Aneuploidy Tolerance in a Polyploid Organ

Endopolyploid cells (hereafter - polyploid cells), which contain whole genome duplications in an otherwise diploid organism, play vital roles in development and physiology of diverse organs such as our heart and liver. Polyploidy is also observed with high frequency in many tumors, and division of such cells frequently creates aneuploidy (chromosomal imbalances), a hallmark of cancer. Despite its frequent occurrence and association with aneuploidy, little is known about the specific role that polyploidy plays in diverse contexts. Using a new model tissue, the Drosophila rectal papilla, we sought to uncover connections between polyploidy and aneuploidy during organ development. Our lab previously discovered that the papillar cells of the Drosophila hindgut undergo developmentally programmed polyploid cell divisions, and that these polyploid cell divisions are highly error-prone. Time-lapse studies of polyploid mitosis revealed that the papillar cells undergo a high percentage of tripolar anaphase, which causes extreme aneuploidy. Despite this massive chromosome imbalance, we found the tripolar daughter cells are viable and support normal organ development and function, suggesting acquiring extra genome sets enables a cell to tolerate the genomic alterations incurred by aneuploidy. We further extended these findings by seeking mechanisms by which the papillar cells tolerated this resultant aneuploidy.

Subfornical organ neurons integrate cardiovascular and metabolic signals

The subfornical organ (SFO) is a critical circumventricular organ involved in the control of cardiovascular and metabolic homeostasis. Despite the abundant literature clearly demonstrating the ability of SFO neurons to sense and respond to a plethora of circulating signals that influence various physiological systems, investigation of how simultaneously sensed signals interact and are integrated in the SFO is lacking. In this study, we use patch clamp techniques to investigate how the traditionally classified ‘cardiovascular’ hormone angiotensin II (ANG), ‘metabolic’ hormone cholecystokinin (CCK) and ‘metabolic’ signal glucose interact and are integrated in the SFO. Sequential bath-application of CCK (10nM) and ANG (10nM) onto dissociated SFO neurons revealed that: 63% of responsive SFO neurons depolarized to both CCK & ANG; 25% depolarized to ANG only; and 12% hyperpolarized to CCK only. We next investigated the effects of glucose by incubating and recording neurons in either hypo-, normo- or hyperglycemic conditions for a minimum of 24 hours and comparing the proportions of responses to ANG (n=55) or CCK (n=83) application in each condition. A hyperglycemic environment was associated with a larger proportion of depolarizing responses to ANG (X2, p<0.05), and a smaller proportion of depolarizing responses along with a larger proportion of hyperpolarizing responses to CCK (X2, p<0.01). These data demonstrate that SFO neurons excited by CCK are also excited by ANG, suggesting that CCK may influence fluid intake or blood pressure via the SFO, complementary to the well-understood actions of ANG at this site. Additionally, the demonstration that glucose environment affects the responsiveness of neurons to both these hormones highlights the ability of SFO neurons to integrate multiple metabolic and cardiovascular signals to affect transmission of information from the circulation to the brain, which has important implications for this structure’s critical role regulation of autonomic function.

Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis

BACKGROUND Levosimendan is a calcium-sensitizing drug with inotropic and other properties that may improve outcomes in patients with sepsis. 
METHODS We conducted a double-blind, randomized clinical trial to investigate whether levosimendan reduces the severity of organ dysfunction in adults with sepsis. Patients were randomly assigned to receive a blinded infusion of levosimendan (at a dose of 0.05 to 0.2 μg per kilogram of body weight per minute) for 24 hours or placebo in addition to standard care. The primary outcome was the mean daily Sequential Organ Failure Assessment (SOFA) score in the intensive care unit up to day 28 (scores for each of five systems range from 0 to 4, with higher scores indicating more severe dysfunction; maximum score, 20). Secondary outcomes included 28-day mortality, time to weaning from mechanical ventilation, and adverse events. 
RESULTS The trial recruited 516 patients; 259 were assigned to receive levosimendan and 257 to receive placebo. There was no significant difference in the mean (±SD) SOFA score between the levosimendan group and the placebo group (6.68±3.96 vs. 6.06±3.89; mean difference, 0.61; 95% confidence interval [CI], −0.07 to 1.29; P=0.053). Mortality at 28 days was 34.5% in the levosimendan group and 30.9% in the placebo group (absolute difference, 3.6 percentage points; 95% CI, −4.5 to 11.7; P=0.43). Among patients requiring ventilation at baseline, those in the levosimendan group were less likely than those in the placebo group to be successfully weaned from mechanical ventilation over the period of 28 days (hazard ratio, 0.77; 95% CI, 0.60 to 0.97; P=0.03). More patients in the levosimendan group than in the placebo group had supraventricular tachyarrhythmia (3.1% vs. 0.4%; absolute difference, 2.7 percentage points; 95% CI, 0.1 to 5.3; P=0.04). 
CONCLUSIONS The addition of levosimendan to standard treatment in adults with sepsis was not associated with less severe organ dysfunction or lower mortality. Levosimendan was associated with a lower likelihood of successful weaning from mechanical ventilation and a higher risk of supraventricular tachyarrhythmia. (Funded by the NIHR Efficacy and Mechanism Evaluation Programme and others; LeoPARDS Current Controlled Trials number, ISRCTN12776039.)

