Assessing brain involvement in Fabry disease with deep learning and the brain-age paradigm.

While neurological manifestations are core features of Fabry disease (FD), quantitative neuroimaging biomarkers allowing to measure brain involvement are lacking. We used deep learning and the brain-age paradigm to assess whether FD patients' brains appear older than normal and to validate brain-predicted age difference (brain-PAD) as a possible disease severity biomarker. MRI scans of FD patients and healthy controls (HCs) from a single Institution were, retrospectively, studied. The Fabry stabilization index (FASTEX) was recorded as a measure of disease severity. Using minimally preprocessed 3D T1-weighted brain scans of healthy subjects from eight publicly available sources (N = 2160; mean age = 33 years [range 4-86]), we trained a model predicting chronological age based on a DenseNet architecture and used it to generate brain-age predictions in the internal cohort. Within a linear modeling framework, brain-PAD was tested for age/sex-adjusted associations with diagnostic group (FD vs. HC), FASTEX score, and both global and voxel-level neuroimaging measures. We studied 52 FD patients (40.6 ± 12.6 years; 28F) and 58 HC (38.4 ± 13.4 years; 28F). The brain-age model achieved accurate out-of-sample performance (mean absolute error = 4.01 years, R2 = .90). FD patients had significantly higher brain-PAD than HC (estimated marginal means: 3.1 vs. -0.1, p = .01). Brain-PAD was associated with FASTEX score (B = 0.10, p = .02), brain parenchymal fraction (B = -153.50, p = .001), white matter hyperintensities load (B = 0.85, p = .01), and tissue volume reduction throughout the brain. We demonstrated that FD patients' brains appear older than normal. Brain-PAD correlates with FD-related multi-organ damage and is influenced by both global brain volume and white matter hyperintensities, offering a comprehensive biomarker of (neurological) disease severity.

Fatigue as hallmark of Fabry disease: role of bioenergetic alterations.

Fabry disease (FD) is a lysosomal storage disorder due to the impaired activity of the α-galactosidase A (GLA) enzyme which induces Gb3 deposition and multiorgan dysfunction. Exercise intolerance and fatigue are frequent and early findings in FD patients, representing a self-standing clinical phenotype with a significant impact on the patient's quality of life. Several determinants can trigger fatigability in Fabry patients, including psychological factors, cardiopulmonary dysfunctions, and primary alterations of skeletal muscle. The "metabolic hypothesis" to explain skeletal muscle symptoms and fatigability in Fabry patients is growing acknowledged. In this report, we will focus on the primary alterations of the motor system emphasizing the role of skeletal muscle metabolic disarrangement in determining the altered exercise tolerance in Fabry patients. We will discuss the most recent findings about the metabolic profile associated with Fabry disease offering new insights for diagnosis, management, and therapy.

Choline PET/CT in recurrent prostate cancer.

Purpose: Biochemical recurrence (BR) occurs in up to 40% of patients with prostate cancer (PCa) treated with primary radical prostatectomy (RP). Choline PET/CT may show, in a single-step examination, the site of tumor recurrence earlier than traditional imaging methods, particularly at low prostate-specific antigen (PSA) levels, thus influencing subsequent treatment. Methods/patients: Patients with recurrent and non-metastatic prostate cancer (nmPCa), who were assessed with choline PET/CT, were included in the analysis. Based on imaging results, the following therapeutic strategies were chosen: radiotherapy to the prostatic bed, androgen deprivation therapy (ADT), and chemotherapy or stereotactic body radiotherapy (SBRT) to either the pelvic lymph nodes or distant metastases. We assessed the impact of age, PSA levels, Gleason score (GS), and adjuvant therapy on oncological outcomes. Results: Data from 410 consecutive nmPCa patients with BR who underwent RP as primary treatment were analyzed. One hundred seventy-six (42.9%) patients had a negative choline PET/CT, and 234 (57.1%) patients resulted positive. In the multivariate analysis, only chemotherapy and PSA at recurrence were significant independent prognostic factors on overall survival (OS). In the PET-positive subgroup, the number of relapses, PSA post-prostatectomy, and chemotherapy impacted on OS. PSA (post-surgery and at recurrence) affected progression-free survival (PFS) in the univariate analysis. In the multivariate analysis, GS, the number of relapse sites, and PSA (post-surgery and at recurrence) were significant prognostic factors for disease-free survival (DFS). Conclusion: Choline PET/CT provides better accuracy than conventional imaging for the assessment of nmPCa with BR after prostatectomy, thereby enabling salvage strategies and improving quality of life.

