Lead Decreases Bone Morphogenetic Protein-7 (BMP-7) Expression and Increases Renal Cell Carcinoma Growth in a Sex-Divergent Manner.

Both tissue and blood lead levels are elevated in renal cell carcinoma (RCC) patients. These studies assessed the impact of the subchronic lead challenge on the progression of RCC in vitro and in vivo. Lead challenge of Renca cells with 0.5 µM lead acetate for 10 consecutive passages decreased E-cadherin expression and cell aggregation. Proliferation, colony formation, and wound healing were increased. When lead-challenged cells were injected into mice, tumor size at day 21 was increased; interestingly, this increase was seen in male but not female mice. When mice were challenged with 32 ppm lead in drinking water for 20 weeks prior to tumor cell injection, there was an increase in tumor size in male, but not female, mice at day 21. To investigate the mechanism underlying the sex differences, the expression of sex hormone receptors in Renca cells was examined. Control Renca cells expressed estrogen receptor (ER) alpha but not ER beta or androgen receptor (AR), as assessed by qPCR, and the expression of ERα was increased in tumors in both sexes. In tumor samples harvested from lead-challenged cells, both ERα and AR were detected by qPCR, yet there was a significant decrease in AR seen in lead-challenged tumor cells from male mice only. This was paralleled by a plate-based array demonstrating the same sex difference in BMP-7 gene expression, which was also significantly decreased in tumors harvested from male but not female mice; this finding was validated by immunohistochemistry. A similar expression pattern was seen in tumors harvested from the mice challenged with lead in the drinking water. These data suggest that lead promotes RCC progression in a sex-dependent via a mechanism that may involve sex-divergent changes in BMP-7 expression.

A repeating fast radio burst source localized to a nearby spiral galaxy.

Fast radio bursts (FRBs) are brief, bright, extragalactic radio flashes1,2. Their physical origin remains unknown, but dozens of possible models have been postulated3. Some FRB sources exhibit repeat bursts4-7. Although over a hundred FRB sources have been discovered8, only four have been localized and associated with a host galaxy9-12, and just one of these four is known to emit repeating FRBs9. The properties of the host galaxies, and the local environments of FRBs, could provide important clues about their physical origins. The first known repeating FRB, however, was localized to a low-metallicity, irregular dwarf galaxy, and the apparently non-repeating sources were localized to higher-metallicity, massive elliptical or star-forming galaxies, suggesting that perhaps the repeating and apparently non-repeating sources could have distinct physical origins. Here we report the precise localization of a second repeating FRB source6, FRB 180916.J0158+65, to a star-forming region in a nearby (redshift 0.0337 ± 0.0002) massive spiral galaxy, whose properties and proximity distinguish it from all known hosts. The lack of both a comparably luminous persistent radio counterpart and a high Faraday rotation measure6 further distinguish the local environment of FRB 180916.J0158+65 from that of the single previously localized repeating FRB source, FRB 121102. This suggests that repeating FRBs may have a wide range of luminosities, and originate from diverse host galaxies and local environments.

Correction: Self-assembled fibrillar networks comprised of a naturally-occurring cyclic peptide-LOB3.

[This corrects the article DOI: 10.1039/C6RA05154E.].

Overexpression of Arginase 1 is linked to DNMT3A and TET2 mutations in lower-grade myelodysplastic syndromes and chronic myelomonocytic leukemia.

