The cross-talk between angiotensin and insulin differentially affects phosphatidylinositol 3-kinase- and mitogen-activated protein kinase-mediated signaling in rat heart: implications for insulin resistance

Insulin and angiotensin II (AngII) may act through overlapping intracellular pathways to promote cardiac myocyte growth. In this report insulin and AngII signaling, through the phosphatidylinositol 3-kinase (PI 3-kinase) and MAPK pathways, were compared in cardiac tissues of control and obese Zucker rats. AngII induced Janus kinase 2 tyrosine phosphorylation and coimmunoprecipitation with insulin receptor substrate 1 (IRS-1) and IRS-2 as well as an increase in tyrosine phosphorylation of IRS and its association with growth factor receptor-binding protein 2. Simultaneous treatment with both hormones led to marked increases in the associations of IRS-1 and -2 with growth factor receptor-binding protein 2 and in the dual phosphorylation of ERK1/2 compared with the administration of AngII or insulin alone. In contrast, an acute inhibition of both basal and insulin-stimulated PI 3-kinase activity was induced by both hormones. Insulin stimulated the phosphorylation of MAPK equally in lean and obese rats. Conversely, insulin-induced phosphorylation of Akt in heart was decreased in obese rats. Pretreatment with losartan did not change insulin-induced activation of ERK1/2 and attenuated the reduction of Akt phosphorylation in the heart of obese rats. Thus, the imbalance between PI 3-kinase-Akt and MAPK signaling pathways in the heart may play a role in the development of cardiovascular abnormalities observed in insulin-resistant states, such as in obese Zucker rats.     

Letter to the editor in response to the article of Dekkers and Søballe (Activities and impairments in the early stage of rehabilitation after Colles' fracture; Vol. 26, No. 11, June 3, 2004)

Aim.?To study psychological well-being (health-related quality of life) in a population of adults 20 years and over with hearing impairment (HI) and its relation to audiological factors, consequences of the HI, sense of humour, and use of communication strategies.

Subjects and methods.?Consecutive adults (n = 343) at the outpatient Unit of Audiology of a Norwegian university hospital answered the Psychological General Well-being inventory (PGWB), Hearing Disability and Handicap Scale (HDHS), Sense of Humour Questionnaire-6 (SHQ-6), and Communication Strategies Scale (CSS) in relation to an audiological examination and medical consultation.

Results.?Mean PGWB index for the whole sample was 81.4 (SD 14.3) and females reported a significantly lower psychological well-being. In multiple linear regression analyses well-being was negatively associated with high levels of activity limitation and participation restriction. PGWB index was positively associated with high sense of humour, but was neither explained by audiological factors nor use of communication strategies.

Conclusions.?Psychological well-being was associated with the outcome of a standard HI assessment of activity limitation and participation restriction, but not with degree of HI and use of communication strategies.     

Effect of amphotericin B and fluconazole on platelet membrane glycoproteins

BACKGROUND : Fever, chills, and reduced platelet recovery may result when platelets are transfused simultaneously with amphotericin B. Amphotericin B reportedly increases the pitting of membranes in stored platelets. STUDY DESIGN AND METHODS : The effects of amphotericin B and another antifungal agent, fluconazole, on platelet membrane glycoproteins (GP) were examined by the incubation of split aliquots of fresh and stored platelet concentrates (PCs) with these drugs for 3 days in storage bags. To determine the effect of storage, PCs were stored for 5 days, and aliquots removed on Days 1 through 5 were placed in platelet storage bags with 4 micrograms per mL of amphotericin B for 2 to 6 hours. Membrane glycoprotein expression was assessed by flow cytometry with fluorescein isothiocyanate-labeled monoclonal antibodies (MoAbs) directed against the following antigens: GPIb (CD42b), CD63 (an activation protein), P-selectin (CD62), and GPIIb/IIIa (CD41a). RESULTS : Amphotericin B produced a concentration-dependent decrease in the surface binding of CD42b MoAb with no consistent changes in the binding of CD41a, CD63, or CD62 MoAbs after a 3-day exposure. Stored but not fresh PCs showed decreased binding of MoAb CD42b after a 6-hour exposure to amphotericin B (4 micrograms/mL). Fluconazole produced no changes. When the binding of MoAb CD42b to permeabilized platelets was used to measure total platelet content, amphotericin B (4 micrograms/mL) decreased MoAb CD42b binding to a similar degree in fresh and stored platelets. Inhibition of aggregation to ADP and collagen and ADP and epinephrine was seen in stored but not fresh PCs. CONCLUSION : Therapeutic levels of amphotericin B resulted in partial loss of total platelet GPIb in fresh and stored PCs, but decreased surface expression of platelet membrane GPIb only in stored platelets. This difference between fresh and stored platelets may be related to the limited reservoir of GPIb available for redistribution to the membrane in the previously stored PCs and may account for the decreased recovery of transfused platelets observed in some patients receiving amphotericin B.     