The ileum as a determinant organ of the functional liver cell mass in rats

PURPOSE: To evaluate if the ileum resection changes the functioning liver cell mass, the hepatic metabolism and the biodistribution of radiopharmaceutical in rats. METHODS: Twelve Wistar rats weighing 285g±34g were randomly divided into the ileum resection group (n = 6) and sham group rats (n = 6). After 30 days, they were anesthetized and 0.1mL of 99m-Tc-phytate(0.66MBq) was injected via femoral vein. After 30 minutes, blood samples were collected for red blood cells radioactive labeling and serum ALT, AST and gammaGT. Liver samples were used for 99m-Tc-phytatepercentage of radioactivity/gram of tissue and histopathology. Student’s t test was used with significance 0.05. RESULTS: There was a higher uptake of 99m-Tc-phytate in the liver of sham rats, compared to the ileum resection group (p<0.05). GammaGT, ALT and AST were increased in ileum resection rats compared to sham (p<0.05). The he patocytes count was significantly lower in ileum resection group than in sham (p<0.05). Liver: body mass ratio was lower in experimental animals than in sham group (p<0.05). CONCLUSION: These data support that the ileum has important role in liver function and liver mass regulation, and they have potential clinical implications regarding the pathogenesis of liver injury following lower bowel resection.

Organ Recital by students of Walter A, Eichinger December 1, 1970

Concert Program

Exploring the cardiovascular disease continuum: blood pressure and target organ damage

Introduction The objectives of this thesis are to: (1) examine how ambulatory blood pressure monitoring (ABPM) refines office blood pressure (BP) measurement; (2) determine if absolute ambulatory BP or dipping status is better associated with target organ damage (TOD); (3) explore the association of isolated nocturnal hypertension (INH) with TOD; and (4) investigate the association of night-time BP with ultrasound markers of cardiovascular damage. Methods Data from the Mitchelstown Cohort Study was analysed to deliver objectives 1 and 2. Objective 3 was addressed by a systematic review and analysis of data from the Mitchelstown Study. A sample of participants from the Mitchelstown Study underwent an echocardiogram for speckle tracking analysis and carotid ultrasound to achieve objective 4. Results ABPM reclassifies hypertension status in approximately a quarter of individuals, with white coat and masked hypertension prevalence rates of 11% and 13% respectively. Night-time systolic BP is better associated with TOD than daytime systolic BP and dipping level. In multi-variable models the odds ratio (OR) for LVH was 1.4 (95% CI 1.1 -1.8) and for albumin:creatinine ratio ≥ 1.1 mg/mmol was 1.5 (95% CI 1.2 – 1.8) for each 10 mmHg rise in night-time systolic BP. The evidence for the association of INH with TOD is inconclusive. Night-time systolic BP is significantly associated with global longitudinal strain (GLS) (beta coefficient 0.85 for every 10 mmHg rise, 95% CI 0.3 – 1.4) and carotid plaques (OR 1.9 for every 10 mmHg rise, 95% CI 1.1 – 3.2) in univariable analysis. The findings persist for GLS in sex and age adjusted models but not in multivariable models. Discussion Hypertension cannot be effectively managed without using ABPM. Night-time systolic BP is better associated with TOD than daytime systolic BP and dipping level, and therefore, may be a better therapeutic target in future studies.

Performance interpretativa das sonatas nº1 em Sí emol maior e nº2 em ré maior de Felix Mendelssohn

Este texto, define o trabalho final do Mestrado em Música da Universidade de Aveiro, e é um documento de apoio ao projeto artístico. Tem por objetivo perceber a importância dos compositores, Bach, Mozart e Beethoven, sobre Felix Mendelssohn “Bartholdy”, analisando o impacto que eles tiveram sobre o curso de vida desta compositor e até a que ponto influenciaram as suas obras. Centro-me na análise das sonatas em Sí bemol Maior, e Ré Maior para violoncelo e piano, que também é apresentada neste projeto, e cuja performance constitui o repertório do recital na defesa do trabalho. Inclui ainda uma reflexão sobre a liberdade criativa no quadro da composição e da interpretação musical, articulando este conceito com os nossos limites enquanto artistas “originais”.

