Selective serotonin reuptake inhibitors directly signal for apoptosis in biopsy-like Burkitt lymphoma cells

Selective serotonin reuptake inhibitors (SSRIs) are the treatment of choice for clinical depression and a range of anxiety-related disorders. They are well tolerated over extended periods with more than 50 million people worldwide benefiting from their use. Here we show that 3 structurally distinct SSRIs--fluoxetine, paroxetine, and citalopram--act directly on Burkitt lymphoma (BL) cells to trigger rapid and extensive programmed cell death. SSRIs unexpectedly stimulated calcium flux, tyrosine phosphorylation, and down-regulation of the c-myc and nm23 genes in Burkitt lymphoma cells remaining faithful to the biopsy phenotype. Resultant SSRI-induced apoptosis was preceded by caspase activation, poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, DNA fragmentation, a loss of mitochondrial membrane potential, and the externalization of phosphatidylserine, and reversed by the overexpression of bcl-2. Normal peripheral blood mononuclear cells and tonsil B cells, whether resting or stimulated into cycle, were largely resistant to SSRI-induced death as were 5 non-BL lymphoid cell lines tested. We discuss these findings within the context of whether the SSRI class of antidepressants could find future application as potential therapeutics for the highly aggressive and-because of its association with AIDS-increasingly more common Burkitt lymphoma.     

5-Hydroxytryptamine drives apoptosis in biopsylike Burkitt lymphoma cells: reversal by selective serotonin reuptake inhibitors

Serotonin (5-HT), a well-known neurotransmitter of the central nervous system, has been implicated in diverse aspects of immune regulation. Here we show that 5-HT can efficiently drive programmed cell death in established Burkitt lymphoma (BL) lines that remain faithful to the original biopsy phenotype (group 1). Group 1 BL cells cultured in the presence of 5-HT exhibited marked suppression of DNA synthesis that was accompanied by extensive apoptosis-serotonin-driven apoptosis was complete within 24 hours, was preceded by early caspase activation, and was accompanied by a decline in mitochondrial membrane potential. BL cells that had drifted to a lymphoblastic group 3 phenotype were relatively resistant to these actions of serotonin, and the forced ectopic expression of either bcl-2 or bcl-x(L) provided substantial protection from 5-HT-induced apoptosis. 5-HT receptor antagonists (SDZ205-557, granisetron, methysergide) failed to inhibit serotonin-induced apoptosis, whereas the selective serotonin reuptake inhibitors (SSRI)-fluoxetine (Prozac), paroxetine (Paxil), and citalopram (Celexa)-substantially blocked the monoamine actions. Western blot analysis showed that BL cells expressed protein for the 5-HT transporter, and transport assays confirmed active uptake of serotonin by the cells. Unlike what was suggested for neuronal cells, there was no evidence that intracellular oxidative metabolites were responsible for the 5-HT-induced programmed death of BL cells. These data indicate that serotonin drives apoptosis in biopsylike BL cells after its entry through an active transport mechanism, and they suggest a novel therapeutic modality for Burkitt lymphoma.     

Soleus H‐reflex modulation during balance recovery after forward falling

Introduction: Our purpose was to examine the Hoffmann reflex (H‐reflex) during balance recovery after a simulated forward fall from 2 different inclination angles. Methods: The soleus H‐reflex of 15 healthy adults was measured in 2 different leaning positions (exerting a horizontal force at 15% and 30% of body weight, respectively), with no release (Int0) and at 2 different intervals (Int1, Int2) after the release (～45 and ～65 ms, respectively). Results: During Int2, the H‐reflex, which was evoked before the onset of the soleus electromyography, was significantly higher than the H‐reflex induced 20 ms earlier (Int1). No significant difference was observed between Int0 and Int1 and between the 2 leaning positions. Conclusions: These findings indicate that Ia afferent input is facilitated before muscle activation during forward falling. This could be important for the timely activation and increased rate of force development required during this task. Muscle Nerve 54 : 952–958, 2016     

Rapid spontaneous resolution of acute subdural haematoma in a patient with chronic alcoholism

Acute subdural haematoma (ASDH) constitutes one of the most critical emergencies in neurosurgery. There are only several reports that show the rapid disappearance of ASDH without surgical intervention. We report a case of a 64-year-old alcoholic man who had a traumatic subdural haematoma after a fall from a height of about eight meters on level ground. The computed tomography (CT) of the brain on admission demonstrated a left parietooccipital ASDH. A follow-up CT scan after 8 hours showed resolution of the hematoma. The patient was discharged 9 days later with no neurological deficit. We discuss the possible mechanisms of the rapid resolution of the ASDH.     