理科大学生网络成瘾与人格特质的关系

目的:分析理科大学生网络成瘾与其人格特质的关系。方法:于2005-09/11在上海某高校以班级为单位,对4个理科专业的220名学生进行问卷调查,4个专业分别是数学教育、计算机教育、物理师范和应用心理学。采用大学生因特网成瘾量表、交往焦虑量表、UCLA孤独量表和YG性格测验等4份问卷进行调查。大学生上网情况调查表共有52个题目,5级计分,成瘾诊断标准有耐受性、脱瘾综合症、计划性、控制性、行为特征、危害性、主观认识和行为等7个维度。按1,2,3,4,5记分,即每题填什么数记什么分,然后将各题得分相加得到维度分。判断标准:每题得1～3分转化为0分,4分转化为1分,5分转化为2分。测验每一部分导出分相加。若测验7部分中有3部分以上得分超过4分,则可基本诊断该大学生为因特网成瘾障碍患者。交往焦虑量表包含15个自陈条目,5级计分,总分从15(社交焦虑程度最低)到75(社交焦虑程度最高)。UCLA孤独量表(第3版)包含20个自陈条目,4级计分,总分从20(孤独程度最低)到80(孤独程度最高)。需要补充说明的是,交往焦虑量表是测量独立于行为的社交焦虑,UCLA孤独量表也主要是特质量表,因此这两个量表所测量的都是焦虑和孤独的人格特质而不是状态。YG性格测验问卷包含12个分量表,每个分量表有10个题目,测量一种特质。结果:共发出220份问卷,收回有效问卷211份。①成瘾者和非成瘾者在焦虑和孤独量表上的得分差异没有显著性意义。②成瘾者和非成瘾者在YG性格测验中的抑郁性、循环性、神经质、非合作性和攻击性等特质得分上,差异十分显著[(9.81±4.97),(5.95±5.10)分;(10.81±4.56),(6.78±4.46)分;(9.63±4.72),(6.51±4.67)分;(11.15±4.19),(7.28±4.43)分;(12.41±4.05),(8.69±3.69)分,均P<0.001],自卑感、主观性和细致性等特质得分上差异显著[(9.15±4.51),(6.83±4.49)分;(10.04±3.50),(7.63±4.09)分;(12.67±3.45),(10.26±4.23)分,P<0.01或P<0.05],在一般活动性、思维外向性、支配性和社会外向性等特质得分上两者没有差异。结论:理科大学生的部分人格特质和网络成瘾密切相关。     

Low salt intake modulates insulin signaling, JNK activity and IRS-1ser307 phosphorylation in rat tissues

A severe restriction of sodium chloride intake has been associated with insulin resistance and obesity. The molecular mechanisms by which the low salt diet (LS) can induce insulin resistance have not yet been established. The c-jun N-terminal kinase (JNK) activity has been involved in the pathophysiology of obesity and induces insulin resistance by increasing inhibitory IRS-1(ser307) phosphorylation. In this study we have evaluated the regulation of insulin signaling, JNK activation and IRS-1(ser307) phophorylation in liver, muscle and adipose tissue by immunoprecipitation and immunoblotting in rats fed with LS or normal salt diet (NS) during 9 weeks. LS increased body weight, visceral adiposity, blood glucose and plasma insulin levels, induced insulin resistance and did not change blood pressure. In LS rats a decrease in PI3-K/Akt was observed in liver and muscle and an increase in this pathway was seen in adipose tissue. JNK activity and IRS-1(ser307) phosphorylation were higher in insulin-resistant tissues. In summary, the insulin resistance, induced by LS, is tissue-specific and is accompanied by activation of JNK and IRS-1(ser307) phosphorylation. The impairment of the insulin signaling in these tissues, but not in adipose tissue, may lead to increased adiposity and insulin resistance in LS rats.     

