Heart failure resulting from different forms of cardiomyopathy is defined as the inability of the heart to pump sufficient blood to meet the body's metabolic demands. It is a major disease burden worldwide and the statistics show that 50% of the people who have the heart failure will eventually die from sudden cardiac death (SCD) associated with an arrhythmia. The central cause of disability and SCD is because of ventricular arrhythmias. Genetic mutations and acquired modifications to RyR2, the calcium release channel from sarcoplasmic reticulum, can increase the pathologic SR Ca2+ leak during diastole, which leads to defects in SR calcium handling and causes ventricular arrhythmias. The mechanism of RyR2 dysfunction includes abnormal phosphorylation, disrupted interaction with regulatory proteins and ions, or altered RyR2 domain interactions. Many pharmacological strategies have shown promising prospects to modulate the RyR2 as a therapy for treating cardiac arrhythmias. Here, we are trying to establish a novel approach to designing new drugs to treat heart failure and cardiac arrhythmias. Previously, we demonstrated that all pharmacological inhibitors of RyR channels are electron donors while all activators of RyR channels are electron acceptors. This was the first demonstration that an exchange of electrons was a common molecular mechanism involved in modifying the function of the RyR. Moreover, we found that there is a strong correlation between the strength of the electron donor/acceptor, and its potency as a channel inhibitor/activator, which could serve as a basis and direction for developing new drugs targeting the RyR. In this study, two new potent RyR inhibitors, 4-methoxy-3-methyl phenol (4-MmC) and the 1,3 dioxole derivative of K201, were synthesized which are derivatives of the known RyR modulators, 4-chloro-3-methyl phenol (4-CmC) and K201. The ability of K201, 1,3 dioxole derivative of K201 and 4-MmC to inhibit the cardiac calcium channel is examined and compared at the single channel level. All of these compounds inhibited the channel activity at low micromolar concentrations or sub-micromolar concentrations.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18450号 / 医博第3905号 / 新制||医||1004(附属図書館) / 31328 / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊達 洋至, 教授 稲垣 暢也, 教授 森田 智視 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19362号 / 医博第4039号 / 新制||医||1011(附属図書館) / 32376 / 新制||医||1011 / 京都大学大学院医学研究科医学専攻 / (主査)教授 横出 正之, 教授 佐藤 俊哉, 教授 森田 智視 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Periodontitis is a disease primarily affecting tooth attachment, i.e. concerning oral cavity, however, its connection to a number of systemic diseases is apparent nowadays. Oral microorganisms and their interaction with the immune system of their host play a significant part in the etiology of this multifactorial disease. Rapid development of DNA-based diagnostic methods in the last 15 years dramatically increased the spectrum of identified oral microorganisms and promoted understanding of how particular taxons correlate with periodontal health or disease. Moreover, next generation sequencing methods also bring new possibilities to study the relationship between periodontitis and other diseases such as diabetes mellitus, cardiovascular diseases (CVD), stroke, lung infection or kidney diseases, etc. The presented work focuses on the use of sequencing methods to compare the taxonomic composition of microbiomes within oral cavity and the tissues of aortic valves in patients suffering from CVD. The characterisation of taxonomic composition of microbiome in the analysed tissues was performed using the method of 454 pyrosequencing of variable region IV-V of the bacterial 16S rDNA. The present taxons were determined by comparing the obtained sequences with the Human Oral Microbiome Database. The common...

