Cardiomyocyte Survival Pathways

In the present thesis, the link between the genotype of the mouse and the concurrent phenotype is investigated employing sophisticated molecular and cellular techniques combined with in vivo cardiac performance measurements. In chapter 1 we focus on the characteristics of cardiac remodeling following an ischemic event in man. The characteristics of remodeling are thoroughly discussed through the results solely derived from studies in genetically modified mice. Despite the data available, intracellular signaling is still a mystery as we lack the tools to study several pathways simultaneously and maybe even more important the temporal changes in signaling cascade interactions. In chapter 2 the molecular processes involved in cardiac hypertrophy are discussed. The concept of beneficial and maladaptive pathways is introduced and related to the detrimental transition of hypertrophy towards heart failure. Open-chest and closed-chest protocols for in vivo left ventricular pressure-volume measurement are illustrated in chapter 3.We have chosen for closed-chest cardiac function assessment protocol in our ischemia-reperfusion studies, because of better systolic and diastolic performance, normal arterial-ventricular coupling and preservation of myocardial integrity. To unravel the importance of specific signaling pathways (e.g. MEK1-ERK1/2 and calcineurin-NFAT) in ischemia-reperfusion-induced cell death techniques of transgenesis (e.g. MEK1 and GSK-3B transgenic mice) and gene targeting (e.g. ERK1 homozygous, ERK2 heterozygous and CnAB homozygous knockout mice) have been used. In chapter 4 we analyzed ERK1 homozygous knockout mice, ERK2 heterozygous knockout mice, and transgenic mice with activated MEK1-ERK1/2 signaling in the heart to determine a direct causal relationship between ERK1/2 signaling and cardioprotection. A direct cardioprotective role for ERK signaling in the heart following ischemia-reperfusion injury was demonstrated. In chapter 5 we investigate the role the calcium/calmodulin-activated protein phosphatase calcineurin plays in modulating cardiac apoptosis following acute ischemia-reperfusion injury in the heart. Calcineurin Aß (CnAB) gene targeted mice showed a greater loss of viable myocardium, more apoptosis, and a greater loss in functional performance following ischemia-reperfusion injury when compared to strain-matched wildtype control mice. Increased cell death was associated with a reduction of NFAT activity. The study presented in chapter 6 was designed to elucidate the role of GSK-3B following ischemia-reperfusion. In GSK-3B transgenic mice, ischemia led to a larger infarct area and subsequent worsened cardiac performance, while post-ischemic hypertrophic remodeling was blunted. In previous studies activation of both MEK1-ERK1/2 and calcineurin-NFAT signaling pathways were associated with hypertrophic cellular growth. The present thesis proves their involvement in anti-apoptotic protection against ischemia-reperfusion injury. The dualistic role of both resuscitative survival pathways in distinct pathogenic conditions as cardiomyocyte hypertrophy and apoptosis, is a fascinating observation. To further delineate the specific roles of individual survival pathways and investigate their potential use in clinical practice, future research should focus on studying multiple signaling cascades simultaneously and their interplay. A possible option is to cross-breed different genetically modified mice, thereby creating double knockout or knockout/transgenic mice. Another possibility could come from dynamic molecular imaging, through which protein function and interaction could be visualized. The treatment of cardiac ischemia will eventually be improved significantly through new developments in molecular science

Amphibian diversity in Serranía de Majé, an isolated mountain range in eastern Panamá

Eastern Panama is within the Mesoamerican biodiversity hotspot and supports an understudied amphibian fauna. Here we characterize the amphibian diversity across an elevational gradient in one of the least studied mountain ranges in eastern Panama, Serrania de Maje. A total of 38 species were found, which represent 17% of all species reported for Panama. Based on expected richness function and individual-based rarefaction curves, it is estimated that this is an underestimate and that at least 44 amphibian species occur in this area. Members of all three amphibian orders were encountered, represented by ten families and 22 genera, including five species endemic to Central America. Estimated species richness decreased with elevation, and the mid-elevation site supported both lowland and highland species. Our study provides a baseline for understanding the distribution pattern of amphibians in Panama, for conservation efforts, and for determining disease-induced changes in amphibian communities.85911713

Absorption of ipratropium and L-carnitine into the pulmonary circulation of the ex-vivo rat lung is driven by passive processes rather than active uptake by OCT/OCTN transporters

