Effect of Anions on the Iron Release Pathways of Human Serum Transferrin

Transferrin, the serum iron transport protein in humans, is used to transport 30-40 mg of iron per day through blood. The accessibility of transferrin makes it an attractive target for iron cheating therapeutic agents used in the treatment of iron overload. There is an ongoing search for ligands which can accelerate the rate of iron release, as the currently approved drug DFO has a very slow rate for iron removal. Previous studies have shown that anions can accelerate the rate of iron release. Studies on the effect of anions on the rates of iron release from C-terminal monoferric transferrin at pH 7.4 have been conducted using the ligands acetohydroxamic acid (AHA) and 1,2-dimethyl-3-hydroxy-pyridinone (L1), which follow saturation kinetics, and the ligands, nitrilotriacetic acid (NTA) and diethylenetriaminepentaacetic acid (DTPA), which follow first order kinetics with respect to the ligand concentration. The effects of sulfonates, phosphonates and phosphonocarboxylates have been studied. The anions are divided into two types, simple (non-coordinating) and complex (capable of chelating iron). The simple anions accelerate the rate of iron release, presumably by binding to an allosteric anion binding site on the transferrin. This binding increase the value of kmax for the saturation pathway for AHA and L1 and introduces a kmax for NTA, which otherwise does not have a saturation component. This changes the kinetic behavior of NTA from a strictly first-order dependence on the ligand concentration to complex kinetics, a combination of saturation and first-order kinetics. The complex anions, which can also chelate iron, decrease the rate of iron release by the reference ligands. These anions can also generate a small first order component for iron removal by ligands that normally follow saturation kinetics. These studies emphasize that the appearance of the first order component is due to the replacement of synergistic anion by the incoming chelating ligand and is not an allosteric effect of the anionic ligand. Distinct effects of anions on the saturation and first-order components for iron release are reported. For NTA, the major impact of anions is a decrease in the value of k’

Subarachnoid haemorrhage mimicking unstable angina: a case report

Subarachnoid haemorrhage (SAH) is medical emergency caused by bleeding into the subarachnoid space. It is caused by rupture of an aneurysm or arteriovenous malformations (AVM). Symptoms of SAH are severe headache, nausea, vomiting, impaired consciousness and seizures. Neck stiffness and neck pain are relatively uncommon. Risk factors are high blood pressure, smoking, family history, alcoholism and even cocaine use. Diagnosis is mainly made by CT scan of head which should be done within six hours of the onset of symptoms and occasionally lumber puncture can also be done. An electrocardiogram (ECG) of all patients with subarachnoid should be done because patient with SAH can have myocardial ischemia due to increased level of circulating catecholamines or due to autonomic stimulation of the brain. ECG changes associated with SAH primarily reflect repolarisation abnormalities involving ST segment, T wave, U wave and QTc interval. Myocardial ischemia or infarction is often suspected in patients with SAH. Even troponin levels may be raised in these patients. However, suspicion of SAH is a contraindication for thrombolytic and anticoagulant therapy. This is a case of SAH which was initially treated for acute coronary syndrome (ACS) on the basis of symptoms and gradually changing ECG findings but on CT Head, patient was having SAH

Rocket Sled Based High Speed Rail Track Test Facilities

The present study introduces and compares several high-speed track based ground test facilities available all over the world to simulate high-speed dynamic events for selected portions of flight trajectories. The scope of performing high speed flight-testing is addressed, which is followed by the requirements of these track based test facilities. The facilities deliver flight test articles under controlled conditions to achieve high velocity impact, acceleration, aerodynamic and other related testing for small and large test articles depending upon the requirements. Sled is designed in such a way so that it can carry the test articles like aircrafts, payloads, warheads, missiles and many other ballistic systems to achieve high velocities ranging from subsonic to hypersonic by accelerating these sleds using solid rocket motors over the rail track. Such facilities provide instrumentation for large set of trial data acquisition and offline analysis for both recovery and non- recovery (impact) trials, which makes such facilities important for test, research and evaluation purposes. Here, the detailed description of test facilities, which are available in many countries such as India, United States (US), Japan, United Kingdom (UK), France, and others countries based on their technical characteristics is presented. Additionally, a brief history and introduction into basic rocket sled test facility aspects, essential technical characteristics and major features to support high speed testing at these facilities as an accurate testing technique based on quality of construction and engineering design are also covered in this paper. Compilation of available or under development facilities is done in one place which provides the information about facilities’ technological gaps. The paper concludes with an explanation of the role, major capabilities and limitations of these test facilities in the present global scenario

Cancer informatics analysis indicates high CHAC2 associated with unfavorable prognosis in breast cancer

