Corrigendum: Blocking soluble Fas Ligand ameliorates pemphigus: PC111 efficacy in ex-vivo human pemphigus models.

[This corrects the article DOI: 10.3389/fimmu.2023.1193032.].

Comprehensive dosimetric characterization of novel silicon carbide detectors with UHDR electron beams for FLASH radiotherapy.

BACKGROUND: The extremely fast delivery of doses with ultra high dose rate (UHDR) beams necessitates the investigation of novel approaches for real-time dosimetry and beam monitoring. This aspect is fundamental in the perspective of the clinical application of FLASH radiotherapy (FLASH-RT), as conventional dosimeters tend to saturate at such extreme dose rates. PURPOSE: This study aims to experimentally characterize newly developed silicon carbide (SiC) detectors of various active volumes at UHDRs and systematically assesses their response to establish their suitability for dosimetry in FLASH-RT. METHODS: SiC PiN junction detectors, recently realized and provided by STLab company, with different active areas (ranging from 4.5 to 10 mm2) and thicknesses (10-20 µm), were irradiated using 9 MeV UHDR pulsed electron beams accelerated by the ElectronFLASH linac at the Centro Pisano for FLASH Radiotherapy (CPFR). The linearity of the SiC response as a function of the delivered dose per pulse (DPP), which in turn corresponds to a specific instantaneous dose rate, was studied under various experimental conditions by measuring the produced charge within the SiC active layer with an electrometer. Due to the extremely high peak currents, an external customized electronic RC circuit was built and used in conjunction with the electrometer to avoid saturation. RESULTS: The study revealed a linear response for the different SiC detectors employed up to 21 Gy/pulse for SiC detectors with 4.5 mm2/10 µm active area and thickness. These values correspond to a maximum instantaneous dose rate of 5.5 MGy/s and are indicative of the maximum achievable monitored DPP and instantaneous dose rate of the linac used during the measurements. CONCLUSIONS: The results clearly demonstrate that the developed devices exhibit a dose-rate independent response even under extreme instantaneous dose rates and dose per pulse values. A systematic study of the SiC response was also performed as a function of the applied voltage bias, demonstrating the reliability of these dosimeters with UHDR also without any applied voltage. This demonstrates the great potential of SiC detectors for accurate dosimetry in the context of FLASH-RT.

A systematic review and meta-analysis of propionyl-L-carnitine effects on exercise performance in patients with claudication.

Propionyl-L-carnitine (PLC) may improve exercise performance in patients with peripheral artery disease, but results from clinical trials have been inconsistent. The safety and efficacy of PLC for treatment of claudication was evaluated by a systematic review and meta-analysis of clinical trials for which data were available through September 2010. Eighty-five studies were identified, of which 13 were randomized controlled trials. Owing to database availability for the six phase III studies carried out with PLC (1 g orally, twice daily), a patient-level meta-analysis was conducted as the primary analysis. Treadmill performance data from these six studies were harmonized to peak walking distance (PWD) on a 7% grade at a speed of 3 km/hour. PLC (n = 440) was associated with a net 16 meter improvement (95% CI, 8-20 meters) in PWD as compared with placebo (n = 427) in the primary analysis (p = 0.002). The effect of PLC was similar in subpopulations defined using clinical and demographic variables, with possible enhanced benefit in patients engaged in an exercise program or enrolled at study sites in Russia. The systematic review of the effect of PLCs on claudication identified seven additional randomized controlled trials for a total of 13 trials, which included 681 patients on placebo and 672 on PLC. This meta-analysis confirmed a 45 meter net improvement on PLC using a random-effects model. In conclusion, oral PLC is associated with a statistically significant increase in PWD in patients with claudication, which may be clinically relevant.

Blocking soluble Fas Ligand ameliorates pemphigus: PC111 efficacy in ex-vivo human pemphigus models.

