Review of Clément Vidal, "The Beginning and the End. The Meaning of Life in a Cosmological Perspective"

No more ground control. Dissertations ideally always have been ambitious, and this one can’t claim to be too humble in these regards. Together the pieces of this work form a world view that the author confesses to finding ‘magnificent’. The story he tells is one in which intelligence and complexity are keys to unlock the universe’s mysteries. Vidal tackles questions like ‘What is philosophy?’, ‘Where does it all come from?’, Where are we going?’, ‘Are we alone in the universe?’ and even ‘What is good and what is evil?’. Questions which philosophers for ages have tried to answer.

Weather and War – Economic and social vulnerability in Switzerland at the end of the First World War

Neutral Switzerland – not embedded in the fighting forces – yet was involved in the Great War mainly in economical terms. Since Switzerland is a landlocked country especially agriculture became an important topic of war economy in regard to food security. Until 1916 national food supply was limited but could be maintained through barter trade. In 1916 a crisis on both supply and production level occurred and led to a decline in food availability and to immense price risings causing social turmoil. This paper aims to outline the factors of vulnerability in respect of food in Switzerland during the First World War and further it will show different coping strategies that were undertaken during that time. The paper takes the work of Mario Aeby and Christian Pfister (University of Bern) into consideration that pointed out to weather anomalies during the years 1916 and 1917 aggravating the already tense food situation. Arguing for an overlap of supply and production crisis the paper focuses on agricultural and economic history including environmental impacts. Further the paper addresses the question of what makes a food system resilient to such unforeseen impacts.

“Delendum est Imperium Ottomanorum“: War Crimes, Crimes against Humanity and the End of the Ottoman Empire

The Ottoman Empire’s status as a full member of the international community of civilized states, which was bound by the rules of international law, had been challenged again and again during the formative period of the international law in the late nineteenth and early twentieth century. When the First World War began, it was the first global military conflict, in which these rules of international law were put to the test. In the case of the Ottoman Empire quite a few questions were not yet settled, not least because the country was still bound by unequal treaties and because it had never ratified the renewed Hague Rules of Land Warfare of 1907, which it had only signed under reservations. Against this background the contribution will therefore focus on the debate amongst legal scholars on violations of the laws of war (and humanity) in regard to the Ottoman Empire during the First World War.

Effects of Prolyl Hydroxylase Inhibitor L-mimosine on Dental Pulp in the Presence of Advanced Glycation End Products

INTRODUCTION Proangiogenic prolyl hydroxylase (PHD) inhibitors represent a novel approach to stimulate tissue regeneration. Diabetes mellitus involves the accumulation of advanced glycation end products (AGEs). Here we evaluated the impact of AGEs on the response of human pulp tissue to the PHD inhibitor L-mimosine (L-MIM) in monolayer cultures of dental pulp-derived cells (DPCs) and tooth slice organ cultures. METHODS In monolayer cultures, DPCs were incubated with L-MIM and AGEs. Viability was assessed based on formazan formation, live-dead staining, annexin V/propidium iodide, and trypan blue exclusion assay. Vascular endothelial growth factor (VEGF), interleukin (IL)-6, and IL-8 production was evaluated by quantitative polymerase chain reaction and immunoassays. Furthermore, expression levels of odontoblast markers were assessed, and alizarin red staining was performed. Tooth slice organ cultures were performed, and VEGF, IL-6, and IL8 levels in their supernatants were measured by immunoassays. Pulp tissue vitality and morphology were assessed by MTT assay and histology. RESULTS In monolayer cultures of DPCs, L-MIM at nontoxic concentrations increased the production of VEGF and IL-8 in the presence of AGEs. Stimulation with L-MIM decreased alkaline phosphatase levels and matrix mineralization also in the presence of AGEs, whereas no significant changes in dentin matrix protein 1 and dentin sialophosphoprotein expression were observed. In tooth slice organ cultures, L-MIM increased VEGF but not IL-6 and IL-8 production in the presence of AGEs. The pulp tissue was vital, and no signs of apoptosis or necrosis were observed. CONCLUSIONS Overall, in the presence of AGEs, L-MIM increases the proangiogenic capacity, but decreases alkaline phosphatase expression and matrix mineralization.

3' end processing of mouse histone pre-mRNA: evidence for additional base-pairing between U7 snRNA and pre-mRNA.

