Effects of the calcineurin dependent signaling pathway inhibition by cyclosporin A on early and late cardiac remodeling following myocardial infarction

BACKGROUND: The calcineurin-mediated signaling pathway has been implicated as one of the crucial pathways in cardiac hypertrophy. However, the role of calcineurin pathway on cardiac remodeling after myocardial infarction (MI) has not been well defined. METHODS: Infarcted rats (n = 45) were randomized into calcineurin inhibitor, cyclosporin A (CsA) or vehicle groups, 3 days after MI and treated for 2 weeks (early post-MI cardiac remodeling stage), or randomized 17 days after MI and treated for 2 weeks (late remodeling stage). RESULTS: Calcineurin pathway inhibition during the early cardiac remodeling stage attenuated the myocardial hypertrophy after MI (P < 0.05). However, left ventricular dimensions were further increased and fractional shortening deteriorated with calcineurin inhibition during this stage (P < 0.05, each). During late remodeling stage, CsA treatment did not affect myocardial hypertrophy and cardiac dilation following MI. CONCLUSION: Our results strongly support the hypothesis that calcineurin pathway mediates compensatory myocardial hypertrophy during the early remodeling stage after MI. However, the calcineurin pathway does not seem to affect the late remodeling after MI.     

High prevalence and little change in TSH receptor blocking antibody titres with thyroxine and antithyroid drug therapy in patients with non-goitrous autoimmune thyroiditis

OBJECTIVE We have reevaluated the prevalence and pathogenetic importance of TSH receptor blocking antibodies (TRBAb) in autoimmune hypothyroidism, and investigated the changes in TRBAb activities during thyroxine and antithyroid drug treatment. DESIGN Serum TSH binding inhibitor immunoglobulin (TBII) and thyroid stimulation blocking antibody (TSBAb) were measured serially in all patients with non-goitrous autoimmune thyroiditis (AT) and measured monthly during methimazole treatment in 6 patients. PATIENTS Ninety patients with non-goitrous AT and 95 patients with goitrous AT were entered consecutively into this study. All patients with non-goitrous AT were treated with thyroxine and followed at intervals of 6 months for 2 years initially and then yearly intervals. The duration of follow-up was 1–8 years. Six patients from the TRBAb-positive non-goitrous AT group who were treated with thyroxine were randomly selected and given additional treatments with methimazole (40 mg per day) for 6 months. MEASUREMENTS Serum TBII was measured by 8 radioreceptor assay, TSBAb by using FRTL-5 cells, and antithyroid peroxidase and antithyroglobulin antibodies by radioimmunoassay. RESULTS The prevalences of TBII and TSBAb in non-goitrous AT were 47–8 and 58.9%, respectively, which were significantly higher than those in goitrous AT (6.3% for TBII, 10.5% for TSBAb). All but one patient showed persistent TBII and TSBAb activities during the thyroxine treatment for up to 8 years. A high dose of methimazole (40 mg per day) did not affect the titres of TBII and TSBAb in 5 out of 6 patients with non-goitrous AT tested. However, antithyroid peroxidase and antithyroglobulin antibodies activities were significantly decreased during the methimazole treatment. CONCLUSION The high prevalence of TSH receptor blocking antibodies (TRBAb) suggests that TRBAb may play a major role in the development of hypothyroidism and thyroid atrophy in the vast majority of patients with non-goitrous autoimmune thyroiditis. Most TRBAb activities are stable for at least 8 years and are not affected by thyroxine and antithyroid drug treatment.     

Effects of continuous administration of clopidogrel before off-pump coronary artery bypass grafting in patients with acute coronary syndrome.