Littlefield Organ Series presents a Guest Artist Recital: Fabio Ciofini September 25, 2012

Concert Program

Technique and outcomes about a new laparoscopic procedure: the Pelvic Organ Prolapse Suspension (POPS)

Pelvic organ prolapse suspension (POPS) is a recent surgical procedure for one-stage treatment of multiorgan female pelvic prolapse. This study evaluates the preliminary results of laparoscopic POPS in 54 women with a mean age of 55.2 and a BMI of 28.3. Patients underwent at the same time stapled transanal rectal resection (STARR) to correct the residual rectal prolapse. We had no relapses and the preliminary results were excellent. We evaluated the patients after 1 year follow-up and we confirmed the validity of our treatment. The technique is simplier than traditional treatments with an important reduction or completely disappearance of the pre-operative symptomatology.

Tracing Beethoven Through the Ten Sonatas for Piano and Violin

Examination of Beethoven’s ten sonatas for piano and violin as a single arc, to uncover linkages between the individual sonatas and observe their stylistic evolution as a set, benefits from placing these works also in relation to the wider realm of Beethoven’s chamber music as a whole. During the years in which his sonatas for piano and violin were written, Beethoven often produced multiple works simultaneously. In fact, the first nine sonatas for piano and violin were written within a mere five-year span (1798 – 1803.) After a gap of nine years, Beethoven completed his tenth and final sonata, marking the end of his “Middle Period.” Because of this distribution, it is important to consider each of these sonatas not only as an interdependent set, but also in relation to the whole of Beethoven’s output for small ensemble. Beethoven wrote the last of his piano and violin sonatas in 1812, with a decade and a half of innovation still ahead of him. This provokes one to look beyond these sonatas to discover the final incarnation of the ideas introduced in these works. In particular, the key creative turning points within the ten sonatas for piano and violin become strikingly apparent when compared to Beethoven’s string quartets, which dramatically showcase Beethoven’s evolution in sixteen works distributed more or less evenly across his career. From the perspective of a string quartet player, studying the ten sonatas for piano and violin provides an opportunity to note similarities between the genres. This paper argues that examining the ten sonatas from a viewpoint primarily informed by Beethoven’s string quartets yields a more thorough understanding of the sonatas themselves and a broader conception of the vast network of interrelationships that produce Beethoven’s definitive voice. The body of this paper contains a full exploration of each of the ten sonatas for piano and violin, highlighting key musical, historical, and theoretical elements. Each of the sonatas is then put not only in context of the set of ten, but is contrasted with Beethoven’s sixteen string quartets, identifying unifying motives, techniques, and structural principles that recur across both bodies of work.

The ileum as a determinant organ of the functional liver cell mass in rats

PURPOSE: To evaluate if the ileum resection changes the functioning liver cell mass, the hepatic metabolism and the biodistribution of radiopharmaceutical in rats. METHODS: Twelve Wistar rats weighing 285g±34g were randomly divided into the ileum resection group (n = 6) and sham group rats (n = 6). After 30 days, they were anesthetized and 0.1mL of 99m-Tc-phytate(0.66MBq) was injected via femoral vein. After 30 minutes, blood samples were collected for red blood cells radioactive labeling and serum ALT, AST and gammaGT. Liver samples were used for 99m-Tc-phytatepercentage of radioactivity/gram of tissue and histopathology. Student’s t test was used with significance 0.05. RESULTS: There was a higher uptake of 99m-Tc-phytate in the liver of sham rats, compared to the ileum resection group (p<0.05). GammaGT, ALT and AST were increased in ileum resection rats compared to sham (p<0.05). The he patocytes count was significantly lower in ileum resection group than in sham (p<0.05). Liver: body mass ratio was lower in experimental animals than in sham group (p<0.05). CONCLUSION: These data support that the ileum has important role in liver function and liver mass regulation, and they have potential clinical implications regarding the pathogenesis of liver injury following lower bowel resection.

The Auld Alliance: Organ music from Scotland and France.

CD recording of the Rieger organ of St Giles' Cathedral Edinburgh, performed by Michael Harris, with music from Scottish composers, and composers based in Scotland, as well as French organ music from the seventeenth to twentieth centuries. Works by James MacMillan, Thomas Wilson, Kenneth Leighton, Alfred Hollins, de Grigny, Guilmant, Fleury and Franck.

The organ works of Kaikhosru Shapurji Sorabji (1892-1988)

This is the first complete critical edition of the organ works of Kaikhosru Shapurji Sorabji (1892--‐1988). Of the three solo symphonies presented here only the first has previously appeared in print (Curwen, 1925). The other two works, both of hugely greater dimensions than the first, have not been published before although, in the late 1980s/early 90s, the present writer produced a hand‐copied edition of the second symphony that has been available in print form and in PDF through the Sorabji Archive since 1991.

Acute Q Fever Presenting with Multi-Organ Failure: Re-Evaluation of the Initial Diagnosis

We present the case of a 48-year-old man admitted to the critical care unit with atrial fibrillation, and acute heart and kidney failure accompanied by coagulopathy and an abnormal liver test. Initially diagnosed as a non-ST elevation myocardial infarction, re-evaluation of the case led to the consideration of severe sepsis. Q fever and leptospirosis were the most probable causes and empiric treatment was initiated. A complete recovery was achieved following treatment.