Economic evaluation of a randomised trial of early return to normal activities versus cardiac rehabilitation after acute myocardial infarction

Background: Although there have been a number of economic evaluations of cardiac rehabilitation after acute myocardial infarction (AMI), none has considered only low-risk patients or control groups with no rehabilitation at all.Methods: An economic evaluation was included in a randomised controlled trial of patients following uncomplicated AMI. Eligible patients were randomised to return to normal activities after 6 weeks of standard rehabilitation (REHAB, n = 70) or to early return to normal activities 2 weeks after AMI with no formal rehabilitation (ERNA, n = 72). Outcomes were assessed weekly for 6 weeks, then 3, 6 and 12 months post-AMI. Outcomes included four quality of life (QOL) measures (physical abilities, distress, usual/social activities, self-care) and four measures of return to normal activities (paid and unpaid return to any work and to pre-AMI level of work). Statistical analysis included repeated-measures regression (QOL outcomes) and survival analysis (work outcomes).Results: There were no statistically significant differences between the two groups in any of the outcomes measured or in the use of other health services. The net cost that could be saved by the health service by targeting rehabilitation to high-risk patients was approximately $300 (Australian, 1999) per low-risk patient.Conclusions: Early return to normal activities without formal rehabilitation is cost-effective for low-risk patients.     

Electrocardiographic Criteria of True Left Bundle Branch Block: A Simple Sign to Predict a Better Clinical and Instrumental Response to CRT

Background: Cardiac resynchronization therapy (CRT) has proved to be very effective in improving morbidity and mortality in patients affected with severe congestive heart failure. Its efficacy has been shown to be greater in patients with left bundle branch block (LBBB). The aim of our study was to verify if newly proposed criteria for true LBBB identify patients with a better clinical and instrumental response to CRT. Methods: Between May 2007 and April 2011, 111 patients with left ventricular ejection fraction (LVEF) ≤ 35% and LBBB morphology received a CRT device and were divided into two groups according to QRS morphology. Group 1 (61 patients) consisted of patients with "true" LBBB morphology; group 2 (50 patients) consisted of patients with "false" LBBB. The primary endpoint was the utility of criteria for true LBBB to predict a composite endpoint of all-cause mortality and hospital admission with heart failure. The secondary endpoint was the utility of the same criteria to predict an absolute increase in LVEF ≥ 10%. Results: "False" LBBB morphology and a dose of bisoprolol <5 mg at last follow-up were the only parameters related to clinical outcome in multivariate analysis (respectively: hazard ratio [HR] 3.98, confidence interval [CI] 95% 1.51-10.48; HR 0.15, CI 95% 0.05-0.43). "True" LBBB morphology was the only variable significantly related to a greater increase in LVEF (HR 4.57, CI 95% 1.36-8.28). Conclusion: True LBBB morphology is related to a higher event-free survival rate in CRT patients and better echocardiographic response. (PACE 2012; 35:927-934).     

Western diet modulates insulin signaling, c-Jun N-terminal kinase activity, and insulin receptor substrate-1ser307 phosphorylation in a tissue-specific fashion

The mechanisms by which diet-induced obesity is associated with insulin resistance are not well established, and no study has until now integrated, in a temporal manner, functional insulin action data with insulin signaling in key insulin-sensitive tissues, including the hypothalamus. In this study, we evaluated the regulation of insulin sensitivity by hyperinsulinemic-euglycemic clamp procedures and insulin signaling, c-jun N-terminal kinase (JNK) activation and insulin receptor substrate (IRS)-1(ser307) phosphorylation in liver, muscle, adipose tissue, and hypothalamus, by immunoprecipitation and immunoblotting, in rats fed on a Western diet (WD) or control diet for 10 or 30 d. WD increased visceral adiposity, serum triacylglycerol, and insulin levels and reduced whole-body glucose use. After 10 d of WD (WD10) there was a decrease in IRS-1/phosphatidylinositol 3-kinase/protein kinase B pathway in hypothalamus and muscle, associated with an attenuation of the anorexigenic effect of insulin in the former and reduced glucose transport in the latter. In WD10, there was an increased glucose transport in adipose tissue in parallel to increased insulin signaling in this tissue. After 30 d of WD, insulin was less effective in suppressing hepatic glucose production, and this was associated with a decrease in insulin signaling in the liver. JNK activity and IRS-1(ser307) phosphorylation were higher in insulin-resistant tissues. In summary, the insulin resistance induced by WD is tissue specific and installs first in hypothalamus and muscle and later in liver, accompanied by activation of JNK and IRS-1(ser307) phosphorylation. The impairment of the insulin signaling in these tissues, but not in adipose tissue, may lead to increased adiposity and insulin resistance in the WD rats.     

