Effects of surgical stress on brain prostaglandin E2 production and on the pituitary-adrenal axis: attenuation by preemptive analgesia and by central amygdala lesion

Surgical stress is the combined result of tissue injury, anesthesia, and postoperative pain. It is characterized by elevated levels of adrenocorticotropin (ACTH), corticosterone (CS), and elevated levels of prostaglandin E2 (PGE2) in the periphery and in the spinal cord. The present study examined the effects of perioperative pain management in rats undergoing laparotomy on serum levels of ACTH, CS, and on the production of PGE2 in several brain regions, including the amygdala. The amygdala is known to modulate the pituitary-adrenal axis response to stress. We, therefore, also examined the effects of bilateral lesions in the central amygdala (CeA) on laparotomy-induced activation of the pituitary-adrenal axis in rats. In the first experiment, rats either underwent laparotomy or were not operated upon. Half the rats received preemptive analgesia extended postoperatively, the other received saline. ACTH, CS serum levels, and ex vivo brain production of PGE2 were determined. In the second experiment, rats underwent bilateral lesions of the CeA. Ten days later, rats underwent laparotomy, and ACTH and CS serum levels were determined. Laparotomy significantly increased amygdala PGE2 production, and CS and ACTH serum levels. This elevation was markedly attenuated by perioperative analgesia. Bilateral CeA lesions also attenuated the pituitary-adrenal response to surgical stress. The present findings suggest that the amygdala plays a regulatory role in mediating the neuroendocrine response to surgical stress. Effective perioperative analgesia attenuated the surgery-induced activation of pituitary-adrenal axis and PGE2 elevation. The diminished elevation of PGE2 may suggest a mechanism by which pain relief mitigates pituitary-adrenal axis activation.     

Efficient method for high-throughput virtual screening based on flexible docking: discovery of novel acetylcholinesterase inhibitors

A method of easily finding ligands, with a variety of core structures, for a given target macromolecule would greatly contribute to the rapid identification of novel lead compounds for drug development. We have developed an efficient method for discovering ligand candidates from a number of flexible compounds included in databases, when the three-dimensional (3D) structure of the drug target is available. The method, named ADAM&EVE, makes use of our automated docking method ADAM, which has already been reported. Like ADAM, ADAM&EVE takes account of the flexibility of each molecule in databases, by exploring the conformational space fully and continuously. Database screening has been made much faster than with ADAM through the tuning of parameters, so that computational screening of several hundred thousand compounds is possible in a practical time. Promising ligand candidates can be selected according to various criteria based on the docking results and characteristics of compounds. Furthermore, we have developed a new tool, EVE-MAKE, for automatically preparing the additional compound data necessary for flexible docking calculation, prior to 3D database screening. Among several successful cases of lead discovery by ADAM&EVE, the finding of novel acetylcholinesterase (AChE) inhibitors is presented here. We performed a virtual screening of about 160 000 commercially available compounds against the X-ray crystallographic structure of AChE. Among 114 compounds that could be purchased and assayed, 35 molecules with various core structures showed inhibitory activities with IC(50) values less than 100 microM. Thirteen compounds had IC(50) values between 0.5 and 10 microM, and almost all their core structures are very different from those of known inhibitors. The results demonstrate the effectiveness and validity of the ADAM&EVE approach and provide a starting point for development of novel drugs to treat Alzheimer's disease.     

Debulking surgery for patients with diffuse large B-cell non-Hodgkin's lymphoma

Chemotherapy and radiotherapy have been the principal modalities of treatment for diffuse large B-cell non-Hodgkin's lymphoma (B-NHL) for over 30 years. Various treatment regimens have been designed over the years to try to increase response and cure rates. The role of surgery has been generally restricted to defined and limited situations including diagnostic tissue biopsies and treating abdominal emergencies such as organ rupture or perforation. We present two cases of refractory B-NHL, where surgery was used as a part of stepwise and multi-modal treatment with curative intent. In both cases, the treatment approach included standard dose chemotherapy, eradication of residual mass by surgery, high dose chemotherapy (HDC) with stem cell support and posttransplantant immunotherapy. Currently, 2 years after completing the therapy, both patients are well with no evidence of active disease. Based on our experience with 2 patients we believe that in specific cases of residual chemo-resistant lymphomatous mass, surgery should be considered as a part of a multimodal approach.     

