Efficacy and tolerability on melasma of a topical cosmetic product acting on melanocytes, fibroblasts and endothelial cells: a randomized comparative trial against 4% hydroquinone.

BACKGROUND: Recent data demonstrated that an altered basal membrane, activated melanocytes and secreted factors from keratinocytes but also fibroblasts and endothelial cells are involved in the pathophysiology of melasma. OBJECTIVES: To evaluate the efficacy and tolerability on melasma of a new topical skin-lightening cosmetic product combination (CCP) targeting several factors identified to be involved in melasma pathogenesis compared to 4% hydroquinone (HQ). METHODS: Forty-three women with melasma were enrolled in a 12-week double-blind, randomized, parallel-group trial and treated with CCP or 4% HQ cream. Efficacy was evaluated with the modified Melasma Area Severity Index (mMASI) score and colorimetric change. Cutaneous tolerability and patient satisfaction were also investigated. RESULTS: The mMASI score decreased for both products from baseline and over the study period. At week 12, 90% of the subjects who received the combination products had an improvement in pigmentation vs. 79% with HQ. Similarly, both products significantly increased Individual Typological Angle parameters. For both measures, no statistically significant difference was observed between CCP and HQ in terms of change from baseline. CPP was very well tolerated. CONCLUSIONS: Cosmetic product combination is as effective as HQ in the management of facial dyspigmentation and represents a safe alternative.

GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons.

Human mutations of the GRID1 gene encoding the orphan delta1 glutamate receptor-channel (GluD1) are associated with schizophrenia but the explicit role of GluD1 in brain circuits is unknown. Based on the known function of its paralog GluD2 in cerebellum, we searched for a role of GluD1 in slow glutamatergic transmission mediated by metabotropic receptor mGlu1 in midbrain dopamine neurons, whose dysfunction is a hallmark of schizophrenia. We found that an mGlu1 agonist elicits a slow depolarizing current in HEK cells co-expressing mGlu1 and GluD1, but not in cells expressing mGlu1 or GluD1 alone. This current is abolished by additional co-expression of a dominant-negative GluD1 dead pore mutant. We then characterized mGlu1-dependent currents in dopamine neurons from midbrain slices. Both the agonist-evoked and the slow postsynaptic currents are abolished by expression of the dominant-negative GluD1 mutant, pointing to the involvement of native GluD1 channels in these currents. Likewise, both mGlu1-dependent currents are suppressed in GRID1 knockout mice, which reportedly display endophenotypes relevant for schizophrenia. It is known that mGlu1 activation triggers the transition from tonic to burst firing of dopamine neurons, which signals salient stimuli and encodes reward prediction. In vivo recordings of dopamine neurons showed that their spontaneous burst firing is abolished in GRID1 knockout mice or upon targeted expression of the dominant-negative GluD1 mutant in wild-type mice. Our results de-orphanize GluD1, unravel its key role in slow glutamatergic transmission and provide insights into how GRID1 gene alterations can lead to dopaminergic dysfunctions in schizophrenia.

Nicotinic receptors mediate stress-nicotine detrimental interplay via dopamine cells' activity.

Epidemiological studies report strong association between mood disorders and tobacco addiction. This high comorbidity requires adequate treatment but the underlying mechanisms are unknown. We demonstrate that nicotine exposure, independent of drug withdrawal effects, increases stress sensitivity, a major risk factor in mood disorders. Nicotine and stress concur to induce long-lasting cellular adaptations within the dopamine (DA) system. This interplay is underpinned by marked remodeling of nicotinic systems, causing increased ventral tegmental area (VTA) DA neurons' activity and stress-related behaviors, such as social aversion. Blocking ß2 or α7 nicotinic acetylcholine receptors (nAChRs) prevents, respectively, the development and the expression of social stress-induced neuroadaptations; conversely, facilitating α7 nAChRs activation specifically in the VTA promotes stress-induced cellular and behavioral maladaptations. Our work unravels a complex nicotine-stress bidirectional interplay and identifies α7 nAChRs as a promising therapeutic target for stress-related psychiatric disorders.

Controlled imbibition in a porous medium from a soft wet material (poultice).

We provide a first approach of the mechanisms of liquid imbibition in a porous medium from a wet paste in contact with this substrate. Through Magnetic Resonance Imaging (MRI) we first show that, in contrast with intuition, the liquid can invade the substrate even if it has a larger pore size than the paste, which induces a lower capillary pressure in the substrate. This phenomenon happens because the paste can easily shrink. We then show that the imbibition stops when the capillary pressure in the substrate balances the stress needed to further contract the paste. The dynamics of the process then mainly results from the competition of these two effects plus the pressure gradient associated with the liquid flow through the paste. This in particular shows that the liquid penetration in a porous medium, from a poultice in contact with this medium, may be controlled by adjusting the poultice characteristics.

Particle-Size-Exclusion Clogging Regimes in Porous Media.

From observations of the progressive deposition of noncolloidal particles by geometrical exclusion effects inside a 3D model porous medium, we get a complete dynamic view of particle deposits over a full range of regimes from transport over a long distance to clogging and caking. We show that clogging essentially occurs in the form of an accumulation of elements in pore size clusters, which ultimately constitute regions avoided by the flow. The clusters are dispersed in the medium, and their concentration (number per volume) decreases with the distance from the entrance; caking is associated with the final stage of this effect (for a critical cluster concentration at the entrance). A simple probabilistic model, taking into account the impact of clogging on particle transport, allows us to quantitatively predict all these trends up to a large cluster concentration, based on a single parameter: the clogging probability, which is a function of the confinement ratio. This opens the route towards a unification of the different fields of particle transport, clogging, caking, and filtration.

