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991.
992.
Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: Role of M1 muscarinic receptors 下载免费PDF全文
Marta Maltese PhD Giuseppina Martella PhD Graziella Madeo MD Irene Fagiolo MD Annalisa Tassone PhD Giulia Ponterio PhD Giuseppe Sciamanna PhD Pierre Burbaud MD PhD P. Jeffrey Conn PhD Paola Bonsi PhD Antonio Pisani MD PhD 《Movement disorders》2014,29(13):1655-1665
Broad‐spectrum muscarinic receptor antagonists have represented the first available treatment for different movement disorders such as dystonia. However, the specificity of these drugs and their mechanism of action is not entirely clear. We performed a systematic analysis of the effects of anticholinergic drugs on short‐ and long‐term plasticity recorded from striatal medium spiny neurons from DYT1 dystonia knock‐in (Tor1a+/Δgag) mice heterozygous for ΔE‐torsinA and their controls (Tor1a+/+ mice). Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, trihexyphenydil, biperiden, orphenadrine, and a novel selective M1 antagonist, VU0255035. Tor1a+/Δgag mice exhibited a significant impairment of corticostriatal synaptic plasticity. Anticholinergics had no significant effects on intrinsic membrane properties and on short‐term plasticity of striatal neurons. However, they exhibited a differential ability to restore the corticostriatal plasticity deficits. A complete rescue of both long‐term depression (LTD) and synaptic depotentiation (SD) was obtained by applying the M1‐preferring antagonists pirenzepine and trihexyphenidyl as well as VU0255035. Conversely, the nonselective antagonist orphenadrine produced only a partial rescue of synaptic plasticity, whereas biperiden and ethopropazine failed to restore plasticity. The selectivity for M1 receptors was further demonstrated by their ability to counteract the M1‐dependent potentiation of N‐methyl‐d ‐aspartate (NMDA) current recorded from striatal neurons. Our study demonstrates that selective M1 muscarinic receptor antagonism offsets synaptic plasticity deficits in the striatum of mice with the DYT1 dystonia mutation, providing a potential mechanistic rationale for the development of improved antimuscarinic therapies for this movement disorder. © 2014 International Parkinson and Movement Disorder Society 相似文献
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Monica Locatelli Simona Buelli Anna Pezzotta Daniela Corna Luca Perico Susanna Tomasoni Daniela Rottoli Paola Rizzo Debora Conti Joshua M. Thurman Giuseppe Remuzzi Carlamaria Zoja Marina Morigi 《Journal of the American Society of Nephrology : JASN》2014,25(8):1786-1798
Shiga toxin (Stx)–producing Escherichia coli is the offending agent of postdiarrhea-associated hemolytic uremic syndrome (HUS), a disorder of glomerular ischemic damage and widespread microvascular thrombosis. We previously documented that Stx induces glomerular complement activation, generating C3a responsible for microvascular thrombosis in experimental HUS. Here, we show that the presence of C3 deposits on podocytes is associated with podocyte damage and loss in HUS mice generated by the coinjection of Stx2 and LPS. Because podocyte adhesion to the glomerular basement membrane is mediated by integrins, the relevance of integrin-linked kinase (ILK) signals in podocyte dysfunction was evaluated. Podocyte expression of ILK increased after the injection of Stx2/LPS and preceded the upregulation of Snail and downregulation of nephrin and α-actinin-4. Factor B deficiency or pretreatment with an inhibitory antibody to factor B protected mice against Stx2/LPS-induced podocyte dysregulation. Similarly, pretreatment with a C3a receptor antagonist limited podocyte loss and changes in ILK, Snail, and α-actinin-4 expression. In cultured podocytes, treatment with C3a reduced α-actinin-4 expression and promoted ILK-dependent nuclear expression of Snail and cell motility. These results suggest that Stx-induced activation of the alternative pathway of complement and generation of C3a promotes ILK signaling, leading to podocyte dysfunction and loss in Stx-HUS. 相似文献
994.
