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.     

Non‐Hodgkin's lymphoma presenting as breast masses: A series of 10 cases diagnosed on FNAC

Primary breast lymphoma (PBL) is a rare disease, which comprises 0.04–0.53% of all primary malignant tumors of the breast. The most frequent histological subtype is diffuse large B‐cell type (DLBCL) (40–70%). Differentiation of PBLs from other breast tumors such as poorly differentiated carcinomas and lobular carcinoma may at times be difficult on cytomorphology alone. An audit of breast lymphomas diagnosed on fine needle aspiration cytology (FNAC) over a period of 9 years (2001–2009) was performed. Ten cases were retrieved and the cytomorphology was reviewed along with immunochemistry (IHC), flow cytometry as well as histopathology, wherever available. The age of patients ranged from 17 to 83 years. Eight cases were diagnosed as non‐Hodgkin's lymphoma, high‐grade on FNAC. Histopathology was available in four of these cases and cell block was available in one case. Lymphoid cells were positive for leukocyte‐common antigen (LCA) and CD20 and negative for CD3 in these cases. The same was confirmed by flow cytometry on aspirated material in one case. A diagnosis of DLBCL was offered in these five cases. One case was a low‐grade NHL and another case was a young male, a known case of acute leukemia and had leukemic infiltration in the breast lump. We wish to emphasize the potential importance of FNAC in breast lymphoma and the same can be helpful to avoid unnecessary surgery in these cases. The differential diagnostic entities have been discussed. IHC and flow cytometry can be performed on the aspirated material and provide valuable information. Diagn. Cytopathol. 2013. © 2011 Wiley Periodicals, Inc.     

Effect of total knee arthroplasty on type II diabetes mellitus and hypertension: A prospective study

Context:

Advanced osteoarthritis of knee joint if bilateral, severely restricts patient mobility. This acts as an aggravating factor for pre existing comorbid elements of metabolical syndrome (MS) like Type II diabetes mellitus and hypertension as patients are unable to carry out therapeutic walks. Successfully implanted total knee arthroplasty (TKA) increases physical activity and enables to carry out therapeutic walks thus may help in better control of type II diabetes mellitus and hypertension. The objective of this prospective study was to find whether TKA for osteoarthritis knee had any effect to improve blood glucose levels and reduce blood pressure.

Materials and Methods:

A prospective study was done in which patients operated for tricompartmental osteoarthritis of knee with associated comorbidities like Type II diabetes mellitus or hypertension during a period of 2008 and 2009 were studied. One hundred and twenty patients were enrolled (55 diabetics, 65 hypertensives) who met our inclusion criteria. Preoperative knee society score, lower extremity activity scale fasting blood glucose level and systolic and diastolic blood pressure were compared with one year followup values. The KSS and LEAS scores were analysed by the Wilcoxon signed ranked test, while the fasting blood glucose (FBG) levels and systolic and diastolic blood pressure levels were analysed by paired ‘t’ test.

Results:

The reduction of systolic blood pressure by 8 mmHg (t = 5.6, P value < 0.05) and diastolic blood pressure by 6 mmHg (t = 7.6, P value < 0.05) was recorded which was statistically significant. However, no statistically significant effect on fasting blood glucose levels was observed (t = -0.77, P value = 0.442). KSS improved in DM from preoperative 29 to 86 and LEAS improved from 6.7 to 11.3.

Conclusions:

Authors are of the opinion that successful total knee replacement results in increased physical activity and reduces blood pressure (systolic and diastolic) in hypertensives. However, the same is not seen in blood glucose level. Increased physical activity and reduced dependence on NSAIDS postoperatively, may be contributing in reduction of systolic and diastolic blood pressure. Further studies in this aspect are necessary.     

CT based evaluation of odontoid morphology in the Indian population

Background:

Anterior fixation using two 3.5 mm screws is typically recommended for type II odontoid fractures. However, it is unsuitable in patients with an odontoid diameter of <9.0 mm. There is no data regarding the morphology of odontoid process in the Indian population. The aim of our study was to: a) Measure the external diameters of odontoid process in the Indian population using CT scan and thus determine the feasibility of two 3.5 mm screw fixation in them. b) Determine if any correlation exists between body height (Ht) and weight (Wt) and external odontoid diameters.