Hypoxia-Inducible Factor Stabilizers in End Stage Kidney Disease: "Can the Promise Be Kept?"

Anemia is a common complication of chronic kidney disease (CKD). The prevalence of anemia in CKD strongly increases as the estimated Glomerular Filtration Rate (eGFR) decreases. The pathophysiology of anemia in CKD is complex. The main causes are erythropoietin (EPO) deficiency and functional iron deficiency (FID). The administration of injectable preparations of recombinant erythropoiesis-stimulating agents (ESAs), especially epoetin and darbepoetin, coupled with oral or intravenous(iv) iron supplementation, is the current treatment for anemia in CKD for both dialysis and non-dialysis patients. This approach reduces patients' dependence on transfusion, ensuring the achievement of optimal hemoglobin target levels. However, there is still no evidence that treating anemia with ESAs can significantly reduce the risk of cardiovascular events. Meanwhile, iv iron supplementation causes an increased risk of allergic reactions, gastrointestinal side effects, infection, and cardiovascular events. Currently, there are no studies defining the best strategy for using ESAs to minimize possible risks. One class of agents under evaluation, known as prolyl hydroxylase inhibitors (PHIs), acts to stabilize hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylase (PH) enzymes. Several randomized controlled trials showed that HIF-PHIs are almost comparable to ESAs. In the era of personalized medicine, it is possible to envisage and investigate specific contexts of the application of HIF stabilizers based on the individual risk profile and mechanism of action.

Switch from enzyme replacement therapy to oral chaperone migalastat for treating fabry disease: real-life data.

The treatment options for Fabry disease (FD) are enzyme replacement therapy (ERT) with agalsidase alfa or beta, and the oral pharmacological chaperone migalastat. Since few data are available on the effects of switching from ERT to migalastat, we performed a single-center observational study on seven male Fabry patients (18-66 years) to assess the effects of the switch on renal, cardiac, and neurologic function, health status, pain, lyso-Gb3, α-Gal A activity and adverse effects. Data were retrospectively collected at time of diagnosis of FD (baseline, T0), and after 12 months of ERT (T1), and prospectively after 1 year of therapy with migalastat (T2). No patient died or reported renal, cardiac, or cerebrovascular events during the study period. The predefined measures for cardiac, renal and neurologic function, and FD-related symptoms and questionnaires were stable between baseline and the switch, and remained unchanged with migalastat. However, a significant improvement was observed in left ventricular mass index from baseline to T2 (p = 0.016), with a significative difference between the treatments (p = 0.028), and in median proteinuria from T2 vs T1 (p = 0.048). Moreover, scores of the BPI improved from baseline to T1, and remained stable with migalastat. Plasma lyso-Gb3 levels significantly decreased from baseline to T1 (P = 0.007) and T2 (P = 0.003), while did not significantly differ between the two treatments. α-Gal A activity increased from T0 to T2 (p < 0.0001). The frequency of adverse effects under migalastat and ERT was comparable (28% for both drugs). In conclusion, switching from ERT to migalastat is valid, safe and well tolerated.

Noninvasive molecular analysis of Helicobacter pylori: Is it time for tailored first-line therapy?

