aOR 2.78, p = 0.0002) and psychiatric (aOR 1.45, p = 0.04) conditions, and robotic nephrectomy (aOR 2.07, p = 0.002), while annual center volume >50 (aOR 0.55, p < 0.0001) was associated with lower risk. Complications after live donor nephrectomy vary with baseline demographic, clinical, procedure, and center factors, but the most serious complications are infrequent. Future work should examine underlying mechanisms and approaches to minimizing the risk of perioperative complications in all donors.     

Three‐month pancreas graft function significantly influences survival following simultaneous pancreas‐kidney transplantation in type 2 diabetes patients

Successful simultaneous pancreas‐kidney transplantation (SPK) improves quality‐of‐life and prolongs kidney allograft and patient survival in type‐1 diabetic (T1DM) patients. However, the use of SPK in type‐2 diabetic (T2DM) patients remains limited. We examined a national transplant registry for 35 849 T2DM kidney disease patients who received transplant between 2000 and 2016 and survived the first 3 months with a functioning kidney, and categorized as: deceased‐donor kidney transplant alone (DD‐KA, 68%), living‐donor kidney transplant alone (LD‐KA, 30%), or SPK (2%). Among SPK recipients, 6% had pancreas allograft failure within 3 months (SPK,P‐) and 94% had a functional pancreas (SPK,P+). Associations of transplant type with kidney allograft failure and death (multivariable‐adjusted hazard ratio, _95%LCLaHR_95%UCL), over follow‐up through December 2018, were quantified by multivariable inverse probability of treatment weighted survival analyses. SPK recipients had better kidney graft and patient survival than LD‐KA or DD‐KA recipients. Compared to SPK,P+, DD‐KA, or LD‐KA recipients had significantly higher risk of kidney allograft failure (DD‐KA: aHR _1.532.20_3.17; LD‐KA: aHR _1.291.87_2.71) and death (DD‐KA: aHR _2.123.25_5.00; LD‐KA: aHR _1.542.35_3.59). SPK,P‐ recipients had significantly higher risk of death (aHR _1.683.30_6.50). Similar to T1DM, T2DM patients with SPK have a survival benefit compared to those with kidney transplant alone, but this benefit depends upon successful early pancreas function.     

Rapid mapping of finger representations in human primary somatosensory cortex applying neuromagnetic steady-state responses

We analyzed somatosensory evoked steady-state fields in order to localize finger representations in the hand area of the primary somatosensory cortex (S1). Using a 122-channel whole-head neuromagnetometer we recorded in six healthy subjects neuromagnetic responses to high frequency electrical stimuli delivered simultaneously to digit I, II, III and V at 22, 24, 27 and 30 Hz, respectively, and to transient stimulation of each single digit with a frequency of 3 Hz. Responses were averaged separately for each digit and were modeled by single equivalent current dipoles. Both conditions yielded the typical somatotopic finger representations within S1 hand area. Dipole locations did not differ significantly between the transient and the steady-state stimulation. Therefore, simultaneous high-frequency stimulation of the digits seems to be a reliable method for rapid and detailed mapping of the S1 hand area. This procedure has potential advantages over recording of transient responses. With simultaneous steady-state stimulation the measurement times are reduced to 2 min for mapping the whole hand area. Because of this our method probably increases spatial accuracy and permits repeated short interval recordings, e.g. in experiments studying short term plasticity.     

Neuromagnetic correlates of sensorimotor synchronization

Sensorimotor synchronization tasks, in which subjects have to tap their finger in synchrony with an isochronous auditory click, typically reveal a synchronization error with the tap preceding the click by about 20 to 50 msec. Although extensive behavioral studies and a number of different explanatory accounts have located the cause of this so-called "negative asynchrony" on different levels of processing, the underlying mechanisms are still not completely understood. Almost nothing is known about the central processes, in particular, which sensory or motor events are synchronized by subjects. The present study examined central-level processing in synchronization tasks with magnetoencephalography (MEG). Eight subjects synchronized taps with their right index finger to an isochronous binaural pacing signal presented at an interstimulus interval of 800 msec. To gain information on central temporal coupling between "tap" and "click," evoked responses were averaged time-locked to the auditory signal and the tap onset. Tap-related responses could be explained with a three dipole model: One source, peaking at approximately 77 msec before tap onset, was localized in contralateral primary motor cortex (MI); the two other sources, peaking approximately at tap onset and 75 msec after tap onset, in contralateral primary somatosensory cortex (SI). Temporal coupling of these sources was compared in relation to different trigger points. The second SI source was equally well time-locked to the tap and to the auditory click. Furthermore, analysis of the time locking of this source activity as a function of the temporal order of tap and click showed that the second event - irrespective whether tap or click - was decisive in triggering the second SI source. This suggests that subjects use mainly sensory feedback in judging and evaluating whether they are "keeping time."