Continuation treatment of major depressive disorder: is there a case for duloxetine?

Duloxetine is a serotonin–noradrenaline reuptake inhibitor with established efficacy for the short-term treatment of major depressive disorder. Efficacy in continuation treatment (greater than six months of continuous treatment) has been established from both open and placebo-controlled relapse prevention and comparative studies. Seven published studies were available for review and showed that in both younger and older populations (aged more than 65 years) the acute efficacy of duloxetine was maintained for up to one year. Response to treatment was based on accepted criteria for remission of depression and in continuation studies remission rates were greater than 70%. Comparative studies showed that duloxetine was superior to placebo and comparable to paroxetine and escitalopram in relapse prevention. Importantly a study of duloxetine in patients prone to relapse of major depressive disorder showed that the medication was more effective than placebo in this difficult to treat population. Side effects of duloxetine during continuation treatment were predictable on the basis of the known pharmacology of the drug. In particular there were no significant life-threatening events which emerged with continued use of the medication. On the other hand vigilance is required since the data base on which to judge very rare events is limited by the relatively low exposure to the drug. Duloxetine has established both efficacy and safety for continuation treatment but its place as a first-line treatment of relapse prevention requires further experience. In particular further comparative studies against established agents would be useful in deciding the place of duloxetine in therapy

Duloxetine in the treatment of generalized anxiety disorder

Duloxetine, a medication with effects on both serotonin and noradrenaline transporter molecules, has recently been approved for the treatment of generalized anxiety disorder. The evidence for its efficacy lies in a limited number of double blind, placebo controlled comparisons. Statistically significant improvements in the Hamilton Anxiety Rating Scale from baseline were demonstrated in all studies at doses of 60 to 120 mg per day. The significance of such changes in terms of clinical improvements compared to placebo is less certain, particularly when the effect size of the change is calculated. In comparative trials with venlafaxine, duloxetine was as effective in providing relief of anxiety symptoms. In addition to improvements in clinical symptoms duloxetine has also been associated with restitution of role function as measured by disability scales. Duloxetine use is associated with nausea, dizziness, dry mouth, constipation, insomnia, somnolence, hyperhidrosis, decreased libido and vomiting. These treatment emergent side effects were generally of mild to moderate severity and were tolerated over time. Using a tapered withdrawal schedule over two weeks in the clinical trials, duloxetine was associated with only a mild withdrawal syndrome in up to about 30% of patients compared to about 17% in placebo treated patients. Duloxetine in doses of up to 200 mg twice daily did not prolong the QTc interval in healthy volunteers. Like other agents with dual neurotransmitter actions duloxetine reduces the symptoms of generalized anxiety disorder in short term treatments. Further evidence for its efficacy and safety in long term treatment is required

A scaling-invariant algorithm for linear programming whose running time depends only on the constraint matrix

Following the breakthrough work of Tardos (Oper. Res. '86) in the bit-complexity model, Vavasis and Ye (Math. Prog. '96) gave the first exact algorithm for linear programming in the real model of computation with running time depending only on the constraint matrix. For solving a linear program (LP) max cx, Ax = b, x ≥ 0, A g m × n, Vavasis and Ye developed a primal-dual interior point method using a g€layered least squares' (LLS) step, and showed that O(n3.5 log(χA+n)) iterations suffice to solve (LP) exactly, where χA is a condition measure controlling the size of solutions to linear systems related to A. Monteiro and Tsuchiya (SIAM J. Optim. '03), noting that the central path is invariant under rescalings of the columns of A and c, asked whether there exists an LP algorithm depending instead on the measure χA∗, defined as the minimum χAD value achievable by a column rescaling AD of A, and gave strong evidence that this should be the case. We resolve this open question affirmatively. Our first main contribution is an O(m2 n2 + n3) time algorithm which works on the linear matroid of A to compute a nearly optimal diagonal rescaling D satisfying χAD ≤ n(χ∗)3. This algorithm also allows us to approximate the value of χA up to a factor n (χ∗)2. This result is in (surprising) contrast to that of Tunçel (Math. Prog. '99), who showed NP-hardness for approximating χA to within 2poly(rank(A)). The key insight for our algorithm is to work with ratios gi/gj of circuits of A - i.e., minimal linear dependencies Ag=0 - which allow us to approximate the value of χA∗ by a maximum geometric mean cycle computation in what we call the g€circuit ratio digraph' of A. While this resolves Monteiro and Tsuchiya's question by appropriate preprocessing, it falls short of providing either a truly scaling invariant algorithm or an improvement upon the base LLS analysis. In this vein, as our second main contribution we develop a scaling invariant LLS algorithm, which uses and dynamically maintains improving estimates of the circuit ratio digraph, together with a refined potential function based analysis for LLS algorithms in general. With this analysis, we derive an improved O(n2.5 lognlog(χA∗+n)) iteration bound for optimally solving (LP) using our algorithm. The same argument also yields a factor n/logn improvement on the iteration complexity bound of the original Vavasis-Ye algorithm