The main problem of Helicobacter pylori (H. pylori) infection management is linked to antibiotic resistances. This phenomenon has grown in the last decade, inducing a dramatic decline in conventional regimen effectiveness. The causes of resistance are point mutations in bacterial DNA, which interfere with antibiotic mechanism of action, especially clarithromycin and levofloxacin. Therefore, international guidelines have recently discouraged their use in areas with a relevant resistance percentage, suggesting first-line schedules with expected high eradication rates, i.e., bismuth containing or non-bismuth quadruple therapies. These regimens require the daily assumption of a large number of tablets. Consequently, a complete adherence is expected only in subjects who may be motivated by the presence of major disorders. However, an incomplete adherence to antibiotic therapies may lead to resistance onset, since sub-inhibitory concentrations could stimulate the selection of resistant mutants. Of note, a recent meta-analysis suggests that susceptibility tests may be more useful for the choice of first than second-line or rescue treatment. Additionally, susceptibility guided therapy has been demonstrated to be highly effective and superior to empiric treatments by both meta-analyses and recent clinical studies. Conventional susceptibility test is represented by culture and antibiogram. However, the method is not available everywhere mainly for methodology-related factors and fails to detect hetero-resistances. Polymerase chain reaction (PCR)-based, culture-free techniques on gastric biopsy samples are accurate in finding even minimal traces of genotypic resistant strains and hetero-resistant status by the identification of specific point mutations. The need for an invasive endoscopic procedure has been the most important limit to their spread. A further step has, moreover, been the detection of point mutations in bacterial DNA fecal samples. Few studies on clarithromycin susceptibility have shown an overall high sensitivity and specificity when compared with culture or PCR on gastric biopsies. On these bases, two commercial tests are now available although they have shown some controversial findings. A novel PCR method showed a full concordance between tissue and stool results in a preliminary experience. In conclusion, despite poor validation, there is increasing evidence of a potential availability of noninvasive investigations able to detect H. pylori resistances to antibiotics. These kinds of analysis are currently at a very early phase of development and caution should be paid about their clinical application. Only further studies aimed to evaluate their sensitivity and specificity will afford novel data for solid considerations. Nevertheless, noninvasive molecular tests may improve patient compliance, time/cost of infection management and therapeutic outcome. Moreover, the potential risk of a future increase of resistance to quadruple regimens as a consequence of their use on large scale and incomplete patient adherence could be avoided.

Mild cerebello-thalamo-cortical impairment in patients with normal dopaminergic scans (SWEDD).

INTRODUCTION: Patients with Scans-Without-Evidence-of-Dopaminergic-Deficit (SWEDD) often present asymmetric rest tremor not responsive to levodopa. Although a dystonic origin of this tremor has been proposed, the underlying pathophysiology of such condition is still unclear. An abnormal activity in the Cerebello-Thalamo-Cortical circuit is involved in the pathogenesis of tremor and other movement disorders. Here we used different paradigms of cerebellar transcranial magnetic stimulation to evaluate the Cerebello-Thalamo-Cortical functioning in patients with normal scans. METHODS: Cerebello-Thalamo-Cortical circuit was investigated in 12 patients with normal scans, 8 patients with Parkinson's Disease (PD), 8 patients with adult-onset isolated dystonia and 9 healthy controls. We studied the effects of a single cerebellar magnetic pulse over the excitability of the contralateral primary motor cortex tested with Motor-Evoked-Potentials (Cerebellar-Inhibition) both at rest and during arm extension. Furthermore, we also tested the effects of cerebellar continuous-Theta-Burst-Stimulation on Motor-Evoked-Potentials amplitude. RESULTS: patients with normal scans compared to controls show a deficient Cerebellar-Inhibition at rest but not in arm extension; in both conditions they differ from PD but not from dystonic patients. Cerebellar Continuous-Theta-Burst-Stimulation induced the expected long-lasting cortical inhibition of Motor-Evoked-Potentials amplitude in patients with normal scans differently from PD and dystonic patients. CONCLUSIONS: patients with normal scans show a mild impairment in Cerebello-Thalamo-Cortical circuit that emerges only at rest. Such neurophysiological phenotype differs from the one observed in PD and dystonic patients, suggesting a distinct involvement of this pathway in the pathophysiology of these disorders.

Management of CKD-MBD in non-dialysis patients under regular nephrology care: a prospective multicenter study.