Immune dysregulation is a common feature of myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), particularly in early stages. However, the genetic basis remains poorly understood. We recently reported that macrophages from mice deficient in tet methylcytosine dioxygenase 2 (Tet2), a model of MDS/CMML, are hyperinflammatory and have increased expression of arginase 1 (Arg1). In macrophages and myeloid derived suppressor cells (MDSCs) expression of Arg1 contributes to T-cell suppression and immune evasion by L-arginine depletion, in the setting of chronic inflammation and cancer. Since human MDS and CMML are driven by TET2 mutations and associated with chronic inflammation, we hypothesized that arginase enzymatic activity and ARG1 expression would be increased in human MDS/CMML bone marrow. Elevated arginase activity was observed in bone marrow mononuclear cells of MDS and CMML patients with lower-grade features. Immunohistochemical studies confirmed that myelomonocytic cells overexpress ARG1. Additionally, mutations in the epigenetic regulators TET2 and DNMT3A corresponded to high ARG1 expression and activity. These findings suggest ARG1 is a biomarker of immune dysregulation in early MDS and CMML. Recent murine findings have implicated Tet2 and Dnmt3a in regulation of innate immunity. Our study suggests similar changes may be driven by human TET2 and DNMT3A mutations.

Effects of unilateral stroke on multi-finger synergies and their feed-forward adjustments.

We explored the changes in multi-finger synergies in patients after a single cortical stroke with mild motor impairments. We hypothesized that both synergy indices and anticipatory synergy adjustments prior to the initiation of a self-paced quick action would be diminished in the patients compared to age-matched controls. The patients with history of cortical stroke, and age-matched controls (n=12 in each group) performed one-finger and multi-finger accurate force production tasks involving both steady-state and quick force pulse production. Finger interdependence (enslaving) and multi-finger synergies stabilizing total force were quantified. The stroke patients showed lower maximal finger forces, in particular in the contralesional hand, which also showed increased enslaving indices. Multi-finger synergies during steady-state force production were, however, unchanged after stroke. In contrast, a drop in the synergy index prior to the force pulse generation was significantly delayed in the stroke patients. Our results show that mild cortical stroke leads to no significant changes in multifinger synergies, but there is impairment in feed-forward adjustments of the synergies prior to a quick action, a drop in the maximal force production, and an increase in enslaving. We conclude that studies of synergies reveal two aspects of synergic control differentially affected by cortical stroke.

Mathematical Model-Based Accelerated Development of Extended-release Metformin Hydrochloride Tablet Formulation.

A computational fluid dynamic (CFD) model was developed to predict metformin release from a hydroxypropylmethylcellulose (HPMC) matrix-based extended-release formulation that took into consideration the physical and chemical properties of the drug substance, composition, as well as size and shape of the tablet. New high dose strength (1000 mg) tablet geometry was selected based on the surface area/volume (SA/V) approach advocated by Lapidus/Lordi/Reynold to obtain the desired equivalent metformin release kinetics. Maintaining a similar SA/V ratio across all extended-release metformin hydrochloride (Met XR) tablet strengths that had different geometries provided similar simulations of dissolution behavior. Experimental dissolution profiles of three lots of high-strength tablets agreed with the simulated release kinetics. Additionally, a pharmacokinetic absorption model was developed using GastroPlus™ software and known physicochemical, pharmacokinetic, and in vitro dissolution properties of metformin to predict the clinical exposure of the new high strength (1000 mg) tablet prior to conducting a human clinical bioequivalence study. In vitro metformin release kinetics were utilized in the absorption model to predict exposures in humans for new 1000-mg Met XR tablets, and the absorption model correctly projected equivalent in vivo exposure across all dose strengths. A clinical bioequivalence study was pursued based on the combined modeling results and demonstrated equivalent exposure as predicted by the simulations.

Prolonged clinical remissions in patients with relapsed or refractory follicular lymphoma treated with autologous stem cell transplantation incorporating rituximab.

