Anticipatory postural adjustments associated with a loading perturbation in children with hemiplegic and diplegic cerebral palsy.

Anticipatory postural adjustments (APAs) in preparation for predictable externally induced loading perturbation were studied in children with typically development (TD), hemiplegic (HEMI), and diplegic (DIPL) cerebral palsy. Twenty-seven children (n = 9 in each group) were asked to stand and catch a load dropped from a pre-specified height. Electrical activity of the leg and trunk muscles and center of pressure (COP) displacements were recorded to quantify the APAs. All groups were able to generate APAs prior to the perturbation, but the magnitude was smaller and the onset was delayed in the dorsal (agonist) postural muscles in both HEMI and DIPL as compared to TD. HEMI and DIPL also generated APAs in the antagonist postural muscles. Anticipatory backward COP displacement was significantly different from the baseline value only in the TD and HEMI. HEMI and DIPL displayed a different postural control strategy; HEMI showed no difference in background postural activity from TD, but with diminished APAs in the agonist postural muscles compared to TD, while DIPL showed a higher background postural activity and diminished APAs in the agonist postural muscles compared to TD. These differences are important to consider when designing rehabilitation programs to improve posture and movement control in children with hemiplegic and diplegic cerebral palsy.

Concurrent chemoradiation for patients with squamous cell carcinoma of the cervical esophagus.

Little is known concerning the role of concurrent chemoradiation (CCRT) in the management of carcinoma of the cervical esophagus. We retrospectively evaluated our treatment approach for patients with cervical esophageal cancer with special emphasis on CCRT with or without surgery. Medical records of 21 consecutive patients with cervical esophageal carcinoma treated mainly with CCRT (1997-2004) were reviewed, and factors that influenced patient survival were analyzed retrospectively. Nineteen received CCRT with cisplatin/5-fluorouracil and five underwent curative surgery. Two patients who were deemed unfit for CCRT received radiation therapy alone. All had three-dimensional treatment planning (median total dose, 40 Gy with surgery, 64 Gy without surgery). Of the 19 patients who received CCRT, 11 patients including five who underwent curative surgery achieved initial local control. Neither of the two patients who received radiation therapy alone achieved local control. Among 19 patients who underwent CCRT, 9/11 with T1-3 grade tumors achieved initial local control, but only 2/8 patients with T4 tumors (P = 0.011, chi(2) test) achieved initial local control. No patient without initial local control survived > 20 months compared with 2-year and 5-year survival rates of 60% and 40% in those who achieved initial local control (P = 0.038). No patient with T4 tumors survived > 18 months, whereas 2- and 5-year survival rates were 62% and 41%, respectively, in those with T1-3 tumors (P = 0.006). The significant effect of T-classification on survival was maintained when analyzed among 19 patients who received CCRT. CCRT shows promise for cervical esophageal carcinoma. T-classification and initial local control had significant impact on survival.

Enhancement of chemosensitivity toward peplomycin by calpastatin-stabilized NF-kappaB p65 in esophageal carcinoma cells: possible involvement of Fas/Fas-L synergism.

Chemosensitivity to anticancer drugs was compared between two human esophageal carcinoma cell lines, T.Tn and YES-6 cells. T.Tn cells were more resistant than YES-6 cells to peplomycin (PEP) but not to the other anticancer drugs such as camptothecin, mitomycin C and cytosine arabinoside. Western blot analysis showed higher expression levels of m-calpain and activated mu-calpain in T.Tn cells than in YES-6 cells. On the other hand, YES-6 cells showed a high expression level of calpastatin, which is a calpain-specific endogenous inhibitor. To investigate whether calpain activity was involved in the chemosensitivity, T.Tn cells were transfected with calpastatin cDNA in an inducible expression vector. The induction of calpastatin was accompanied by increased chemosensitivity to PEP. The increases in calpastatin levels were followed by serial increases in the expression levels of NF-kappaB p65 and Fas. Since purified m- or mu-calpain degraded NF-kappaB p65 in vitro, it is possible that calpastatin suppressed calpain-mediated degradation of NF-kappaB p65. Fas ligand (Fas-L) protein levels increased after treatment of the parental T.Tn and calpastatin-transfected cells with PEP, suggesting the synergism between calpastatin-induced Fas and PEP-induced Fas-L. These results suggest that calpain/calpastatin expression levels are effective markers for predicting the sensitivity of human esophageal carcinoma cells to PEP.

