Long-term therapy with elamipretide normalizes activation of the mitochondrial signal transducer and activator of transcription 3 (mstat3) in of left ventricular myocardium of dogs with chronic heart failure

Introduction: The signal transducer and activator of transcription 3 (STAT3) has been identified in mitochondria (MITO) of cardiomyocytes (mSTAT3). In STAT3 -/- cells, the activities of MITO complexes I and II of the electron transport chain (ETC) were reduced suggesting that mSTAT3 is required for optimal ETC function. Deactivation of STAT3, equated with dephosphorylation of tyrosine residues, has been shown to adversely impacted MITO respiration and, consequently, oxidative phosphorylation. We previously showed that long-term (3 months) therapy with elamipretide (ELAM, previously referred to as Bendavia TM, MTP131 or SS31), a novel MITO-targeting peptide, improves LV function and normalizes MITO respiration and rate of ATP synthesis in MITO of LV myocardium of dogs with heart failure (HF). Hypothesis: This study tested the hypothesis that phosphorylation of mSTAT3 (mpSTAT3) is reduced in MITO of LV myocardium of HF dogs and is restored after long-term therapy with ELAM. Methods: LV tissue was obtained from 14 dogs with microembolization-induced HF (LV ejection fraction ∼30%) randomized to 3 months therapy with subcutaneous injections of ELA (0.5 mg/kg once daily, n=7) or saline (Control, n=7). LV tissue from 6 normal (NL) dogs was used for comparison. Protein levels of mSTAT3 and mpSTAT3 were determined in MITO fraction by Western blotting coupled with chemiluminiscence and band intensity was quantified in densitometric units (du). Results: Protein level of mSTAT3 was 0.82±0.05 du in NL, decreased to 0.29±0.03 du in Controls (p Conclusions: mpSTAT3 level is reduced in MITO from LV of HF dogs and restored after chronic therapy with ELAM. Normalization of mpSTAT3 by ELAM likely contributed to be observed improvement in MITO function following therapy with ELAM in HF dogs

Effects of Elamipretide on Skeletal Muscle in Dogs with Experimentally Induced Heart Failure

AIMS: Elamipretide (ELAM), an aromatic-cationic tetrapeptide, interacts with cardiolipin and normalizes dysfunctional mitochondria of cardiomyocytes. This study examined the effects of ELAM on skeletal muscle mitochondria function in dogs with chronic heart failure (HF). METHODS AND RESULTS: Studies were performed in skeletal muscle biopsy specimens obtained from normal dogs (n = 7) and dogs with chronic intracoronary microembolization-induced HF (n = 14) treated with subcutaneous ELAM 0.5 mg/kg (HF + ELAM, n = 7) or vehicle (normal saline control, HF-CON, n = 7). After 3 months of therapy, triceps skeletal muscle samples were obtained from all dogs, and the proportion of type 1 and type 2 fibres was assessed. Mitochondria isolated from myofibrils of the vastus lateralis skeletal muscle exposed in vitro to ELAM for 1 h were used to assess mitochondrial function. The proportion of skeletal muscle type 1 fibres was lower in HF-CON dogs compared with normal dogs (23 ± 4 vs. 32 ± 5%, P \u3c 0.05). Treatment with ELAM restored a near-normal fibre-type composition (31 ± 7%, P \u3c 0.05 vs. HF-CON). Skeletal muscle mitochondria showed significantly lower levels of adenosine diphosphate-dependent mitochondrial respiration (100 ± 9 vs. 164 ± 15 natom O/min/mg protein, P \u3c 0.05), mitochondrial membrane potential (0.17 ± 0.03 vs. 0.53 ± 0.03 red/green fluorescence ratio, P \u3c 0.05), mitochondrial permeability transition pore (38 ± 3 vs. 62 ± 2 relative light units, P \u3c 0.05), maximum rate of adenosine triphosphate synthesis (3284 ± 418 vs. 8835 ± 423 RLU/μg protein, P \u3c 0.05), and cytochrome c oxidase activity (1390 ± 108 vs. 2459 ± 210 natom O/min/mg protein, P \u3c 0.05) compared with normal dogs. Exposure of skeletal muscle myofibrillar mitochondria from HF dogs to ELAM showed a dose-dependent improvement/normalization of all measures of mitochondrial function. In mitochondria from skeletal muscle of HF dogs exposed to 0.10 μM ELAM, adenosine diphosphate-dependent mitochondrial respiration increased to 183 ± 18 natom O/min/mg protein, membrane potential increased to 0.30 ± 0.03 red/green fluorescence ratio, mitochondrial permeability transition pore increased to 54 ± 4 RLU, maximum rate of adenosine triphosphate synthesis increased to 4423 ± 414, and cytochrome c oxidase activity increased to 2033 ± 191 natom O/min/mg protein. Exposure of skeletal muscle myofibrillar mitochondria from normal dogs to ELAM had no effect on mitochondrial function parameters. CONCLUSIONS: The results indicate that ELAM, previously shown to positively influence mitochondrial function of the failing heart, can also positively impact mitochondrial function of skeletal muscle and potentially help restore skeletal muscle function and improve exercise tolerance

