Postural responses to multidirectional stance perturbations in cerebellar ataxia

Previous studies of patients with focal cerebellar damage underscored the importance of the cerebellum for balance control. These studies were restricted to postural control in the pitch plane, and focused mainly on leg muscle responses. Here, we examined the effect of degenerative cerebellar lesions on postural control in multiple directions, and studied how such lesions affect intersegmental coordination of the legs, trunk and arms. We formulated two main questions. (a) Do patients with cerebellar ataxia predominantly have balance problems in the sagittal or frontal planes? (b) Is instability in cerebellar ataxia associated with increased joint motion or with reduced joint motion? We selected nine patients with autosomal dominant spinocerebellar ataxia (SCA)--three with pure ataxia and six with mild extra-cerebellar features--and 12 matched controls. Upright standing subjects received support surface rotations (7.5 degrees at 60 degrees /s) that were randomly delivered in eight different directions of pitch or roll. We used full body kinematics to determine displacements of the center of mass (COM) and of individual body segments. We also collected surface EMG from 10 leg, trunk and arm muscles. Primary variables of interest were COM displacement and trunk control (angles and muscle responses). Secondary analyses focused on angles and muscle responses of the legs and arms. COM analysis demonstrated that SCA patients had greatest instability following backward and laterally directed perturbations. Major factors in causing this instability were, first, a marked reduction of stimulus-induced knee flexion and, second, excessive "hypermetric" motion of the pelvis (in roll) and trunk (in pitch). Muscle responses of SCA patients were characterized by increased late balance correcting activity. Responses of patients with pure ataxia were comparable to those of patients with mild extra-cerebellar features. A main underlying cause of postural instability in SCA patients appears to be "locking" of the knees, which may reflect compensation (by reducing interaction between body links) or reduced vestibulocerebellar control over leg muscles. The observed pathophysiology is very different from that seen in other patient populations.     

Repetitive transcranial magnetic stimulation to improve mood and motor function in Parkinson's disease

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that can produce lasting changes in excitability and activity in cortical regions underneath the stimulation coil (local effect), but also within functionally connected cortical or subcortical regions (remote effects). Since the clinical presentation of Parkinson's disease (PD) is related to abnormal neuronal activity within the basal ganglia and cortical regions, including the primary motor cortex, the premotor cortex and the prefrontal cortex, several studies have used rTMS to improve brain function in PD. Here, we review the studies that have investigated the possible therapeutic effects of rTMS on mood and motor function in PD patients. We highlight some methodological inconsistencies and problems, including the difficulty to define the most effective protocol for rTMS or to establish an appropriate placebo condition. We finally propose future directions of research that may help to improve the therapeutic efficacy of rTMS in PD.     

Popeye proteins: muscle for the aging sinus node

The electrical impulses that dictate the rhythm of the heartbeat in normal situations and during exercise or stress are initiated by a small number of sinus node pacemaker cells. Senescence and dysfunction of the sinus node affects many people later in life, causing physiologically inappropriate heart rates, but the underlying mechanisms are not well understood. In this issue of the JCI, Froese and colleagues show that deficiency in either Popeye domain containing 1 (Popdc1) or Popdc2 leads to sinus node dysfunction under stressed conditions in aged mice. The mechanism reported to underlie the effects of Popdc1/2 deficiency in mice may cause the stress-induced sinus node dysfunction found in many aged individuals and may point to new strategies for therapeutic intervention.     

Comparison of different risk-adjustment models in assessing short-term surgical outcome after transthoracic esophagectomy in patients with esophageal cancer

Background

Different risk-prediction models have been developed, but none is generally accepted in selecting patients for esophagectomy. This study evaluated 5 most frequently used risk-prediction models, including the American Society of Anesthesiologists, Portsmouth-modified Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (P-POSSUM), and the adjusted version for Oesophagogastric surgery (O-POSSUM), Charlson and the Age adjusted Charlson score to assess postoperative mortality after transthoracic esophagectomy.

Methods

Data were obtained from 278 consecutive esophageal cancer patients between 1991 and 2007. Performance in predicting postoperative mortality (in-hospital and 90-day mortality) were analyzed regarding calibration (Hosmer and Lemeshow goodness-of-fit test) and discrimination (area under the receiver operator curve).

Results

The Hosmer and Lemeshow goodness-of-fit test was applied to each model and showed a significant outcome for only the P-POSSUM score (P = .035). The receiver operator curve indicated discriminatory power for P-POSSUM (.766) and for O-POSSUM (.756), other models did not exceed the minimal surface of .7.

Conclusions

Postoperative mortality after esophagectomy was best predicted by O-POSSUM. However, it still overpredicted postoperative mortality.     

Survival After Stereotactic Body Radiation Therapy for Clinically Diagnosed or Biopsy-Proven Early-Stage NSCLC: A Systematic Review and Meta-Analysis

Introduction

Stereotactic body radiation therapy (SBRT) is a promising curative treatment for early-stage NSCLC. It is unclear if survival outcomes for SBRT are influenced by a lack of pathological confirmation of malignancy and staging of disease in these patients. In this systematic review and meta-analysis, we assess survival outcomes after SBRT in studies with patients with clinically diagnosed versus biopsy-proven early-stage NSCLC.