Neoadjuvant chemoradiotherapy followed by esophagectomy for initially resectable squamous cell carcinoma of the esophagus with multiple lymph node metastasis.

Neoadjuvant chemoradiotherapy (CRT) was expected to improve surgical curability and prognosis for advanced esophageal cancer. However, the clinical efficacy of neoadjuvant CRT followed by esophagectomy with three-field lymphadenectomy (3FL) for initially resectable esophageal squamous cell carcinoma (SCC) remains unclear. Since 1998, we have defined the status of metastases to five or more nodes, or nodal metastases present in all three fields as multiple lymph node metastasis, which was previously shown to be associated with poor prognosis. Between 1998 and 2002, 83 patients with initially resectable esophageal SCC were prospectively allocated into two groups, according to the clinical status of nodal metastasis. Nineteen patients clinically accompanied by multiple lymph node metastasis initially underwent neoadjuvant CRT followed by curative esophagectomy with 3FL (CRT group). The other 64 patients clinically without multiple lymph node metastasis immediately received curative esophagectomy with 3FL (control group). Although the overall morbidity rate was significantly higher in the CRT group, no in-hospital death occurred in either group. Patients without pathologic multiple lymph node metastasis in the CRT group showed a significantly better disease-free survival rate than either patients pathologically with multiple lymph node metastasis in the control group or those in the CRT group. However, the differences in the overall survival rate among the groups were not significant. Thus, the significant survival benefit by neoadjuvant CRT in addition to esophagectomy with 3FL was not confirmed, although it may have been advantageous, without increase in mortality, to at least some patients who responded well to neoadjuvant CRT. Therefore, neoadjuvant CRT can be an initial treatment of choice for resectable esophageal SCC clinically with multiple lymph node metastasis. The prediction of response to CRT and the development of alternative treatment for hematogenous recurrence could achieve a further survival benefit of this trimodality treatment.

Development of less invasive surgical procedures for thoracic esophageal cancer.

In order to minimize the invasiveness of the operative procedure for thoracic esophageal cancer, several procedures have been introduced since January 1997. They included: (i) perioperative use of steroids; (ii) muscle-sparing thoracotomy without costectomy; (iii) preparation of the gastric tube with preservation of sufficient blood supply; (iv) reconstruction of the alimentary tract via posterior-mediastinal route; and (v) formation of anastomosis between the remaining esophagus and the gastric tube at a location between the gastroepiploic arteries of the gastric greater curvature. Twenty-one patients who did not receive preoperative chemoradiotherapy underwent the newly developed procedure, and were compared with those receiving the original procedure. Hospital mortality was zero, and postoperative systemic inflammatory response syndrome was suppressed. The mean postoperative hospital stay was 21.5 days, and the actuarial 3-year survival rate was 76.2%. From the comparison with those receiving the original procedure, it can be concluded that the newly developed procedures were effective in minimizing surgical invasiveness and were sufficiently curative in terms of cancer treatment.

Expression of angiogenic factors predicts response to chemoradiotherapy and prognosis of oesophageal squamous cell carcinoma.

The ability to predict patients' responses to chemoradiotherapy by analyzing pre-treatment biopsy specimens would be valuable for managing oesophageal squamous-cell cancer. To this end, the expression of p53, thymidine phosphorylase and vascular endothelial cell growth factor was analyzed by immunohistochemistry in 52 patients with oesophageal squamous-cell cancer prior to chemoradiotherapy. Treatment consisted of radiotherapy (40 Gy) and 5 day-infusion of 5-Fluorouracil (500 mg m(-2) per day) combined with cisplatin (10 mg m(-2) per day). Following treatment, imaging and endoscopic reassessment was performed to establish treatment response. Thirty-one patients underwent radical surgery and 21 patients were treated with an additional 20 Gy of radiotherapy. Of the tumours studied, 58% were p53-positive, 40% thymidine phosphorylase-positive and 44% vascular endothelial cell growth factor-positive. A clinical response was observed in 36 patients (69%) and was negatively associated with thymidine phosphorylase expression (P=0.02) and vascular endothelial cell growth factor expression (P<0.001). However, the 5-year survival rate was significantly lower only in patients with vascular endothelial cell growth factor-positive tumours (P=0.037). Multivariate analysis identified vascular endothelial cell growth factor as a significant independent prognostic factor (P=0.0147). These results suggest that expression of angiogenic factors has predictive value for the treatment response and outcome of patients with oesophageal cancer.