The organic cation transporters OCT and OCTN have been reported to play a significant role in the cellular uptake of substrates within in vitro lung cells. However, no studies to date have investigated the effect of these transporters upon transepithelial absorption of substrates into the pulmonary circulation. We investigated the contribution of OCT and OCTN transporters to total pulmonary absorption of L-carnitine and the anti-muscarinic drug, ipratropium, across an intact isolated perfused rat lung (IPRL). The results obtained from the IPRL were contrasted with active transport in vitro using three human pulmonary cell lines and primary rat alveolar epithelial cells. Ex-vivo studies showed that OCT/OCTN transporters do not play a role in the overall pulmonary absorption of L-carnitine or ipratropium, as evidenced by the effect of chemical inhibition of these transporters upon pulmonary absorption. In contrast, in-vitro studies showed that OCT/OCTN transporters play a significant role in cellular accumulation of substrates with preferential uptake of ipratropium by OCTs, and of L-carnitine uptake by OCTNs. The results show that in-vitro uptake studies cannot be predictive of airway to blood absorption in-vivo. Nevertheless, localised submucosal pulmonary concentrations of inhaled drugs and their pulmonary pharmacodynamic profiles may be influenced by OCT/OCTN transport activity

Meta-analysis of the impact of successful chronic total occlusion percutaneous coronary intervention on left ventricular systolic function and reverse remodeling

We sought to examine the impact of coronary chronic total occlusion (CTO) percutaneous coronary intervention (PCI) on left ventricular (LV) function.We performed a systematic review and meta-analysis of studies published between January 1980 and November 2017 on the impact of successful CTO PCI on LV function.A total of 34 observational studies including 2735 patients were included in the meta-analysis. Over a weighted mean follow-up of 7.9 months, successful CTO PCI was associated with an increase in LV ejection fraction by 3.8% (95%CI 3.0-4.7, P < 0.0001, I2 = 45%). In secondary analysis of 15 studies (1248 patients) that defined CTOs as occlusions of at least 3-month duration and reported follow-up of at least 3-months after the procedure, successful CTO PCI was associated with improvement in LV ejection fraction by 4.3% (95%CI [3.1, 5.6], P < 0.0001). In the 10 studies (502 patients) that reported LV end-systolic volume, successful CTO PCI was associated with a decrease in LV end-systolic volume by 4 mL, (95%CI -6.0 to -2.1, P < 0.0001, I2 = 0%). LV end-diastolic volume was reported in 9 studies with 403 patients and did not significantly change after successful CTO PCI (-2.3 mL, 95%CI -5.7 to 1.2 mL, P = 0.19, I2 = 0%).Successful CTO PCI is associated with a statistically significant improvement in LV ejection fraction and decrease in LV end-systolic volume, that may reflect a beneficial effect of CTO recanalization on LV remodeling. The clinical implications of these findings warrant further investigation

Soft matter science and the COVID-19 pandemic

Much of the science underpinning the global response to the COVID-19 pandemic lies in the soft matter domain. Coronaviruses are composite particles with a core of nucleic acids complexed to proteins surrounded by a protein-studded lipid bilayer shell. A dominant route for transmission is via air-borne aerosols and droplets. Viral interaction with polymeric body fluids, particularly mucus, and cell membranes control their infectivity, while their interaction with skin and artificial surfaces underpins cleaning and disinfection and the efficacy of masks and other personal protective equipment. The global response to COVID-19 has highlighted gaps in the soft matter knowledge base. We survey these gaps, especially as pertaining to the transmission of the disease, and suggest questions that can (and need to) be tackled, both in response to COVID-19 and to better prepare for future viral pandemics.Comment: 15 page

Pigmentation and Vitamin D Metabolism in Caucasians: Low Vitamin D Serum Levels in Fair Skin Types in the UK

Background: Vitamin D may play a protective role in many diseases. Public health messages are advocating sun avoidance to reduce skin cancer risk but the potential deleterious effects of these recommendations for vitamin D metabolism have been poorly investigated. Methodology/Principal Findings: We investigated the association between 25-hydroxy-vitamin D (25(OH)D), skin type and ultraviolet exposure in 1414 Caucasian females in the UK. Mean age of the cohort was 47 years (18–79) and mean 25(OH)D levels were 77 nmol/L (6–289). 25(OH)D levels were strongly associated with season of sampling with higher levels in the spring and summer months (p,0.0001). Light skin types (skin type 1 and 2) have lower levels of 25(OH)D (mean 71 nmol/L) compared to darker skin types (skin type 3 and 4) (mean 82 nmol/L) after adjusting for multiple confounders (p,0.0001). The trend for increasing risk of low vitamin D with fairer skin types was highly significant despite adjustment for all confounders (p = 0.001). Conclusions/Significance: Contrary to previous studies across different ethnic backgrounds, this study within Caucasian UK females shows that fair skin types have lower levels of 25(OH)D compared to darker skin types with potential detrimental health effects. Public health campaigns advocating sun avoidance in fair skinned individuals may need to be revised in vie