Pemphigus is a life-threatening, chronic, autoimmune bullous disease affecting both the skin and the mucous membranes. Based on the mainstream concept that blister formation occurs upon binding of autoantibodies to their antigen proteins (desmoglein1, DSG1 and desmoglein3, DSG3), current therapies mostly aim to suppress the immune system. To avoid the severe side effects associated with the chronic use of immunosuppressive treatments, we have developed PC111, a fully human monoclonal antibody targeting human Fas ligand (FasL). We have provided a number of in vitro and in vivo evidences showing that soluble FasL induces keratinocyte apoptosis followed by acantholysis. An anti-murine FasL prevents blister formation in the pemphigus neonatal mouse model. To confirm the mechanism of action (MoA) and the efficacy of PC111 in a human pemphigus context, we used the keratinocyte dissociation assay and two independent Human Skin Organ Cultures (HSOC) pemphigus models. PC111 reduced acantholysis in vitro, as shown by the dose-dependent reduction of fragments in the monolayer cultures. In the first HSOC model, normal human skin was subcutaneously injected with a scFv antibody fragment directed against DSG1 and DSG3, resulting in a severe acantholysis (70-100%) after 24 hours. PC111 inhibited blister formation to around 50% of control. In the second model, normal human skin was injected with a mixture of pemphigus patients' autoantibodies resulting in a less severe acantholysis (20-30%). PC111 significantly suppressed blister formation to more than 75% up to 72 hours. These results confirm PC111 MoA and demonstrates the efficacy of the anti-FasL antibody also in a pemphigus setting.

A Novel Injectable Hydrogel Matrix Loaded With 90Y Microspheres for the Treatment of Solid Tumors.

BACKGROUND/AIM: The need to concentrate the anti-tumoral activity of 90Y only to the targeted tumor, while minimizing its off-target effects, led to the development of an innovative device (BAT-90) composed of a hydrogel matrix and 90Y microspheres. MATERIALS AND METHODS: This in vivo randomized study was planned to assess the efficacy, safety, and biodistribution of BAT-90 in 46 rabbits implanted with a VX2 tumor. The effects of BAT-90 were compared to those of 90Y microspheres and the hydrogel matrix. RESULTS: BAT-90 localized effectively the 90Y radiation in the injection site, minimizing dispersion of the microspheres in the target and distant organs of the treated animals. CONCLUSION: BAT-90 can be administered as an adjuvant treatment to clear surgical margins from any potential minimal residual disease, or as an alternative to other loco-regional treatments for non-resectable tumors.

Modelling a new approach for radio-ablation after resection of breast ductal carcinoma in-situ based on the BAT-90 medical device.

The majority of local recurrences, after conservative surgery of breast cancer, occurs in the same anatomical area where the tumour was originally located. For the treatment of ductal carcinoma in situ (DCIS), a new medical device, named BAT-90, (BetaGlue Technologies SpA) has been proposed. BAT-90 is based on the administration of 90Y ß-emitting microspheres, embedded in a bio-compatible matrix. In this work, the Geant4 simulation toolkit is used to simulate BAT-90 as a homogenous cylindrical 90Y layer placed in the middle of a bulk material. The activity needed to deliver a 20 Gy isodose at a given distance z from the BAT-90 layer is calculated for different device thicknesses, tumour bed sizes and for water and adipose bulk materials. A radiobiological analysis has been performed using both the Poisson and logistic Tumour Control Probability (TCP) models. A range of radiobiological parameters (α and ß), target sizes, and densities of tumour cells were considered. Increasing α values, TCP increases too, while, for a fixed α value, TCP decreases as a function of clonogenic cell density. The models predict very solid results in case of limited tumour burden while the activity/dose ratio could be further optimized in case of larger tumour beds.

In Vivo Models for the Performance and Safety of BAT-90, a Novel 90-Yttrium-based Internal Radiotherapy Platform.

