Siobhan V. Glavey

Uterorelaxant effect of ghrelin on human myometrial contractility

OBJECTIVE Ghrelin is a peptide that regulates maternal appetite and energy expenditure as well as playing a role in fetal nutrition. The purpose of the study was to investigate the effects of ghrelin on human myometrial contractility in vitro. STUDY DESIGN Biopsy specimens of human myometrium were obtained at elective cesarean section (n = 21). Dissected myometrial strips suspended under isometric conditions, undergoing spontaneous and oxytocin-induced contractions, were exposed to cumulative additions of ghrelin in the concentration range of 1 nmol/L to 1 micromol/L. Control experiments were performed simultaneously. RESULT Ghrelin exerted an inhibitory effect on contractility, compared with control strips. The mean maximal inhibition values were as follows: 33.66% +/- 2.63% for spontaneous contractions (n = 6; P < .05), and 31.55% +/- 4.64% for oxytocin-induced contractions (n = 6; P < .05). CONCLUSION This inhibitory effect of ghrelin on uterine contractions suggests it plays a physiologic role in regulation of myometrial activity and further studies to evaluate the signaling pathways involved may help to define this role. These findings highlight the emerging role of metabolic modulation of myometrium, and particularly at extremes of body mass index measurements.

Long-term outcome of patients with mutiple myeloma-related advanced renal failure following auto-SCT

Renal failure commonly complicates multiple myeloma (MM) and is associated with reduced survival. It is not clear whether auto-SCT results in improved renal function or attainment of independence from dialysis in patients with advanced renal impairment due to MM. We conducted a retrospective cohort study of all patients who underwent auto-SCT for MM complicated by advanced renal failure at our institution over a 10-year period (2000–2010). We aimed to assess the association between auto-SCT and renal outcome in patients with serum creatinine (SCr) over 3 mg/dL, attributable to MM, including those who were dialysis dependent. Thirty patients (2.8% of all auto-SCT patients) met inclusion criteria. Fourteen of 15 patients who were dialysis dependent before auto-SCT remained dialysis dependent in the long term despite hematological response (HR). Of the remaining 15 patients with SCr >3 mg/dL, an improvement in glomerular filtration rate (GFR) from 15 to 19.4 mL/min/1.73 m2 was noted post auto-SCT (P=0.035); however, neither HR post auto-SCT or pre-existing renal function were independently associated with renal outcome. Auto-SCT was not associated with independence from dialysis in patients with renal failure due to MM at our institution. Although auto-SCT was associated with an improvement in GFR in patients with SCr >3 mg/dL, this improvement was not related to HR.

Monoclonal gammopathy: The good, the bad and the ugly.

Monoclonal gammopathy of undetermined significance (MGUS) is a condition characterized by the presence of a monoclonal gammopathy (MG) in which the clonal mass has not reached a predefined state in which the condition is considered malignant. It is a precursor to conditions such as multiple myeloma or lymphoma at a rate of ~1%/year. Thus, from a hematologic standpoint, MGUS is a fairly benign condition. However, it is now recognized that organ damage resulting from just the MG without the need MM or lymphoma can occur. One of the most recognized is nephropathy secondary to monoclonal gammopathy of renal significance (MGRS). Other well-recognized conditions include neuropathies, oculopathies and dermopathies. Some conditions such as autoimmune diseases and coagulopathies are less common and recognized. Finally, systemic involvement of multiple organs is well described in several entities. In all of these conditions, the role of the MG is no longer insignificant. Thus, the term MGUS should be avoided when describing these entities.

AKT as a therapeutic target in multiple myeloma

Introduction: Multiple myeloma remains an incurable malignancy with poor survival. Novel therapeutic approaches capable of improving outcomes in patients with multiple myeloma are urgently required. AKT is a central node in the phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin signaling pathway with high expression in advanced and resistant multiple myeloma. AKT contributes to multiple oncogenic functions in multiple myeloma which may be exploited therapeutically. Promising preclinical data has lent support for pursuing further development of AKT inhibitors in multiple myeloma. Lead drugs are now entering the clinic. Areas covered: The rationale for AKT inhibition in multiple myeloma, pharmacological subtypes of AKT inhibitors in development, available results of clinical studies of AKT inhibitors and suitable drug partners for further development in combination with AKT inhibition in multiple myeloma are discussed. Expert opinion: AKT inhibitors are a welcome addition to the armamentarium against multiple myeloma and promising clinical activity is being reported from ongoing trials in combination with established and/or novel treatment approaches. AKT inhibitors may be set to improve patient outcomes when used in combination with synergistic drug partners.