Bakgrund: Hjärtinfarkt är en vanlig hjärt-kärlsjukdom som årligen drabbar många personer i Sverige och internationellt. Livsstilsförändringar är en viktig del av sekundärpreventionen för att minska risken för att återinsjukna. Svårigheter med att genomföra livsstilsförändringar ställer därmed höga krav på att vårdpersonal har adekvat kunskap i ämnet.  Syfte: Att beskriva personers erfarenheter av att genomföra livsstilsförändringar efter genomgången hjärtinfarkt.   Metod: En litteraturöversikt med kvalitativ metod och induktiv ansats. Artikelsökningar utfördes i databaserna Cinahl och Medline och inkluderade artiklar publicerade mellan 2013-01-01 och 2023-03-03. Elva resultatartiklar analyserades utifrån Fribergs analysmetod i fem steg.   Resultat: I resultatet framkom två huvudkategorier och sju underkategorier. Huvudkategorin att påbörja en livsstilsförändring påvisar personers erfarenheter av förändrade kostvanor, fysisk aktivitet och att sluta röka. Vidare i resultatet framkom det hur en vilja att göra en förändring hade en betydande roll i genomförandet av livsstilsförändringar. Huvudkategorin externa resurser som påverkar livsstilsförändringar visar hur vården, familjen och rehabiliteringsprogram var externa stöd som påverkade personers förmåga till livsstilsförändring.   Slutsats: Att genomföra livsstilsförändringar var krävande för personerna då erfarenheterna påverkas av viljan att genomföra förändringar samt externa resurser. Stöttning och information från vården hade en betydande roll för att lyckas genomföra livsstilsförändringar och där vårdpersonal är i behov av ytterligare kunskap. / Background: Heart attack is a common cardiovascular disease that annually affects many people in Sweden and internationally. Lifestyle changes are an important part of secondary prevention to reduce the risk of relapse. Difficulties in implementing lifestyle changes therefore place high demands on healthcare professionals to have adequate knowledge on the subject.  Aim: To describe people’s experiences of implementing lifestyle changes after suffering a heart attack.   Method: A literature review with qualitative method and inductive approach. Article searches were performed in the databases Cinahl and Medline and included articles published between 2013-01-01 and 2023-03-03. Eleven scientific articles were analysed based on Friberg´s analysis method in five steps.  Result: The results revealed two main categories and seven subcategories. The main category of starting a lifestyle change shows people's experiences of changing dietary habits, physical activity and quitting smoking after the heart attack. Further in the results, it emerged how a willingness to make a change had a role in the implementation of lifestyle changes. The main category external resources that influence lifestyle changesshows how healthcare, family and rehabilitation programs were a form external support that influenced people's ability to change lifestyles.   Conclusion: Making lifestyle changes was demanding for the people as the experiences are influenced by a desire to make a change and external resources. Support and information from healthcare professionals had a significant role in successfully implementing lifestyle changes and where healthcare professionals need additional knowledge.

The cost and duration of cardiovascular care was studied for 4,804 episodes of hospitalization in patients between 45 and 64 years of age. Men were more likely than women to be treated in urban medical centers for shorter, more expensive hospital care; women were more likely to be treated in rural hospitals for longer, less expensive care. Cost of treatment per day was not dependent on the type of insurance, but Medicaid claims (which represent low income patients) were associated with greater lengths of stay.

Ischemic colitis is a known complication of abdominal aortic aneurysm (AAA) repair. There is still no established consensus regarding the individual significance of factors related to this phenomenon. We detail the hospital course of a patient who unexpectedly developed acute colonic ischemia following open AAA repair. The pathophysiology, diagnostic modalities, potential preventative measures, and effect on patient morbidity and mortality will be presented. Reviewing the current literature, this will focus on the reported statistical importance of various risk factors including the incidence following traditional open repair and endovascular aneurysm repair.

OBJECTIVE: The effects of a computer-assisted instruction (CAI) tutorial program on learning clinical reasoning skills were compared in undergraduate dietetics students. DESIGN: A drill-and-practice program to control for time on task, and tutorial program, and a simulation program, as the test vehicle, were developed. The tutorial and simulation programs presented data on a patient with cardiovascular disease. SETTING: Subjects were tested in 30 undergraduate dietetics programs. SUBJECTS: Participants were 413 undergraduate diet therapy students enrolled in a coordinated program in dietetics (CPD) or a didactic program in dietetics (DPD). INTERVENTION: After completion of lectures on cardiovascular disease, subjects were given the drill-and-practice program plus a simulation test (group 1), the tutorial plus a simulation test (group 2), or the simulation test only (group 3). MAIN OUTCOME MEASURES: Scores on the simulation test were compared. Variables included type of CAI, dietetics program, year in school, computer experience, and experience using a medical chart. Mastery of objectives related to lower- and higher-level clinical reasoning skills introduced in the tutorial program was computed. STATISTICAL ANALYSIS: One-way analysis of variance and Student-Newman Keuls tests were conducted to determine any differences among the three groups. Reliability was determined using the Kuder-Richardson Formula 20. RESULTS: The reliability coefficient of the stimulation test was 0.93. Group 2 higher on the simulation test than group 1 or group 3. As a group, the CPD students scored higher than the DPD students. When CPD and DPD students were divided into the three experimental groups, there was no significant difference between the CPD and DPD student simulation scores. Group 2 mastered all objectives for lower-level reasoning skills and the higher-level decision-making objective better than groups 1 and 3. APPLICATIONS/CONCLUSIONS: A computer tutorial program enhanced clinical reasoning skills in undergraduate dietetics students. This type of program could be used to supplement many topics taught in diet therapy and provide DPD students with experimental learning before their clinical intern practicums.