Pigmentation and Vitamin D Metabolism in Caucasians: Low Vitamin D Serum Levels in Fair Skin Types in the UK

Background: Vitamin D may play a protective role in many diseases. Public health messages are advocating sun avoidance to reduce skin cancer risk but the potential deleterious effects of these recommendations for vitamin D metabolism have been poorly investigated. Methodology/Principal Findings: We investigated the association between 25-hydroxy-vitamin D (25(OH)D), skin type and ultraviolet exposure in 1414 Caucasian females in the UK. Mean age of the cohort was 47 years (18–79) and mean 25(OH)D levels were 77 nmol/L (6–289). 25(OH)D levels were strongly associated with season of sampling with higher levels in the spring and summer months (p,0.0001). Light skin types (skin type 1 and 2) have lower levels of 25(OH)D (mean 71 nmol/L) compared to darker skin types (skin type 3 and 4) (mean 82 nmol/L) after adjusting for multiple confounders (p,0.0001). The trend for increasing risk of low vitamin D with fairer skin types was highly significant despite adjustment for all confounders (p = 0.001). Conclusions/Significance: Contrary to previous studies across different ethnic backgrounds, this study within Caucasian UK females shows that fair skin types have lower levels of 25(OH)D compared to darker skin types with potential detrimental health effects. Public health campaigns advocating sun avoidance in fair skinned individuals may need to be revised in vie

Ductal carcinoma in situ: to treat or not to treat, that is the question

Abstract: Ductal carcinoma in situ (DCIS) now represents 20–25% of all ‘breast cancers’ consequent upon detection by population-based breast cancer screening programmes. Currently, all DCIS lesions are treated, and treatment comprises either mastectomy or breast-conserving surgery supplemented with radiotherapy. However, most DCIS lesions remain indolent. Difficulty in discerning harmless lesions from potentially invasive ones can lead to overtreatment of this condition in many patients. To counter overtreatment and to transform clinical practice, a global, comprehensive and multidisciplinary collaboration is required. Here we review the incidence of DCIS, the perception of risk for developing invasive breast cancer, the current treatment options and the known molecular aspects of progression. Further research is needed to gain new insights for improved diagnosis and management of DCIS, and this is integrated in the PRECISION (PREvent ductal Carcinoma In Situ Invasive Overtreatment Now) initiative. This international effort will seek to determine which DCISs require treatment and prevent the consequences of overtreatment on the lives of many women affected by DCIS

Dietary intake and stress fractures among elite male combat recruits

<p>Abstract</p> <p>Background</p> <p>Appropriate and sufficient dietary intake is one of the main requirements for maintaining fitness and health. Inadequate energy intake may have a negative impact on physical performance which may result in injuries among physically active populations. The purpose of this research was to evaluate a possible relationship between dietary intake and stress fracture occurrence among combat recruits during basic training (BT).</p> <p>Methods</p> <p>Data was collected from 74 combat recruits (18.2 ± 0.6 yrs) in the Israeli Defense Forces. Data analyses included changes in anthropometric measures, dietary intake, blood iron and calcium levels. Measurements were taken on entry to 4-month BT and at the end of BT. The occurrence of stress reaction injury was followed prospectively during the entire 6-month training period.</p> <p>Results</p> <p>Twelve recruits were diagnosed with stress fracture in the tibia or femur (SF group). Sixty two recruits completed BT without stress fractures (NSF). Calcium and vitamin D intakes reported on induction day were lower in the SF group compared to the NSF group-38.9% for calcium (589 ± 92 and 964 ± 373 mg·d^-1, respectively, <it>p </it>< 0.001), and-25.1% for vitamin D (117.9 ± 34.3 and 157.4 ± 93.3 IU·d^-1, respectively, <it>p </it>< 0.001). During BT calcium and vitamin D intake continued to be at the same low values for the SF group but decreased for the NSF group and no significant differences were found between these two groups.</p> <p>Conclusions</p> <p>The development of stress fractures in young recruits during combat BT was associated with dietary deficiency before induction and during BT of mainly vitamin D and calcium. For the purpose of intervention, the fact that the main deficiency is before induction will need special consideration.</p