Activation of cyclin E-dependent kinase activity in colorectal cancer.

Although cyclin E gene amplification is reported to be an important event in various cancers, it is rarely found in human colorectal cancers. As one of the candidate factors of other mechanisms relating to cyclin E, we analyzed cyclin E-dependent kinase activity in colorectal cancer. Protein levels of cyclin E, its catalytic subunit, cyclin-dependent kinase 2 (Cdk2), and p21 and p27 were determined by western blot or immunohistochemistry in 27 colorectal cancers and 10 colorectal adenomas, and compared with adjacent normal colonic mucosa. Enzymatic activity of cyclin E-Cdk2 complex in the colorectal neoplasm was measured using in-gel kinase assay using glutathione S-transferase-retinoblastoma (GST-Rb) fusion protein as substrate, and compared with that of normal mucosa. We clearly showed that although the protein level of cyclin E in colorectal cancer and adenoma was similar to that of adjacent normal mucosa, cylin E-dependent kinase activity was increased in all the cases of colorectal cancers and 90% of colorectal adenomas. The relative kinase activity was significantly higher in colorectal cancer (3.7 +/- 1.7 -fold) than colorectal adenomas (2.0 +/- 0.8-fold) (P < 0.004). The relative expression level of Cdk2 protein in cancer was significantly higher than adenoma (4.4 +/- 2.4 vs 2.7 +/- 1.3, P < 0.04), and p21 and p27 were not detected in colorectal cancer and notably decreased in adenoma. The results of this study strongly suggest that activation of cyclin E-dependent kinase activity may play an important role in colorectal cancer, and its level appears to be related to increased Cdk2 and decreased p21 and p27 amounts rather than cyclin E protein level.

Anticipatory postural adjustments during load catching by standing subjects.

OBJECTIVES: (1) To study differences in the generation of anticipatory postural adjustments (APAs) in arm and trunk/leg muscles prior to catching a load released either by the subject him-/herself or by the experimenter. (2) To study the importance of different mechanical characteristics of the load at impact for the generation of APAs prior to load catching. METHODS: Standing subjects were asked to catch loads dropped onto the left hand from different heights either by the experimenter or by the subject's right hand. The load mass and release height were manipulated to keep either the mass or the momentum of the load at impact constant. APAs were quantified with integral electromyographic indices. RESULTS: APAs were observed in leg, trunk and arm muscles prior to load impact for both self- and experimenter-release trials. Kinetic energy showed higher correlations with the magnitude of APA than momentum, but only in experimenter-release trials. CONCLUSIONS: Subjects can generate APAs in both arm and trunk/leg muscles in the absence of an explicit voluntary action. The relative importance of kinetic energy and momentum for defining the magnitude of APAs can reflect the difference in the sources of information used to prepare for the forthcoming perturbation during self- and experimenter-released load catch.

The role of action in postural preparation for loading and unloading in standing subjects.

The main purpose of the present study has been to find an answer to the question: Can the subject generate anticipatory postural adjustments (APAs) when a predictable postural perturbation occurs in the absence of a voluntary action? Answering this question would allow us to distinguish between two competing hypotheses on the relation between APAs and voluntary movements. One hypothesis considers both APAsigma and voluntary "focal" movements different peripheral patterns associated with a single control process, while the alternative hypothesis considers them outcomes of two parallel control processes. Healthy subjects performed series of loading and unloading trials that included: (1) catching a falling load onto another load held in extended hands; (2) catching a falling load onto a tray attached to the trunk; (3) allowing a falling load to hit another load out of the extended hands, causing an unloading; and (4) releasing a load held in extended hands by a voluntary shoulder movement. In series 1, precautions were taken to avoid possible small hand movements prior to the impact of the falling load. Available visual information on the trajectory of the falling load was manipulated. In all conditions, except when the subject's eyes were closed, APAs were seen with patterns that were adequate for counteracting expected perturbations. Quantitative electromyographic indices of APAs depended on the availability of visual information and particular methods of introducing postural perturbations despite the fact that the magnitude of the perturbation was always the same. Our findings support a hypothesis that control processes resulting in APAs can be different from control processes associated with focal voluntary movements.

Analysis of kinematically redundant reaching movements using the equilibrium-point hypothesis.

