Role of p34cdc2-mediated phosphorylations in two-step activation of pp60c-src during mitosis.

Phosphorylation of pp60c-src by p34cdc2 at three amino-proximal serine/threonine residues is temporally correlated with, but insufficient for, mitotic activation of c-Src kinase. The direct cause of activation during mitosis appears to be temporally correlated partial dephosphorylation of Tyr-527, a residue whose phosphorylation strongly suppresses pp60c-src activity. Site-directed mutagenesis of the serine/threonine phosphorylation sites blocks half the mitosis-specific decrease in Tyr-527 phosphorylation and half the increase in pp60c-src kinase activity. We conclude that p34cdc2 partially activates pp60c-src by a two-step process in which its serine/threonine phosphorylations either sensitize pp60c-src to a Tyr-527 phosphatase or desensitize it to a Tyr-527 kinase. Furthermore, additional events, independent of these p34cdc2-mediated phosphorylations, participate in mitotic activation of pp60c-src.     

Reduced-intensity conditioning is effective and safe for transplantation of patients with Shwachman-Diamond syndrome

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment for the BM dysfunction seen in patients with Shwachman-Diamond syndrome (SDS). Historically, these patients have fared poorly with intensive conditioning regimens with increased regimen-related toxicity especially involving the heart and lungs. We report our institutional experience with a reduced-intensity-conditioning protocol in seven patients with SDS and BM aplasia or myelodysplastic syndrome/AML. The preparative regimen consisted of Campath-1H, fludarabine and melphalan. Four patients received matched related marrow and three received unrelated stem cells (two PBSCs and one marrow). All but one was 8 of 8 allele HLA matched. All patients established 100% donor-derived hematopoiesis. No patient in this cohort developed grades III-IV GVHD. One patient had grade II skin GVHD that responded to systemic corticosteroids and one had grade I skin GVHD, treated with topical corticosteroids. Two out of seven patients developed bacterial infections in the early post transplant period. Viral infections were seen in four out of seven patients and were successfully treated with appropriate antiviral therapy. All patients are currently alive. These data indicate that HSCT with reduced-intensity conditioning is feasible in patients with SDS and associated with excellent donor cell engraftment and modest morbidity.     

Mechanism-based Classification and Physical Therapy Management of Persons with Cancer Pain: A Prospective Case Series

Context:

Mechanism-based classification (MBC) was established with current evidence and physical therapy (PT) management methods for both cancer and for noncancer pain.

Aims:

This study aims to describe the efficacy of MBC-based PT in persons with primary complaints of cancer pain.

Settings and Design:

A prospective case series of patients who attended the physiotherapy department of a multispecialty university-affiliated teaching hospital.

Material and Methods:

A total of 24 adults (18 female, 6 male) aged 47.5 ± 10.6 years, with primary diagnosis of heterogeneous group of cancer, chief complaints of chronic disabling pain were included in the study on their consent for participation The patients were evaluated and classified on the basis of five predominant mechanisms for pain. Physical therapy interventions were recommended based on mechanisms identified and home program was prescribed with a patient log to ensure compliance. Treatments were given in five consecutive weekly sessions for five weeks each of 30 min duration.

Statistical Analysis Used:

Pre–post comparisons for pain severity (PS) and pain interference (PI) subscales of Brief pain inventory-Cancer pain (BPI-CP) and, European organization for research and treatment in cancer-quality of life questionnaire (EORTC-QLQ-C30) were done using Wilcoxon signed-rank test at 95% confidence interval using SPSS for Windows version 16.0 (SPSS Inc, Chicago, IL).

Results:

There were statistically significant (P < 0.05) reduction in pain severity, pain interference and total BPI-CP scores, and the EORTC-QLQ-C30.

Conclusion:

MBC-PT was effective for improving BPI-CP and EORTC-QLQ-C30 scores in people with cancer pain.     

Association of UGT1A6 gene polymorphism with clinical outcome in pediatric epileptic patients on sodium valproate monotherapy

Pediatric epilepsy comprises chronic neurological disorders characterized by recurrent seizures. Sodium valproate is one of the common antiseizure medications used for treatment. Glucuronide conjugation is the major metabolic pathway of sodium valproate, carried out by the enzyme uridine 5′-diphosphate (UDP) glucuronosyl transferase (UGT) whose gene polymorphisms may alter the clinical outcome. The objective of this study was to assess the association between UGT1A6 genetic polymorphism and clinical outcome in terms of efficacy and tolerability in pediatric epileptic patients on sodium valproate monotherapy. Pediatric epileptic patients (n=65) aged 2-18 years receiving sodium valproate monotherapy for the past one month were included. Genetic polymorphism patterns of UGT1A6 (T19G, A541G, A552C) were evaluated by PCR-RFLP. Clinical outcome was seizure control during the 6 months observation period. Tolerability was measured by estimating the hepatic, renal, and other lab parameters. Out of 65 patients, TT (40%), TG (57%), and GG (3%) patterns were observed in UGT1A6 (T19G) gene, AA (51%), AG (40%), and GG (9%) in (A541G) gene, and AA (43%), AC (43%), and CC (14%) in (A552C) gene. No statistical difference in clinical outcome was found for different UGT1A6 genetic polymorphism patterns. We concluded that different patterns of UGT1A6 genetic polymorphism were not associated with the clinical outcome of sodium valproate in terms of efficacy and tolerability. Sodium valproate was well-tolerated among pediatric patients with epilepsy and can be used as an effective antiseizure medication.     

Perioperative blood transfusion affects hepatitis C virus (HCV)-specific immune responses and outcome following liver transplantation in HCV-infected patients

Objectives:Perioperative factors can affect outcomes of liver transplantation (LT) in recipients with hepatitis C virus (HCV) infection. This study was conducted to investigate whether the immunomodulatory effects of packed red blood cells (PRBC) and platelets administered in the perioperative period might affect immune responses to HCV and thus outcomes in LT recipients.Methods:Data for a total of 257 HCV LT recipients were analysed. Data on clinical demographics including perioperative transfusion (during and within the first 24 h), serum cytokine concentration, HCV-specific interferon-γ (IFN-γ) and interleukin-17 (IL-17) producing cells, and outcomes including graft and patient survival were analysed.Results:Patient survival was higher in HCV LT recipients who did not receive transfusions (Group 1, n = 65) than in those who did (Group 2, n = 192). One-year patient survival was 95% in Group 1 and 88% in Group 2 (P = 0.02); 5-year survival was 77% in Group 1 and 66% in Group 2 (P = 0.05). Group 2 had an increased post-transplant viral load (P = 0.032) and increased incidence of advanced fibrosis at 1 year (P = 0.04). After LT, Group 2 showed increased IL-10, IL-17, IL-1β and IL-6, and decreased IFN-γ, and a significantly increased rate of IL-17 production against HCV antigen. Increasing donor age (P = 0.02), PRBC transfusion (P < 0.01) and platelets administration were associated with worse survival.Conclusions:Transfusion had a negative impact on LT recipients with HCV. The associated early increase in pro-HCV IL-17 and IL-6, with decreased IFN-γ, suggests that transfusion may be associated with the modulation of HCV-specific responses, increased fibrosis and poor transplant outcomes.