Three sequential phase II trials were conducted with different immunotherapy approaches to enhance the outcome of autologous transplant (high-dose therapy and autologous stem cell transplantation (HDT/ASCT)) for recurrent follicular lymphoma. Seventy-three patients were enrolled from 1996 to 2009. Patients received HDT/ASCT combined with (1) interferon-α 3 MU/m(2) subcutaneously (SC) three times per week (TIW) for 2 years post-ASCT, (2) rituximab (R) 375 mg/m(2) for in vivo purging 3-5 days pre-stem cell collection and 2 × 4 weekly R at 2 and 6 months post-ASCT, respectively, or (3) three infusions of R pre-stem cell collection followed by 6× R weekly and interferon-α 3 MU/m(2) SC TIW. Although not statistically significant, progression-free survival (PFS) for patients who received rituximab was 56.4 and 49.1% at 5 and 10 years compared to 36 and 21% in those who did not receive rituximab. Molecular relapse post-HDT/ASCT was the strongest predictor of PFS in a multivariate analysis. Molecular relapse was coincident with or preceded clinical relapses in 84% of patients who relapsed­median of 12 months (range 0-129 months). Adverse events included secondary malignancy, transformation to diffuse large B cell lymphoma, prolonged mostly asymptomatic hypogammaglobulinemia, and pulmonary fibrosis. The long-term toxicity profile must be considered when selecting patients for this treatment.

Analysis of the pentafecta learning curve for laparoscopic radical prostatectomy.

PURPOSE: Laparoscopic radical prostatectomy (LRP) has a long learning curve; however, little is known about the pentafecta learning curve for LRP. We analysed the learning curve for a fellowship trained surgeon with regard to the pentafecta with up to 6-year follow-up. METHODS: A retrospective review was performed in 550 cases, by dividing these cases into 11 groups of 50 patients. Outcomes analysed were the following: (1) the pentafecta (complication rate, positive surgical margin (PSM) rate, continence, potency and biochemical recurrence); (2) operative time and blood loss; and (3) overall pentafecta attainment. RESULTS: The mean complication rate for the entire series was 9 %; this plateaued after 150 cases. The overall PSM rate for the series was 23.5 %, 16.3 % for pT2 and 40.5 % for pT3. PSM plateaued after 200 cases. Excluding the first 100 cases, the overall PSM rate for pT2 was 10.9 % and 37.8 % for pT3. The continence rate stabilised after approximately 250 cases. The rate of male sling/artificial urinary sphincter plateaued after 200 cases. The potency learning curve continues to improve after 250 cases of nerve-sparing (ns) endoscopic extraperitoneal radical prostatectomy (EERPE) as does the pentafecta learning curve which closely follows the pattern of the potency learning curve. The last group of nsEERPE achieved pentafecta in 63 %. CONCLUSION: This study shows multiple learning curves: an initial for peri-operative outcomes, then stabilisation of oncologic outcomes and the final for stabilisation of functional outcomes. In this series over 250 cases were required to achieve the learning curve.

Examining network dynamics after traumatic brain injury using the extended unified SEM approach.

The current study uses effective connectivity modeling to examine how individuals with traumatic brain injury (TBI) learn a new task. We make use of recent advancements in connectivity modeling (extended unified structural equation modeling, euSEM) and a novel iterative grouping procedure (Group Iterative Multiple Model Estimation, GIMME) in order to examine network flexibility after injury. The study enrolled 12 individuals sustaining moderate and severe TBI to examine the influence of task practice on connections between 8 network nodes (bilateral prefrontal cortex, anterior cingulate, inferior parietal lobule, and Crus I in the cerebellum). The data demonstrate alterations in networks from pre to post practice and differences in the models based upon distinct learning trajectories observed within the TBI sample. For example, better learning in the TBI sample was associated with diminished connectivity within frontal systems and increased frontal to parietal connectivity. These findings reveal the potential for using connectivity modeling and the euSEM to examine dynamic networks during task engagement and may ultimately be informative regarding when networks are moving in and out of periods of neural efficiency.

The impact of rolling theatre closures on core urology training.