The effects of various therapeutic measures on shoulder strength and muscle soreness after baseball pitching

AIM: This study was intended as an investigation of the effects of various therapeutic measures on the shoulder strength and muscle soreness after baseball pitching. METHODS: Experimental design: participants threw 98 pitches in a simulated single game. The mode of the therapeutic measures after pitching were classified into 4 groups; the control group (CON), the ice treatment group (IT), the light shoulder exercise group (LSE) and the ice treatment with LSE group (ILSE). Each therapeutic measure was applied to the dominant shoulder immediately after pitching. Participants: 7 healthy, skilled baseball pitchers. Measures: both shoulder strength and muscle soreness were measured before pitching, immediately after pitching (Post-P), at the time of the therapeutic measure (Post-TM), and 24 hours after pitching (Post-24 h). RESULTS: All 4 groups showed shoulder strength losses in shoulder abduction, internal/external rotation with no shoulder abduction or with the shoulder abducted to 90 degrees immediately after pitching. ILSE had greater recovery from Post-P values at Post-TM or Post-24 h than the other methods in all 5 shoulder strengths. On the other hand, the soreness in shoulder internal rotation was increased significantly from Post-P and continued by Post-24 h. Both IT and ILSE had beneficial effects on reducing the shoulder muscle soreness at Post-TM or Post-24 h. CONCLUSION: The findings of this study suggested that ILSE was the optimal therapeutic measure against decreased shoulder strength or increased shoulder muscle soreness resulting from the repetitive baseball pitching.     

Effects of preemptive analgesia on pain and cytokine production in the postoperative period

BACKGROUND: The postoperative period is associated with increased production of proinflammatory cytokines, which are known to augment pain sensitivity, among other effects. In a previous study, the authors found that patients treated with patient-controlled epidural analgesia (PCEA) exhibited attenuated proinflammatory cytokine response in the postoperative period. In the present study, the authors examined whether preemptive analgesia continued with PCEA may further attenuate the proinflammatory cytokine response and reduce pain sensitivity in the postoperative period. They compared cytokine production in two groups of patients, one receiving PCEA, the other receiving preemptive epidural analgesia continued by PCEA. METHODS: Female patients hospitalized for transabdominal hysterectomy were randomly assigned to one of two pain management techniques: PCEA or preemptive epidural analgesia followed by PCEA (PA + PCEA). Postoperative pain was assessed using the visual analog scale. Blood samples were collected before, 24, 48, and 72 h following surgery. Production of the following cytokines was assessed in stimulated peripheral blood mononuclear cells: interleukin (IL)-1beta, tumor necrosis factor alpha, IL-6, IL-1ra, IL-10, and IL-2. RESULTS: Patients of the PA + PCEA group exhibited lower pain scores throughout the 72 h postoperatively, compared with patients of the PCEA group. In patients of the PA + PCEA group in the postoperative period, production of IL-1beta, IL-6, IL-1ra, and IL-10 was significantly less elevated, while IL-2 production was significantly less suppressed. CONCLUSIONS: Proinflammatory cytokines are key mediators of illness symptoms, including hyperalgesia. The present results suggest that preemptive epidural analgesia is associated with reduced postoperative pain and attenuated production of proinflammatory cytokines.     

