Amyloid formation results in recurrence of hyperglycaemia following transplantation of human IAPP transgenic mouse islets

Aims/hypothesis Islet transplantation is a potential cure for diabetes; however, rates of graft failure remain high. The aim of the present study was to determine whether amyloid deposition is associated with reduced beta cell volume in islet grafts and the recurrence of hyperglycaemia following islet transplantation.

Methods We transplanted a streptozotocin-induced mouse model of diabetes with 100 islets from human IAPP (which encodes islet amyloid polypeptide) transgenic mice that have the propensity to form islet amyloid (n = 8–12) or from non-transgenic mice that do not develop amyloid (n = 6–10) in sets of studies that lasted 1 or 6 weeks.

Results Plasma glucose levels before and for 1 week after transplantation were similar in mice that received transgenic or non-transgenic islets, and at that time amyloid was detected in all transgenic grafts and, as expected, in none of the non-transgenic grafts. However, over the 6 weeks following transplantation, plasma glucose levels increased in transgenic but remained stable in non-transgenic islet graft recipients (p < 0.05). At 6 weeks, amyloid was present in 92% of the transgenic grafts and in none of the non-transgenic grafts. Beta cell volume was reduced by 30% (p < 0.05), beta cell apoptosis was twofold higher (p < 0.05), and beta cell replication was reduced by 50% (p < 0.001) in transgenic vs non-transgenic grafts. In summary, amyloid deposition in islet grafts occurs prior to the recurrence of hyperglycaemia and its accumulation over time is associated with beta cell loss.

Conclusions/interpretation Islet amyloid formation may explain, in part, the non-immune loss of beta cells and recurrence of hyperglycaemia following clinical islet transplantation.

Incidence and persistence/recurrence of women’s sexual difficulties : findings from the Australian longitudinal study of health and relationships

This study presents data on the prevalence, incidence, and persistence/recurrence of 8 sexual difficulties among women. Australian women participated in 2 computer-assisted interviews approximately 12 months apart. Analyses were based on a weighted sample of 2,252 women who were 20–64 years of age, sexually active in the past 12 months, and in the same heterosexual relationship at both interviews. Upon recruitment, two-thirds of women (66%) reported having one or more sexual difficulties. At follow-up, 36% reported a new sexual difficulty. The two highest incident difficulties were “lacking interest in having sex” (26%) and “taking too long to orgasm” (11%). In addition, 68% of women with 1 or more sexual difficulties at recruitment reported having at least 1 of these again at follow-up. Lacking interest in having sex had the highest persistence/recurrence (65%). Logistic regression modeling revealed a lower incidence of sexual difficulties among women in their 40s. Age was also a predictor of the persistence/recurrence, with persistence/recurrence most likely among older women. Tobacco and alcohol use predicted the incidence, but not persistence/recurrence, of lacking interest in sex. Health professionals need to take note of the sociodemographic groups most prone to developing and having persistent/recurrent sexual difficulties.

Study protocol for "Moving bright, eating smart"- a phase 2 clinical trial on the acceptability and feasibility of a diet and physical activity intervention to prevent recurrence in colorectal cancer survivors

Background: Colorectal cancer is the second most common cancer and cancer-killer in Hong Kong with an alarming increasing incidence in recent years. The latest World Cancer Research Fund report concluded that foods low in fibre, and high in red and processed meat cause colorectal cancer whereas physical activity protects against
colon cancer. Yet, the influence of these lifestyle factors on cancer outcome is largely unknown even though cancer survivors are eager for lifestyle modifications. Observational studies suggested that low intake of a Western-pattern diet and high physical activity level reduced colorectal cancer mortality. The Theory of Planned
Behaviour and the Health Action Process Approach have guided the design of intervention models targeting a wide range of health-related behaviours.
Methods/design: We aim to demonstrate the feasibility of two behavioural interventions intended to improve colorectal cancer outcome and which are designed to increase physical activity level and reduce consumption of a Western-pattern diet. This three year study will be a multicentre, randomised controlled trial in a 2x2 factorial
design comparing the “Moving Bright, Eating Smart” (physical activity and diet) programme against usual care. Subjects will be recruited over a 12-month period, undertake intervention for 12 months and followed up for a further 12 months. Baseline, interim and three post-intervention assessments will be conducted. Two hundred and twenty-two colorectal cancer patients who completed curative treatment without evidence of recurrence will be recruited into the study. Primary outcome measure will be whether physical activity and dietary targets are met at the end of the 12-month intervention. Secondary outcome measures include the magnitude and
mechanism of behavioural change, the degree and determinants of compliance, and the additional health benefits and side effects of the intervention.
Discussion: The results of this study will establish the feasibility of targeting the two behaviours (diet and physical activity) and demonstrate the magnitude of behaviour change. The information will facilitate the design of a further larger phase III randomised controlled trial with colorectal cancer outcome as the study endpoint to determine whether this intervention model would reduce colorectal cancer recurrence and mortality.

