Antidepressants, but not antipsychotics, modulate GR function in human whole blood: an insight into molecular mechanisms.

Clinical studies have demonstrated an impairment of glucocorticoid receptor (GR)-mediated negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis in patients with major depression (GR resistance), and its resolution by antidepressant treatment. Recently, we showed that this impairment is indeed due to a dysfunction of GR in depressed patients (Carvalho et al., 2009), and that the ability of the antidepressant clomipramine to decrease GR function in peripheral blood cells is impaired in patients with major depression who are clinically resistant to treatment (Carvalho et al. 2008). To further investigate the effect of antidepressants on GR function in humans, we have compared the effect of the antidepressants clomipramine, amytriptiline, sertraline, paroxetine and venlafaxine, and of the antipsychotics, haloperidol and risperidone, on GR function in peripheral blood cells from healthy volunteers (n=33). GR function was measured by glucocorticoid inhibition of lypopolysaccharide (LPS)-stimulated interleukin-6 (IL-6) levels. Compared to vehicle-treated cells, all antidepressants inhibited dexamethasone (DEX, 10-100nM) inhibition of LPS-stimulated IL-6 levels (p values ranging from 0.007 to 0.1). This effect was specific to antidepressants, as antipsychotics had no effect on DEX-inhibition of LPS-stimulated IL-6 levels. The phosphodiesterase (PDE) type 4 inhibitor, rolipram, potentiated the effect of antidepressants on GR function, while the GR antagonist, RU-486, inhibited the effect of antidepressants on GR function. These findings indicate that the effect of antidepressants on GR function are specific for this class of psychotropic drugs, and involve second messenger pathways relevant to GR function and inflammation. Furthermore, it also points towards a possible mechanism by which one maybe able to overcome treatment-resistant depression. Research in this field will lead to new insights into the pathophysiology and treatment of affective disorders.

Musculoskeletal model of the upper limb based on the visible human male dataset.

A mathematical model of the human upper limb was developed based on high-resolution medical images of the muscles and bones obtained from the Visible Human Male (VHM) project. Three-dimensional surfaces of the muscles and bones were reconstructed from Computed Tomography (CT) images and Color Cryosection images obtained from the VHM cadaver. Thirteen degrees of freedom were used to describe the orientations of seven bones in the model: clavicle, scapula, humerus, radius, ulna, carpal bones, and hand. All of the major articulations from the shoulder girdle down to the wrist were included in the model. The model was actuated by 42 muscle bundles, which represented the actions of 26 muscle groups in the upper limb. The paths of the muscles were modeled using a new approach called the Obstacle-set Method [33]. The calculated paths of the muscles were verified by comparing the muscle moment arms computed in the model with the results of anatomical studies reported in the literature. In-vivo measurements of maximum isometric muscle torques developed at the shoulder, elbow, and wrist were also used to estimate the architectural properties of each musculotendon actuator in the model. The entire musculoskeletal model can be reconstructed using the data given in this paper, along with information presented in a companion paper which defines the kinematic structure of the model [26].

Optimal control of non-ballistic muscular movements: a constraint-based performance criterion for rising from a chair.

To understand how humans perform non-ballistic movements, we have developed an optimal control model to simulate rising from a chair. The human body was modeled as a three-segment, articulated, planar linkage, with adjacent links joined together by frictionless revolutes. The skeleton was actuated by eight musculotendinous units with each muscle modeled as a three-element entity in series with tendon. Because rising from a chair presents a relatively ambiguous performance criterion, we chose to evaluate a number of different performance criteria, each based upon a fundamental dynamical property of movement; muscle force. Through a quantitative comparison of model and experiment, we found that neither a minimum-impulse nor a minimum-energy criterion is able to reproduce the major features of standing up. Instead, we introduce a performance criterion based upon an important and previously overlooked dynamical property of muscle: the time derivative of force. Our motivation for incorporating such a quantity into a mathematical description of the goal of a motor task is founded upon the belief that non-ballistic movements are controlled by gradual increases in muscle force rather than by rapid changes in force over time. By computing the optimal control solution for rising from a static squatting position, we show that minimizing the integral of a quantity which depends upon the time derivative of muscle force meets an important physiological requirement: it minimizes the peak forces developed by muscles throughout the movement. Furthermore, by computing the optimal control solution for rising from a chair, we demonstrate that multi-joint coordination is dictated not only by the choice of a performance criterion but by the presence of a motion constraint as well.

The use of hepatobiliary scintigraphy in patients with acalculous biliary colic.

Twelve patients with biliary colic had no evidence of gallstones but underwent cholecystokinin-augmented hepatobiliary scintigraphy that revealed gallbladder ejection fractions of less than 35%. All 12 patients underwent cholecystectomy. Biliary colic was relieved in all patients at a mean postoperative follow-up of 2.5 years. The biliary colic in these patients was probably caused by abnormal gallbladder emptying, itself apparently produced by either cystic duct obstruction or abnormal motility. Biliary abnormality was seen at operation in most patients, and all patients had abnormalities of the gallbladder or cystic duct seen grossly or histologically. These abnormalities included cystic duct stenosis or adhesions, chronic inflammation, and cholesterolosis.