Next generation sequencing in synovial sarcoma reveals novel gene mutations

Over 95% of all synovial sarcomas (SS) share a unique translocation, t(X;18), however, they show heterogeneous clinical behavior. We analyzed multiple SS to reveal additional genetic alterations besides the translocation. Twenty-six SS from 22 patients were sequenced for 409 cancer-related genes using the Comprehensive Cancer Panel (Life Technologies, USA) on an Ion Torrent platform. The detected variants were verified by Sanger sequencing and compared to matched normal DNAs. Copy number variation was assessed in six tumors using the Oncoscan array (Affymetrix, USA). In total, eight somatic mutations were detected in eight samples. These mutations have not been reported previously in SS. Two of these, in KRAS and CCND1, represent known oncogenic mutations in other malignancies. Additional mutations were detected in RNF213, SEPT9, KDR, CSMD3, MLH1 and ERBB4. DNA alterations occurred more often in adult tumors. A distinctive loss of 6q was found in a metastatic lesion progressing under pazopanib, but not in the responding lesion. Our results emphasize t(X;18) as a single initiating event in SS and as the main oncogenic driver. Our results also show the occurrence of additional genetic events, mutations or chromosomal aberrations, occurring more frequently in SS with an onset in adults.     

Current Perspectives on Aerobic Exercise in People with Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurological disorder characterized by motor and non-motor symptoms for which only symptomatic treatments exist. Exercise is a widely studied complementary treatment option. Aerobic exercise, defined as continuous movement of the body’s large muscles in a rhythmic manner for a sustained period that increases caloric requirements and aims at maintaining or improving physical fitness, appears promising. We performed both a scoping review and a systematic review on the generic and disease-specific health benefits of aerobic exercise for people with PD. We support this by a meta-analysis on the effects on physical fitness (VO₂max), motor symptoms (Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor section), and health-related quality of life (39-item Parkinson’s disease Questionnaire (PDQ-39)). Aerobic exercise has generic health benefits for people with PD, including a reduced incidence of cardiovascular disease, a lower mortality, and an improved bone health. Additionally, there is level 1 evidence that aerobic exercise improves physical fitness (VO₂max) and attenuates motor symptoms (MDS-UPDRS motor section) in the off-medication state, although the long-term effects (beyond 6 months) remain unclear. Dosing the exercise matters: improvements appear to be greater after training at higher intensities compared with moderate intensities. We found insufficient evidence for a beneficial effect of aerobic exercise on health-related quality of life (PDQ-39) and conflicting results regarding non-motor symptoms. Compliance to exercise regimes is challenging for PD patients but may be improved by adding exergaming elements to the training program. Aerobic exercise seems a safe intervention for people with PD, although care must be taken to avoid falls in at-risk individuals. Further studies are needed to establish the long term of aerobic exercise, including a focus on non-motor symptoms and health-related quality of life.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00904-8) contains supplementary material, which is available to authorized users.Key Words: Exercise, Parkinson’s disease, endurance training, locomotion, health-related quality of life, mobility limitation     

A protocol for quantifying cardiogenic oscillations in dynamic 129Xe gas exchange spectroscopy: The effects of idiopathic pulmonary fibrosis

The spectral parameters of hyperpolarized ¹²⁹Xe exchanging between airspaces, interstitial barrier, and red blood cells (RBCs) are sensitive to pulmonary pathophysiology. This study sought to evaluate whether the dynamics of ¹²⁹Xe spectroscopy provide additional insight, with particular focus on quantifying cardiogenic oscillations in the RBC resonance. ¹²⁹Xe spectra were dynamically acquired in eight healthy volunteers and nine subjects with idiopathic pulmonary fibrosis (IPF). ¹²⁹Xe FIDs were collected every 20 ms (T_E = 0.932 ms, 512 points, dwell time = 32 μs, flip angle ≈ 20°) during a 16 s breathing maneuver. The FIDs were pre‐processed using the spectral improvement by Fourier thresholding technique (SIFT) and fit in the time domain to determine the airspace, interstitial barrier, and RBC spectral parameters. The RBC and gas resonances were fit to a Lorentzian lineshape, while the barrier was fit to a Voigt lineshape to account for its greater structural heterogeneity. For each complex resonance the amplitude, chemical shift, linewidth(s), and phase were calculated. The time‐averaged spectra confirmed that the RBC to barrier amplitude ratio (RBC:barrier ratio) and RBC chemical shift are both reduced in IPF subjects. Their temporal dynamics showed that all three ¹²⁹Xe resonances are affected by the breathing maneuver. Most notably, several RBC spectral parameters exhibited prominent oscillations at the cardiac frequency, and their peak‐to‐peak variation differed between IPF subjects and healthy volunteers. In the IPF cohort, oscillations were more prominent in the RBC amplitude (16.8 ± 5.2 versus 9.7 ± 2.9%; P = 0.008), chemical shift (0.43 ± 0.33 versus 0.083 ± 0.05 ppm; P < 0.001), and phase (7.7 ± 5.6 versus 1.4 ± 0.8°; P < 0.001). Dynamic ¹²⁹Xe spectroscopy is a simple and sensitive tool that probes the temporal variability of gas exchange and may prove useful in discerning the underlying causes of its impairment.