Comparison of the efficacy and safety of norethisterone vs. combined oral contraceptive pills for the management of puberty menorrhagia

Background: The most common cause of puberty menorrhagia is immaturity of the hypothalamic pituitary ovarian axis. Treatment is directed towards stabilizing the endometrium and treating the hormonal alterations. The objective of this study was to compare the efficacy and safety of norethisterone and combined oral contraceptive (COC) pills for the management of puberty menorrhagia.Methods: A total of 60 young girls from age of menarche to 19 years with menorrhagia were randomized to receive either norethisterone or COC pills. The end points included change from baseline in health-related quality-of-life parameters, estimation of blood loss and effect on hemoglobin level. Health-related quality-of-life question scores at baseline and after treatment were calculated as mean for norethisterone group and COC pills group.Results: Norethisterone and COC pills treatment groups showed mean improvement in Menorrhagia Impact Questionnaire (MIQ) scores compared to baseline. However, the total mean score was higher in norethisterone group compared to COC pills group after three treatment cycles (21 Vs 17). The treatment failure was less in norethisterone group compared to COC pills group.Conclusions: Use of norethisterone was more effective and better tolerated compared to combined oral contraceptive pills for the management of puberty menorrhagia

Lymphocytic Infiltration and Immune Escape Mechanisms in Human Chordoma

Recent advances in immunotherapy for cancer have led to increasing interest in the role of the immune system in the pathogenesis and treatment of various tumors. Tumor-infiltrating lymphocytes have been associated with more favorable prognoses in a number of malignancies, though the mechanism of such outcomes remains unclear. This study, to our knowledge, is the first to describe lymphocytic infiltration in chordoma. Slides from 62 patients with chordoma were evaluated for lymphocyte infiltrates. Lymphocytic infiltration was found in 84% of tumors. Twenty-four tumors were selected for immunohistochemical (IHC) analysis. All of the tumors with lymphocytic infiltration that underwent IHC staining had CD4-positive lymphocytes present. CD8-positive lymphocytes were noted in 52% of tumors. HLA class I antigen defects were noted in 79% of chordoma tumors. These included negative membranous and/or cytoplasmic staining patterns, weakly positive staining, and heterogeneous combinations of these defects. Both heavy chain isoforms and beta-2-microglobulin components were affected. Our novel finding of intratumoral lymphocytes in chordoma tumors suggests that a patient’s immune system mounts a response against their tumor. The absence of HLA class I antigen components is compatible with the possibility that a patient’s immune response imposes selective pressure that facilitates the outgrowth of chordoma cell subpopulations that have developed escape mechanisms from host immune recognition. While the clinical significance requires further evaluation, these data have implications in optimally selecting patients for appropriate treatment regimens. We believe these data will spark further inquiry into the role of immunotherapy in the treatment of chordoma and other bone tumors

Functional and radiological outcome of proximal femoral nailing versus dynamic hip screw in unstable intertrochanteric femur fractures

Background: Intertrochanteric femur fractures account half of the hip fractures in elderly, the other majority being neck of femur fracture. 35-40% of intertrochanteric are unstable (Tronzo’s classification type 3, 4 and 5). The dynamic hip screw (DHS) has achieved widespread acclaim in the last few years and is currently considered to be the standard device for outcome assessment. Though, the DHS has been shown to produce good results, but complications are frequent, particularly in unstable inter-trochanteric fracture. The advantage of Proximal Femur Nailing fixation is that it provides a more biomechanically stable construct by reducing the distance between hip joint and implant. The goal of this study is to assess the clinical and radiographical outcomes of the DHS (load bearing implant) and PFN (load sharing implant) for the treatment of Intertrochanteric hip fractures.Methods: We assessed the same in 52 cases of unstable femur fracture 26 operated with DHS and 26 with PFN and followed up with sequential radiographs for radiological union and sequential interview with Harris hip score calculation for functional outcome assessment.Results: Patients operated for unstable intertrochanteric femur fracture with Proximal femoral nailing had better Harris hip scores (excellent 4, good 14) compared to dynamic hip screw group (Excellent 6, good 5) and earlier weight bearing (At 18 weeks, 100% in PFN compared to 65.5% in DHS). PFN has lesser incidence of postoperative complications (15% in PFN compared to 38% in DHS).Conclusions:The proximal femoral nail has better functional outcome in terms of Harris hip score and early radiologic union in unstable intertrochanteric fractures of femur. 

Structural Elucidation of Alkali Degradation Impurities of Favipiravir from the Oral Suspension: UPLC-TQ-ESI-MS/MS and NMR

A novel stability-indicating, reversed-phase, high-performance liquid chromatography (RP-HPLC) method was developed and validated for the determination of favipiravir in an oral suspension. The effective separation of favipiravir and its degradation products was achieved on a Zorbax Eclipse Plus C18 column (5 μm particle size, 150 mm length × 4.6 mm diameter). The mobile phase was prepared by mixing 5 mM of phosphate buffer (pH 3.5) and methanol in a 75:25 v/v ratio delivered at a 1.0 mL/min flow rate. The eluents were monitored using a photodiode array detector at a wavelength of 322 nm. The stability-indicating nature of this method was evaluated by performing force degradation studies under various stress conditions, such as acidic, alkali, oxidative, thermal, and photolytic degradation. Significant degradation was observed during the alkali stress degradation condition. The degradation products generated during various stress conditions were well separated from the favipiravir peak. In addition, the major degradation product formed under alkali stress conditions was identified using UPLC-ESI-TQ-MS/MS and NMR. Method validation was performed according to the ICH Q2 (R1) guideline requirements. The developed method is simple, accurate, robust, and reliable for routine quality control analysis of favipiravir oral suspensions