BACKGROUND: Knowledge about mineral bone disorder (MBD) management in non-dialysis chronic kidney disease (ND-CKD) patients is scarce, although essential to identifying areas for therapeutic improvement. METHODS: We prospectively evaluated current management of CKD-MBD in two visits, performed 6 months apart, in 727 prevalent ND-CKD stage 3b-5 patients from 19 nephrology clinics. Therapeutic inertia was defined as lack of treatment despite hyperphosphatemia and/or hypocalcemia, and/or hyperparathyroidism. The primary endpoint was the prevalence of achieved target for CKD-MBD parameters and related treatments (phosphate binders, vitamin D and calcium supplements). The secondary endpoint was the assessment of prevalence and clinical correlates of therapeutic inertia. RESULTS: Over 65 % of patients did not reach parathormone (PTH) targets, while 15 and 19 % did not reach phosphate and calcium targets, respectively. The proportion of untreated patients decreased from stage 3b to 5 (at baseline, from 60 to 16 %, respectively). From baseline to the 6-month visit, the achievement of targets remained stable. Low protein diet was prescribed in 26 % of patients, phosphate binders in 17.3 % (calcium-based binders 15.5 %, aluminium binders 1.8 %), and vitamin D in 50.5 %. The overall prevalence of therapeutic inertia at the 6-month visit was 34.0 % (for hyperphosphatemia, 54.3 %). Compared to CKD stage 3, the likelihood of therapeutic inertia was 40 and 68 % lower at stage 4 and 5, respectively. CONCLUSIONS: PTH, calcium and phosphate targets were not reached in a significant proportion of patients. One-third of patients with at least one MBD parameter not-at-target remained untreated. Therapeutic inertia regarding CKD-MBD treatment may be a major barrier to optimizing the prevention and cure of CKD-MBD.

Optogenetic stimulation reveals distinct modulatory properties of thalamostriatal vs corticostriatal glutamatergic inputs to fast-spiking interneurons.

Parvalbumin-containing fast-spiking interneurons (FSIs) exert a powerful feed-forward GABAergic inhibition on striatal medium spiny neurons (MSNs), playing a critical role in timing striatal output. However, how glutamatergic inputs modulate their firing activity is still unexplored. Here, by means of a combined optogenetic and electrophysiological approach, we provide evidence for a differential modulation of cortico- vs thalamo-striatal synaptic inputs to FSIs in transgenic mice carrying light-gated ion channels channelrhodopsin-2 (ChR2) in glutamatergic fibers. Corticostriatal synapses show a postsynaptic facilitation, whereas thalamostriatal synapses present a postsynaptic depression. Moreover, thalamostriatal synapses exhibit more prominent AMPA-mediated currents than corticostriatal synapses, and an increased release probability. Furthermore, during current-evoked firing activity, simultaneous corticostriatal stimulation increases bursting activity. Conversely, thalamostriatal fiber activation shifts the canonical burst-pause activity to a more prolonged, regular firing pattern. However, this change in firing pattern was accompanied by a significant rise in the frequency of membrane potential oscillations. Notably, the responses to thalamic stimulation were fully abolished by blocking metabotropic glutamate 1 (mGlu1) receptor subtype, whereas both acetylcholine and dopamine receptor antagonists were ineffective. Our findings demonstrate that cortical and thalamic glutamatergic input differently modulate FSIs firing activity through specific intrinsic and synaptic properties, exerting a powerful influence on striatal outputs.

Reversal of radiocontrast medium toxicity in human renal proximal tubular cells by white grape juice extract.