BACKGROUND: Clopidogrel has become standard treatment after urgent percutaneous coronary revascularization. Due to its enhanced and irreversible platelet inhibition, patients undergoing urgent surgical revascularization have a higher risk of bleeding complications and transfusions. Therefore, the effect of preoperative continuous administration of clopidogrel on the incidence of hemorrhagic complications in patients undergoing off-pump coronary artery bypass surgery with acute coronary syndrome was evaluated. METHODS AND RESULTS: From March 2004 to September 2006, 172 patients with acute coronary syndrome underwent isolated off-pump coronary artery bypass surgery; 70 (40.7%) and 102 (59.3%) of these patients did or did not take clopidogrel before surgery respectively. Seventy patients in each group were matched using propensity scores and associations between preoperative continuous administration of clopidogrel and postoperative bleeding, hemostatic reoperation, blood products received, the need for multiple transfusions and early graft patency by coronary computed tomography were assessed. Univariate analysis showed the continuous clopidogrel group had similar levels of postoperative bleeding for 24 h (601.4+/-312.6 ml vs 637.2+/-452.4 ml, p=0.616) and rates of reexploration (1.4% vs 1.4%), perioperative blood transfusion (33.3% vs 34.3%, p>0.05) and platelet transfusion (2.9% vs 7.1%, p=0.44) compared with the non-continuous group. CONCLUSIONS: Preoperative continuous administration of clopidogrel did not increase the risk of hemorrhagic complications in patients with acute coronary syndrome undergoing isolated off-pump coronary artery bypass surgery. These findings indicate that surgery after clopidogrel treatment in patients with acute coronary syndrome should not be delayed until platelet function returns to normal because they may have a higher risk of recurrent myocardial ischemic events.     

Close correlation of p53 mutation to microvascular invasion in hepatocellular carcinoma

Mutation of p53 is a poor prognostic indicator of hepatocellular carcinoma (HCC). Although poor histologic differentiation of HCC has been associated with p53 mutations, the exact reasons for unfavorable clinical outcomes in patients with HCC remain to be clarified. In this study, we evaluate the association between p53 mutation and histopathologic features of HCCs, as well as tumor recurrences and survival. We examined 20 HCCs and surrounding liver tissues from patients who underwent surgical resection, and we performed direct sequencing of p53 gene. p53 mutations were found in 9 of 20 HCCs; none were found in the surrounding liver tissue. p53 mutations were frequent in large, multinodular, and poorly differentiated HCCs. Five of 9 with p53 mutation (in contrast, none of 11 with wild-type mutation) showed microvascular invasions. Hepatocellular carcinoma recurred in 6 of 9 with p53 mutation, in contrast to only 2 of 11 with wild-type mutation. The 1-year survival rate with p53 mutation was significantly lower than that with wild-type. In conclusion, it is suggested that p53 mutations tend to be commonly associated with microvascular invasions, which may result in micrometastasis, followed by frequent recurrences.     

Effects of robot-assisted gait training on the balance and gait of chronic stroke patients: focus on dependent ambulators

[Purpose] The purpose of this study was to confirm the effect of robot-assisted gait training on the balance and gait ability of stroke patients who were dependent ambulators. [Subjects and Methods] Twenty stroke patients participated in this study. The participants were allocated to either group 1, which received robot-assisted gait training for 4 weeks followed by conventional physical therapy for 4 weeks, or group 2, which received the same treatments in the reverse order. Robot-assisted gait training was conducted for 30 min, 3 times a week for 4 weeks. The Berg Balance Scale, Modified Functional Reach Test, Functional Ambulation Category, Modified Ashworth Scale, Fugl-Meyer Assessment, Motricity Index, and Modified Barthel Index were assessed before and after treatment. To confirm the characteristics of patients who showed a significant increase in Berg Balance Scale after robot-assisted gait training as compared with physical therapy, subgroup analysis was conducted. [Results] Only lateral reaching and the Functional Ambulation Category were significantly increased following robot-assisted gait training. Subscale analyses identified 3 patient subgroups that responded well to robot-assisted gait training: a subgroup with hemiplegia, a subgroup in which the guidance force needed to be decreased to needed to be decreased to ≤45%, and a subgroup in which weight bearing was decreased to ≤21%. [Conclusion] The present study showed that robot-assisted gait training is not only effective in improving balance and gait performance but also improves trunk balance and motor skills required by high-severity stroke patients to perform activities daily living. Moreover, subscale analyses identified subgroups that responded well to robot-assisted gait training.Key words: Stroke, Robotics, Gait     

Unstable Simple Elbow Dislocation Treated with the Repair of Lateral Collateral Ligament Complex

Background

Unstable simple elbow dislocation (USED) repair is challenged by the maintenance of joint reduction; hence, primary repair or reconstruction of disrupted ligaments is required to maintain the congruency and allow early motion of the elbow. We evaluated the effectiveness and the outcome of lateral collateral ligament (LCL) complex repair with additional medial collateral ligament (MCL) repair in cases of USED.