Symptoms of depression and anxiety are independently associated with clinical recurrence of inflammatory bowel disease

BACKGROUND & AIMS: We examined the relationship between symptoms of depression and anxiety and clinical recurrence of inflammatory bowel disease (IBD) in a large patient cohort. We considered the progression of depression and anxiety over time. METHODS: We collected clinical and treatment data on 2007 adult participants of the Swiss IBD study (56% with Crohn's disease [CD], 48% male) performed in Switzerland from 2006 through 2015. Depression and anxiety symptoms were quantified by using the Hospital Anxiety and Depression Scale. The relationship between depression and anxiety scores and clinical recurrence was analyzed by using survival-time techniques. RESULTS: We found a significant association between symptoms of depression and clinical recurrence over time (for all patients with IBD, P = .000001; for subjects with CD, P = .0007; for subjects with ulcerative colitis, P = .005). There was also a significant relationship between symptoms of anxiety and clinical recurrence over time in all subjects with IBD (P = .0014) and in subjects with CD (P = .031) but not ulcerative colitis (P = .066). CONCLUSIONS: In an analysis of a large cohort of subjects with IBD, we found a significant association between symptoms of depression or anxiety and clinical recurrence. Patients with IBD should therefore be screened for clinically relevant levels of depression and anxiety and referred to psychologists or psychiatrists for further evaluation and treatment.

Renal transplantation in patients with primary immunoglobulin A nephropathy

Background. Opinions on the clinical course and outcome of renal transplantation in patients with primary immunoglobulin A nephropathy (IgAN) have been controversial.
Methods. We conducted a retrospective single-centre study on 542 kidney transplant recipients over the period 1984–2001. Long-term outcome and factors affecting recurrence in recipients with primary IgAN were analysed.
Results. Seventy-five patients (13.8%) had biopsy-proven IgAN as the cause of renal failure, and their mean duration of follow-up after transplantation was 100 ± 5.8 months. Fourteen (18.7%) of the 75 patients had biopsy-proven recurrent IgAN, diagnosed at 67.7 ± 11 months after transplantation. The risk of recurrence was not associated with HLA DR4 or B35. Graft failure occurred in five (35.7%) of the 14 patients: three due to IgAN and two due to chronic rejection. Three (4.9%) of the 61 patients without recurrent IgAN had graft failure, all due to chronic rejection. Graft survival was similar between living-related and cadaveric/living-unrelated patients (12-year graft survival, 88 and 72%, respectively, P = 0.616). Renal allograft survival within the first 12 years was better in patients with primary IgAN compared with those with other primary diseases (80 vs 51%, P = 0.001). Thereafter, IgAN patients showed an inferior graft survival (74 vs 97% in non-IgAN patients, P = 0.001).
Conclusions. Our data suggested that around one-fifth of patients with primary IgAN developed recurrence by 5 years after transplantation. Recurrent IgA nephropathy in allografts runs an indolent course with favourable outcome in the first 12 years. However, the contribution of recurrent disease to graft loss becomes more significant on long-term follow up.

Psychosocial factors and survival of young women with breast cancer: a population-based prospective cohort study

Purpose: Most women with early-stage breast cancer believe that psychosocial factors are an important influence over whether their cancer will recur. Studies of the issue have produced conflicting results.

Patients and Methods: A population-based sample of 708 Australian women diagnosed before age 60 years with nonmetastatic breast cancer was observed for a median of 8.2 years. Depression and anxiety, coping style, and social support were assessed at a median of 11 months after diagnosis. Hazard ratios for distant disease-free survival (DDFS) and overall survival (OS) associated with psychosocial factors were estimated separately using Cox proportional hazards survival models, with and without adjustment for known prognostic factors.

Results: Distant recurrence occurred in 209 (33%) of 638 assessable patients, and 170 (24%) of 708 patients died during the follow-up period. There were no statistically significant associations between any of the measured psychosocial factors and DDFS or OS from the adjusted analyses. From unadjusted analyses, associations between greater anxious preoccupation and poorer DDFS and OS were observed (P = .02). These associations were no longer evident after adjustment for established prognostic factors; greater anxious preoccupation was associated with younger age at diagnosis (P = .03), higher tumor grade (P = .02), and greater number of involved axillary nodes (P = .008).

Conclusion: The findings do not support the measured psychosocial factors being an important influence on breast cancer outcomes. Interventions for adverse psychosocial factors are warranted to improve quality of life but should not be expected to improve survival.