The effects of various therapeutic measures on shoulder range of motion and cross-sectional areas of rotator cuff muscles after baseball pitching

AIM: The purpose of this study was to investigate the effects of various therapeutic measures on the shoulder range of motion (ROM) and muscle cross-sectional area (mCSA) of rotator cuff muscles after baseball pitching. METHODS: Experimental design: a mode of therapeutic measures was classified in 4 groups; the control (CON), ice treatment (IT), light shoulder exercise (LSE) and ice treatment with LSE (ILSE) groups. Each therapeutic measure was performed after pitching. Participants: 7 healthy, skilled baseball pitchers. Measures: ROM and mCSA were measured before pitching, immediately after pitching, at the time of the therapeutic measure, and 24 hours after pitching. Shoulder ROM at 90 inverted exclamation mark of abduction included internal rotation (IROM), maximum internal rotation (IMROM), external rotation (EROM) and maximum external rotation (EMROM). RESULTS: In all groups, both IROM and IMROM were significantly decreased after pitching compared with the pre-exercise values and conversely both EROM and EMROM were significantly increased. The mCSA of all rotator cuff muscles were increased significantly after pitching. For IMROM, ILSE showed a significant recovery at the post-therapeutic measure compared with the others and at 24 hours after pitching compared with IT, respectively. For IROM, both LSE and ILSE showed significant recovery compared with CON at the post-therapeutic measure. For the mCSA of external muscles, ILSE showed a greater decrease at the post-therapeutic measure than the others, and at 24 hours after pitching than CON. CONCLUSION: This study suggested the possibility that ILSE was more effective to recover ROM and decrease mCSA than the other methods.     

Magnetic resonance imaging of the rotator cuff muscles after baseball pitching

AIM: The purposes of present study were to investigate quantitatively using functional MR imaging the effect of a series of throwing activities on rotator cuff muscles and to compare the effect of pitching with that of all-out shoulder external rotator exercise as the targeted external rotator muscle group (the infraspinatus and the teres minor). METHODS: Experimental design: MRI measurements after 135 baseball pitches or all-out shoulder external rotator exercise (concentric mode) in each subject's nondominant shoulder. Participants: 6 amateur baseball pitchers. Measures: serial T2-weighted images of rotator cuff muscles were obtained before pitching (or shoulder exercise) and immediately, 30, 60 min, 24, 48, 96 hrs after pitching (or shoulder exercise). T2 relaxation times (T2) at each measurement time were calculated for the rotator cuff muscles. RESULTS: Both the supraspinatus and the external rotator muscle group showed significant T2 elevations until 96 hrs after pitching. The subscapularis also showed significantly increased T2 until postpitching 48 hrs. On the other hand, a significant T2 elevation continued until 60 min after shoulder exercise, but thereafter returned towards the value at rest over the next 24 hrs. CONCLUSION: Long lasting T2 elevations in rotator cuff muscles would be associated with an increase in each intramuscular water content, and may be attributed to the muscle damage that resulted from eccentric contraction during pitching. This information should serve as a useful complement to shoulder injury prevention for baseball pitchers.     

Accelerated dynamic MR imaging with a parallel imaging technique for hypervascular hepatocellular carcinomas: usefulness of a test bolus in examination and subtraction imaging

PURPOSE: To assess the impact of the accelerated dynamic MR imaging (ADMRI) approach using parallel imaging for detecting hypervascular hepatocellular carcinomas (HCCs) and to evaluate the usefulness of a test bolus in examination and subtraction imaging in this setting. MATERIALS AND METHODS: Thirty patients with 135 HCCs underwent ADMRI using a two-dimensional gradient-recalled echo sequence with parallel imaging. Seventeen patients were evaluated without a test bolus and 13 patients with a test bolus. The detectability of HCCs was calculated between the groups with and without a test bolus. ADMRI was evaluated regarding the signal-to-noise ratio (SNR) of the lesion and the liver, the contrast-to-noise ratio (CNR) of the lesion vs. the liver, and the feasibility of subtraction images. RESULTS: ADMRI with and without a test bolus had almost equal sensitivity (92.5% and 92.6%). No significant difference was seen in the SNR of lesions and the CNR of lesions vs. livers between both groups. With a test bolus, ADMRI could depict the peak enhancement of nodules on the 2nd or 3rd dynamic phases and optimized the timing of peak lesion enhancement. Subtraction images could be obtained regarding minimal slice misregistration. CONCLUSION: ADMRI had high detectability of HCCs with and without a test bolus.