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Introduction: Mutations in the LMNA gene, encoding Lamin A/C (LMNA), are established causes of dilated cardiomyopathy (DCM). The phenotype is typically characterized by progressive cardiac conduction defects, arrhythmias, heart failure, and premature death. DCM is primarily considered a disease of cardiac myocytes. However, LMNA is also expressed in other cardiac cell types, including fibroblasts. Aim: The purpose of the study was to determine the contribution of the fibroblasts to DCM caused by LMNA deficiency. Methods and Results: The Lmna gene was deleted by crossing the platelet-derived growth factor receptor α-Cre recombinase (Pdgfra-Cre) and floxed Lmna (LmnaF/F) mice. The LMNA protein was nearly absent in ~80% of the cardiac fibroblasts and ~25% of cardiac myocytes in the Pdgfra-Cre:LmnaF/F mice. The Pdgfra-Cre:LmnaF/F mice showed an early phenotype characterized by cardiac conduction defects, arrhythmias, cardiac dysfunction, myocardial fibrosis, apoptosis, and premature death within the first six weeks of life. The Pdgfra-Cre:LmnaWild type/F(LmnaW/F) mice also showed a similar but slowly evolving phenotype that was expressed within one year of age. RNA sequencing of LMNA-deficient and wild-type cardiac fibroblasts identified differential expression of ~410 genes, which predicted activation of the TP53 and TNFA/NFκB and suppression of the cell cycle pathways. In agreement with these findings, levels of phospho-H2AFX, ATM, phospho-TP53, and CDKN1A, markers of the DNA damage response (DDR) pathway, were increased in the Pdgfra-Cre:LmnaF/F mouse hearts. Moreover, expression of senescence-associated beta-galactosidase was induced and levels of the senescence-associated secretory phenotype (SASP) proteins TGFβ1, CTGF (CCN2), and LGLAS3 were increased as well as the transcript levels of additional genes encoding SASP proteins in the Pdgfra-Cre:LmnaF/F mouse hearts. Finally, expression of pH2AFX, a bonafide marker of the double-stranded DNA breaks, was increased in cardiac fibroblasts isolated from the Pdgfra-Cre:LmnaF/F mouse hearts. Conclusion: Deletion of the Lmna gene in fibroblasts partially recapitulates the phenotype of the LMNA-associated DCM, likely through induction of double-stranded DNA breaks, activation of the DDR pathway, and induction of expression of the SASP proteins. The findings indicate that the phenotype in the LMNA-associated DCM is the aggregate consequence of the LMNA deficiency in multiple cardiac cells, including cardiac fibroblasts.

Earlier, we reported that elevated anxiety-like behavior and high aggression in aged retired breeder Long-Evans (L-E) rats was associated with increased plasma corticosterone and elevated oxidative stress levels. In the present study, we examined how this aged aggressive and anxious rat strain responds to acute sleep deprivation (24 h) and whether their behaviors can be modulated via antioxidant tempol treatment. Four groups of L-E rats were utilized: naïve control (NC), tempol treated control (T+NC), sleep deprived (SD), tempol treated and sleep deprived (T+SD). Thus, two groups were treated with tempol (1mM in drinking water for 2 weeks) while the other two were not. Two groups were subjected to acute sleep deprivation (24 h) using the columns-in-water model while the other two were not. Sleep deprivation induced anxiety-like behavior, led to significant depression-like behavior and short-term memory impairment in SD rats. And, decision-making behavior also was compromised in SD rats. These behavioral and cognitive impairments were prevented with tempol treatment in T+SD rats. Tempol treatment also reduced SD-induced increase in corticosterone and oxidative stress levels in T+SD rats. These results suggest potential involvement of oxidative stress mechanisms in regulation of sleep deprivation induced behavioral and cognitive deficits in male aged-aggressive rats.

OBJECTIVE:  To determine the frequency and causes of maternal near miss and mortality among pregnant women. METHODS: This cross-sectional study was conducted Jan 2016 - Dec 2018. All near miss cases, admitted in Gynecology department of Services Hospital Lahore during the study period, were prospectively recruited. WHO criteria was used to identify maternal near miss cases. Primary outcome measures were frequency and causes of near miss and maternal mortality to near miss ratio. Secondary outcome measures were delays, need for massive blood transfusion, ICU admission, obstetric hysterectomy and hospital stay> 7 days. RESULTS: During the study period, there were 10,739 live births, 305 near miss cases and 29 maternal deaths. Frequency of near miss was 28.4/ 1000 live births and maternal mortality to near miss ratio was 1:10.5. There were 215(70.4%) unbooked patients and 23(79.3%) of them died (p<0.001). Hemorrhage accounted for 150 (49.18%), hypertensive disorders 102 (33.44%),cardiac disease 25 (8.28%) and infection for 12 (3.97%) near miss cases respectively. Maternal mortality was significantly low for hemorrhage, hypertension, sepsis and cardiac disease; 6 vs 150, 8 vs102, 3vs 12 and 10 vs 25 respectively (p<0.001). Massive blood transfusion was given to 20.98%patients, 15.74% underwent hysterectomy, 32.13% required ICU admission. First and second delay was seen in 78.6% of patients with 86.2% deaths (p<0.001) CONCLUSION: Hemorrhage and hypertension are major reasons for near miss but timely intervention can prevent mortality. Strengthening care at primary and secondary level can reduce the burden of maternal morbidity.  Continuous....