Since 2008, government funding of the Health Service Executive (HSE) has decreased significantly. Our hospital, Cork University Hospital (CUH), implemented "cost saving" measures including scheduled operating theatre closures. We studied their affect on urological surgical activity at the hospital. A retrospective review was performed using theatre log books and theatre records to determine the number, type and training status of procedures performed for years 2009 and 2011. Scheduled theatre closures in 2011 resulted in 33 more theatre session cancelations compared to 2009. There was a reduction in the total number of procedures performed from 555 cases in 2009 to 443 in 2011 a 20.2(%) reduction. The number of "training" cases reduced from 325 (58.9%) in 2009 to 216 (48.7%) in 2011 a 10.2% reduction (Table 2). Eight out of the nine "core urology training" procedures reduced in number from 2009 to 2011 (Table 1). We have shown that scheduled theatre closures have reduced the number of procedures performed and have impacted on urology training. Scheduled theatre closures are expected to become more frequent in the future. Potential solutions to lessen the impact include providing simulation training using the Royal College of Surgeons in Ireland (RCSI) mobile skills unit during these theatre closures.

Bilateral Synergy: A Framework for Post-Stroke Rehabilitation.

BACKGROUND: Unilateral stroke produces debilitating deficits in voluntary control in the contralesional arm, and significant motor coordination deficits in the ipsilesional arm. In addition, patients tend to avoid bilateral arm patterns and during performance of activities of daily living. Nevertheless, upper extremity physical rehabilitation predominantly focuses on motor training activities with only the paretic arm. This can be limiting because of persistent deficits in the ipsilesional arm, and because of the tendency of patients to avoid spontaneous bilateral arm patterns. PROPOSITION: Rehabilitation should focus on bilateral training to advance recovery of function in both arms of stroke patients, as well as to facilitate spontaneous bilateral arm use. This paper reviews the rationale for this approach, citing evidence for significant hemisphere specific bilateral motor deficits in stroke patients, which affect both the contralesional and the ipsilesional arm. The rationale for, and advantages of, training both arms simultaneously through bilateral tasks is reviewed. Although bilateral training has been employed to treat stroke patients previously, this has tended to focus on bimanual 'coupling' as a rationale for performing parallel, but not cooperative bilateral tasks. Bilateral synergy provides a more functional framework for structuring post-stroke upper extremity rehabilitation. CONCLUSION: Bilateral synergy may be causally linked to spontaneous bilateral arm use, suggesting that rehabilitation should be focused on bilateral cooperative tasks, such as bilateral object transport. Further research is required to determine whether this approach could be efficacious for patients with hemiparesis, and whether both left and right hemisphere strokes can benefit from such intervention.

Increased throughput of proteomics analysis by multiplexing high-resolution tandem mass spectra.

High-resolution and high-accuracy Fourier transform mass spectrometry (FTMS) is becoming increasingly attractive due to its specificity. However, the speed of tandem FTMS analysis severely limits the competitive advantage of this approach relative to faster low-resolution quadrupole ion trap MS/MS instruments. Here we demonstrate an entirely FTMS-based analysis method with a 2.5-3.0-fold greater throughput than a conventional FT MS/MS approach. The method consists of accumulating together the MS/MS fragments ions from multiple precursors, with subsequent high-resolution analysis of the mixture. Following acquisition, the multiplexed spectrum is deconvoluted into individual MS/MS spectra which are then combined into a single concatenated file and submitted for peptide identification to a search engine. The method is tested both in silico using a database of MS/MS spectra as well as in situ using a modified LTQ Orbitrap mass spectrometer. The performance of the method in the experiment was consistent with theoretical expectations.

Popliteo-pedal bypass surgery for critical limb ischemia.