Six subjects performed a planar reaching arm movement to a target while unpredictable perturbations were applied to the endpoint; the perturbations consisted of pulling springs having different stiffness. Two conditions were applied; in the first, subjects had to reach for the target despite the perturbation, in the second condition, the subjects were asked to not correct the motion as a perturbation was applied. We analyzed the kinematics profiles of the three arm segments and, by means of inverse dynamics, calculated the joint torques. The framework of the equilibrium-point (EP) hypothesis, the lambda model, allowed the reconstruction of the control variables, the "equilibrium trajectories", in the "do not correct" condition for the wrist and the elbow joints as well as for the end point final position, while for the other condition, the reconstruction was less reliable. The findings support and extend to a multiple-joint planar movement, the paradigm of the EP hypothesis along with the "do not correct" instruction.

The roles of proximal and distal muscles in anticipatory postural adjustments under asymmetrical perturbations and during standing on rollerskates.

OBJECTIVES: The study addresses two controversial issues surrounding the nature of anticipatory postural adjustments (APAs). The first deals with the reproducible APA patterns in proximal postural muscles and variable APA patterns reported for the muscles controlling the ankle joint (TA-SOL). We hypothesized that the TA-SOL muscles participate mainly in the compensation of lateral and rotational perturbations, in particular those associated with asymmetrical movements. The second issue deals with decreased APAs reported during both very stable and unstable standing. We hypothesized that APA changes during unstable standing might depend on the actual mechanical nature of instability. METHODS: Eight healthy subjects were recruited who had had no prior experience with rollerskates. They performed series of bilateral and unilateral, flexion and extension movements during regular standing and bilateral movements during standing on rollerskates. EMG changes and shifts of the center of pressure were analyzed within a time window typical of APAs. RESULTS: We found that APAs in proximal muscles were decreased during unilateral shoulder movements as compared to APAs during bilateral movements but did not show right-left differences. In contrast, the distal muscles (TA-SOL) showed little involvement during bilateral movements, while a clear right-left asymmetry was seen during unilateral movements. Bilateral movements performed while standing on rollerskates were accompanied by unchanged APAs in the proximal muscle pairs and increased APAs in the TA-SOL pair. CONCLUSIONS: We conclude that the proximal muscles provide a general pattern counteracting expected perturbations in the anterior-posterior direction while the distal muscles deal with asymmetrical perturbations and the modulation of APAs in unusual conditions such as standing on rollerskates. There seems to be no unambiguous relation between the magnitude of APAs and the stability of standing: Depending on the exact mechanical nature of postural instability, it could be associated with qualitatively different changes in the APAs.

[Immunosuppressive treatment of ulcerative colitis].

5-aminosalicylic compounds and corticosteroids are standard drugs, which have been used for treatment of ulcerative colitis (UC). Although unusually we experience severe active UC, such as refractory cases to these drugs. Immunosuppressive agents are introduced and effective for these cases. In the treatment for UC, 6-mercaptopurine and azathioprine are effective, but it takes a few months until their optimum effect. So these drugs are not suitable for severe active UC which needs rapid treatment. On the other hand, newer immunosuppressive agents such as cyclosporin, tacrolimus have a rapid onset of action. These drugs are very effective, but have side effects. We will review immunosuppressive treatment strategy of UC.

Comparison between in vivo and in vitro pharmacokinetics of succinylcholine in humans.

PURPOSE: To compare the in vivo and in vitro pharmacokinetics of succinylcholine (SCh) in humans. METHODS: A bolus of SCh 1 mg.kg(-1) (n = 7) or 2 mg.kg(-1) (n = 11) was given to 18 patients anesthetized with thiopental. Arterial blood samples for determination of in vivo SCh concentrations were collected every 30 s for 5 min. Another 20-ml blood sample was obtained before induction of anesthesia for determination of in vitro SCh. Concentrations of SCh were measured by high-performance liquid chromatography. In vivo and in vitro concentrations of SCh vs time data were analyzed by the one-compartment model. RESULTS: The respective in vivo and in vitro pharmacokinetic parameters (SCh 1 mg.kg(-1) vs SCh 2 mg.kg(-1)) were as follows: Plasma clearance was 4.17 +/- 2.37 and 1.85 +/- 0.28 l.min(-1), P < 0.05, vs 2.91 +/- 2.01 and 1.27 +/- 0.43 l.min(-1), P < 0.05. Elimination half-life was 25.4 +/- 10.6 and 47.4 +/- 5.4 s, P < 0.002 vs 26.3 +/- 10.0 and 75.2 +/- 21.8 s, P < 0.00005. CONCLUSION: These results suggest that the rapid disappearance of SCh from the circulation is due to diffusion out of the blood vessels rather than to enzymatic hydrolysis.