Materials and Methods:

CT images of odontoid process of 100 consecutive patients were analyzed. Antero- posterior (AP) and transverse (TD), outer diameters of the odontoid process were measured from the base and at 1 mm interval upwards on axial CT images.

Results:

The mean AP and mean TD were 11.52 mm and 9.85 mm, respectively. Fifty-five (55%) of the patients had at least one TD <9.0 mm. Five (5%) patients had at least one TD <7.4 mm. None of the patients had any diameter <5.5 mm. Body Ht correlated significantly with mean AP and mean TD of the odontoid process (AP: r = 0.276, P = 0.013; TD: r = 0.359, P = 0.001), whereas body Wt correlated significantly only with mean TD (AP: r = 0.162, P = 0.15; TD: r = 0.297, P = 0.007).

Conclusion:

More than half of the study population (55%) was unsuitable for two 3.5 mm screw fixation for type II odontoid fracture. Two 2.7 mm screws can be safely used in 95% of the population. A 4.5 mm Herbert screw can be safely used in the entire population. We recommend two 2.7 mm screws or a 4.5 mm Herbert screw for fixation of these fractures in the Indian population. Body height showed a significant correlation with external odontoid diameters, whereas weight showed significant correlation only with TD of the odontoid process.     

In vivo laser speckle imaging reveals microvascular remodeling and hemodynamic changes during wound healing angiogenesis

Laser speckle contrast imaging (LSCI) is a high-resolution and high contrast optical imaging technique often used to characterize hemodynamic changes in short-term physiological experiments. In this study, we demonstrate the utility of LSCI for characterizing microvascular remodeling and hemodynamic changes during wound healing angiogenesis in vivo. A 2 mm diameter hole was made in the mouse ear and the periphery of the wound imaged in vivo using LSCI over 12 days. We were able to visualize and quantify the vascular and perfusion changes that accompanied wound healing in the microenvironment proximal to the wound, and validated these changes with histology. We found that consistent with the stages of wound healing, microvessel density increased during the initial inflammatory phase (i.e., day 0–3), stayed elevated through the tissue formation phase (i.e., until day 7) and returned to baseline during the tissue remodeling phase (i.e., by day 12). Concomitant “wide area mapping” of blood flow revealed that tissue perfusion in the wound periphery initially decreased, gradually increased from day 3–7, and subsided as healing completed. Interestingly, some regions exhibited a reestablishment of tissue perfusion approximately 6 days earlier than the ~18 days usually reported for the long term remodeling phase. The results from this study demonstrate that LSCI is an ideal platform for elucidating in vivo changes in microvascular hemodynamics and angiogenesis, and has the potential to offer invaluable insights in a range of disease models involving abnormal hemodynamics, such as diabetes and tumors.     

Biosimilar DMARD in rheumatology: A general perspective with focus on India

Biologic disease modifying anti-rheumatic drugs (DMARD) have revolutionized the management of several rheumatic disorders, especially those with autoimmune inflammatory etiology. A decade of experience has further endorsed their efficacy and unraveled safety issues. Treat to target remission is the current mantra. Infections remain the single most important complication. However, the access to biologics has been severely restricted by their exorbitant cost. Several biologics will lose their patent in the imminent future. An exact replica of a protein molecule is difficult if not impossible. Molecules seemingly similar to biologics called biosimilars or ‘follow on biologics’ are likely to flood the markets world wide at a challenging and affordable price. However, the acceptability of biosimilars will be driven by several contentious issues connected with manufacture, standardization, extent of validation (compared to source innovator biologic), interchangeability (with biologic), regulatory issues, and other patient centric socioeconomic issues. India is likely to provide a fertile field for biosimilar drugs and patients stand to gain from an expanded access and newer treatment paradigms. The fierce competition between several pharmaceutical companies (Indian and multinationals) to gain supremacy will fuel better affordability, equity and access to medicine while upholding the science of quality drugs. The stage is now set for this next big revolution in therapeutics.