Piero Ruggenenti Barbara Ruggiero Paolo Cravedi Marina Vivarelli Laura Massella Maddalena Marasà Antonietta Chianca Nadia Rubis Bogdan Ene-Iordache Michael Rudnicki Rosa Maria Pollastro Giovambattista Capasso Antonio Pisani Marco Pennesi Francesco Emma Giuseppe Remuzzi 《Journal of the American Society of Nephrology : JASN》2014,25(4):850-863
The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and with major treatment toxicity. This academic, multicenter, off-on trial (ClinicalTrials.gov #) primarily evaluated the effects of rituximab therapy followed by immunosuppression withdrawal on disease recurrence in 10 children and 20 adults with MCD/MesGN (n=22) or FSGS who had suffered ≥2 recurrences over the previous year and were in steroid-induced remission for ≥1 month. Participants received one dose (n=28) or two doses of rituximab (375 mg/m2 intravenously). At 1 year, all patients were in remission: 18 were treatment-free and 15 never relapsed. Compared with the year before rituximab treatment, total relapses decreased from 88 to 22 and the per-patient median number of relapses decreased from 2.5 (interquartile range [IQR], 2–4) to 0.5 (IQR, 0–1; P<0.001) during 1 year of follow-up. Reduction was significant across subgroups (children, adults, MCD/MesGN, and FSGS; P<0.01). After rituximab, the per-patient steroid maintenance median dose decreased from 0.27 mg/kg (IQR, 0.19–0.60) to 0 mg/kg (IQR, 0–0.23) (P<0.001), and the median cumulative dose to achieve relapse remission decreased from 19.5 mg/kg (IQR, 13.0–29.2) to 0.5 mg/kg (IQR, 0–9.4) (P<0.001). Furthermore, the mean estimated GFR increased from 111.3±25.7 to 121.8±29.2 ml/min per 1.73 m2 (P=0.01), with the largest increases in children and in FSGS subgroups. The mean height z score slope stabilized in children (P<0.01). Treatment was well tolerated. Rituximab effectively and safely prevented recurrences and reduced the need for immunosuppression in steroid-dependent or frequently relapsing nephrotic syndrome, and halted disease-associated growth deficit in children.Idiopathic nephrotic syndrome (NS) in children and young adults is almost invariably the clinical counterpart of a continuum of glomerular diseases ranging from the relatively frequent minimal change disease (MCD) and the less frequent mesangial proliferative GN (MesGN), which are predominantly observed in children, to the relatively uncommon FSGS that is observed more frequently in adult patients. NCT009818381 In a small minority of patients that are generally resistant to immunosuppressive therapies, the disease is due to molecular defects of one of the podocyte genes.2 In all of the other cases, it appears to be immune-mediated, but the pathophysiologic process underlying glomerular injury remains poorly understood.3Independent of the underlying renal pathology, prednisone continues to be the cornerstone treatment at disease onset, achieving remission within 4 weeks in approximately 90% of children with MCD and in 20%–60% of those with FSGS.4,5 However, 60%–70% of patients relapse after steroid tapering or withdrawal, and most require repeat courses of prednisone to achieve remission of recurrent episodes and/or the addition of other immunosuppressive medications, such as calcineurin inhibitors, mycophenolate mofetil, or alkylating agents, to reduce the number of relapses and prevent major side effects of steroid treatment.6 According to their relapse rate, these patients are classically labeled as “steroid-dependent” or “frequently relapsing”. In these patients, serious adverse effects of treatment associate with complications of relapsing episodes of heavy proteinuria. These are the patients in most urgent need of more effective and safer treatment.The possibility of a specific and, hopefully, safer approach to patients with steroid-dependent or frequently relapsing NS emerged in 2004 when the B cell–depleting mAb rituximab was reported to induce remission of proteinuria in a child with frequently relapsing NS secondary to MCD who had received this medication to cure a supervened idiopathic thrombocytopenic purpura.7 Subsequent uncontrolled observations found some effect of rituximab in patients with steroid-dependent or frequently relapsing MCD,8–11 suggesting that B-cell immunity could play a key role in the pathophysiology of the disease. Controlled studies in support of this hypothesis, however, have been both scanty and almost confined to children12,13 or to patients with MCD who were evaluated in the context of a retrospective, observational design.14 Indeed, less attention was given to adults and patients with FSGS given difficulties in designing adequately powered trials.Here, we designed a longitudinal, off-on study (ClinicalTrials.gov #) to evaluate the efficacy of rituximab in reducing the incidence of relapses and need for steroid and other immunosuppressive medications in children and adults with steroid-dependent or frequently relapsing NS due to MCD, MesGN, or FSGS. To minimize the side effects and costs of rituximab, we abandoned the standard four-dose protocol originally implemented for the treatment of B-cell lymphomas, NCT0098183815 and adopted a new B cell–driven regimen we found to achieve remission of NS in patients with idiopathic membranous nephropathy (IMN) as effectively as the standard protocol, but with fewer side effects and less costs.16 相似文献
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996.