Resistance of Fc receptor- deficient mice to fatal glomerulonephritis.

Immune complex-mediated inflammation is a common mechanism of various autoimmune diseases. Glomerulonephritis (GN) is one of these diseases, and the main mechanism of the induction of GN has been unclear. We examined the contribution of Fc receptors in the induction of nephrotoxic GN by establishing and analyzing mice deficient in the Fc receptor gamma chain (FcRgamma). Whereas all wild-type mice died from severe glomerulonephritis with hypernitremia by administration of anti-glomerular basement membrane (GBM) antibodies, all FcRgamma-deficient mice survived. Histologically, wild-type mice showed glomerular hypercellularity and thrombotic changes, whereas the renal tissue in FcRgamma-deficient mice was almost intact. Deposition of anti-GBM antibody as well as complement components in the GBM were equally observed in both wild-type and knockout mice. These results demonstrate that the triggering of this type of glomerulonephritis is completely dependent on FcR+ cells.

A novel acyl-CoA thioesterase enhances its enzymatic activity by direct binding with HIV Nef.

In addition to playing a crucial role in the pathogenesis of AIDS, HIV nef induces down-regulation of CD4 expression and TCR signaling and also regulates the sorting pathway in host T cells. To elucidate the Nef function in HIV progression, we searched for a cellular component which interacts with Nef. A human cDNA encoding a novel acyl-CoA thioesterase (hACTE-III) was isolated as an HIV nef-binding protein by yeast two-hybrid system. hACTE-III is homologous to E. coli thioesterase II but to none of the mammalian thioesterases and therefore belongs to a new type. hACTE-III exhibits enzymatic specificity for a broad range of fatty acyl-CoAs. The hACTE-III-binding region within Nef is localized in the central region (amino acids 109-152). hACTE-III greatly enhances its enzymatic activity upon direct binding to Nef. Considering that either Nef-overexpression or impaired fatty acid regulation induces alteration of subcellular morphology, the augmented hACTE-III function by Nef-binding might induce dysfunction of T cells.

Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2.

CTLA-4 is a costimulation receptor that binds to the same ligands, CD80 and CD86, as CD28 with high affinity and is transiently expressed on the cell surface of activated T cells. CTLA-4 delivers an inhibitory signal through association of a phosphotyrosine-containing motif in the cytoplasmic domain with Syp tyrosine phosphatase. We now demonstrate that CTLA-4 interacts with the mu2 subunit of the plasma membrane-associated adaptor complex, AP-2, through the same motif involved in the interaction with Syp, except that the interaction with mu2 requires unphosphorylated tyrosine. The interaction with mu2 likely induces rapid internalization of CTLA-4 from the cell surface. Our results suggest that the phosphorylation state of a single tyrosine residue determines whether CTLA-4 delivers a negative signal or is internalized.

[Out line of measurement of gastric emptying using by radioisotope and its problems awaiting solution].

The radioisotopic technique has been recognized as the best method of measuring gastric emptying all over the world, but several problems which must be solved have remained in it. The first is the confusion in the choice of a standard meal of ordinary food labeled with radioisotope. A meal for use in this studies must be reproducible in quality, and radioisotope must be homogenously distributed in it. It is necessary to consider the efficiency of examination, and to release a examinee's agony, therefore a meal must leave the stomach within the tolerable limits of a patient who keeps himself unshaken during measurement. If a liquid meal is used, we can easily make use of foods on the market. But, if a solid meal, a practical difficulty stands in front of us; Who prepares to cook it? Unless this problem has been solved, the radioisotopic method is never found general acceptance as a clinical examination. The second is the confusion in the choice of a posture during measurement. We must select such posture that never alter a patient's characteristics of his gastric emptying. For example, it is difficult to prove rapid evacuation in a patient with dumping syndrome, if we examine him in supine position. A final problem is to re-examine what kinds of index are necessary to investigate the gastric emptying curve with many variations except of half-emptying time which has been used popularly as the index of the rate of it. We gave an out-line of the methods of measuring gastric emptying using radioisotope and a suggestion of its some problems awaiting solution.