Radiocontrast media (RCM)-induced nephrotoxicity (CIN) is a major clinical problem accounting for 12% of all hospital-acquired cases of acute kidney injury. The pathophysiology of CIN is not well understood, but direct toxic effects on renal cells have been postulated as contributing to CIN. We have investigated the effect of a white grape (Vitis vinifera) juice extract (WGJe) on human renal proximal tubular (HK-2) cells treated with the radiocontrast medium (RCM) sodium diatrizoate. WGJe caused an increase in phosphorylation of the prosurvival kinases Akt and ERK1/2 in HK-2 cells. Treatment of HK-2 cells with 75 mgI/ml sodium diatrizoate for 2.5h and then further incubation (for 27.5h) after removal of the RCM caused a drastic decrease in cell viability. However, pre-treatment with WGJe, prior to incubation with diatrizoate, dramatically improved cell viability. Analysis of key signaling molecules by Western blotting showed that diatrizoate caused a drastic decrease in phosphorylation of Akt (Ser473), FOXO1 (Thr24) and FOXO3a (Thr32) during the initial 2.5h incubation period, and WGJe pre-treatment caused a reversal of these effects. Further analysis by Western blotting of samples from HK-2 cells cultured for longer periods of time (for up to 27.5h after an initial 2.5h exposure to diatrizoate with or without WGJe pre-treatment) showed that WGJe pre-treatment caused a negative effect on phosphorylation of p38, NF-κB (Ser276) and pERK1/2 whilst having a positive effect on the phosphorylation of Akt, FOXO1/FOXO3a and maintained levels of Pim-1 kinase. WGJe may alleviate RCM toxicity through modulation of signaling molecules that are known to be involved in cell death and cell survival and its possible beneficial effects should be further investigated.

Nutritional treatment in chronic kidney disease: the concept of nephroprotection.

Low-protein diets have been advocated for many decades as the cornerstone in the treatment of chronic kidney disease. Initially, the low intake of protein was used to reduce uremic symptoms; thereafter, albeit controversial, evidences suggested that dietary protein restriction can also slow the rate of progression of renal failure and the time until end-stage renal disease. This reviews focuses on the dietary factors and their influence on the loss of renal function and on the evidences in the literature supporting a nephroprotective role of the low-protein diet.

Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: role of M1 muscarinic receptors.

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.

Effects of two weeks of cerebellar theta burst stimulation in cervical dystonia patients.

Dystonia is generally regarded as a disorder of the basal ganglia and their efferent connections to the thalamus and brainstem, but an important role of cerebellar-thalamo-cortical (CTC) circuits in the pathophysiology of dystonia has been invoked. Here in a sham controlled trial, we tested the effects of two-weeks of cerebellar continuous theta burst stimulation (cTBS) in a sample of cervical dystonia (CD) patients. Clinical evaluations were performed by administering the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). We used TMS to measure the inhibitory connectivity between the cerebellum and the contralateral motor cortex (cerebellar brain inhibition [CBI]), and the excitability of the contralateral primary motor cortex assessing intracortical inhibition (SICI), intracortical facilitation (ICF) and cortical silent period (CSP). Paired associative stimulation (PAS) was tested to evaluate the level and the topographical specificity of cortical plasticity, which is abnormally enhanced and non-focal in CD patients. Two weeks of cerebellar stimulation resulted in a small but significant clinical improvement as measured by the TWSTRS of approximately 15%. Cerebellar stimulation modified the CBI circuits and reduced the heterotopic PAS potentiation, leading to a normal pattern of topographic specific induced plasticity. These data provide novel evidence CTC circuits could be a potential target to partially control some dystonic symptoms in patients with cervical dystonia.

Engineering animal models of dystonia.

Dystonia is a neurological disorder characterized by abnormal involuntary movements that are prolonged and often cause twisting and turning. Several genetically modified worms, fruit flies, and rodents have been generated as models of genetic dystonias, in particular DYT1, DYT11, and DYT12 dystonias. Although these models do not show overt dystonic symptoms, the rodent models exhibit motor deficits in specialized behavioral tasks, such as the rotarod and beam-walking tests. For example, in a rodent model of DYT12 dystonia, which is generally stress triggered, motor deficits are observed only after the animal is stressed. Moreover, in a rodent model of DYT1 dystonia, the motor and electrophysiological deficits can be rescued by trihexyphenidyl, a common anticholinergic medication used to treat dystonic symptoms in human patients. Biochemically, the DYT1 and DYT11 animal models also share some similarities to patients, such as a reduction in striatal D2 dopamine receptor and binding activities. In addition, conditional knockout mouse models for DYT1 and DYT11 dystonia demonstrate that loss of the causal dystonia-related proteins in the striatum leads to motor deficits. Interestingly, loss of the DYT1 dystonia causal protein in Purkinje cells shows an improvement in motor performance, suggesting that gene therapy targeting of the cerebellum or intervention in its downstream pathways may be useful. Finally, recent studies using DYT1 dystonia worm and mouse models led to a potential novel therapeutic agent, which is currently undergoing clinical trials. These results indicate that genetic animal models are powerful tools to elucidate the pathophysiology and to further develop new therapeutics for dystonia.

