Spry1 as a novel regulator of erythropoiesis, EPO/EPOR target, and suppressor of JAK2

Sprouty proteins are established modifiers of receptor tyrosine kinase (RTK) signaling and play important roles in vasculogenesis, bone morphogenesis, and renal uteric branching. Little is understood, however, concerning possible roles for these molecular adaptors during hematopoiesis. Within erythroid lineage, Spry1 was observed to be selectively and highly expressed at CFU-e to erythroblast stages. In analyses of possible functional roles, an Mx1-Cre approach was applied to conditionally delete Spry1. At steady state, Spry1 deletion selectively perturbed erythroid development and led to reticulocytosis plus heightened splenic erythropoiesis. When challenged by hemolysis, Spry1-null mice exhibited worsened anemia and delayed recovery. During short-term marrow transplantation, Spry1-null donor marrow also failed to efficiently rescue the erythron. In each anemia model, however, hyperexpansion of erythroid progenitors was observed. Spry function depends on phosphorylation of a conserved N-terminal PY motif. Through an LC-MS/MS approach, Spry1 was discovered to be regulated via the erythropoietin receptor (EPOR), with marked EPO-induced Spry1-PY53 phosphorylation observed. When EPOR signaling pathways were analyzed within Spry1-deficient erythroid progenitors, hyperactivation of not only Erk1,2 but also Jak2 was observed. Studies implicate Spry1 as a novel regulator of erythropoiesis during anemia, transducer of EPOR signals, and candidate suppressor of Jak2 activity.     

Prospective study of histomorphometry,biochemical bone markers and bone densitometric response to pamidronate in β-thalassaemia presenting with osteopenia-osteoporosis syndrome

This study aimed to evaluate bone remodelling disorders in thalassaemia by using pamidronate (PD) infusion with or without hormone replacement therapy (HRT) as a diagnostic-therapeutic tool. In this prospective study, 24 adult thalassaemia major (TM) and 10 thalassaemia intermedia (TI) patients received either PD and HRT or HRT only (controls) for 3 years. Eugonadal patients with TI had PD only. Bone remodelling was assessed by dual energy X ray absorptiometry (DXA scan), type 1-collagen biochemical bone markers (BBM) and histomorphometry of iliac crest biopsy before and after PD. As a group, thalassaemics had a significant improvement in spinal and femoral bone mineral density Z scores following PD (P < 0·01) compared to the controls. Although BBM were comparable pre-therapy, they were significantly lower in the PD cohort (P < 0·001) compared to the control group. All patients had osteopenia, diminished osteoid formation and bone volume on histomorphometry pre-therapy with high turnover bone disease (HTO) in TM and low-turnover disease (LTO) in TI. In TM, bone volume improved significantly, whereas TI patients showed little or no response to PD. In conclusion, histomorphometry data suggest that TM patients have a distinct pathology of high turnover bone disease compared to TI patients, who have low-turnover disease.     

Comorbidities,Treatment and Ensuing Survival in Men with Prostate Cancer

Background  

Comorbidity is poorly integrated into prostate cancer decision making.     

Screening and Management of Hepatocellular Carcinoma: The Australian Perspective

Hepatocellular cancer (HCC) remains relatively uncommon in Australia, however incidence rates have been progressively rising, as in many other western countries, over the last few decades. Currently, chronic hepatitis B (HBV) or hepatitis C (HCV) infections accounts for the majority of primary liver cancers, but as the incidence of HBV declines with the implementation of immunization programs and HCV is eradicated by direct acting anti viral therapies, more cases will be due to metabolic causes such as non-alcoholic fatty liver disease. The cornerstone of management involves identifying potential risk factors and implementing both preventative and therapeutic strategies. As we gain more knowledge about the pathogenesis of HCC, newer agents such as multikinase inhibtors have been developed to target specific pathways and have been shown to delay time to disease progression. Well defined screening, diagnostic and management algorithms will allow for standardisation of protocols and enable classification of patients and treatment modalities offering some prediction of outcome and prognosis. It is anticipated that effective screening and surveillance programs will enable the detection of tumours at an early stage thereby allowing for a wider range of therapeutic options with improved outcomes.     

Assessment of Hemodialysis Adequacy by Ionic Dialysance: Comparison to Standard Method of Urea Removal

Background. The hemodialysis adequacy is one of the most important issues influencing the survival of patients on maintenance hemodialysis (HD). Assessment of measuring the delivered dialysis dose using clearance × time/volume (Kt/V) index requires multiple blood sampling. New methods for assessment of dialysis dose based on ionic dialysance (ID) have been suggested. Online conductivity monitoring (using sodium flux as a surrogate for urea) allows the repeated noninvasive measurement of Kt/V on each HD treatment. In this study we have compared this method with the standard method of estimating Kt/V. Methods. We studied 24 established HD patients over a 4 week time period. Patients were dialyzed using Fresenius 4008S dialysis monitors, equipped with modules to measure ID. Data were manually collected and analyzed using the appropriate statistical software. Urea removal (UR) was measured once a week by a two-pool calculation, estimating an eKt/V. Results. The Kt/V measured by ID highly correlated with the one derived from the measurement of the UR (r = 0.8959, p< 0.0001). The ID underestimated UR by the mean of 6%. The ID varied greatly within individual patients with a median of 1.29 ± 0.22. If the eKt/V ≥ 1.2 is considered adequate, 33% of the patients would have been inadequately dialyzed. The mean HD duration to achieve an adequate dialysis was 4 hours and 47 minutes with high interpatient variability. Conclusion. The ID seems to be an easily obtained measure of the delivered dialysis dose, correlating well with standard UR method. Substantial individual variations imply that repeated measures (ideally for all treatments) are necessary to obtain a real answer to the mean treatment dose being delivered to the patients.     

Prediction of atrial fibrillation in patients with severe mitral stenosis—role of atrial contribution to ventricular filling

Objective—Atrial contribution to ventricular filling was studied to assess its role in predicting the future development of atrial fibrillation (AF) in patients with severe mitral stenosis (MS) and sinus rhythm.

Design—Two hundred and eight patients with severe MS and sinus rhythm were followed up for 1 year. Baseline data were compared between group I (who developed AF at follow‐up) and group II (who maintained sinus rhythm). Left atrial size, severity of MS, velocity time integral (VTI) of mitral valve flow and VTI due to atrial systole (A‐VTI) were noted. Percentage contribution of A‐VTI to the total VTI (A‐%) was calculated. Sensitivity and specificity of A‐% to predict the onset of AF was obtained.

Results—Left atrial size, severity of MS and total VTI were similar in the two groups. Group I patients were older (31.1?±?9.1 and 18.4?±?6.5 years, respectively, p?<?0.03) with smaller A‐VTI (5.3?±?2.2 and 6.7?± 3.4?cm, respectively, p?<?0.01) and A‐% (8.9?±?1.8 and 11.2?±?2.7, respectively, p?<?0.003). A‐% of <9% (mean value of A‐VTI in group I) had high sensitivity (84%, positive predictive value 76%) and specificity (80%, negative predictive value 87%) to predict the development of AF.

Conclusion—Atrial contribution to ventricular filling is reduced in patients prone to develop AF (due to inefficient left atrial contraction, much before its dilatation). It can be used for early identification of patients likely to develop AF with high sensitivity and specificity. It is simple, easily available, cost‐effective and will guide earlier intervention and more frequent follow‐up. There is a preclinical loss in atrial pump function much before the eventual onset of AF.