Plasmodium yoelii 17XL infection up-regulates RANTES, CCR1, CCR3 and CCR5 expression, and induces ultrastructural changes in the cerebellum

BACKGROUND: Malaria afflicts 300–500 million people causing over 1 million deaths globally per year. The immunopathogenesis of malaria is mediated partly by co mplex cellular and immunomodulator interactions involving co-regulators such as cytokines and adhesion molecules. However, the role of chemokines and their receptors in malaria immunopathology remains unclear. RANTES (Regulated on Activation Normal T-Cell Expressed and Secreted) is a chemokine involved in the generation of inflammatory infiltrates. Recent studies indicate that the degradation of cell-cell junctions, blood-brain barrier dysfunction, recruitment of leukocytes and Plasmodium-infected erythrocytes into and occlusion of microvessels relevant to malaria pathogenesis are associated with RANTES expression. Additionally, activated lymphocytes, platelets and endothelial cells release large quantities of RANTES, thus suggesting a unique role for RANTES in the generation and maintenance of the malaria-induced inflammatory response. The hypothesis of this study is that RANTES and its corresponding receptors (CCR1, CCR3 and CCR5) modulate malaria immunopathogenesis. A murine malaria model was utilized to evaluate the role of this chemokine and its receptors in malaria. METHODS: The alterations in immunomodulator gene expression in brains of Plasmodium yoelii 17XL-infected mice was analysed using cDNA microarray screening, followed by a temporal comparison of mRNA and protein expression of RANTES and its corresponding receptors by qRT-PCR and Western blot analysis, respectively. Plasma RANTES levels was determined by ELISA and ultrastructural studies of brain sections from infected and uninfected mice was conducted. RESULTS: RANTES (p < 0.002), CCR1 (p < 0.036), CCR3 (p < 0.033), and CCR5 (p < 0.026) mRNA were significantly upregulated at peak parasitaemia and remained high thereafter in the experimental mouse model. RANTES protein in the brain of infected mice was upregulated (p < 0.034) compared with controls. RANTES plasma levels were significantly upregulated; two to three fold in infected mice compared with controls (p < 0.026). Some d istal microvascular endothelium in infected cerebellum appeared degraded, but remained intact in controls. CONCLUSION: The upregulation of RANTES, CCR1, CCR3, and CCR5 mRNA, and RANTES protein mediate inflammation and cellular degradation in the cerebellum during P. yoelii 17XL malaria

The Australian Cancer Anaemia Survey: a snapshot of anaemia in adult patients with cancer

The document attached has been archived with permission from the editor of the Medical Journal of Australia (09 January 2008). An external link to the publisher’s copy is included.Objective: To evaluate the frequency and management of anaemia in Australian adults with solid and haematological malignancies. Design: 6-month observational, prospective, multicentre study. Participants: 694 patients recruited from outpatient oncology clinics in 24 hospitals in five Australian states between 9 April 2001 and 31 July 2001. Main outcome measures: Frequency of anaemia (haemoglobin [Hb] level < 120 g/L) at enrolment and over ensuing 6 months, by tumour type, disease status and cancer treatment; anaemia treatment and “trigger” Hb level for this treatment. Results: Participants had median age 60 years, and 61% were women. Prevalence of anaemia at enrolment was 35% (199/562), with 78% of these 199 having mild anaemia (Hb, 100–119 g/L). Frequency of anaemia (either present at enrolment or developing during the study) was 57% overall (323/566), and varied with tumour type, from 49% (lymphoma/myeloma) to 85% (urogenital cancer). Patients who received radiotherapy either in combination or concomitant with chemotherapy were more likely to have anaemia (73%) than those receiving chemotherapy alone (58%) (P = 0.004). Of all chemotherapy patients not anaemic at enrolment, 23% developed anaemia by the second monthly follow-up. Independent predictors for anaemia in chemotherapy patients were low baseline Hb level (odds ratio [OR], 5.4; 95% CI, 2.7–10.9) and use of platinum chemotherapeutic agents (OR, 4.8; 95% CI, 2.1–11.4) (P < 0.001). Anaemia was treated in 41% of patients with anaemia at enrolment — by transfusion (36%), iron (5%) and erythropoietic agents (2%). Frequency of anaemia treatment varied between tumour types, from 19% (breast cancer) to 60% (leukaemia). The mean “trigger Hb” for initiating transfusion was 95 g/L. Conclusions: Anaemia is prevalent among Australian patients with cancer managed in hospital oncology units. Its management varies between tumour types. Many patients do not receive treatment for their anaemia.Tara Seshadri, H Miles Prince, David R Bell, Paul B Coughlin, Philip P B James, Gary E Richardson, Boris Chern, Peter Briggs, John Norman, Ian N Olver, Chris Karapetis and John Stewart, for the Australia Cancer Anaemia Study (ACAS) Grou