BACKGROUND/AIM: BAT-90 is an innovative active implantable device designed for the irradiation of unresectable tumors (e.g., liver cancer) or surgical tumor beds, based on the combination of Yttrium-90 beta-emitting microspheres and a tissue adhesive hydrogel, currently used in cardio-vascular surgery. The rationale behind BAT-90 is to localize the Yttrium-90 activity on the administration site, while minimizing its body dispersion. MATERIALS AND METHODS: The effective induction of necrosis in the target injection area was tested in a pig liver model, whereas the safety of BAT-90 was assessed and demonstrated in biocompatibility tests for acute systemic toxicity, intracutaneous reactivity, delayed hypersensitivity and subcutaneous implantation. RESULTS: BAT-90 administration induced necrosis into the target site, while the safety experiments in the treated animals highlighted results very similar to the controls. CONCLUSION: BAT-90 could be considered as a safe and innovative treatment option for inoperable solid tumors of the liver.

Pilot clinical study on the prevention of complications after lung biopsy by the MIPP kit PNX device.

Background: Pneumothorax (PNX), pulmonary hemorrhage, hemothorax and chest wall hematoma are the most commonly reported complications of percutaneous lung biopsy (PLB). Sealing the biopsy tract with different types of materials is an emerging way to prevent PLB complications. Methods: To investigate the safety and efficacy of a new device, Minimally Invasive Percutaneous Procedure Kit for Pneumothorax (MIPP-Kit PNX), when used in association with a resorbable bio-compatible glue in the prevention of PLB complications. A prospective, multicenter, open-label, single-arm study was performed to evaluate the complication rate after glue administration by the new investigational device during PLBs. Results: Fourty-three patients were enrolled after informed consent signature (40 underwent PLB, while three were screening failures). Only 3 patients (7.5%, 95% CI: 0.0-15.7%) developed complications within 48 h after glue injection during PLB: two developed minor pneumothoraces and one a pulmonary hemorrhage. No patients who showed procedural complications before glue administration were reported with any recurrent or new complications after glue administration. Conclusions: In comparison with the data reported in the literature, this trial results support the safe and effective use of the MIPP kit PNX in the prevention of PLB complications. These promising preliminary results warrant further confirmation in larger clinical trials. Trial Registration: ClinicalTrials.gov identifier: NCT04071509.

Automated Detection of Exercise Sessions in Patients With Peripheral Artery Disease: EVIDENCE FOR AN EXERCISE DOSE RESPONSE TO TRAINING.

PURPOSE: Monitoring home exercise using accelerometry in patients with peripheral artery disease (PAD) may provide a tool to improve adherence and titration of the exercise prescription. However, methods for unbiased analysis of accelerometer data are lacking. The aim of the current post hoc analysis was to develop an automated method to analyze accelerometry output collected during home-based exercise. METHODS: Data were obtained from 54 patients with PAD enrolled in a clinical trial that included a home-based exercise intervention using diaries and an accelerometer. Peak walking time was assessed on a graded treadmill at baseline and 6 mo. In 35 randomly selected patient data sets, visual inspection of accelerometer output confirmed exercise sessions throughout the 6 mo. An algorithm was developed to detect exercise sessions and then compared with visual inspection of sessions to mitigate the heterogeneity in session intensity across the population. Identified exercise sessions were characterized on the basis of total step count and activity duration. The methodology was then applied to data sets for all 54 patients. RESULTS: The ability of the algorithm to detect exercise sessions compared with visual inspection of the accelerometer output resulted in a sensitivity of 85% and specificity of 90%. Algorithm-detected exercise sessions (total) and intensity (steps/wk) were correlated with change in peak walking time (r = 0.28; r = 0.43). CONCLUSIONS: An algorithm to assess data from an accelerometer successfully detected home-based exercise sessions. Algorithm-identified exercise sessions were correlated with improvements in performance after 6 mo of training in patients with PAD, supporting the effectiveness of monitored home-based exercise.

Phase I and pharmacokinetic study of gimatecan given orally once a week for 3 of 4 weeks in patients with advanced solid tumors.