Pregnancy and labor outcomes in squat versus western style sitting toilet users: a pilot study

Background: Squatting posture may appear outdated and primitive, but in the antenatal period, it is an important resistance exercise to strengthen the abdominal and pelvic floor muscles which are believed to potentially prepare the women for a more natural delivery. No study till date has evaluated the effect of type of toilet seat regularly used during pregnancy. This was a pilot study to assess obstetric outcomes in antenatal women using squat versus western style sitting toilet seat.Methods: In an observational prospective pilot study, low risk primigravida at 28-32 weeks gestation were recruited from the outpatient department and divided into two groups after matching baseline characteristics. Group I (n=50) included women regularly using squatting type toilet seat and group II (n=50) comprised women using western style toilet seat. Pregnancy was followed till delivery; obstetric and neonatal outcomes were noted.Results: Squatting group, as compared to sitting type seat users, had lower incidence of vaginal discharge (10% vs 16%), urinary tract infection(12% vs. 24%), constipation (2% vs. 6%), labor induction (52% vs. 58%), shorter second-stage duration (0.60 vs. 1.24 hours) and a higher incidence of normal vaginal delivery (94% vs. 86%), albeit not statistically significant. NICU admissions (16% vs. 20%) and mean birth weight (2.83 vs. 2.97 kg) were comparable in the two groups.Conclusions: Squatting type toilet seat users had many favourable obstetric outcomes, especially a higher incidence of normal vaginal delivery; although, the difference was not statistically significant. Large community based surveys in this regard can reveal the true effects of squatting type toilet seat on pregnancy and labour outcomes

Placenta accreta: the silent invader

Background: To review incidence causes, clinical presentations, management, maternal mortality and morbidity associated with placenta accreta.Methods: A prospective study was carried out at the Department of Obstetrics and Gynaecology, GSVM Medical College, Kanpur during the period of January 2010 to December 2014. During this period all the patients who were diagnosed with placenta accreta were included in the study.Results: Majority of patients presenting with placenta accreta belonged to age group 30-35 years (46%) were multigravida (95%) came from both rural and urban background. Majority of deliveries complicated by placenta accrete were booked cases (78%). Previous LSCS with placenta previa proved to be the major cause (86%). Out of whole spectrum including placenta accreta, increta, percreta, placenta accreta was the commonest of all and placenta percreta required maximum number of blood transfusions (5-6 units of blood on an average). Hysterectomy was required in 29 cases out of 37 (78%), 6 women suffered from bladder injury which were repaired. Among total of 37 women 7women couldn't be saved even after our best of efforts.Conclusions: Incidence of placenta accrete has increased now a days because of increased incidence of cesarian sections, placenta accreta was seen in primi due to uterine procedures  done deliberately  in both diagnostic and therapeutic indications. Morbidly adherent placenta is always a nightmare for the obstetrician. Suspicion of a case on history, preoperative confirmation of diagnosis, planned management with bundle of care, with multi-disciplinary approach can save many patients from the clutches of inevitable death

Obstetric outcome in twin pregnancies complicated with single intrauterine fetal demise

