Risk factors for still birth: a hospital based case control study

Background: The study of the risk factors contributing to still birth is imperative in our attempts to bring about a decline in the still birth rate.  By identifying the risk factors, we can understand the areas where specific interventions may be applied to bring about a reduction in the still birth rate. The aim of the present study was to identify the risk factors for stillbirth among the mothers attending Sri Avittom Thirunal Hospital, TrivandrumMethods: This was a prospective hospital based case control study conducted from March 2014- September 2015. Sample size was calculated as 100 cases and 200 controls. Odds ratios with 95% confidence interval were calculated using multi variate logistic regression.Results: The major risk factors associated with still births were maternal age, socio economic status, and obesity, sleep position during pregnancy, primi parity, hypertension and febrile illness during pregnancy. The risk of still birth was 3 times higher among mothers with hypertension compared to the control group.  Although the prevalence of diabetes slightly more in the case group it was not statistically significant. By analyzing all the risk factors in preparing a model 42% of the risk for still birth was contributed by these factors.Conclusions: The modifiable risk factors seen in this study to prevent still births are maternal sleep position during pregnancy, diabetes, hypertension and febrile illness especially urinary tract infection. By better antenatal care we can detect complications like diabetes, hypertension and manage appropriately thereby preventing complications. By screening for urinary tract infections in every trimester morbidity can be reduced

Pattern of congenital abnormalities in a tertiary hospital and its impact on neonatal mortality

Background: Congenital abnormalities are major contributors of neonatal mortality and stillbirths. However, there is not sufficient data in our country on the prevalence of various congenital malformations and their impact on neonatal mortality. Objectives: To study the prevalence and pattern of congenital anomalies among neonates delivered in a tertiary hospital setting in 3 years and its impact on perinatal and neonatal mortality. Materials and Methods: This hospital based prospective descriptive study was undertaken at tertiary care hospital in Kerala. All babies born in the hospital from January 2013 to December 2015 (3 years) were included in the study. The baby was examined by a pediatrician during the first 24 h to identify any birth defects. A detailed history including familial and gestational factors was taken in babies with birth defects. Photographs, radiographs, ultrasound examination, echocardiography, and chromosomal studies were undertaken as required. The details were entered in a pro forma. The anomalies are classified as per ICD-10 criteria. Results were analyzed by simple statistical techniques recording number and percentage of cases. Results: The prevalence of birth defects in live born newborn was 1.9% whereas, in stillbirths, it was 15.3%. Congenital anomalies also contributed a major risk factor for neonatal death as 22% of the newborns, died in the immediate neonatal period, had some form of congenital anomaly. The major maternal risk factor found to be associated with congenital anomalies was gestational diabetes (21.3%). The patterns of congenital anomalies were musculoskeletal anomalies (25%), central nervous system (18%), genitourinary system (14%), congenital diaphragmatic hernia (12%), cardiovascular system (10%), gastrointestinal (7%), syndromes (6%), non-immune hydrops (5%), and others (3%). Conclusion: Prevalence of birth defects in this birth cohort was 1.9% comparable to other Indian data. In Kerala, one of the major causes of perinatal and neonatal mortality is congenital malformations

Autophagy Plays an Essential Role in Mediating Regression of Hypertrophy during Unloading of the Heart

Autophagy is a bulk degradation mechanism for cytosolic proteins and organelles. The heart undergoes hypertrophy in response to mechanical load but hypertrophy can regress upon unloading. We hypothesize that autophagy plays an important role in mediating regression of cardiac hypertrophy during unloading. Mice were subjected to transverse aortic constriction (TAC) for 1 week, after which the constriction was removed (DeTAC). Regression of cardiac hypertrophy was observed after DeTAC, as indicated by reduction of LVW/BW and cardiomyocyte cross-sectional area. Indicators of autophagy, including LC3-II expression, p62 degradation and GFP-LC3 dots/cell, were significantly increased after DeTAC, suggesting that autophagy is induced. Stimulation of autophagy during DeTAC was accompanied by upregulation of FoxO1. Upregulation of FoxO1 and autophagy was also observed in vitro when cultured cardiomyocytes were subjected to mechanical stretch followed by incubation without stretch (de-stretch). Transgenic mice with cardiac-specific overexpression of FoxO1 exhibited smaller hearts and upregulation of autophagy. Overexpression of FoxO1 in cultured cardiomyocytes significantly reduced cell size, an effect which was attenuated when autophagy was inhibited. To further examine the role of autophagy and FoxO1 in mediating the regression of cardiac hypertrophy, beclin1+/2 mice and cultured cardiomyocytes transduced with adenoviruses harboring shRNA-beclin1 or shRNA-FoxO1 were subjected to TAC/ stretch followed by DeTAC/de-stretch. Regression of cardiac hypertrophy achieved after DeTAC/de-stretch was significantly attenuated when autophagy was suppressed through downregulation of beclin1 or FoxO1. These results suggest that autophagy and FoxO1 play an essential role in mediating regression of cardiac hypertrophy during mechanical unloading

Personalizing cardiac regenerative therapy: At the heart of Pim1 kinase

During cardiac aging, DNA damage and environmental stressors contribute to telomeric shortening and human cardiac progenitor cells acquire a senescent phenotype that leads to decreased stem cell function. Reversion of this phenotype through genetic modification is essential to advance regenerative therapy. Studies in the cardiac specific overexpression and subcellular targeting of Pim1 kinase demonstrate its influence on regeneration, proliferation, survival, metabolism and senescence. The cardioprotective effects of Pim1 modification can be picked apart and enhanced by targeting the kinase to distinct subcellular compartments, allowing for selection of specific phenotypic traits after molecular modification. In this perspective, we examine the therapeutic implications of Pim1 to encourage the personalization of cardiac regenerative therapy

Is autophagy in response to ischemia and reperfusion protective or detrimental for the heart?