PURPOSE: A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of gimatecan, a lipophilic camptothecin analogue, administered orally once a week for 3 weeks. EXPERIMENTAL DESIGN: Adult patients with advanced solid tumors with good performance status and adequate hematologic, hepatic, and renal function were eligible for the study. The plasma pharmacokinetics of the drug was characterized during the initial 28-day cycle. RESULTS: A total of 33 patients were evaluated at 7 dose levels ranging from 0.27 to 3.20 mg/m(2)/wk. Anemia, fatigue, neutropenia, nausea, and vomiting were the principal toxicities. DLTs experienced by 3 of 7 patients in dose level 7 (3.20 mg/m(2)) were grade 2 hyperbilirubinemia and grade 3 to 4 fatigue. DLT (anorexia and nausea) occurred in only 1 of 11 patients evaluated at the MTD of 2.40 mg/m(2). There were no objective responses, although disease stabilization was observed in 4 patients. Gimatecan has a very long apparent biological half-life (mean +/- SD, 77 +/- 37 h) and exists in plasma almost entirely as the pharmacologically active intact lactone form. At the MTD, mean peak concentrations of the drug in plasma ranged from 67 to 82 ng/mL for the 3 weekly doses and the mean concentration 7 days after dosing was 15 +/- 18 ng/mL. CONCLUSIONS: Administration of gimatecan orally once a week at doses that are well tolerated provides continuous exposure to potentially effective plasma concentrations of the biologically active form of the drug. This regimen deserves further evaluation to define its antitumor activity in specific tumor types either alone or in combination with other agents.

Valorization of clinical trials from the Italian National Health Service perspective: definition and first application of a model to estimate avoided costs.

Introduction: From the perspective of healthcare organizations and public health care systems, the value of a clinical trial can be assessed from a clinical and economical perspective. However, to date, there is no standardized model for systematically capturing the economic value of clinical trials at organizational and system levels. The aim of this study was to develop and test a methodology for estimating the avoided costs deriving from the management of patients as part of a clinical trial. Methods: Our methodology is based on the assumption that the economic value of a clinical trial derives from 1) the funding received by the experimental site from a trial's sponsor, and from 2) the cost avoided by the experimental site with the treatment of patients within a study and not according to standard care by the experimental site. Results: By applying the methodology to onco-hematological clinical trials conducted in two academic hospitals from 2011 to 2016, we demonstrate that savings between 2 million and 4 million euros were achieved over a five-year period. Thus, for every 1,000 euros invested by the pharmaceutical company into the clinical studies conducted at these hospitals, the hospitals saved on average 2,200 euros due to costs not incurred as a result of the trials. Conclusions: The study has proposed and tested a methodology for estimating the economic value of clinical trials by taking into account avoided costs deriving from the treatment of patients enrolled in sponsored trials. The study has proposed a management tool for healthcare institutions to govern clinical trials.

Carnitine in metabolic disease: potential for pharmacological intervention.

L-carnitine (LC) deficiency is commonly observed in chronic hemodialysis (HD) patients. As a result of this and other causes of secondary LC deficiencies, LC has been described as a "conditionally essential nutrient" or "conditional vitamin". Although a large number of clinical trials regarding the beneficial effects of LC administration in HD patients have been published, some controversy about its use in this indication persists. In this article, we will review the use of LC in dialysis patients, by focussing mainly on those experimental and clinical data supporting the notion that supra-physiological concentrations of LC in plasma and target organs may exert beneficial effects on several metabolic parameters that have derangements of a common origin (e.g. insulin resistance, type 2 diabetes, dyslipidemia) and which are frequently present in end-stage renal disease (ESRD) patients undergoing dialysis.

Hemodynamic properties of a new-generation positive luso-inotropic agent for the acute treatment of advanced heart failure.

