Icodextrin as salvage therapy in peritoneal dialysis patients with refractory fluid overload

BACKGROUND: Icodextrin is a high molecular weight, starch-derived glucose polymer, which is capable of inducing sustained ultrafiltration over prolonged (12–16 hour) peritoneal dialysis (PD) dwells. The aim of this study was to evaluate the ability of icodextrin to alleviate refractory, symptomatic fluid overload and prolong technique survival in PD patients. METHODS: A prospective, open-label, pre-test/post-test study was conducted in 17 PD patients (8 females/9 males, mean age 56.8 ± 2.9 years) who were on the verge of being transferred to haemodialysis because of symptomatic fluid retention that was refractory to fluid restriction, loop diuretic therapy, hypertonic glucose exchanges and dwell time optimisation. One icodextrin exchange (2.5 L 7.5%, 12-hour dwell) was substituted for a long-dwell glucose exchange each day. RESULTS: Icodextrin significantly increased peritoneal ultrafiltration (885 ± 210 ml to 1454 ± 215 ml, p < 0.05) and reduced mean arterial pressure (106 ± 4 to 96 ± 4 mmHg, p < 0.05), but did not affect weight, plasma albumin concentration, haemoglobin levels or dialysate:plasma creatinine ratio. Diabetic patients (n = 12) also experienced improved glycaemic control (haemoglobin Alc decreased from 8.9 ± 0.7% to 7.9 ± 0.7%, p < 0.05). Overall PD technique survival was prolonged by a mean of 11.6 months (95% CI 6.0–17.3 months). On multivariate Cox proportional hazards analysis, extension of technique survival by icodextrin was only significantly predicted by baseline net daily peritoneal ultrafiltration (adjusted HR 2.52, 95% CI 1.13–5.62, p < 0.05). CONCLUSIONS: Icodextrin significantly improved peritoneal ultrafiltration and extended technique survival in PD patients with symptomatic fluid overload, especially those who had substantially impaired peritoneal ultrafiltration

A computational study on altered theta-gamma coupling during learning and phase coding

There is considerable interest in the role of coupling between theta and gamma oscillations in the brain in the context of learning and memory. Here we have used a neural network model which is capable of producing coupling of theta phase to gamma amplitude firstly to explore its ability to reproduce reported learning changes and secondly to memory-span and phase coding effects. The spiking neural network incorporates two kinetically different GABAA receptor-mediated currents to generate both theta and gamma rhythms and we have found that by selective alteration of both NMDA receptors and GABAA,slow receptors it can reproduce learning-related changes in the strength of coupling between theta and gamma either with or without coincident changes in theta amplitude. When the model was used to explore the relationship between theta and gamma oscillations, working memory capacity and phase coding it showed that the potential storage capacity of short term memories, in terms of nested gamma-subcycles, coincides with the maximal theta power. Increasing theta power is also related to the precision of theta phase which functions as a potential timing clock for neuronal firing in the cortex or hippocampus

Significance of Metastatic Lymph Node Ratio on Stimulated Thyroglobulin Levels in Papillary Thyroid Carcinoma after Prophylactic Unilateral Central Neck Dissection

Background: Prognostic significance of metastatic central lymph node ratio (CLNR) in papillary thyroid carcinoma (PTC) remains unknown. Because postsurgical detectable stimulated thyroglobulin (DsTg) after radioiodine ablation may imply persistent or recurrent disease, we evaluated the association between CLNR and rate of DsTg in patients with PTC who underwent unilateral prophylactic central neck dissection. Methods: To be eligible for analysis, the prophylactic central neck dissection specimen had to contain ≥3 central lymph nodes (CLNs) with ≥1 harboring metastasis. Of 129 specimens, 51 (39.5%) were eligible. CLNR was calculated as follows: (number of metastatic CLNs/number of CLNs retrieved) × 100. They were categorized into group 1 (CLNR 66.67%) (n = 22). Postablation sTg level was measured 6 months after radioiodine ablation. A multivariate analysis was conducted to identify factors for postablation DsTg. Results: Young age, palpable neck swelling, large tumor size, advanced tumor, node, metastasis system (TNM) stage, and large number of metastatic CLNs were significantly associated with high CLNR (Ppublished_or_final_versionSpringer Open Choice, 21 Feb 201

Non-compartment model to compartment model pharmacokinetics transformation meta-analysis – a multivariate nonlinear mixed model

Background To fulfill the model based drug development, the very first step is usually a model establishment from published literatures. Pharmacokinetics model is the central piece of model based drug development. This paper proposed an important approach to transform published non-compartment model pharmacokinetics (PK) parameters into compartment model PK parameters. This meta-analysis was performed with a multivariate nonlinear mixed model. A conditional first-order linearization approach was developed for statistical estimation and inference. Results Using MDZ as an example, we showed that this approach successfully transformed 6 non-compartment model PK parameters from 10 publications into 5 compartment model PK parameters. In simulation studies, we showed that this multivariate nonlinear mixed model had little relative bias (<1%) in estimating compartment model PK parameters if all non-compartment PK parameters were reported in every study. If there missing non-compartment PK parameters existed in some published literatures, the relative bias of compartment model PK parameter was still small (<3%). The 95% coverage probabilities of these PK parameter estimates were above 85%. Conclusions This non-compartment model PK parameter transformation into compartment model meta-analysis approach possesses valid statistical inference. It can be routinely used for model based drug development