Autophagy is a catabolic process that degrades long-lived proteins and damaged organelles by sequestering them into double membrane structures termed "autophagosomes" and fusing them with lysosomes. Autophagy is active in the heart at baseline and further stimulated under stress conditions including starvation, ischemia/reperfusion, and heart failure. It plays an adaptive role in the heart at baseline, thereby maintaining cardiac structure and function and inhibiting age-related cardiac abnormalities. Autophagy is activated by ischemia and nutrient starvation in the heart through Sirt1-FoxO- and adenosine monophosphate (AMP)-activated protein kinase (AMPK)-dependent mechanisms, respectively. Activation of autophagy during ischemia is essential for cell survival and maintenance of cardiac function. Autophagy is strongly activated in the heart during reperfusion after ischemia. Activation of autophagy during reperfusion could be either protective or detrimental, depending on the experimental model. However, strong induction of autophagy accompanied by robust upregulation of Beclin1 could cause autophagic cell death, thereby proving to be detrimental. This review provides an overview regarding both protective and detrimental functions of autophagy in the heart and discusses possible applications of current knowledge to the treatment of heart disease

BIN1 Induces the Formation of T-Tubules and Adult-Like Ca2+ Release Units in Developing Cardiomyocytes.

Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) are at the center of new cell-based therapies for cardiac disease, but may also serve as a useful in vitro model for cardiac cell development. An intriguing feature of hESC-CMs is that although they express contractile proteins and have sarcomeres, they do not develop transverse-tubules (T-tubules) with adult-like Ca2+ release units (CRUs). We tested the hypothesis that expression of the protein BIN1 in hESC-CMs promotes T-tubules formation, facilitates CaV 1.2 channel clustering along the tubules, and results in the development of stable CRUs. Using electrophysiology, [Ca2+ ]i imaging, and super resolution microscopy, we found that BIN1 expression induced T-tubule development in hESC-CMs, while increasing differentiation toward a more ventricular-like phenotype. Voltage-gated CaV 1.2 channels clustered along the surface sarcolemma and T-tubules of hESC-CM. The length and width of the T-tubules as well as the expression and size of CaV 1.2 clusters grew, as BIN1 expression increased and cells matured. BIN1 expression increased CaV 1.2 channel activity and the probability of coupled gating within channel clusters. Interestingly, BIN1 clusters also served as sites for sarcoplasmic reticulum (SR) anchoring and stabilization. Accordingly, BIN1-expressing cells had more CaV 1.2-ryanodine receptor junctions than control cells. This was associated with larger [Ca2+ ]i transients during excitation-contraction coupling. Our data support the view that BIN1 is a key regulator of T-tubule formation and CaV 1.2 channel delivery. By studying the role of BIN1 during the differentiation of hESC-CMs, we show that BIN1 is also important for CaV 1.2 channel clustering, junctional SR organization, and the establishment of excitation-contraction coupling. Stem Cells 2019;37:54-64

Personalizing cardiac regenerative therapy: At the heart of Pim1 kinase

During cardiac aging, DNA damage and environmental stressors contribute to telomeric shortening and human cardiac progenitor cells acquire a senescent phenotype that leads to decreased stem cell function. Reversion of this phenotype through genetic modification is essential to advance regenerative therapy. Studies in the cardiac specific overexpression and subcellular targeting of Pim1 kinase demonstrate its influence on regeneration, proliferation, survival, metabolism and senescence. The cardioprotective effects of Pim1 modification can be picked apart and enhanced by targeting the kinase to distinct subcellular compartments, allowing for selection of specific phenotypic traits after molecular modification. In this perspective, we examine the therapeutic implications of Pim1 to encourage the personalization of cardiac regenerative therapy

Autophagy Plays an Essential Role in Mediating Regression of Hypertrophy during Unloading of the Heart

<div><p>Autophagy is a bulk degradation mechanism for cytosolic proteins and organelles. The heart undergoes hypertrophy in response to mechanical load but hypertrophy can regress upon unloading. We hypothesize that autophagy plays an important role in mediating regression of cardiac hypertrophy during unloading. Mice were subjected to transverse aortic constriction (TAC) for 1 week, after which the constriction was removed (DeTAC). Regression of cardiac hypertrophy was observed after DeTAC, as indicated by reduction of LVW/BW and cardiomyocyte cross-sectional area. Indicators of autophagy, including LC3-II expression, p62 degradation and GFP-LC3 dots/cell, were significantly increased after DeTAC, suggesting that autophagy is induced. Stimulation of autophagy during DeTAC was accompanied by upregulation of FoxO1. Upregulation of FoxO1 and autophagy was also observed <em>in vitro</em> when cultured cardiomyocytes were subjected to mechanical stretch followed by incubation without stretch (de-stretch). Transgenic mice with cardiac-specific overexpression of FoxO1 exhibited smaller hearts and upregulation of autophagy. Overexpression of FoxO1 in cultured cardiomyocytes significantly reduced cell size, an effect which was attenuated when autophagy was inhibited. To further examine the role of autophagy and FoxO1 in mediating the regression of cardiac hypertrophy, <em>beclin1+/−</em> mice and cultured cardiomyocytes transduced with adenoviruses harboring shRNA-<em>beclin1</em> or shRNA-FoxO1 were subjected to TAC/stretch followed by DeTAC/de-stretch. Regression of cardiac hypertrophy achieved after DeTAC/de-stretch was significantly attenuated when autophagy was suppressed through downregulation of <em>beclin1</em> or FoxO1. These results suggest that autophagy and FoxO1 play an essential role in mediating regression of cardiac hypertrophy during mechanical unloading.</p> </div