Lower safety factor for old adults during walking at preferred velocity

Older adults are more prone to falls during walking than young adults, although they walk more slowly and demonstrate higher stability state. This paradox of higher stability state but less safe locomotion let us hypothesize that older people may move closer to their dynamic stability limits. In order to investigate this hypothesis, the present study examined the safety factor of dynamic stability in old and young individuals when walking at their preferred velocity. Twelve older and 12 young male participants walked at their (a) walk-to-run transition velocity (WRV, i.e., maximum capacity) and (b) preferred walking velocity (PWV, i.e., actual applied load). Whole body kinematic data and ground reaction forces were captured. Dynamic stability was assessed using the “margin of stability (MoS)” as a criterion for the stability state of the body (extrapolated center of mass concept). The safety factor was calculated as the ratio between MoS at WRV and MoS at PWV. We found that, although older participants walked slower and provided a higher stability state compared to young ones, they showed a significantly reduced safety factor during preferred walking. This confirmed our hypothesis. Old adults do not walk slowly enough in relation to their maximum walking velocity, resulting to a lower safety factor during normal locomotion. Apparently, the age-related muscle degeneration affects WRV more than PWV. The resulting lower safety factor for the older participants may partly explain the increased risk of falls in their daily life, in spite of slower locomotion.     

Fiber type characterization in skeletal muscle by diffusion tensor imaging

Fiber type distribution within a skeletal muscle, i.e. the quantification of the relative amount of type 1 (slow‐twitching) and type 2 (fast‐twitching) muscle fibers, is of great interest for the monitoring of the effects of training or the treatment of muscle diseases. The purpose of this study was to determine the feasibility of diffusion tensor imaging (DTI) as a tool for noninvasive fiber type quantification in human skeletal muscle. The right calves of 12 healthy volunteers were examined using DTI at 1.5 T. Standard DTI parameters, including fractional anisotropy (FA), and mean, radial and parallel diffusivity (MD, RD and PD, respectively), were determined in the soleus muscle. Fiber type proportion and mean fiber diameter within the soleus muscle were quantified from tissue specimens obtained via a fine needle biopsy. Linear regression analysis tested for associations between DTI and biopsy results. FA values were correlated significantly with fiber type proportion, such that higher FA values indicated a higher proportion of type 1 fibers (R² = 0.5, p = 0.01). This was based on lower diffusivity perpendicular to the main axis of the fiber in subjects with a higher type 1 fiber proportion (RD: R² = 0.52, p = 0.008). MD was also correlated with the proportion of type 1 fibers (R² = 0.37, p = 0.037), whereas PD showed no significant correlation. DTI is a promising method for the noninvasive estimation of fiber type proportion in skeletal muscle. This technique may be used to monitor training effects or may be further developed as a biomarker in certain muscle diseases. Copyright © 2013 John Wiley & Sons, Ltd.     

Interaction of the human body and surfaces of different stiffness during drop jumps

PURPOSE: The purpose of this study was to examine two hypotheses: (a) the stiffness of the surface influences the leg stiffness of the subjects during drop jumps, and (b) drop jumping performance (jumping height and energy rates of the subject's center of mass during the contact phase) increases when decreasing surface stiffness due to a greater energy storage capacity of the surface for a given acting force. METHODS: Ten female subjects performed a series of drop jumps from 40-cm height onto two sprung surfaces with different stiffness. Those trials of each subject displaying the maximal mechanical power during the upward phase were analyzed. The ground reaction forces were measured using a force plate. Sagittal kinematics of the subject's body positions and the deformation of the surface were recorded using two high-speed video cameras. RESULTS: On the soft surface, the jumping height and the energy rates of the subjects during the contact phase were greater than on the hard one. The energy delivered by the subjects during the upward phase, the leg and joint stiffness, as well as the range of motion of the subjects remained unchanged for both surfaces. CONCLUSIONS: The absolute energy loss is lower for the hard surface, but the jumping performance is greater for the soft one. The reason is a higher ratio of positive to negative mechanical work done by the subjects during the contact phase. The adjustment of the subjects to different surfaces is not only dependent on the stiffness of the surface but also on the intensity of the movement.     

Reproducibility of fascicle length and pennation angle of gastrocnemius medialis in human gait in vivo

The purpose of the current study was to examine the reproducibility of fascicle length and pennation angle of gastrocnemius medialis while human walking. To the best of our knowledge, this is the first study of the reproducibility of fascicle length and pennation angle of gastrocnemius medialis in vivo during human gait. Twelve males performed 10 gait trials on a treadmill, in 2 separate days. B-mode ultrasonography, with the ultrasound probe firmly adjusted in the transverse and frontal planes using a special cast, was used to measure the fascicle length and the pennation angle of the gastrocnemius medialis (GM). A Vicon 624 system with three cameras operating at 120 Hz was also used to record the ankle and knee joint angles. The results showed that measurements of fascicle length and pennation angle showed high reproducibility during the gait cycle, both within the same day and between different days. Moreover, the root mean square differences between the repeated waveforms of both variables were very small, compared with their ranges (fascicle length: RMS = ～3 mm, range: 38–63 mm; pennation angle: RMS = ～1.5°, range: 22–32°). However, their reproducibility was lower compared to the joint angles. It was found that representative data have to be derived by a wide number of gait trials (fascicle length ～six trials, pennation angle more than 10 trials), to assure the reliability of the fascicle length and pennation angle in human gait.