We have analysed the extent of base-pairing interactions between spacer sequences of histone pre-mRNA and U7 snRNA present in the trans-acting U7 snRNP and their importance for histone RNA 3' end processing in vitro. For the efficiently processed mouse H4-12 gene, a computer analysis revealed that additional base pairs could be formed with U7 RNA outside of the previously recognised spacer element (stem II). One complementarity (stem III) is located more 3' and involves nucleotides from the very 5' end of U7 RNA. The other, more 5' located complementarity (stem I) involves nucleotides of the Sm binding site of U7 RNA, a part known to interact with snRNP structural proteins. These potential stem structures are separated from each other by short internal loops of unpaired nucleotides. Mutational analyses of the pre-mRNA indicate that stems II and III are equally important for interaction with the U7 snRNP and for processing, whereas mutations in stem I have moderate effects on processing efficiency, but do not impair complex formation with the U7 snRNP. Thus nucleotides near the processing site may be important for processing, but do not contribute to the assembly of an active complex by forming a stem I structure. The importance of stem III was confirmed by the ability of a complementary mutation in U7 RNA to suppress a stem III mutation in a complementation assay using Xenopus laevis oocytes. The main role of the factor(s) binding to the upstream hairpin loop is to stabilise the U7-pre-mRNA complex. This was shown by either stabilising (by mutation) or destabilising (by increased temperature) the U7-pre-mRNA base-pairing under conditions where hairpin factor binding was either allowed or prevented (by mutation or competition). The hairpin dependence of processing was found to be inversely related to the strength of the U7-pre-mRNA interaction.

Variable effects of the conserved RNA hairpin element upon 3' end processing of histone pre-mRNA in vitro.

We have studied the requirements for efficient histone-specific RNA 3' processing in nuclear extract from mammalian tissue culture cells. Processing is strongly impaired by mutations in the pre-mRNA spacer element that reduce the base-pairing potential with U7 RNA. Moreover, by exchanging the hairpin and spacer elements of two differently processed H4 genes, we find that this difference is exclusively due to the spacer element. Finally, processing is inhibited by the addition of competitor RNAs, if these contain a wild-type spacer sequence, but not if their spacer element is mutated. Conversely, the importance of the hairpin for histone RNA 3' processing is highly variable: A hairpin mutant of the H4-12 gene is processed with almost wild-type efficiency in extract from K21 mouse mastocytoma cells but is strongly affected in HeLa cell extract, whereas an identical hairpin mutant of the H4-1 gene is affected in both extracts. The hairpin defect of H4-12-specific RNA in HeLa cells can be overcome by a compensatory mutation that increases the base complementarity to U7 snRNA. Very similar results were also obtained in RNA competition experiments: processing of H4-12-specific RNA can be competed by RNA carrying a wild-type hairpin element in extract from HeLa, but not K21 cells, whereas processing of H4-1-specific RNA can be competed in both extracts. With two additional histone genes we obtained results that were in one case intermediate and in the other similar to those obtained with H4-1. These results suggest that hairpin binding factor(s) can cooperatively support the ability of U7 snRNPs to form an active processing complex, but is(are) not directly involved in the processing mechanism.

If hunters end up in the emergency room: a retrospective analysis of hunting injuries in a swiss emergency department.

Aim. to characterize the mechanisms, patterns, and outcomes of nonfatal hunting-related injuries in patients presenting to Bern University Hospital, Switzerland, and compare these to reports of hunting injuries worldwide. Methods. patients presenting with hunting-related injuries to the Emergency Department at Bern University hospital from 2000 to 2014 were identified by retrospectively searching the department database using the keyword "hunt." Each case was analyzed in terms of the patient age and gender, the mechanism and pattern of injury, and management and patient follow-up. Results. 19 patients were identified. 16 were male with a mean age of 50 years (range: 16-74). Mechanisms of injury included firearm-related injuries, falls, and knife wounds. The most common patterns of injury were head injuries (7), followed by injuries to the upper (5) or lower limb (5) and trunk (2). Over half of the patients were admitted, and nine required emergency surgery. Conclusion. Nonfatal hunting accidents in Bern, Switzerland, are largely caused by firearms and falls and tend to occur in male hunters with a mean age of 50 years. The most common patterns of injury are orthopedic and head injuries, often requiring surgery. These findings are consistent with international studies of nonfatal hunting accidents.

PP080. First trimester umbilical artery end-diastolic flow and pulsatility index: Comparison between preeclampsia and control.