Background: It has been reported that single intrauterine fetal death in twin pregnancy occurs in 3.7-6.8% all twin pregnancies. The objective of this study was to evaluate the maternal and fetal demographic features and feto-maternal outcomes in twin pregnancies complicated with single intrauterine fetal demise and evaluation of available management guidelines.Methods: This retrospective study was conducted at obstetrics and gynecology department of SGRRIM and HS, Dehradun, Uttarakhand between January 2015 and December 2019. There was a total of 182 twin deliveries at study hospital during this period and 35 of these cases were complicated with single intrauterine fetal demise. Maternal age, parity, chorionicity of twin gestation, gestational age at single intrauterine fetal demise, gestational age at delivery, mode of delivery, birth weight, Apgar Score at birth, neonatal intensive care unit stay of newborn,  maternal fibrinogen levels during pregnancy and delivery time and associated obstetric complications were analyzed in these cases of single intrauterine fetal demise with twin gestation. All monochorionic twin pregnancies were included in the study Group A and dichorionic twin in Group B.Results: The mean age of 32 patients included in study was 29.7±4.6 years. Twenty (62.5%) of these patients were dichorionic and 12 (37.5%) of these were monochorionic twin gestation. Single intrauterine fetal demise occurred in first trimester in 8 (25%) patients, during the second trimester 20 (62.5%) and 4 (12.5%) patients had third trimester single intrauterine fetal demise. Preterm deliveries occurred in 18 (56.3%) of patients and 8 (44.4%) of patients were of monochorionic and 10 (55.6%) of dichorionic twin patients. Among thirty-two patients, 11 (34.4%) patients had caesarean delivery and 21 (65.6%) patient had vaginal birth. No maternal or fetal mortality noted and none of the patients had maternal coagulation disorder.Conclusions: This study indicates that in cases of twin pregnancies with single fetal intrauterine demise with individualized management plan at higher centre and close maternal and fetal surveillance live fetus can be saved without any maternal risk

Sporotrichosis in Sub-Himalayan India

Sporotrichosis is endemic in the Sub-Himalayan belt, which ranges from the northern to the north-eastern Indian subcontinent. Similar to many parts of the developing world, sporotrichosis is commonly recognized clinically in this region however consolidated epidemiological data is lacking. We report epidemiological, clinical and microbiological data from a hundred culture positive cases of sporotrichosis. Out of 305 clinically suspicious cases of sporotrichosis, a total of 100 isolates were identified as Sporothrix schenckii species complex (S. schenckii) on culture. Out of the culture proven cases 71% of the cases presented with lymphocutaneous type of lesions while 28% had fixed localized type and 1% had disseminated sporotrichosis. Presentation with lesions on hands was most frequently seen in 32% with arm (23%) and face (21%) in that sequence. The male to female ratio was 1∶1.27. Age ranged from 1 ½ years to 88 years. Mean age was 43.25 years. Disease was predominantly seen in the fourth to sixth decade of life with 58% cases between 31 and 60 years of age. Since the first report from the region there has been a steady rise in the number of cases of sporotrichosis. Seasonal trends reveal that most of the patients visited for consultation in the beginning of the year between March and April. This is the first study, from the most endemic region of the Sub-Himalayan belt, to delve into epidemiological and clinical details of such a large number of culture proven cases over a period of more than eighteen years which would help in the understanding of the local disease pattern of sporotrichosis

Intravenous Infusion of the β(3)-Adrenergic Receptor Antagonist APD418 Improves Left Ventricular Systolic Function in Dogs with Systolic Heart Failure: β(3)-Adrenergic Receptor Antagonist in Heart Failure

