Inhibition of prostaglandin E2 restores defective lymphocyte proliferation and cell-mediated lympholysis in recipients after allogeneic marrow grafting

Prostaglandins are said to influence T and B cell function by inhibiting the generation of interleukin 2 (IL 2) and the formation of suppressor lymphocytes. After bone marrow transplantation, patients usually have a profound immunodeficiency that persists in recipients with chronic graft-v-host disease (GVHD) and generally resolves in long- term survivors without GVHD. In vitro tests of lymphocyte function such as allogeneic mixed lymphocyte culture (MLC) and cell-mediated lympholysis (CML) have been shown to be impaired in many patients. We postulated that prostaglandin E2 (PGE2) plays a role in the impaired in vitro tests. To test this hypothesis, we studied in vitro tests in the presence of PGE2 antagonists, indomethacin, and anti-PGE2 antiserum with cells from 22 short-term patients (less than 100 days postgrafting) and 32 long-term survivors with or without GVHD. Results show that blockade of PGE2 release by indomethacin and anti-PGE2 significantly (P less than .01) enhanced the MLC (+67%) and the CML responses (+10.5%) of cells from long-term survivors with chronic GVHD but not from those of long-term, stable recipients. No enhancement of MLC and CML activity was observed with cells from donors of long-term recipients. In patients shortly after marrow grafting, enhancement in the MLC was not significant. However, CML activity in this patient group was significantly increased (+12.5% in recipients with no GVHD, 8.5% in those with acute GVHD, P less than .01). Indomethacin also suppressed the activity of nonspecific suppressor cells in patients with chronic GVHD. When cells from patients with chronic GVHD were treated with recombinant IL 2 and IL 2 combined with indomethacin, it was possible to get an additional augmentation of lymphocyte proliferation after the addition of indomethacin to IL 2-treated cultures. Thus it is very likely that PGE2 inhibits T lymphocyte proliferation, not exclusively by inhibition of IL2 production or activity. We conclude that PGE2, among other factors, may play a role in the pathogenesis of the immunodeficiency after transplantation. PGE2 does not act primarily by interfering with IL2 but presumably by inducing a suppressorlike activity.     

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.     

Prognostic role of non-sustained ventricular tachycardia in a large cohort of patients with idiopathic dilated cardiomyopathy.

BACKGROUND: The identification of patients with idiopathic dilated cardiomyopathy (IDC) at higher risk of sudden death (SD) is still an unsolved issue, and the role of non-sustained ventricular tachycardia (NSVT) uncertain. METHODS: The effect of NSVT on total mortality, SD and life-threatening arrhythmias was evaluated in 554 patients with IDC on optimal medical treatment and at long-term follow-up (81 +/- 58 months). RESULTS: At diagnosis, 240 patients (43%) had NSVT at Holter monitoring and 314 (57%) did not. During follow-up, 189 patients (5/100 patients-year) died or underwent heart transplantation; SD occurred in 53 patients (1.4/100 patients-year); SD + non-fatal ventricular arrhythmias occurred in 75 patients (2/100 patients-year). Patients with and without NSVT at diagnosis had the same 5-year transplant-free survival rate (76 vs 76%, p = NS) and a similar incidence of SD (10 vs 7%, p = NS). The length and rate of NSVT did not show any significant relationship with the outcome. Only heart failure symptoms (NYHA class III-IV) (hazard ratio [HR] 1.9, p = 0.015) and severe left ventricular impairment (left ventricular ejection fraction < or = 0.30 and left ventricular end-diastolic diameter > or = 70 mm) (HR 2.7, p < 0.0001) were independently associated with higher SD risk. At multivariate analysis the presence of frequent NSVT episodes (> or = 3 runs/day) was associated with an increased risk of total mortality (HR 1.68, p = 0.041) and of major ventricular arrhythmias (HR 2.11, p = 0.037), but only in the subgroup of patients with severe left ventricular impairment. CONCLUSIONS: Patients with advanced heart failure symptoms, severe left ventricular dysfunction and dilation had a higher risk of SD independently of NSVT. The finding of more frequent NSVT was associated with an increased risk of all-cause mortality and of major ventricular arrhythmias in patients with severe left ventricular impairment.     

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.     

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.     

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.     

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.     

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.