Brain Stem Death as the Vital Determinant for Resumption of Spontaneous Circulation after Cardiac Arrest in Rats

BACKGROUND:Spontaneous circulation returns to less than half of adult cardiac arrest victims who received in-hospital resuscitation. One clue for this disheartening outcome arises from the prognosis that asystole invariably takes place, after a time lag, on diagnosis of brain stem death. The designation of brain stem death as the point of no return further suggests that permanent impairment of the brain stem cardiovascular regulatory machinery precedes death. It follows that a crucial determinant for successful revival of an arrested heart is that spontaneous circulation must resume before brain stem death commences. Here, we evaluated the hypothesis that maintained functional integrity of the rostral ventrolateral medulla (RVLM), a neural substrate that is intimately related to brain stem death and central circulatory regulation, holds the key to the vital time-window between cardiac arrest and resumption of spontaneous circulation. METHODOLOGY/PRINCIPAL FINDINGS:An animal model of brain stem death employing the pesticide mevinphos as the experimental insult in Sprague-Dawley rats was used. Intravenous administration of lethal doses of mevinphos elicited an abrupt cardiac arrest, accompanied by elevated systemic arterial pressure and anoxia, augmented neuronal excitability and enhanced microvascular perfusion in RVLM. This period represents the vital time-window between cardiac arrest and resumption of spontaneous circulation in our experimental model. Animals with restored spontaneous circulation exhibited maintained neuronal functionality in RVLM beyond this critical time-window, alongside resumption of baseline tissue oxygen and enhancement of local blood flow. Intriguingly, animals that subsequently died manifested sustained anoxia, diminished local blood flow, depressed mitochondrial electron transport activities and reduced ATP production, leading to necrotic cell death in RVLM. That amelioration of mitochondrial dysfunction and bioenergetic failure in RVLM by coenzyme Q10, the mobile electron carrier in mitochondrial respiratory chain, or oxygenation restored spontaneous circulation further established a causal relationship between functionality of RVLM and resumed spontaneous circulation after cardiac arrest. CONCLUSIONS/SIGNIFICANCE:We conclude that whereas necrotic cell death because of bioenergetic failure triggered by anoxia in RVLM, which precipitates brain stem death, negates resuscitation of an arrested heart, maintained functional integrity of this neural substrate holds the key to resumption of spontaneous circulation after cardiac arrest in rats

Risk Factors of Peritoneal Recurrence and Outcome of Resected Peritoneal Recurrence After Liver Resection in Hepatocellular Carcinoma: Review of 1222 Cases of Hepatectomy in a Tertiary Institution

10.1245/s10434-012-2260-3Annals of Surgical Oncology1972246-225

miRNA-135a promotes breast cancer cell migration and invasion by targeting HOXA10

<p>Abstract</p> <p>Background</p> <p>miRNAs are a group of small RNA molecules regulating target genes by inducing mRNA degradation or translational repression. Aberrant expression of miRNAs correlates with various cancers. Although miR-135a has been implicated in several other cancers, its role in breast cancer is unknown. <it>HOXA10 </it>however, is associated with multiple cancer types and was recently shown to induce p53 expression in breast cancer cells and reduce their invasive ability. Because <it>HOXA10 </it>is a confirmed miR-135a target in more than one tissue, we examined miR-135a levels in relation to breast cancer phenotypes to determine if miR-135a plays role in this cancer type.</p> <p>Methods</p> <p>Expression levels of miR-135a in tissues and cells were determined by poly (A)-RT PCR. The effect of miR-135a on proliferation was evaluated by CCK8 assay, cell migration and invasion were evaluated by transwell migration and invasion assays, and target protein expression was determined by western blotting. GFP and luciferase reporter plasmids were constructed to confirm the action of miR-135a on downstream target genes including <it>HOXA10</it>. Results are reported as means ± S.D. and differences were tested for significance using 2-sided Student"s t-test.</p> <p>Results</p> <p>Here we report that miR-135a was highly expressed in metastatic breast tumors. We found that the expression of miR-135a was required for the migration and invasion of breast cancer cells, but not their proliferation. <it>HOXA10</it>, which encodes a transcription factor required for embryonic development and is a metastasis suppressor in breast cancer, was shown to be a direct target of miR-135a in breast cancer cells. Our analysis showed that miR-135a suppressed the expression of <it>HOXA10 </it>both at the mRNA and protein level, and its ability to promote cellular migration and invasion was partially reversed by overexpression of <it>HOXA10</it>.</p> <p>Conclusions</p> <p>In summary, our results indicate that miR-135a is an onco-miRNA that can promote breast cancer cell migration and invasion. <it>HOXA10 </it>is a target gene for miR-135a in breast cancer cells and overexpression of <it>HOXA10 </it>can partially reverse the miR-135a invasive phenotype.</p

Effective Inhibition of Xenografts of Hepatocellular Carcinoma (HepG2) by Rapamycin and Bevacizumab in an Intrahepatic Model

10.1007/s11307-009-0213-4Molecular Imaging and Biology115334-342CPIM

Randomised double-blind trial of megestrol acetate vs placebo in treatment-naive advanced hepatocellular carcinoma

10.1038/bjc.2011.333British Journal of Cancer1057945-952BJCA