Currently available positive inotropic agents, such as dobutamine and milrinone, although needed as "rescue therapy" for patients with acute decompensated heart failure (ADHF), are not ideal drugs because of an inherent adverse side-effect profile. This study examined the hemodynamic effects of istaroxime, a novel agent with positive inotropic and lusitropic (luso-intropic) effects, under investigation for the treatment of ADHF. Studies were performed in 7 dogs with advanced heart failure (HF). Each dog received intravenous istaroxime or saline solution in random order 1 week apart in equal volume/volume escalating doses, with each dose maintained for 1 hour. Escalating istaroxime doses of 0.5, 1.0, 2.0, 3.0, and 5.0 microg/kg per min were used. Hemodynamic, ventriculographic, and 2-dimensional echocardiographic and Doppler indices of left ventricular (LV) systolic and diastolic function were made at baseline and at the end of each hour of each dose of istaroxime or saline solution used. Electrocardiographic results were monitored throughout the study for development of de novo arrhythmias. Results showed that saline solution had no effect on any hemodynamic, ventriculographic, echocardiographic, or Doppler indices of LV function. Compared with baseline, istaroxime had no effect on heart rate, with only a modest reduction of mean aortic pressure at high doses. Istaroxime decreased LV end-diastolic and end-systolic volumes and significantly increased LV ejection fraction in a dose-dependent manner from 0.25+/-0.01 to 0.42+/-0.02 at the highest dose (p<0.05), without increasing myocardial oxygen consumption (194+/-21 micromol/min at baseline to 144+/-20 micromol/min at the highest dose, p<0.05). In addition, istaroxime significantly reduced LV end-diastolic pressure and end-diastolic wall stress and increased deceleration time of early mitral inflow velocity. None of the doses administered were associated with the development of de novo arrhythmias. In dogs with advanced HF, istaroxime elicits potent positive luso-intropic effects. Unlike classic cyclic adenosine monophospate-dependent positive inotropic agents, istaroxime elicits its benefits without increasing myocardial oxygen consumption or heart rate. These results suggest that istaroxime may be a unique positive luso-inotropic agent for the treatment of patients with ADHF.

A phase 1-2 dose-escalating study evaluating the safety and tolerability of istaroxime and specific effects on electrocardiographic and hemodynamic parameters in patients with chronic heart failure with reduced systolic function.

Istaroxime (PST2744) is a luso-inotrope that stimulates the sarcoplasmic reticulum calcium adenosine triphosphatase isoform 2a without chronotropic effects. Additionally, it has beneficial effects on myocardial energetics. This phase 1-2 clinical trial in patients with chronic stable heart failure (HF) is the first evaluation of istaroxime in humans. Three cohorts of 6 patients each were exposed to 4 sequentially increasing 1-hour infusions with a random placebo. Doses were 0.005-5.0 micro/kg per min. Safety and hemodynamics were evaluated by impedance cardiography, digital Holter recorder, and electrocardiography. Pharmacokinetic data were obtained for 1 hour during treatment and for 6 hours after dosing. The mean age was 53+/-7 years, and the mean left ventricular ejection fraction was 0.27+/-0.08. Impedance cardiography demonstrated enhanced contractility as measured by the acceleration index, left cardiac work index, cardiac index, and pulse pressure at doses>or=1 micro/kg per min, with evidence of activity at doses of 0.5 micro/kg per min. Istaroxime shortened QTc. After infusion, the hemodynamic effect rapidly dissipated over 1-2 hours. Istaroxime was pharmacologically active and well tolerated at doses up to 3.33 micro/kg per min. Side effects were related to gastrointestinal symptoms and injection site pain at higher doses, which dissipated within minutes after the infusion ended. Ventricular ectopy was not altered. This study suggests that istaroxime is potentially useful in the treatment of HF and may offer a unique treatment for systolic and/or diastolic dysfunction. Additional studies are under way to further define its utility in acute HF.

Acetyl-L-carnitine (ALC) in attention-deficit/hyperactivity disorder: a multi-site, placebo-controlled pilot trial.