Pharmacological pain management in chronic pancreatitis

Intense abdominal pain is a prominent feature of chronic pancreatitis and its treatment remains a major clinical challenge.Basic studies of pancreatic nerves and experimental human pain research have provided evidence that pain processing is abnormal in these patients and in many cases resembles that seen in neuropathic and chronic pain disorders.An important ultimate outcome of such aberrant pain processing is that once the disease has advanced and the pathophysiological processes are firmly established,the generation of pain can become self-perpetuating and independent of the initial peripheral nociceptive drive.Consequently,the management of pain by traditional methods based on nociceptive deafferentation(e.g.,surgery and visceral nerve blockade)becomes difficult and often ineffective.This novel and improved understanding of pain aetiology requires a paradigm shift in pain management of chronic pancreatitis.Modern mechanism based pain treatments taking into account altered pain processing are likely to increasingly replace invasive therapies targeting the nociceptive source,which should be reserved for special and carefully selected cases.In this review,we offer an overview of the current available pharmacological options for pain management in chronic pancreatitis.In addition,future options for pain management are discussed with special emphasis on personalized pain medicine and multidisciplinarity.     

Outcome for patients who relapse after allogeneic bone marrow transplantation for chronic myeloid leukemia. Chronic Leukemia Working Party. European Bone Marrow Transplantation Group

We studied the clinical course of 130 chronic myeloid leukemia (CML) patients (89 males and 41 females) in the European Bone Marrow Transplantation Group (EBMT) registry who received transplants before January 1, 1988 and who subsequently had evidence of recurrent leukemia. All patients had received a pretransplant conditioning regimen including total body irradiation (TBI). The first evidence of relapse was cytogenetic only in 74 (57%) patients and hematologic in 56 (43%). The overall actuarial survival from relapse was 36% at 6 years, with a significantly higher proportion of survivors among female patients (53% v 30%; P < .002). In univariate analysis, the 6-year probability of survival was 52% for patients with cytogenetic relapse and 30% for patients relapsing in chronic phase (CP), while no patient who relapsed in advanced phase (AP or BC) survived more than 3.5 years from relapse (P < .0001). The actuarial survival of patients relapsing before 6 months, between 6 and 12 months, and later than 12 months after transplant was 27%, 26%, and 45%, respectively (P < .002). Among patients with cytogenetic relapse, partial or complete disappearance of Ph-positive cells occurred in 40% of untreated patients and in 42% of those treated with interferon (IFN). However, IFN therapy significantly delayed progression toward hematologic disease. Cytogenetic responses were observed in 25% of patients who received IFN for relapse into CP, while only one minor cytogenetic response was reported in patients on conventional chemotherapy. For patients presenting with cytogenetic relapse as well as for those in hematologic relapse, IFN therapy significantly improved the 2-year probability of survival. However, long-term survival for IFN-treated patients in either group was not different from long-term survival in comparable patients not receiving IFN therapy. Twenty-nine patients of this series underwent a second bone marrow transplant (BMT) and the projected survival at 4 years after the second transplant is 28%. In multivariate Cox regression analysis, four factors remained significantly associated with survival: disease phase at relapse (P < .0001), duration of time interval from BMT to relapse (P = .0001), interferon therapy at relapse (P = .0024), and patient sex (P = .0032). This retrospective study provides evidence that some patients who relapse after BMT may benefit from treatment with IFN; a second BMT may offer the chance of cure. Data from this analysis may be useful in designing future prospective trials on posttransplant CML relapse.