Breast cancer remains the most commonly diagnosed cancer worldwide and exhibits a poor prognosis. The induction of genetic changes deregulates several genes that increase the disposal towards this life-threatening disease. CHAC2, a member of the glutathione degrading enzyme family has been shown to suppress gastric and colorectal cancer progression, however, the expression of CHAC2 in breast cancer has not been reported. We did an analysis of CHAC2 expression in breast cancer patients from various online tools like UALCAN, GEPIA2, GENT2, TIMER2, and bcGenExminer v4.8. Further, we used the Kaplan-Meier plotter to establish the significance of CHAC2 in BC patient survival and prognosis while TISIDB and TIMER databases were used to investigate the filtration of immune cells. The results showed that CHAC2 levels were high in breast cancer patients and elevated CHAC2 was associated with low overall survival. Taken together, the results of the present study show that like its paralog CHAC1, CHAC2 may also be an important biomarker and could have a potential therapeutic implication in breast cancer

Impact of patient positioning on radiotherapy dose distribution: An assessment in parotid tumor

Purpose: We intended to study the impact of patient positioning on the dose distribution within target volume and organs at risk in patients with parotid malignancies treated with 3D conformal radiotherapy (3D-CRT) with photon wedge pair (WP) or intensity modulated radiotherapy (IMRT).Methods: Three patients with a non-Hodgkin’s lymphoma of the right parotid gland were consecutively immobilized using thermoplastic cast in 2 positions: supine with head in neutral position (HN) and with head turned 90° to the left side (HT). Images for treatment planning purpose were acquired in both positions. For both positions, photon WP plans and 5 field IMRT plans were generated, after contouring clinical target volume (CTV), planning target volume (PTV= CTV + 5 mm margin) and organs at risk (OAR). All plans were evaluated for target coverage and dose to OARs.Results: Both CTV and PTV were apparently larger in HN compared with HT (31.76±8.89 cc, 30.31±7.83 cc and 62.49±19.01 cc, 58.89±15.33 cc) respectively. The CI value for PTV was slightly better for HT compared to HN position in both the WP and IMRT plans. The homogeneity was comparable in both the head positions in case of WP plan. The mean HI of PTV was increased in case of IMRT plan at HT versus HN position (1.108 vs. 1.097). A change in head position from HN to HT with wedge pair plan resulted in a reduction of brainstem Dmax and Dmean. Lesser dose was observed in HN position for contralateral parotid. A difference of 0.9 Gy in the average Dmax to spinal cord was seen. The values of Dmean to mandible, oral cavity, ipsilateral and contralateral cochlea were higher in the HT position. A change in head position from HN to HT with IMRT plan resulted in a dose reduction in average Dmax to brainstem. The spinal cord Dmax increased at the HT position by 1.2 Gy. The dose to contralateral parotid and cochlea was comparable in both the positions. However, the Dmean to oral cavity was reduced at HT position. Whereas for IMRT versus wedge pair plan at head neutral position average Dmean to the contralateral parotid was reduced with the IMRT plan. A considerable reduction in Dmax to spinal cord and Dmean to ipsilateral cochlea was observed. A slight increase in average Dmax to brainstem and was observed with the IMRT plan. The doses to the remaining OARs were lesser in case of IMRT plan. For IMRT versus wedge pair plan at head tilt position slight increase in average Dmax to brainstem was observed in case of IMRT plan. A considerable reduction in Dmax to spinal cord and Dmean to ipsilateral cochlea was observed. The doses to the remaining OARs were reduced with IMRT plan.Conclusion: Change in head position from neutral to 90° contralateral tilt for wedge pair plan in parotid tumor may considerably reduce dose to the brainstem and spinal cord with a modest increase in dose to mandible, oral cavity, contralateral parotid, and bilateral cochlea. The alteration in head position has minimal impact on IMRT planning

Insights into Marker Assisted Selection and Its Applications in Plant Breeding

Burgeoning the human population with its required food demand created a burden on ever-decreasing cultivated land and our food production systems. This situation prompted plant scientists to breed crops in a short duration with specific traits. Marker-assisted selection (MAS) has emerged as a potential tool to achieve desirable results in plants with the help of molecular markers and improves the traits of interest in a short duration. The MAS has comprehensively been used in plant breeding to characterize germplasm, diversity analysis, trait stacking, gene pyramiding, multi-trait introgression, and genetic purity of different cereals, pulses, oilseeds, and fiber crops, etc. Mapping studies pointed out several marker-trait associations from different crop species, which specifies the potential application of MAS in accelerating crop improvement. This chapter presents an overview of molecular markers, their genesis, and potential use in plant breeding

Impact of head immobilization position on dose distribution in patients of brainstem glioma

Purpose: The purpose of this study is to investigate the impact of patient position (supine and prone) on conventional bilateral field, three dimensional conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT) treatment plans in patients of brainstem glioma with a view to exploring the possibility of avoiding beam entry through immobilization accessories. Methods: Five patients of brainstem glioma were immobilized and scanned in supine and prone positions with a combination of head rest and thermoplastic cast. Each patient was planned with three techniques: (i) 2-fields bilateral (ii) 3-fields 3DCRT, and (iii) 5-fields IMRT. Plan quality was analyzed in terms of planning target volume (PTV) coverage and dose to various critical organs at risk (OAR) for both the supine and prone treatment positions. Results: In case of bilateral fields (parallel opposed) planning, the PTV coverage and dose to the OAR were almost similar for both the supine and prone positions. In 3DCRT plan, although the PTV coverage and dose to critical structures were comparable for both the supine and prone position, dose to cochlea was lower for the prone position plan. A modest decrease in maximum dose to optic nerves and mean dose to temporal lobes were also observed for the prone position plan. In IMRT plans, the PTV coverage and homogeneity were comparable in both the supine and prone positions. Reduction in average maximum and mean doses to all OARs with functional subunit (FSU) in series and parallel respectively was observed in the IMRT plan for prone position when compared to the supine position.Conclusion: Supine and prone positions resulted in almost similar dose distribution in all the three techniques applied. At some instances, the prone position showed better normal tissues sparing when compared to supine. Moreover, prone position is more likely to avoid attenuation due to immobilization devices and uncertainty in dose calculation under large inhomogeneities