BACKGROUND: Critical limb ischaemia due to distal arterial disease represents a significant challenge. Randomised controlled evidence suggests that open surgery may be superior to endovascular intervention but there is limited data on the specific clinical cohort with exclusively infra-popliteal disease. AIM: We analysed indications for, and outcome from all, popliteo-pedal bypass procedures performed between July 1998 to November 2008. PATIENTS AND METHODS: Twenty-eight bypass procedures were performed in 24 patients. Autologous vein was used exclusively. The proximal anastomosis was to the below-knee popliteal artery in all the patients; the distal anastomosis was to plantar artery (n = 15) or dorsalis pedis artery (n = 13). Mean patient age was 63.Eight years of age (range 37-92 years). Indications for surgery were tissue loss (n = 21) and rest pain (n = 7). Ultrasound graft surveillance was performed every 6-months. RESULTS: Using life table analysis, primary graft patency was 63.3% at 1-, 3- and 5-years and secondary patency (after three interventions) was 74.6% at 1-, 3- and 5-years. Limb salvage rate was 81.8% after 1-, 3- and 5-years as all five limb amputations were performed in the first 3-months following the surgery. Overall survival was 75, 75 and 47.1% at 1-, 3- and 5-years, respectively. The major amputation free survival rate was 54.2, 54.2 and 21.3% at 1-, 3- and 5-years, respectively. Seventy-nine percent (n = 19) patients were diabetic. CONCLUSION: Our data supports popliteo-pedal bypass as an effective treatment for distal vascular disease. Comparison with endovascular treatment in a randomised trial needs to be performed.

Changes in resting connectivity during recovery from severe traumatic brain injury.

In the present study we investigate neural network changes after moderate and severe traumatic brain injury (TBI) through the use of resting state functional connectivity (RSFC) methods. Using blood oxygen level dependent functional MRI, we examined RSFC at 3 and 6 months following resolution of posttraumatic amnesia. The goal of this study was to examine how regional off-task connectivity changes during a critical period of recovery from significant neurological disruption. This was achieved by examining regional changes in the intrinsic, or "resting", BOLD fMRI signal in separate networks: 1) regions linked to goal-directed (or external-state) networks and 2) default mode (or internal-state) networks. Findings here demonstrate significantly increased resting connectivity internal-state networks in the TBI sample during the first 6 months following recovery. The most consistent finding was increased connectivity in both internal and external state networks to the insula and medial temporal regions during recovery. These findings were dissociable from repeat measurements in a matched healthy control sample.

Expression of the hypothalamic transcription factor Nhlh2 is dependent on energy availability.

Mice with a deletion of the hypothalamic basic helix-loop-helix transcription factor Nhlh2 display adult onset obesity, implicating Nhlh2 in the neuronal circuits regulating energy availability. Nhlh2 colocalises with the hypothalamic thyrotrophin-releasing hormone (TRH) neurones in the paraventricular nucleus (PVN) and pro-opiomelanocortin (POMC) neurones in the arcuate nucleus. We show that Nhlh2 expression is significantly reduced in response to 24-h food deprivation in the arcuate nucleus, PVN, lateral hypothalamus, ventromedial hypothalamus (VMH) and dorsomedial hypothalamus (DMH). Food intake for 2 h following deprivation stimulates Nhlh2 expression in the arcuate nucleus and the PVN, and leptin injection following deprivation results in increased Nhlh2 expression in the arcuate nucleus, PVN, lateral hypothalamus, VMH, and DMH. Hypothalamic Nhlh2 expression in response to leptin injection is maximal by 2 h. Following leptin injection, Nhlh2 mRNA colocalises in POMC neurones in the arcuate nucleus and TRH neurones in the PVN. Nhlh2 mRNA expression in POMC neurones in the arcuate nucleus and TRH neurones in the PVN is reduced with energy deprivation and is stimulated with food intake and leptin injection. Modulation of POMC expression in response to changes in energy availability is not affected in mice with a targeted deletion of Nhlh2. However, deletion of Nhlh2 does result in loss of normal TRH mRNA expression in mice exposed to food deprivation and leptin stimulation. These data implicate Nhlh2 as a regulatory target of the leptin-mediated energy availability network of the hypothalamus, and TRH as a putative downstream target of Nhlh2.

Minimal model for tumor angiogenesis.