Phytoestrogens/insoluble fibers and colonic estrogen receptor ß: randomized, double-blind, placebo-controlled study.

AIM: To assess the safety and effect of the supplementation of a patented blend of dietary phytoestrogens and insoluble fibers on estrogen receptor (ER)-ß and biological parameters in sporadic colonic adenomas. METHODS: A randomized, double-blind placebo-controlled trial was performed. Patients scheduled to undergo surveillance colonoscopy for previous sporadic colonic adenomas were identified, and 60 eligible patients were randomized to placebo or active dietary intervention (ADI) twice a day, for 60 d before surveillance colonoscopy. ADI was a mixture of 175 mg milk thistle extract, 20 mg secoisolariciresinol and 750 mg oat fiber extract. ER-ß and ER-α expression, apoptosis and proliferation (Ki-67 LI) were assessed in colon samples. RESULTS: No adverse event related to ADI was recorded. ADI administration showed a significant increases in ER-ß protein (0.822 ± 0.08 vs 0.768 ± 0.10, P = 0.04) and a general trend to an increase in ER-ß LI (39.222 ± 2.69 vs 37.708 ± 5.31, P = 0.06), ER-ß/ER-α LI ratio (6.564 ± 10.04 vs 2.437 ± 1.53, P = 0.06), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (35.592 ± 14.97 vs 31.541 ± 11.54, P = 0.07) and Ki-67 (53.923 ± 20.91 vs 44.833 ± 10.38, P = 0.07) approximating statistical significance. A significant increase of ER-ß protein (0.805 ± 0.13 vs 0.773 ± 0.13, P = 0.04), mRNA (2.278 ± 1.19 vs 1.105 ± 1.07, P < 0.02) and LI (47.533 ± 15.47 vs 34.875 ± 16.67, P < 0.05) and a decrease of ER-α protein (0.423 ± 0.06 vs 0.532 ± 0.11, P < 0.02) as well as a trend to increase of ER-ß/ER-α protein in ADI vs placebo group were observed in patients without polyps (1.734 ± 0.20 vs 1.571 ± 0.42, P = 0.07). CONCLUSION: The role of ER-ß on the control of apoptosis, and its amenability to dietary intervention, are supported in our study.

[Liposomial iron: a new proposal for the treatment of anaemia in chronic kidney disease]. / Il ferro liposomiale: una nuova proposta per il trattamento dell'anemia nei pazienti affetti da insufficenza renale cronica.

Iron supplementation is essential for the treatment of anemia in the chronic kidney disease (CKD) population. Liposomial iron is a preparation of ferric pyrophosphate carried within a phospholipidic membrane. Compared to other oral formulations, it is well absorbed from the gut and demonstrates high bioavailability together with a lower incidence of side effects. The aim of our study was to evaluate the effectiveness of treatment with liposomial iron compared to intravenous iron in a CKD population with anemia and iron deficiency. Our study is a single-center, prospective, randomized, fourth-phase study. Enrollment for the study began in October 2011 and CKD 3, 4 and 5 patients were randomized to receive either intravenous iron or liposomial iron in a 1:2 ratio. The primary outcome was set as the increase of hemoglobin from baseline. The secondary outcomes were the reduction of erythropoietin dosage by at least 25% in patients treated with erythropoiesis-stimulating agents and an increase in serum ferritin of 100 ng/ml from baseline values. In the preliminary study, 21 patients were analyzed, 14 of whom were treated with oral liposomial iron and 7 with intravenous iron. The observed increase of hemoglobin at 8 weeks compared to baseline was similar in both groups but was significant in the liposomial group only.

Cholinergic dysfunction alters synaptic integration between thalamostriatal and corticostriatal inputs in DYT1 dystonia.