Monocyte chemotactic protein-1 (MCP-1) plays a critical role in the development of cardiovascular diseases. How MCP-1 contributes to the development of heart disease is not understood. We present evidence that MCP-1 causes death in cardiac myoblasts, H9c2 by inducing oxidative stress, ER stress and autophagy via a novel Znfinger protein, MCP-1 induced protein (MCPIP). MCPIP expression caused cell death and knockdown of MCPIP, attenuated MCP-1 induced cell death. Expression of MCPIP resulted in induction of iNOS and production of reactive oxygen (ROS). It caused induction of NADPH oxidase subunit phox47 and its translocation to the cytoplasmic membrane. Oxidative stress led to the induction of ER stress markers HSP40, PDI, GRP78 and IRE1α. ER stress lead to autophagy as indicated by beclin-1 induction, cleavage of LC3 to LCII and autophagolysosome formation. Here, MCPIP-induced processes lead to apoptosis as indicated by caspase 3 activation and TUNEL assay. This cell death involved caspase 2 and caspase 12 as specific inhibitors of these caspases prevented MCPIP-induced cell death. Inhibitors of oxidative stress inhibited ER stress, and cell death. Specific inhibitors of ER stress inhibited autophagy and cell death. Inhibition of autophagy inhibited cell death. Microarray analysis showed that MCPIP expression caused induction of a variety of genes known to be involved in cell death. MCPIP caused activation of JNK and p38 and induction of p53 and PUMA. These results collectively suggest that MCPIP induces ROS/RNS production that causes ER stress which leads to autophagy and apoptosis through caspase 2/12 and IRE1α –JNK/p38-p53-PUMA pathway. These results provide the first molecular insights into the mechanism by which elevated MCP-1 levels associated with chronic inflammation may contribute to the development of heart failure. A role for inflammation and MCP-1 in obesity and diabetes has been implicated. Adipogenesis is a key process involved in obesity and associated diseases such as type 2 diabetes. This process involves temporally regulated genes controlled by a set of transcription factors, C/EBPβ, C/EBPδ, C/EBPα, and PPARγ. Currently PPARγ is considered the master regulator of adipogenesis as no known factor can induce adipogenesis without PPARγ. We present evidence that a novel Zn-finger protein, MCPIP, can induce adipogenesis without PPARγ. Classical adipogenesis-inducing medium induces MCP-1 production and MCPIP expression in 3T3-L1 cells before the induction of the C/EBP family of transcription factors and PPARγ. Knockdown of MCPIP prevents their expression and adipogenesis. Treatment of 3T3-L1 cells with MCP-1 or forced expression of MCPIP induces expression of C/EBPβ, C/EBPδ, C/EBPα, PPARγ and adipogenesis without any other inducer. Forced expression of MCPIP induces adipogenesis in PPARγ-/- fibroblasts. Thus, MCPIP is a newly identified master controller that can induce adipogenesis without PPARγ. Heart failure is a major cause of death in diabetic patients. Hyperglycemia is a major factor associated with diabetes that causes cardiomyocyte apoptosis that leads to diabetic cardiomyopathy. Cardiomyoycte apoptosis is a key event involved in the pathophysiological progression of diabetic cardiomyopathy. We have recently found that in ischemic hearts, MCP-1 can induce the zinc-finger protein, MCP-1 induced protein (MCPIP) that causes cardiomyocyte apoptosis. Although there is evidence that inflammation may play a role in diabetic cardiomyopathy, the underlying mechanisms are poorly understood. In this study, we show that treatment of H9c2 cardiomyoblasts and Neonatal Rat Ventricular Myocytes (NRVM) with 28mmol/L glucose concentration results in the induction of both transcript and protein levels of MCP-1 and MCPIP. Inhibition of MCP-1 interaction with CCR2 via specific antibody or with the G-coupled receptor inhibitors propagermanium and pertussis toxin attenuated glucose-induced cell death. Knockdown of MCPIP with specific siRNA yielded similar results. Treatment of cells with 28mmol/L glucose resulted in increased ROS production and phox47 activation. Knockdown of MCPIP attenuated these effects. The increased ROS production observed in H9c2 cardiomyoblasts and NRVM's resulted in increased ER stress proteins GRP78 and PDI. Knockdown of MCPIP attenuated expression of both GRP78 and PDI. Inhibition of ER stress with TUDC and 4'PBA prevented high glucoseinduced cell death death. Treatment of cells with 28mmol/l glucose resulted in autophagy as determined by an increase in expression of beclin-1 and through increased cleavage of LC3I to LC3II. Knockdown of MCPIP attenuated expression of beclin-1 and prevented cleavage of LC3. Addition of the autophagy inhibitors 3'methyladenine and LY294002 attenuated high glucose-induced H9c2 cardiomyoblast death. We conclude that high glucose-induced H9c2 cardiomyoblast death is mediated via MCP-1 induction of MCPIP that results in ROS that leads to ER stress that causes autophagy and eventual apoptosis.