BACKGROUND: Unlike β(1)- and β(2)-adrenergic receptors (ARs), β(3)-AR stimulation inhibits cardiac contractility and relaxation. In the failing left ventricular (LV) myocardium, β(3)-ARs are upregulated, and can be maladaptive in the setting of decompensation by contributing to LV dysfunction. This study examined the effects of intravenous (i.v.) infusions of the β(3)-AR antagonist APD418 on cardiovascular function and safety in dogs with systolic heart failure (HF). METHODS AND RESULTS: Three separate studies were performed in 21 dogs with coronary microembolization-induced HF (LV ejection fraction [LVEF] of approximately 35%). Studies 1 and 2 (n = 7 dogs each) were APD418 dose escalation studies (dosing range, 0.35-15.00 mg/kg/h) designed to identify an effective dose of APD418 to be used in study 3. Study 3, the sustained efficacy study, (n = 7 dogs) was a 6-hour constant intravenous infusion of APD418 at a dose of 4.224 mg/kg (0.70 mg/kg/h) measuring key hemodynamic endpoints (e.g., EF, cardiac output, the time velocity integral of the mitral inflow velocity waveform representing early filling to time-velocity integral representing left atrial contraction [Ei/Ai]). Studies 1 and 2 showed a dose-dependent increase of LVEF and Ei/Ai, the latter being an index of LV diastolic function. In study 3, infusion of APD418 over 6 hours increased LVEF from 31 ± 1% to 38 ± 1% (P \u3c .05) and increased Ei/Ai from 3.4 ± 0.4 to 4.9 ± 0.5 (P \u3c .05). Vehicle had no effect on the LVEF or Ei/Ai. In study 3, APD418 had no significant effects on the HR or the systemic blood pressure. CONCLUSIONS: Intravenous infusions of APD418 in dogs with systolic HF elicit significant positive inotropic and lusitropic effects. These findings support the development of APD418 for the in-hospital treatment of patients with an acute exacerbation of chronic HF

Symbolic analysis of slow solar wind data using rank order statistics

We analyze time series data of the fluctuations of slow solar wind velocity using rank order statistics. We selected a total of 18 datasets measured by the Helios spacecraft at a distance of 0.32 AU from the sun in the inner heliosphere. The datasets correspond to the years 1975-1982 and cover the end of the solar activity cycle 20 to the middle of the activity cycle 21. We first apply rank order statistics to time series from known nonlinear systems and then extend the analysis to the solar wind data. We find that the underlying dynamics governing the solar wind velocity remains almost unchanged during an activity cycle. However, during a solar activity cycle the fluctuations in the slow solar wind time series increase just before the maximum of the activity cycleComment: 10 pages, 7 figures, 1 tabl

Radial Oscillations of Neutron Stars in Strong Magnetic Fields

The eigen frequencies of radial pulsations of neutron stars are calculated in a strong magnetic field. At low densities we use the magnetic BPS equation of state(EOS) similar to that obtained by Lai and Shapiro while at high densities the EOS obtained from the relativistic nuclear mean field theory is taken and extended to include strong magnetic field. It is found that magnetised neutron stars support higher maximum mass where as the effect of magnetic field on radial stability for observed neutron star masses is minimal.Comment: latex2e file with five postscript figure

Field emission scanning electron microscopic, X-ray diffraction and ultraviolet spectroscopic analysis of Terminalia bellerica based silver nanoparticles and evaluation of their antioxidant, catalytic and antibacterial activity

In recent years, scientists have come up with ways to make nanoparticles that are inexpensive and good for the environment. Terminalia bellerica-based silver nanoparticles (TBAgNPs) were made in this study using methanol extract from T. bellerica fruits. This method was quick, economical, and good for the environment. The biosynthesized TBAgNPs were used as antioxidants, antibacterial agents, and anti-catalytic agents. Analytical techniques like XRD, FESEM, and UV–Vis were used to find out more about the spherical TBAgNPs that were made. Also, Cefotaxime-resistant bacteria found in hospitals were used to test how well the TBAgNPs killed bacteria. With the Bauer-agar Kirby's gel diffusion and Mueller-Hinton broth methods, the ability of the synthesized TBAgNPs to stop bacterial growth was tested. After the TBAgNPs were studied, it was found that the average size of their crystals was between 10 and 25 nm. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) reducing tests showed that these AgNPs could act as antioxidants, and TBAgNPs (%inhibition = 20.90% to 94.94%) were better antioxidant than ascorbic acid (%inhibition = 13.80% to 86.10%) and extract (%inhibition = 16.90% to 80.50%). The reduction of methylene blue (MB) to leucomethylene blue (LMB) with sodium borohydride (NaBH4) was used as a model to test the catalytic potential of TBAgNPs. On UV spectroscopic analysis at room temperature, TBAgNPs at different concentrations were able to reduce methylene blue effectively. For Escherichia coli and Klebsiella pneumoniae, the minimum inhibitory concentration (MIC) for TBAgNPs was 0.625 μg/mL and 1.25 μg/mL, respectively. Based on these results, silver nanoparticles made with Terminalia bellerica extract may have much biological importance and could be used in making useful therapeutic applications