INTRODUCTION The appearance of end-diastolic flow velocities (EDF) in the umbilical artery (UA), usually between 10 and 14 weeks of gestation, has been associated with the opening of the spiral arteries and consequently of the intervillous space. OBJECTIVES The aim of our study was to compare first trimester UA pulsatility index (PI) and EDF between women who developed preeclampsia (cases) and controls. METHODS Our database was searched for cases who had UA Doppler between 10-14 weeks. UA PI and EDF were compared between cases and two gestational age (GA) matched controls. RESULTS 15 cases with severe preeclampsia (PE) were matched to 30 controls. GA with negative EDF was lower than with positive EDF (12.1±0.79 vs. 12.8±0.34; p=0.001). UA PI in cases was higher than in controls, although not significant (cases: 2.18±0.6 vs. CONTROLS 1.92±0.48; p=0.12). However, comparing groups with negative EDF, the difference became significant (PI cases: 2.45±0.57 vs. PI controls: 1.94±0.56; p=0.038), while no difference was found comparing groups with positive EDF. CONCLUSION First trimester UA PI is significantly higher in women which will develop PE than in controls. Interestingly, the timing of screening for PE by UA Doppler seems to play an important issue.

Phylogenetic analysis of receptor FgfrL1 shows divergence of the C-terminal end in rodents

FGFRL1 is a member of the fibroblast growth factor receptor (FGFR) family. Similar to the classical receptors FGFR1-FGFR4, it contains three extracellular Ig-like domains and a single transmembrane domain. However, it lacks the intracellular tyrosine kinase domain that would be required for signal transduction, but instead contains a short intracellular tail with a peculiar histidine-rich motif. This motif has been conserved during evolution from mollusks to echinoderms and vertebrates. Only the sequences of FgfrL1 from a few rodents diverge at the C-terminal region from the canonical sequence, as they appear to have suffered a frameshift mutation within the histidine-rich motif. This mutation is observed in mouse, rat and hamster, but not in the closely related rodents mole rat (Nannospalax) and jerboa (Jaculus), suggesting that it has occurred after branching of the Muridae and Cricetidae from the Dipodidae and Spalacidae. The consequence of the frameshift is a deletion of a few histidine residues and an extension of the C-terminus by about 40 unrelated amino acids. A similar frameshift mutation has also been observed in a human patient with a craniosynostosis syndrome as well as in several patients with colorectal cancer and bladder tumors, suggesting that the histidine-rich motif is prone to mutation. The reason why this motif was conserved during evolution in most species, but not in mice, is not clear.

Days spent in acute care hospitals at the end of life of cancer patients in four Swiss cantons: a retrospective database study (SAKK 89/09).

Number of days spent in acute hospitals (DAH) at the end of life is regarded as an important care quality indicator for cancer patients. We analysed DAH during 90 days prior to death in patients from four Swiss cantons. Claims data from an insurance provider with about 20% market share and patient record review identified 2086 patients as dying of cancer. We calculated total DAH per patient. Multivariable generalised linear modelling served to evaluate potential explanatory variables. Mean DAH was 26 days. In the multivariable model, using complementary and alternative medicine (DAH = 33.9; +8.8 days compared to non-users) and canton of residence (for patient receiving anti-cancer therapy, Zürich DAH = 22.8 versus Basel DAH = 31.4; for other patients, Valais DAH = 22.7 versus Ticino DAH = 33.7) had the strongest influence. Age at death and days spent in other institutions were additional significant predictors. DAH during the last 90 days of life of cancer patients from four Swiss cantons is high compared to most other countries. Several factors influence DAH. Resulting differences are likely to have financial impact, as DAH is a major cost driver for end-of-life care. Whether they are supply- or demand-driven and whether patients would prefer fewer days in hospital remains to be established.

Occupational performance of Mexican Americans with end-stage-renal-disease living on dialysis in the lower Rio Grande Valley

The number of people with end-stage-renal-disease (ESRD) and living with dialysis is a growing public health concern. Most studies about the impact of ESRD on people’s lives have placed attention on the medical and clinical dimension of ESRD. Very few have given attention to the environmental and cultural context in which people with ESRD live, the adaptation that these individuals must make to adjust to living with ESRD and dialysis, or the occupations in which they engage. Additionally these studies have not focused on Mexican Americans who are disproportionately affected by this illness and condition. This qualitative study explores the needs, perceptions, and issues facing Mexican Americans with ESRD living with dialysis as well as their families. Participants were residents of the Lower Rio Grande Valley and included individuals with ESRD, family members, and the healthcare providers who give care to them. The Health Belief Model and Lifestyle Performance Model served as the theoretical frameworks. The study also explored the daily occupations of this population. ^ In-depth interviews were conducted on 15 Mexican Americans with ESRD living with dialysis, 15 family members, and six dialysis healthcare providers. A video documentary of the day-to-day life of three individuals with ESRD and their families was produced. Such data do not currently exist and will greatly enhance the understanding of the human experience of living with ESRD. The results suggest that a collective effort of the family unit is at work to deal with the demands of dialysis. An imbalance and disharmony exist among the occupational activities, which creates occupational deprivation and disruption for both the individuals and family members. Implications for practice and recommendations for further research are described. ^