In this work, we show a mathematical model for the angiogenesis by endothelial cells. We present the model at the level of partial differential equations, describing the spatiotemporal evolution of the cell population, the extracellular matrix macromolecules, the proteases, the tumor angiogenic factors, and the possible presence of inhibitors. We mainly focus, however, on a complementary, more physiologically realistic, hybrid approach in which the cells are treated as individual particles. We examine the model numerically in two-dimensional settings, discussing its comparison with experimental results.

Genetic analysis of NHLH2 and its putative role in bovine body weight control.

The control of energy balance is fundamental to adult animals and is necessary for weight gain/loss, reproductive capacity and general health. In mice, targeted deletion of the neuronal transcription factor Nhlh2 results in adult-onset obesity because of reduced exercise and infertility because of reduced sexual behaviour. Nhlh2 (NHLH2 for humans) is expressed in the hypothalamus, particularly in neurons that have been shown to regulate energy balance. We have cloned the bovine Nhlh2 gene (bNHLH2) and we have shown that bNHLH2 is also expressed in the hypothalamus. Phylogenetic analysis of Nhlh2 reveals that it is very highly conserved in humans, mice, chimps and cattle, and found in organisms with simpler nervous systems, including Caenorhabditis elegans and Drosophila. Using a cattle-human comparative map and online databases, we have evidence that bNHLH2 is located near a quantitative trait locus for marbling on bovine chromosome 3 between microsatellite markers BM723 and BMS963. Cloning of the bNHLH2 gene from Holstein cattle and a mixed breed individual and comparison with Hereford sequences shows that the gene is highly conserved among bovine breeds.

Methylene blue for the treatment and prophylaxis of ifosfamide-induced encephalopathy.

Ifosfamide (IFOS) is used in cancer treatment. Ifosfamide-induced encephalopathy (IIE) can result in treatment delay or discontinuation as well as morbidity and mortality. Cases using methylene blue (MB) in acute and prophylactic treatments are discussed. For acute use, marked central nervous system (CNS) improvement occurred within 24h of MB administration. For prophylactic use, the severity of the symptoms decreased significantly compared with previous treatment cycles, and enabled patients to continue further IFOS therapy. MB has potential use in both the acute treatment and prophylaxis of IIE.

[Plasticity of motor maps in primates: recent advances and therapeutical perspectives]. / Plasticité des aires motrices corticales: progrès récents et perspectives thérapeutiques.

In the past decade, there have been considerable advances in understanding the neuronal bases of sensory and motor map reorganisation in adults and it is now clear that cortical representations are not invariant and stable, but rather, are dynamic and can continuously be modified. In human subjects, substantial advances in this field have been possible because of the spectacular development of non-invasive imaging and brain stimulation techniques. This review addresses specific questions about the capacity of motor maps in adult primates, including man, to change in response to behaviourally relevant experiences or as a result of central or peripheral lesion. The first part of this review deals with recent progress in understanding the role of the primary motor cortex (M1) in both motor control and cognition. The organisation and function of multiple "non-primary" motor areas located rostrally to the primary motor cortex and in the cingulate cortex are also discussed. This review then focuses on advances made in understanding motor cortex plasticity in different conditions. Firstly, since representations in M1 have been shown to change after motor learning, the contribution of M1 in motor learning has been insinuated; arguments against and in favour of this view are discussed. In addition, data suggesting that intracortical circuitry of M1 may play a role in map reorganisation following motor learning are also evaluated. Secondly, a large body of evidence from both animal and human observations is reviewed that confirms that M1 representations can also be altered as a result of changes in availability of effectors or following sensory deprivation. The mechanisms underlying such a plasticity of cortical maps following peripheral lesions are increasingly well understood. Thirdly, we discuss data showing that a corticospinal system lesion can lead to a complete reorganisation of the area allocated to the hand representation in the primary motor cortex or to a reorganization of the whole network of motor areas responsible for voluntary movements. As a conclusion, therapeutical perspectives that result from a better understanding of those various mechanisms responsible for motor map plasticity are briefly discussed.