Usage Pattern of Glimepiride/Metformin Fixed-dose Combination in Type 2 Diabetes Patients with CVD or at Risk of CVD: An Experience in Indian Setting

Background: Diabetes is associated with almost twofold increased risk of cardiovascular diseases (CVD). The present case-based questionnaire survey evaluated the treatment pattern and clinical experience of healthcare professionals in prescribing glimepiride/metformin fixed-dose combination (FDC) to type 2 diabetes mellitus (T2DM) patients with CVD or those patients who are at risk of CVD in the Indian settings. Material and methods: A retrospective, multicenter, observational, case-based questionnaire survey was conducted in Indian healthcare centers using medical records of patients having T2DM, with CVD or are at risk of CVD, who were prescribed any strength of glimepiride/metformin FDC. Data was collected from the patients’ medical records and was analyzed using statistical tests. Results: A total of 680 patients with T2DM with CVD or at risk of CVD were included in this study. Mean duration of diabetes in the patients was 5.7 ± 4.8 years. About 68.5% patients had hypertension, 47.9% had dyslipidemia, 25.4% had coronary artery disease (CAD), 3.6% had transient ischemic attack (TIA), 4.8% had peripheral arterial disease (PAD) and 2.9% had heart failure. Around 18.1% patients had CVD after diabetes was diagnosed, while 81.9% presented with cardiovascular (CV) issues at the time of diabetes diagnosis. All patients received glimepiride/metformin FDC as first-line therapy. About 68.2% patients on glimepiride/metformin FDC had blood pressure within optimal limits. A large proportion of patients had improvement in glycemic parameters. Weight change was noted in 18.4% of the patients overall. Of these, 59.2% had reduction in weight. There were no major adverse events and treatment efficacy and tolerability were reported as good to excellent for 94.6% and 92.9% patients, respectively. Conclusion: This case-based questionnaire survey demonstrates the usage pattern of various strengths of glimepiride/metformin FDC and the clinicians’ practice approach regarding early initiation of this combination in Indian patients with diabetes who have or are at risk of CVD

Influence of collimator rotation on dose distribution and delivery in intensity modulated radiation therapy for parotid cancer

Purpose: To evaluate the influence of collimator rotation in IMRT planning with respect to the target coverage and dose to critical structures. In addition, the delivery efficiency of desired fluence with collimator rotation is assessed.Methods: The computed tomography (CT) datasets of 5 patients with parotid cancer were employed for this study. Dynamic IMRT plans were generated with a dose prescription of 60 Gy in 30 fractions. IMRT plans were generated with five unilateral fields using 6MV X-rays. Four different plans were generated for each patient by keeping the collimator angle at 0, 30, 60, and 90 degree. All plans were analyzed using dose volume histogram. Conformity index (CI) and heterogeneity index (HI) were calculated. The total monitor units (MU) required to deliver one fraction were noted and compared. To verify the delivery efficiency; the measured fluence on IBA I’mRT MatriXX ionization chamber array detector was compared with the TPS dose plan with 2D gamma evaluation.Results: There is not much difference in the PTV Dmax and Dmean with respect to the different collimator angles. The PTV coverage is best at collimator angle of 0 degree. A slight reduction in CI was observed with plans at other collimator angles as compared to 0 degree. The HI values were almost similar for plans with collimator angle 0, 30, and 60 degree. The plan with 90 degree collimator showed a slightly higher heterogeneity for the PTV. A slight reduction in the average Dmax to spinal cord was observed for the plan with collimator angle 30 degree as compared to other angles whereas maximum value of Dmax to spinal cord was at collimator angle 60 degree. No clinically relevant difference was observed among the plans with respect to brainstem and mandible Dmax. An increase in average of oral cavity Dmax and Dmean was observed for collimator angle 60 and 90 degree as compared to collimator angle 0 and 30 degree. Not much difference was observed with respect to Dmax and Dmean for contralateral parotid and cochlea with plans at different collimator angles. A decrease in MU required to deliver a fraction was observed for the plan with collimator angle 30 degree as compared to other angles. The plan with 90 degree collimator required maximum MU. The 2D γ index evaluation of planned and delivered fluence showed almost similar results for plans with different collimator angles.Conclusion: An individual case-specific collimator rotation may aid in achieving the desired dose distribution and relative sparing of critical structures in IMRT.  

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701