OBJECTIVE: To determine whether acetyl-L-carnitine (ALC), a metabolite necessary for energy metabolism and essential fatty acid anabolism, might help attention-deficit/hyperactivity disorder (ADHD). Trials in Down's syndrome, migraine, and Alzheimer's disease showed benefit for attention. A preliminary trial in ADHD using L-carnitine reported significant benefit. METHOD: A multi-site 16-week pilot study randomized 112 children (83 boys, 29 girls) age 5-12 with systematically diagnosed ADHD to placebo or ALC in weight-based doses from 500 to 1500 mg b.i.d. The 2001 revisions of the Conners' parent and teacher scales (including DSM-IV ADHD symptoms) were administered at baseline, 8, 12, and 16 weeks. Analyses were ANOVA of change from baseline to 16 weeks with treatment, center, and treatment-by-center interaction as independent variables. RESULTS: The primary intent-to-treat analysis, of 9 DSM-IV teacher-rated inattentive symptoms, was not significant. However, secondary analyses were interesting. There was significant (p = 0.02) moderation by subtype: superiority of ALC over placebo in the inattentive type, with an opposite tendency in combined type. There was also a geographic effect (p = 0.047). Side effects were negligible; electrocardiograms, lab work, and physical exam unremarkable. CONCLUSION: ALC appears safe, but with no effect on the overall ADHD population (especially combined type). It deserves further exploration for possible benefit specifically in the inattentive type.

A harmonized and efficient clinical research environment would benefit patients and enhance European competitiveness. Commentary.

The forthcoming implementation of the European Clinical Trial Regulation (Regulation (EU) No. 536/2014), which is expected to facilitate the conduct of clinical trials across the European Union, will require National Authorities to create the best conditions for the implementation of the new Regulation through national guidelines, so that sponsors may reconsider Europe as a prime location for planning clinical trials. During a meeting titled "Innovation in Clinical Research", an expert panel discussed potential local advances fostering competitiveness of European clinical research with representatives of the pharmaceutical industry, patient organisations and Italian regulatory agency in view of the forthcoming implementation of (EU) No. 536/2014 on clinical trials of medicinal products. In this article we summarise the findings of the meeting, describe features characterising clinical research patterns and offer some suggestions on the possible involvement of all stakeholders in order to foster research innovation and allow the timely access to novel medicines for patients.

Effects of L-carnitine pretreatment in methamphetamine and 3-nitropropionic acid-induced neurotoxicity.

Adult, male Sprague-Dawley rats were injected with 3-ni-tropropionic acid (3-NPA) at 30 mg/kg or methamphetamine (METH) at 20 mg/kg alone or following pretreatment with L-cartnitine (LC) at 100 mg/kg. Rectal temperature was measured before and 4 h following treatment. Animals were sacrificed at 4 h posttreatment. Monoamine neurotransmitters, dopamine (DA) and serotonin (5-HT), and their metabolites were analyzed in the striatum using high-performance liquid chromatography method coupled with electrochemical detection (HPLC/ED). Transcripts of several genes related to DA metabolism were quantified using real time reverse transciption polymerase chain reaction (RT-PCR). Core temperature decreased significantly after 3-NPA acid and increased in METH-treated rats (P < 0.05). Temperature change at 4 h exhibited a significant LC effect for 3-NPA, preventing hypothermia (P < 0.05) and no effect for METH. Concentration of DA and 5-HT, and their metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), increased significantly in 3-NPA and decreased in METH-treated rats. An increase in DOPAC/DA turnover and serotonin observed after 3-NPA was abolished in LC-/3-NPA-treated rats. In both 3-NPA- and METH-treated rats, LC prevented an increase in DA receptor D(1) gene expression. It appears that carnitine effect preventing hypothermia after 3-NPA treatments may be related not only to its mitochondriotropic actions but also to inhibitory effect on the DA and 5-HT systems activated after the exposure to 3-NPA. The same effect observed at the transcriptional level, at least for the DA receptor D(1), may account for protection against METH toxicity.

Co-regulation of dopamine D1 receptor and uncoupling protein-2 expression in 3-nitropropionic acid-induced neurotoxicity: neuroprotective role of L-carnitine.