Structural Elucidation of Alkali Degradation Impurities of Favipiravir from the Oral Suspension: UPLC-TQ-ESI-MS/MS and NMR

A novel stability-indicating, reversed-phase, high-performance liquid chromatography (RP-HPLC) method was developed and validated for the determination of favipiravir in an oral suspension. The effective separation of favipiravir and its degradation products was achieved on a Zorbax Eclipse Plus C18 column (5 μm particle size, 150 mm length × 4.6 mm diameter). The mobile phase was prepared by mixing 5 mM of phosphate buffer (pH 3.5) and methanol in a 75:25 v/v ratio delivered at a 1.0 mL/min flow rate. The eluents were monitored using a photodiode array detector at a wavelength of 322 nm. The stability-indicating nature of this method was evaluated by performing force degradation studies under various stress conditions, such as acidic, alkali, oxidative, thermal, and photolytic degradation. Significant degradation was observed during the alkali stress degradation condition. The degradation products generated during various stress conditions were well separated from the favipiravir peak. In addition, the major degradation product formed under alkali stress conditions was identified using UPLC-ESI-TQ-MS/MS and NMR. Method validation was performed according to the ICH Q2 (R1) guideline requirements. The developed method is simple, accurate, robust, and reliable for routine quality control analysis of favipiravir oral suspensions

Examining the Electrical Excitation, Calcium Signaling, and Mechanical Contraction Cycle in a Heart Cell

As the leading cause of death in the United States, heart disease has become a principal concern in modern society. Cardiac arrhythmias can be caused by a dysregulation of calcium dynamics in cardiomyocytes. Calcium dysregulation, however, is not yet fully understood and is not easily predicted; this provides motivation for the subsequent research. Excitation-contraction coupling (ECC) is the process through which cardiomyocytes undergo contraction from an action potential. Calcium induced calcium release (CICR) is the mechanism through which electrical excitation is coupled with mechanical contraction through calcium signaling. The study of the interplay between electrical excitation, calcium signaling, and mechanical contraction has the potential to improve our understanding of the regular functioning of the cardiomyocytes and help us understand how any dysregulation can lead to potential cardiac arrhythmias. ECC, of which CICR is an important part, can be modeled using a system of partial differential equations that link the electrical excitation, calcium signaling, and mechanical contraction components of a cardiomyocyte. We extend a previous model [Angeloff et al., Spora, 2016] to implement a seven-variable model that includes for the first time the mechanical component of the ECC. We study how the interaction of electrical and calcium systems can impact the cardiomyocyte\u27s levels of contraction

Scar heterogeneity on cardiovascular magnetic resonance as a predictor of appropriate implantable cardioverter defibrillator therapy

Background: Despite the survival benefit of implantable-cardioverter-defibrillators (ICDs), the vast majority of patients receiving an ICD for primary prevention do not receive ICD therapy. We sought to assess the role of heterogeneous scar area (HSA) identified by late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) in predicting appropriate ICD therapy for primary prevention of sudden cardiac death (SCD). Methods: From September 2003 to March 2011, all patients who underwent primary prevention ICD implantation and had a pre-implantation LGE-CMR were identified. Scar size was determined using thresholds of 4 and 6 standard deviations (SD) above remote normal myocardium; HSA was defined using 3 different criteria; as the region between 2 SD and 4 SD (HSA2-4SD), between 2SD and 6SD (HSA2-6SD), and between 4SD and 6SD (HSA4-6SD). The end-point was appropriate ICD therapy. Results: Out of 40 total patients followed for 25 ± 24 months, 7 had appropriate ICD therapy. Scar size measured by different thresholds was similar in ICD therapy and non-ICD therapy groups (P = NS for all). However, HSA2-4SD and HSA4-6SD were significantly larger in the ICD therapy group (P = 0.001 and P = 0.03, respectively). In multivariable model HSA2-4SD was the only significant independent predictor of ICD therapy (HR = 1.08, 95%CI: 1.00-1.16, P = 0.04). Kaplan-Meier analysis showed that patients with greater HSA2-4SD had a lower survival free of appropriate ICD therapy (P = 0.026). Conclusions: In primary prevention ICD implantation, LGE-CMR HSA identifies patients with appropriate ICD therapy. If confirmed in larger series, HSA can be used for risk stratification in primary prevention of SCD

Blocking the formation of radiation–induced breast cancer stem cells

The goal of adjuvant (post-surgery) radiation therapy (RT) for breast cancer (BC) is to eliminate residual cancer cells, leading to better local tumor control and thus improving patient survival. However, radioresistance increases the risk of tumor recurrence and negatively affects survival. Recent evidence shows that breast cancer stem cells (BCSCs) are radiation-resistant and that relatively differentiated BC cells can be reprogrammed into induced BCSCs (iBCSCs) via radiation-induced re-expression of the stemness genes. Here we show that in irradiation (IR)-treated mice bearing syngeneic mammary tumors, IR-induced stemness correlated with increased spontaneous lung metastasis (51.7%). However, IR-induced stemness was blocked by targeting the NF-κB- stemness gene pathway with disulfiram (DSF)and Copper (Cu2+). DSF is an inhibitor of aldehyde dehydrogenase (ALDH) and an FDA-approved drug for treating alcoholism. DSF binds to Cu2+ to form DSF-Cu complexes (DSF/Cu), which act as a potent apoptosis inducer and an effective proteasome inhibitor, which, in turn, inhibits NF-κB activation. Treatment of mice with RT and DSF significantly inhibited mammary primary tumor growth (79.4%) and spontaneous lung metastasis (89.6%) compared to vehicle treated mice. This anti-tumor efficacy was associated with decreased stem cell properties (or stemness) in tumors. We expect that these results will spark clinical investigation of RT and DSF as a novel combinatorial treatment for breast cancer