Projections from thalamic intralaminar nuclei convey sensory signals to striatal cholinergic interneurons. These neurons respond with a pause in their pacemaking activity, enabling synaptic integration with cortical inputs to medium spiny neurons (MSNs), thus playing a crucial role in motor function. In mice with the DYT1 dystonia mutation, stimulation of thalamostriatal axons, mimicking a response to salient events, evoked a shortened pause and triggered an abnormal spiking activity in interneurons. This altered pattern caused a significant rearrangement of the temporal sequence of synaptic activity mediated by M(1) and M(2) muscarinic receptors in MSNs, consisting of an increase in postsynaptic currents and a decrease of presynaptic inhibition, respectively. Consistent with a major role of acetylcholine, either lowering cholinergic tone or antagonizing postsynaptic M(1) muscarinic receptors normalized synaptic activity. Our data demonstrate an abnormal time window for synaptic integration between thalamostriatal and corticostriatal inputs, which might alter the action selection process, thereby predisposing DYT1 gene mutation carriers to develop dystonic movements.

NR2B subunit exerts a critical role in postischemic synaptic plasticity.

BACKGROUND AND PURPOSE: We characterized the differential effect of the NR2B subunit antagonist ifenprodil in the induction of activity-dependent long-term potentiation (LTP) and of postischemic LTP as well as in the neuronal damage induced by focal ischemia. METHODS: Intracellular recordings were obtained from rat corticostriatal slice preparations. High-frequency stimulation of corticostriatal fibers was used as a LTP-inducing protocol. In vitro ischemia was induced by oxygen and glucose deprivation. In vivo ischemia was induced by permanent middle cerebral artery occlusion. Intracellular recordings were also performed in the ischemic penumbra. RESULTS: Antagonists selectively targeting N-methyl-d-aspartate receptors containing the NR2B subunit blocked postischemic LTP without affecting activity-dependent LTP. In a model of focal ischemia, blockade of NR2B subunit in vivo caused reduction of brain damage, amelioration of neurological outcome, and normalization of the synaptic levels of NR2B subunits. Moreover, the antagonism of NR2B subunit was able to rescue the activity-dependent LTP in the ischemic penumbra. CONCLUSIONS: We suggest that NR2B subunits contribute to the striatal damage caused by in vivo and in vitro ischemia and play a critical role in the induction of postischemic LTP as well as in the suppression of activity-dependent LTP in the ischemic penumbra.

Inhibition of persistent sodium current fraction and voltage-gated L-type calcium current by propofol in cortical neurons: implications for its antiepileptic activity.

PURPOSE: Although it is widely used in clinical practice, the mechanisms of action of 2,6-di-isopropylphenol (propofol) are not completely understood. We examined the electrophysiologic effects of propofol on an in vitro model of epileptic activity obtained from a slice preparation. METHODS: The effects of propofol were tested both on membrane properties and on epileptiform events consisting of long-lasting, paroxysmal depolarization shifts (PDSs) induced by reducing the magnesium concentration from the solution and by adding bicuculline and 4-aminopyridine. These results were integrated with a patch-clamp analysis of Na(+) and high-voltage activated (HVA) calcium (Ca(2+)) currents from isolated cortical neurons. RESULTS: In bicuculline, to avoid any interference by gamma-aminobutyric acid (GABA)-A receptors, propofol (3-100 microM) did not cause significant changes in the current-evoked, sodium (Na(+))-dependent action-potential discharge. However, propofol reduced both the duration and the number of spikes of PDSs recorded from cortical neurons. Interestingly, relatively low concentrations of propofol [half-maximal inhibitory concentration (IC(50)), 3.9 microM) consistently inhibited the "persistent" fraction of Na(+) currents, whereas even high doses (< or =300 microM) had negligible effects on the "fast" component of Na(+) currents. HVA Ca(2+) currents were significantly reduced by propofol, and the pharmacologic analysis of this effect showed that propofol selectively reduced L-type HVA Ca(2+) currents, without affecting N or P/Q-type channels. CONCLUSIONS: These results suggest that propofol modulates neuronal excitability by selectively suppressing persistent Na(+) currents and L-type HVA Ca(2+) conductances in cortical neurons. These effects might cooperate with the opening of GABA-A-gated chloride channels, to achieve depression of cortical activity during both anesthesia and status epilepticus.