This study tested the hypothesis that the expression of uncoupling proteins (UCPs) and dopamine (DA) system genes is responsive to 3-nitropropionic acid (3-NPA) neurotoxic effects and to the neuroprotective effects of the mitochondrial enhancer, L-carnitine (LC), in the rat striatum. Inactivation of mitochondrial succinate dehydrogenase (SDH) by 3-NPA results in hypoxic brain damage. Hypoxic conditions induce uncoupling protein-2 (UCP-2). An increase in UCP-2 expression may lead to a decrease in production of reactive oxygen species (ROS) associated with energy depletion. However, this adaptive response can also lead to a reduction of ATP that may further contribute to energy deficit and mitochondrial dysfunction. Here, male adult Sprague-Dawley rats (n=5/group) were injected either with saline or 3-NPA at 30 mg/kg, s.c. alone or 30 min after pre-treatment with LC (100mg/kg, i.p.). Rectal temperature was monitored before treatment and 4h following 3-NPA administration. Animals were sacrificed 4h post-treatment. Total RNA was isolated from the striatum and transcripts of UCP-2, UCP-4 and UCP-5 genes, as well as genes related to dopamine metabolism, such as DA D(1) and D(2) receptors, tyrosine hydroxylase (TH), monoamine oxidase-B (MAO-B), and vesicular monoamine transporter-2 (VMAT-2), were measured using real-time reverse transcription polymerase chain reaction (RT-PCR). While core temperature decreased significantly in 3-NPA-treated rats, LC significantly inhibited the hypothermic effect of 3-NPA (p<0.05). 3-NPA caused a significant increase in UCP-2 and DA D(1) receptor gene expression in the striatum and both effects were attenuated by pre-treatment with LC. Since LC maintains the ATP/ADP ratio and was previously shown to be neuroprotective against 3-NPA toxicity, the modulation of UCP-2 expression by LC suggests that LC counteracts energy dissipation and thus prevents the negative effects of ATP decline on DA neurotransmission.

Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials.

OBJECTIVE: We evaluated frozen databases from two 52-week randomized placebo-controlled clinical diabetic neuropathy trials testing two doses of acetyl-L-carnitine (ALC): 500 and 1,000 mg/day t.i.d. RESEARCH DESIGN AND METHODS: Intention-to-treat patients amounted to 1,257 or 93% of enrolled patients. Efficacy end points were sural nerve morphometry, nerve conduction velocities, vibration perception thresholds, clinical symptom scores, and a visual analogue scale for most bothersome symptom, most notably pain. The two studies were evaluated separately and combined. RESULTS: Data showed significant improvements in sural nerve fiber numbers and regenerating nerve fiber clusters. Nerve conduction velocities and amplitudes did not improve, whereas vibration perception improved in both studies. Pain as the most bothersome symptom showed significant improvement in one study and in the combined cohort taking 1,000 mg ALC. CONCLUSIONS: These studies demonstrate that ALC treatment is efficacious in alleviating symptoms, particularly pain, and improves nerve fiber regeneration and vibration perception in patients with established diabetic neuropathy.

Identification of rat hippocampal mRNAs altered by the mitochondrial toxicant, 3-NPA.

3-Nitropropionic acid (3-NPA) is a model mitochondrial inhibitor that causes selective neurodegeneration in brain. 3-NPA-induced neurodegeneration occurs via a secondary neurotoxicity, caused initially by ATP depletion and redox changes in the cell. It is known that the hippocampal degeneration caused by mitochondrial dysfunction affects learning and memory, cognitive functions commonly disturbed in neurodegenerative diseases. The 3-NPA- treated animal model can be used to study molecular mechanisms underlying selective degeneration in the brain. In this study, a microarray approach was utilized to define changes in the expression of 530 genes in the rat hippocampus after acute exposure to 3-NPA at 30 mg/kg, sc. The microarray data were collected at 30 min, 2 h, and 4 h post-3-NPA. Statistical modeling using an ANOVA mixed model applied to Van der Waerden scores of rank-transformed intensity data was used to assign statistical significance to 44 transcripts. These transcripts represent genes associated with energy metabolism, calcium homeostasis, the cytoskeleton, neurotransmitter metabolism, and other cellular functions. Changes in the transcripts of genes encoding 2 transporters [blood-brain specific anion transporter (Slco1c1) and sodium-dependent inorganic phosphate cotransporter (Slc17a7)] were confirmed by real-time RT-PCR. In conclusion, this study identified 2 new potential targets for enhancement of neuroprotection or inhibition of neurodegeneration associated with ATP depletion in the hippocampus.