Application of real and functional analysis to solve boundary value problems

This thesis is about using appropriate tools in functional analysis arid classical analysis to tackle the problem of existence and uniqueness of nonlinear partial differential equations. There being no unified strategy to deal with these equations, one approaches each equation with an appropriate method, depending on the characteristics of the equation. The correct setting of the problem in appropriate function spaces is the first important part on the road to the solution. Here, we choose the setting of Sobolev spaces. The second essential part is to choose the correct tool for each equation. In the first part of this thesis (Chapters 3 and 4) we consider a variety of nonlinear hyperbolic partial differential equations with mixed boundary and initial conditions. The methods of compactness and monotonicity are used to prove existence and uniqueness of the solution (Chapter 3). Finding a priori estimates is the main task in this analysis. For some types of nonlinearity, these estimates cannot be easily obtained, arid so these two methods cannot be applied directly. In this case, we first linearise the equation, using linear recurrence (Chapter 4). In the second part of the thesis (Chapter 5), by using an appropriate tool in functional analysis (the Sobolev Imbedding Theorem), we are able to improve previous results on a posteriori error estimates for the finite element method of lines applied to nonlinear parabolic equations. These estimates are crucial in the design of adaptive algorithms for the method, and previous analysis relies on, what we show to be, unnecessary assumptions which limit the application of the algorithms. Our analysis does not require these assumptions. In the last part of the thesis (Chapter 6), staying with the theme of choosing the most suitable tools, we show that using classical analysis in a proper way is in some cases sufficient to obtain considerable results. We study in this chapter nonexistence of positive solutions to Laplace's equation with nonlinear Neumann boundary condition. This problem arises when one wants to study the blow-up at finite time of the solution of the corresponding parabolic problem, which models the heating of a substance by radiation. We generalise known results which were obtained by using more abstract methods.

Multicellular spheroids in ovarian cancer metastases: Biology and pathology

Epithelial ovarian cancer (EOC) has a relatively high mortality rate (~55%). One of the presiding causes is that the current chemotherapeutic regimes are unable to achieve sustained remission, despite frequently producing a positive response at first treatment. One of the reasons that EOC is difficult to treat is that the mechanism of dissemination is unusual. EOC dissemination characteristically involves local invasion of pelvic and abdominal organs. Unlike many epithelial cancers, initial dissemination rarely requires the vasculature, although the vasculature is often implicated in the advanced stages of disease. Recently, it has become apparent that aggregates of malignant cells (spheroids) contained within malignant ascites represent a significant impediment to efficacious treatment of late stage EOC. In vivo, spheroids are present in the malignant ascites of EOC patients, while in vitro cultured spheroids are capable of tumorgenesis in vivo and display a reduced response to chemotherapeutic drugs when compared to monolayers. A major problem associated with the current generation of chemotherapy agents is that they do not address the anchorage and vascular-independent growth conditions associated with a 3-dimensional structure that has formed and/or grown in suspension. Thus, spheroid formation may represent a key component of platinum/taxanesensitive recurrence. If this is correct, a better understanding of spheroid biology may contribute to the identification of new treatment opportunities for the sustained treatment of metastatic EOC. This review article outlines the key biological features of spheroids, specifically discussing their role in EOC dissemination and chemo-response as well as providing insights into spheroid functionality.

Combination pharmacotherapy in unipolar depression

It is estimated that between 60 and 80% of those with major depressive disorder do not achieve full symptomatic remission from first-line antidepressant monotherapy. Residual depressive symptoms substantially impair quality of life and add to the risk of recurrence. It is now clear that depression would benefit from more vigorous treatment, in order to ameliorate its disease burden. While there are established algorithms in situations of treatment resistance, the use of combination pharmacotherapy in unipolar depression is a relatively under-investigated area of treatment and may be an effective and tolerable strategy that maximizes the available resources. This paper reviews the current evidence for combination pharmacotherapy in unipolar depression and discusses its clinical applications.

A randomised trial of robotic and open prostatectomy in men with localised prostate cancer

Background
Prostate cancer is the most common male cancer in the Western world however there is ongoing debate about the optimal treatment strategy for localised disease. While surgery remains the most commonly received treatment for localised disease in Australia more recently a robotic approach has emerged as an alternative to open and laparoscopic surgery. However, high level data is not yet available to support this as a superior approach or to guide treatment decision making between the alternatives. This paper presents the design of a randomised trial of Robotic and Open Prostatectomy for men newly diagnosed with localised prostate cancer that seeks to answer this question.

Methods
200 men per treatment arm (400 men in total) are being recruited after diagnosis and before treatment through a major public hospital outpatient clinic and randomised to 1) Robotic Prostatectomy or 2) Open Prostatectomy. All robotic prostatectomies are being performed by one surgeon and all open prostatectomies are being performed by one other surgeon. Outcomes are being measured pre-operatively and at 6 weeks and 3, 6, 12 and 24 months post-surgery. Oncological outcomes are being related to positive surgical margins, biochemical recurrence +/ the need for further treatment. Non-oncological outcome measures include: pain, physical and mental functioning, fatigue, summary (preference-based utility scores) and domain-specific QoL (urinary incontinence, bowel function and erectile function), cancer specific distress, psychological distress, decision-related distress and time to return to usual activities. Cost modelling of each approach, as well as full economic appraisal, is also being undertaken.