997.
Giuseppe Malleo Alessandra Pulvirenti Giovanni Marchegiani Giovanni Butturini Roberto Salvia Claudio Bassi 《Langenbeck's archives of surgery / Deutsche Gesellschaft fur Chirurgie》2014,399(7):801-810
Background
Postoperative pancreatic fistula (POPF) is the leading complication after partial pancreatic resection and is associated with increased length of hospital stay and resource utilization. The introduction of a common definition in 2005 by the International Study Group of Pancreatic Surgery (ISGPS), which has been since employed in the vast majority of reports, has allowed a reliable comparison of surgical results. Despite the systematic investigation of risk factors and of surgical techniques, the incidence of POPF did not change in recent years, whereas the associated mortality has decreased.Purpose
The purposes of this review article were to summarize the current evidence on the diagnosis and management strategies of POPF and to provide a concise reference for the practicing surgeons and physicians.Conclusion
The high incidence of POPF was accompanied by a shift from operative to non-operative management. However, the current management strategy is driven by the patient’s condition and local expertise and is generally based on poor evidence. A randomized trial showed that enteral nutrition is superior to total parenteral nutrition, and pooled data of randomized trials failed to show any advantage of somatostatin analogs for accelerating fistula closure. The choice of percutaneous versus endoscopic drainage of peripancreatic collections remains arbitrary, and—when re-operation is needed—there are very few comparative data regarding local drainage with or without main pancreatic stenting as opposed to anastomotic revision or salvage re-anastomosis. The continuous development of specialist, high-volume units with appropriate resources and multidisciplinary experience in complication management might further improve the evidence and the outcomes. 相似文献998.
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Gian C. Winkler Ester Lovsin Barle Giuseppe Galati William M. Kluwe 《Regulatory toxicology and pharmacology : RTP》2014
There is no nationally or internationally binding definition of the term “cytotoxic drug” although this term is used in a variety of regulations for pharmaceutical development and manufacturing of drugs as well as in regulations for protecting medical personnel from occupational exposure in pharmacy, hospital, and other healthcare settings. The term “cytotoxic drug” is frequently used as a synonym for any and all oncology or antineoplastic drugs. Pharmaceutical companies generate and receive requests for assessments of the potential hazards of drugs regularly – including cytotoxicity. This publication is intended to provide functional definitions that help to differentiate between generically-cytotoxic cancer drugs of significant risk to normal human tissues, and targeted cancer therapeutics that pose much lesser risks. Together with specific assessments, it provides comprehensible guidance on how to assess the relevant properties of cancer drugs, and how targeted therapeutics discriminate between cancer and normal cells. The position of several regulatory agencies in the long-term is clearly to regulate all drugs regardless of classification, according to scientific risk based data. Despite ongoing discussions on how to replace the term “cytotoxic drugs” in current regulations, it is expected that its use will continue for the near future. 相似文献