The impact of dialysis on the survival of patients with immunoglobulin light chain (AL) amyloidosis undergoing autologous stem cell transplantation

BACKGROUND Acute renal failure requiring dialysis is associated with high mortality during autologous stem cell transplantation (ASCT). This study examined the association between acute renal failure and mortality in immunoglobulin light chain (AL) amyloidosis during ASCT. METHODS Between 1996 and 2010, 408 ASCT patients were evaluated. Data were collected from electronic medical records. RESULTS Dialysis was performed on 72 (17.6%) patients. Eight patients started dialysis >30 days prior to ASCT (Group II), 36 started ±30 days after ASCT (Group III) and 28 initiated dialysis >1 month after ASCT (Group IV). Patients who never dialyzed were assigned to Group I. There were no significant age or sex differences. Median overall survival (OS) had not been reached in Groups I and II but was 7.0 months in Group III and 48.5 months in Group IV (P < 0.001). Treatment-related mortality (TRM) was observed in 44.4% of the patients in Group III, 6-fold higher than the next highest group (P < 0.001). The most common causes of TRM were cardiac and sepsis. In the multivariate analysis, only hypoalbuminemia (<2.5 g/dL, P < 0.001) and estimated glomerular filtration rate (eGFR) <40 mL/min/1.73 m(2) (P < 0.001) were independently associated with starting dialysis within 30 days of ASCT. CONCLUSIONS The study found significant differences in the OS depending on when the acute renal failure occurred. Patients who required dialysis within 30 days of ASCT had the highest rate of TRM. Screening with serum albumin and eGFR may reduce the risk.

Umbilical artery tone in maternal obesity

BackgroundThe increasing prevalence of obesity constitutes a major health problem in obstetrics with implications for feto-maternal growth and wellbeing. This study investigated and compared the contractile properties of umbilical arteries excised from obese women, with those excised from women with a normal body mass index (BMI).MethodsSections of umbilical artery were obtained from umbilical cord samples immediately after delivery and mounted for isometric recording in organ tissue baths under physiological conditions. Cumulative additions of 5-Hydroxytryptamine (5-HT) and Prostaglandin F-2alpha (PgF2alpha) were added in the concentration range of 1 nmol/L to 10 micromol/L. Control vessels were exposed to Krebs physiological salt solution (PSS) only. The resultant effects of each drug addition were measured using the Powerlab hardware unit.Results5-HT exerted a significant effect on human umbilical artery tone at concentrations of 100 nmol/L, 1 micromol/L, and 10 micromol/L in normal (n = 5; P < 0.05) and obese (n = 5; P < 0.05) women. The contractile effect was significantly greater in vessels from obese women {Mean Maximum Tension (MMT) = 4.2532 g} than in those from women of normal BMI (MMT = 2.97 g; P < 0.05). PgF2alpha exerted a significant contractile effect on vessels at 1 micromol/L and 10 micromol/L concentrations when compared with controls (n = 5; P < 0.05). There was a non-significant trend towards an enhanced tone response in vessels from obese women (MMT = 3.02 g; n = 5), in comparison to vessels from women of a normal BMI (MMT = 2.358 g; n = 5; P > 0.05).ConclusionThese findings support the hypothesis that endogenous regulation of umbilical artery tone is altered in association with maternal obesity. This may be linked to the cardiovascular effects of secretory products of adipose tissue, with implications for the feto-maternal circulation.

Erratum: Long-term outcome of patients with multiple myeloma-related advanced renal failure following auto-SCT (Bone Marrow Transplantation (2014) 49 (996) DOI:10.1038/bmt.2014.24)

Department of Hematology, Galway University Hospital, Galway, Ireland; Division of Nephrology, Mayo Clinic, Rochester, MN, USA and Division of Hematology, Mayo Clinic, Rochester, MN, USA. Correspondence: Dr SV Glavey, Department of Hematology, Galway University Hospital, Newcastle Road, Galway, Ireland. E-mail: siobhan.glavey@nuigalway.ie Bone Marrow Transplantation (2014) 49, 996 & 2014 Macmillan Publishers Limited All rights reserved 0268-3369/14