Discussion
The study will provide recommendations about the relative benefits of Robotic and Open Prostatectomy to support informed patient decision making about treatment for localised prostate cancer; and to assist in treatment services planning for this patient group. Trial Registration ACTRN12611000661976

Maintenance N-acetyl cysteine treatment for bipolar disorder : a double-blind randomised placebo controlled trial

Background N-acetyl cysteine (NAC) is a glutathione precursor that has been shown to have antidepressant efficacy in a placebo-controlled trial. The current study aimed to investigate the maintenance effects of NAC following eight weeks of open-label treatment for bipolar disorder.

Method The efficacy of a double blind randomized placebo controlled trial of 2 g/day NAC as adjunct maintenance treatment for bipolar disorder was examined. Participants (n = 149) had a Montgomery Asberg Depression Rating Score of [greater than or equal to]12 at trial entry and, after eight weeks of open-label NAC treatment, were randomized to adjunctive NAC or placebo, in addition to treatment as usual. Participants (primarily outpatients) were recruited through public and private services and through newspaper advertisements. Time to intervention for a mood episode was the primary endpoint of the study, and changes in mood symptoms, functionality and quality of life measures were secondary outcomes.

Results There was a substantial decrease in symptoms during the eight-week open-label NAC treatment phase. During the subsequent double-blind phase, there was minimal further change in outcome measures with scores remaining low. Consequently, from this low plateau, between-group differences did not emerge on recurrence, clinical functioning or quality of life measures.

Conclusions There were no significant between-group differences in recurrence or symptomatic outcomes during the maintenance phase of the trial; however, these findings may be confounded by limitations. Trial Registration The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12607000074493).

Monumental vision : a confrontation with the image of the Eternal Return

"Monumental Vision” is a nuanced summary of Nietzschean nihilism and the Eternal Return as rite of passage for free subjects and as condensed image of speculative intelligence proper. Utilizing Gerhard Richter’s “Sheet 692” from Atlas, a series of photographs of the mountains and lake at Sils Maria, Switzerland, as summary judgment of the limit imposed by this condition on all systems of representation, this form of vision discloses the chiasmus embedded in consciousness itself. In constantly revisiting Sils, the very location where Nietzsche “suffered” the vision of the Eternal Return, Richter has engaged repeatedly this origin for what has come into his work via Nietzsche – that is, an elective veil that refuses all compromises with transcendence until such is merged with immanence.

As situated amidst modernist “ideology as intellection”, and subsequent nascent forms of anti-modernism, the Eternal Return as image also signals the return of the Kantian “aesthetic-teleological” synthesis in non-discursive or purely visual agency. As an elective form of aesthetic vision, and as image of time insofar as it registers an overwhelming externality (Other) that nominally swallows and empowers the subject at once, this excoriating sense of universal praxis underwrites artistic and architectural production of the highest order, renegotiating concepts of the paradigmatic.

Utilizing Georg Simmel’s late work on Rembrandt (1916) and his encounter with Schopenhauer and Nietzsche (1907), the essay suggests that by the 1920s the avant-garde premises of modernism had already come under attack by an ahistorical and synoptic vision here denoted “monumental vision,” which also contains the imprint of eschatological time (invoking a schism present in rationality as such). The two readings of this image perpetrated by Karl Löwith in Nietzsche’s Philosophy of the Eternal Recurrence of the Same (Nietzsches Philosophie der ewigen Wiederkehr des Gleichen, 1935), or the cosmological and the ethical, while considered irreconcilable by Löwith, have since the 1960s been recalibrated through the figure of the event to pose possible scenarios out of the stalemate of the confrontation between Self and Other (ipseity and alterity) buried within this image as limit. In this manner, the image of the Eternal Return stands at the boundary between two forms of time (or two worlds) and signals the irreducible confrontation present in speculative thought and the necessity of closure through an aesthetic vision that produces a unitary field for all creative acts.

Notably, Nietzsche’s startling vision from Zarathustra suggests that the limit imposed by the Eternal Return is also a mask for an austere condition within subjectivity closely resembling the conundrum of Fichte’s I facing I, or thought turned toward thought itself (absolute subjectivity as cipher for Being). In Alenka Zupančič’s reading, in The Shortest Shadow: Nietzsche’s Philosophy of the Two (2003), the Eternal Return effectively contains a secret formal function that grinds all “error” to dust – a highly suggestive interpretation that also neutralizes the schism introduced by Löwith between the cosmological and the ethical.