High intensity aerobic exercise training improves deficits of cardiovascular autonomic function in a rat model of type 1 diabetes mellitus with moderate hyperglycemia

© 2016 Kenneth N. Grisé et al. Indices of cardiovascular autonomic neuropathy (CAN) in experimental models of Type 1 diabetes mellitus (T1DM) are often contrary to clinical data. Here, we investigated whether a relatable insulin-treated model of T1DM would induce deficits in cardiovascular (CV) autonomic function more reflective of clinical results and if exercise training could prevent those deficits. Sixty-four rats were divided into four groups: sedentary control (C), sedentary T1DM (D), control exercise (CX), or T1DM exercise (DX). Diabetes was induced via multiple low-dose injections of streptozotocin and blood glucose was maintained at moderate hyperglycemia (9-17 mM) through insulin supplementation. Exercise training consisted of daily treadmill running for 10 weeks. Compared to C, D had blunted baroreflex sensitivity, increased vascular sympathetic tone, increased serum neuropeptide Y (NPY), and decreased intrinsic heart rate. In contrast, DX differed from D in all measures of CAN (except NPY), including heart rate variability. These findings demonstrate that this T1DM model elicits deficits and exercise-mediated improvements to CV autonomic function which are reflective of clinical T1DM

Singularity analysis, Hadamard products, and tree recurrences

We present a toolbox for extracting asymptotic information on the coefficients of combinatorial generating functions. This toolbox notably includes a treatment of the effect of Hadamard products on singularities in the context of the complex Tauberian technique known as singularity analysis. As a consequence, it becomes possible to unify the analysis of a number of divide-and-conquer algorithms, or equivalently random tree models, including several classical methods for sorting, searching, and dynamically managing equivalence relationsComment: 47 pages. Submitted for publicatio

Hypercomplex Integrable Systems

In this paper we study hypercomplex manifolds in four dimensions. Rather than using an approach based on differential forms, we develop a dual approach using vector fields. The condition on these vector fields may then be interpreted as Lax equations, exhibiting the integrability properties of such manifolds. A number of different field equations for such hypercomplex manifolds are derived, one of which is in Cauchy-Kovaleskaya form which enables a formal general solution to be given. Various other properties of the field equations and their solutions are studied, such as their symmetry properties and the associated hierarchy of conservation laws.Comment: Latex file, 19 page

Increasing subsequences and the hard-to-soft edge transition in matrix ensembles

Our interest is in the cumulative probabilities Pr(L(t) \le l) for the maximum length of increasing subsequences in Poissonized ensembles of random permutations, random fixed point free involutions and reversed random fixed point free involutions. It is shown that these probabilities are equal to the hard edge gap probability for matrix ensembles with unitary, orthogonal and symplectic symmetry respectively. The gap probabilities can be written as a sum over correlations for certain determinantal point processes. From these expressions a proof can be given that the limiting form of Pr(L(t) \le l) in the three cases is equal to the soft edge gap probability for matrix ensembles with unitary, orthogonal and symplectic symmetry respectively, thereby reclaiming theorems due to Baik-Deift-Johansson and Baik-Rains.Comment: LaTeX, 19 page

On Self-Dual Gravity I

(One typo corrected and one incorrect statement removed. Extra details on conserved quantities and symmetry algebras added).Comment: 17 pages, Latex, DAMTP-R92/4