Understanding the roles of Non-homologous end joining and p53 after DNA damage

The inability to maintain genomic stability and control proliferation are hallmarks of many cancers, which become exacerbated in the presence of unrepaired DNA damage. Such genotoxic stresses trigger the p53 tumor suppressor network to activate transient cell cycle arrest allowing for DNA repair; if the damage is excessive or irreparable, apoptosis or cellular senescence is triggered. One of the major DNA repair pathway that mends DNA double strand breaks is non-homologous end joining (NHEJ). Abrogating the NHEJ pathway leads to an accumulation of DNA damage in the lymphoid system that triggers p53-mediated apoptosis; complete deletion of p53 in this system leads to aggressive lymphomagenesis. Therefore, to study the effect of p53-dependent cell cycle arrest, we utilized a hypomorphic, separation-of-function mutant, p53p/p, which completely abrogates apoptosis yet retains partial cell cycle arrest ability. We crossed DNA ligase IV deficiency, a downstream ligase crucial in mending breaks during NHEJ, into the p53p/p background (Lig4-/-p53p/p). The accumulation of DNA damage activated the p53/p21 axis to trigger cellular senescence in developing lymphoid cells, which absolutely suppressed tumorigenesis. Interestingly, these mice progressively succumb to severe diabetes. Mechanistic analysis revealed that spontaneous DNA damage accumulated in the pancreatic b-cells, a unique subset of endocrine cells solely responsible for insulin production to regulate glucose homeostasis. The genesis of adult b-cells predominantly occurs through self-replication, therefore modulating cellular proliferation is an essential component for renewal. The progressive accumulation of DNA damage, caused by Lig4-/-, activated p53/p21-dependent cellular senescence in mutant pancreatic b-cells that lead to islet involution. Insulin levels subsequently decreased, deregulating glucose homeostasis driving overt diabetes. Our Lig4-/-p53p/p model aptly depicts the dichotomous role of cellular senescence—in the lymphoid system prevents tumorigenesis yet in the endocrine system leads to the decrease of insulin-producing cells causing diabetes. To further delineate the function of NHEJ in pancreatic b-cells, we analyzed mice deficient in another component of the NHEJ pathway, Ku70. Although most notable for its role in DNA damage recognition and repair within the NHEJ pathway, Ku70 has NHEJ-independent functions in telomere maintenance, apoptosis, and transcriptional regulation/repression. To our surprise, Ku70-/-p53p/p mutant mice displayed a stark increase in b-cell proliferation, resulting in islet expansion, heightened insulin levels and hypoglycemia. Augmented b-cell proliferation was accompanied with the stabilization of the canonical Wnt pathway, responsible for this phenotype. Interestingly, the progressive onset of cellular senescence prevented islet tumorigenesis. This study highlights Ku70 as an important modulator in not only maintaining genomic stability through NHEJ-dependent functions, but also reveals a novel NHEJ-independent function through regulation of pancreatic b-cell proliferation. Taken in aggregate, these studies underscore the importance for NHEJ to maintain genomic stability in b-cells as well as introduces a novel regulator for pancreatic b-cell proliferation.

Attitudes toward end-of-life decision making in South Texas

Advance care planning has the potential to create positive outcomes in the realm of end-of-life health care. The completion of advance directives and living wills are vital in equipping patients with autonomy and ensuring that their end-of-life wishes are respected. However, there remains a lack of knowledge and low completion rates of advance directives despite their possible improvements and ramifications on health care at the end of life. This study seeks to determine the knowledge of and attitudes towards end-of-life decision-making in South Texas. The study is designed as a cross-sectional, exploratory survey using a descriptive survey instrument to query 71 subjects in South Texas. The setting for the study includes three distinct groups, two in San Antonio, Texas and one in Brownsville, Texas. Unique differences in demographics between the three groups, such as variability in age, ethnicity, language and religious affiliation allowed for preliminary associations to be concluded in describing the results of the survey instrument. Ultimately, this study describes the attitudes and perceptions of advance care planning in South Texas and reveals the need for further education and awareness of the topic, perhaps indicating the need for a public health initiative in this regard.^