Methods

We retrospectively reviewed 21 cases of diagnosed USED without fractures around the elbow that were treated with primary ligament repair. In all cases, anatomical repair of LCL complex with or without common extensor origin was performed using suture anchor and the bone tunnel method. Next, the instability and congruency of elbow for a full range of motion were evaluated under the image intensifier. MCL was repaired only if unstable or incongruent elbow was observed. Clinical outcomes were evaluated using the Mayo elbow performance score (MEPS) and radiographic outcomes on last follow-up images.

Results

All cases achieved a stable elbow on radiographic and clinical results. LCL complex repair alone was sufficient to obtain the stable elbow in 17 of 21 cases. Four cases required additional MCL repair after restoration of the LCL complex. The overall mean MEPS was 91 (range, 70 to 100): excellent in 12 cases, good in 7 cases, and fair in 2 cases. All 17 cases with LCL complex repair only and 2 of 4 cases with additional MCL repair had excellent or good results by MEPS.

Conclusions

USED requires surgical treatment to achieve a congruent and stable joint. If the repair of lateral stabilizer such as LCL complex acquires enough joint stability to maintain a full range of motion, it may not be necessary to repair the medial stabilizer in all cases of USED.     

Ghrelin enhances the proliferating effect of thyroid stimulating hormone in FRTL-5 thyroid cells

Ghrelin regulates cell proliferation through the growth hormone secretagogue receptor (GHS-R). We confirmed the expression of GHS-R in FRTL-5 thyroid cells and investigated the effects of ghrelin in thyrocytes using FRTL-5 cells. Ghrelin increased intracellular calcium levels but not intracellular cyclic AMP levels. Ghrelin activated Erk within 2min, then activated Akt and STAT3. Erk phosphorylation was inhibited by the calcium inhibitor cyclopiazonic acid (CPA). Ghrelin alone did not stimulate FRTL-5 cell proliferation but enhanced the effects of thyroid stimulating hormone (TSH). Pretreatment with TSH potentiates the growth effects of ghrelin in thyroid cells, and p66Shc, a growth factor receptor adaptor protein, might mediate these synergistic effects. Ghrelin phosphorylated TSH-induced p66Shc, which was inhibited by CPA. Ghrelin did not affect the proliferation of ARO cells, which showed no increased expression of p66Shc after TSH treatment. Thus, ghrelin-induced intracellular calcium signaling enhanced the TSH-induced proliferation of thyrocytes, possibly mediated by the p66Shc pathway.     

Impact of prior lamivudine use on the antiviral efficacy and development of resistance to entecavir in chronic hepatitis B patients

Background/Aims

To determine the efficacies of entecavir (ETV) in nucleos(t)ide analogue (NA)-naïve chronic hepatitis B (CHB) patients and in those with prior lamivudine (LAM) use who did not develop resistance.

Methods

We retrospectively enrolled 337 patients with CHB who were treated with ETV (0.5 mg daily) for at least 30 months. The study included 270 (80.1%) NA-naïve patients and 67 (19.9%) LAM-use patients. Ten of the LAM-use patients were refractory to LAM therapy without developing resistance.

Results

Genotypic resistance to ETV developed more frequently in the LAM-use group (13.1%) than in the NA-naïve group (2.6%) at 60 months (P=0.009). In subgroup analysis, after excluding the 10 patients who were refractory to LAM therapy, the cumulative probability of ETV resistance did not differ significantly between the two groups (P=0.149). Prior LAM refractoriness and a higher hepatitis B virus DNA level at month 12 were independent predictive factors for the development of ETV resistance.

Conclusions

ETV resistance developed more frequently in LAM-use patients with CHB. However, prior LAM use without refractoriness did not affect the development of ETV resistance. The serum hepatitis B virus DNA level at month 12 was a major predictor for the development of ETV resistance.