Socioeconomic disparities in thyroid cancer incidence within the Surveillance, Epidemiology, and End Results (SEER) registry, 1980--2008

Background. In the past two decades, the incidence of thyroid cancer in the United States (US) has been increasing. There has been debate on whether the increase is real or an artifact of improved diagnostic scrutiny. Methods. We linked SEER9 database with 2000 US Census to obtain county-level SES (Socioeconomic Status) and compared thyroid cancer incidence trends between high and low SES counties. Joinpoint analysis was used to assess the thyroid cancer incidence trends. Annual Percentage Changes (APCs) were calculated to evaluate incidence trends. Results . The thyroid cancer incidence in high SES counties increased moderately (APC1=+2.5*, *P<0.05) before late 1990s and dramatically increased (APC2=+6.3*) after late 1990s, whereas incidence in low SES counties increased moderately (APC=+3.5*) during the entire time period (1980–2008). For smaller tumors (≤4cm), the APCs in high and low SES counties are similar to each other before late 1990s, but the incidence in high SES counties increased dramatically after late 1990s while that in low SES counties continued at a moderate increase. For large tumors (>4cm), the incidence trends in high SES counties are similar to those of low SES counties, which had a steady moderate increase. Conclusion. Our findings indicate that enhanced detection likely contributed to the increased thyroid cancer incidence in the past decades but cannot fully explain the increase, suggesting that a true increase also exists. Efforts should be made on identifying the cause of this observed increased incidence as well as more refined/selected screening and prevention measures.^

Impact of donor-recipient gender and race mismatching on patient survival in patients with end-stage liver diseases undergoing liver transplantation

Background. End-stage liver disease (ESLD) is an irreversible condition that leads to the imminent complete failure of the liver. Orthotopic liver transplantation (OLT) has been well accepted as the best curative option for patients with ESLD. Despite the progress in liver transplantation, the major limitation nowadays is the discrepancy between donor supply and organ demand. In an effort to alleviate this situation, mismatched donor and recipient gender or race livers are being used. However, the simultaneous impact of donor and recipient gender and race mismatching on patient survival after OLT remains unclear and relatively challenging to surgeons. ^ Objective. To examine the impact of donor and recipient gender and race mismatching on patient survival after OLT using the United Network for Organ Sharing (UNOS) database. ^ Methods. A total of 40,644 recipients who underwent OLT between 2002 and 2011 were included. Kaplan-Meier survival curves and the log-rank tests were used to compare the survival rates among different donor-recipient gender and race combinations. Univariate Cox regression analysis was used to assess the association of donor-recipient gender and race mismatching with patient survival after OLT. Multivariable Cox regression analysis was used to model the simultaneous impact of donor-recipient gender and race mismatching on patient survival after OLT adjusting for a list of other risk factors. Multivariable Cox regression analysis stratifying on recipient hepatitis C virus (HCV) status was also conducted to identify the variables that were differentially associated with patient survival in HCV + and HCV − recipients. ^ Results. In the univariate analysis, compared to male donors to male recipients, female donors to male recipients had a higher risk of patient mortality (HR, 1.122; 95% CI, 1.065–1.183), while in the multivariable analysis, male donors to female recipients experienced an increased mortality rates (adjusted HR, 1.114; 95% CI, 1.048–1.184). Compared to white donors to white recipients, Hispanic donors to black recipients had a higher risk of patient mortality (HR, 1.527; 95% CI, 1.293–1.804) in the univariate analysis, and similar result (adjusted HR, 1.553; 95% CI, 1.314–1.836) was noted in multivariable analysis. After the stratification on recipient HCV status in the multivariable analysis, HCV + mismatched recipients appeared to be at greater risk of mortality than HCV − mismatched recipients. Female donors to female HCV − recipients (adjusted HR, 0.843; 95% CI, 0.769–0.923), and Hispanic HCV + recipients receiving livers from black donors (adjusted HR, 0.758; 95% CI, 0.598–0.960) had a protective effect on patient survival after OLT. ^ Conclusion. Donor-recipient gender and race mismatching adversely affect patient survival after OLT, both independently and after the adjustment for other risk factors. Female recipient HCV status is an important effect modifier in the association between donor-recipient gender combination and patient survival.^