Mutagenicity assessment of environmental contaminations in a hospital centralized reconstitution unit.

INTRODUCTION: Cytotoxic drug exposure of hospital staff preparing intravenous chemotherapy is a major issue and related mutagenic risks should be more explored. The aim of this study was to assess the mutagenicity of several cytotoxic mixtures prepared at fixed concentrations, and the mutagenicity of environmental samples collected in a hospital centralized reconstitution unit. In parallel cytotoxic exposure in environmental samples was quantified. METHODS: Environmental samples were performed by wiping method using swabs in five critical production unit areas. Mutagenicity was assessed with a liquid microplate AMES test using two salmonella typhimurium strains (TA98 and TA100), in prepared cytotoxic mixtures containing 14 cytotoxic drugs (cyclophosphamide, cytarabine, dacarbazine, docetaxel, doxorubicin, epirubicin, etoposide, 5-fluorouracil, gemcitabine, ifosfamide, irinotecan, methotrexate, paclitaxel and pemetrexed) according a dichotomous strategy and in environmental samples. Cytotoxic drugs were quantified in samples using liquid chromatography coupled to mass tandem spectrometry. RESULTS: Mutagenesis was observed for the mix of 14 cytotoxic drugs with TA98 strain ±â€¯S9 fraction but not TA100 strain. After dichotomous approach, only doxorubicin and epirubicin exposure were associated to mutagenesis. The mutagenesis observed was expressed at lower concentrations with the mix of the 14 drugs than with anthracyclins alone, assuming a synergistic effect. Despite measurable level of cytotoxic contamination in environmental samples, no mutagenesis was highlighted in Ames tests performed on these environmental samples. CONCLUSIONS: The analyses carried out show the conservation of the mutagenicity of cytotoxic drugs found in very low quantities in the environment. The traces of cytotoxic drugs found in our unit regularly exceed the limits given by some authors. This approach may be considered as a new tool to monitor environmental contamination by cytotoxic drugs.

[Defusing of victims of the terrorist attacks in Paris. Elements of assessment one-month post-event]. / Defusing des victimes des attentats de Paris. Éléments d'évaluation un mois après.

The terrorist attacks (fusillades and suicide attacks) in Paris on 13 November 2015 have had a major psychic impact on all individuals directly or secondarily exposed to them. Medico-psychological unit (CUMP) of the Paris Île-de-France region's immediate care services were immediately mobilized and rapidly strengthened by all regional medico-psychological units (CUMP) throughout the country. Psychological assistance has been provided in several key points of Paris and specifically in the 11th district City Hall of Paris where Lyon's Medico-psychological unit was located. These specific immediate psychological assistances, referred to as a "defusing process" by the medico-psychological unit (CUMP), are mostly devoted to provide the victims with an entry point to a psychological healthcare relationship and give them a first sense of soothing and relief even though they do not prevent further psychological care follow up for the victims. Nonetheless, the potential therapeutic effect of this "defusing process" has not yet been sufficiently established nor demonstrated by any scientific study. A phoning survey was carried out one-month post-terrorist attacks and interviewed the 129 victims who benefited from the "defusing process" conducted by Lyon's medico-psychological unit (CUMP) in order to collect data and assess its effects. These people, whether directly exposed, bereaved relatives or witnesses, whose average age is 35, are mostly living in the Île-de-France region. Most of them present a high score on the IES-R scale, whether they were directly exposed, bereaved relatives or witnesses. Almost all of them (96.5%) experienced at least one medical care contact within this one-month post-trauma period with psychotropic medication for 37% of them. Regarding the defusing conducted by Lyon's medico-psychological unit (CUMP) in the 11th district City Hall of Paris, it appears that 93% of the victims who were looked after indicated that they were satisfied and 87.4% of them stated that they were soothed afterwards.

Determination of rifampicin in human plasma by high-performance liquid chromatography coupled with ultraviolet detection after automatized solid-liquid extraction.

A precise and accurate high-performance liquid chromatography (HPLC) quantification method of rifampicin in human plasma was developed and validated using ultraviolet detection after an automatized solid-phase extraction. The method was validated with respect to selectivity, extraction recovery, linearity, intra- and inter-day precision, accuracy, lower limit of quantification and stability. Chromatographic separation was performed on a Chromolith RP8 column using a mixture of 0.05 m acetate buffer pH 5.7-acetonitrile (35:65, v/v) as mobile phase. The compounds were detected at a wavelength of 335 nm with a lower limit of quantification of 0.05 mg/L in human plasma. Retention times for rifampicin and 6,7-dimethyl-2,3-di(2-pyridyl) quinoxaline used as internal standard were respectively 3.77 and 4.81 min. This robust and exact method was successfully applied in routine for therapeutic drug monitoring in patients treated with rifampicin.

Nicotine consumption is regulated by a human polymorphism in dopamine neurons.

Smoking is the most important preventable cause of morbidity and mortality worldwide. Recent genome-wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer. Several polymorphisms in the CHRNA3-CHRNA5-CHRNB4 cluster coding for the nicotinic acetylcholine receptor (nAChR) α3, α5 and ß4 subunits were implicated. In mouse models, we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic (DAergic) neurons of the ventral tegmental area (VTA). We first investigated the reinforcing effects of nicotine in drug-naive α5(-/-) mice using an acute intravenous nicotine self-administration task and ex vivo and in vivo electrophysiological recordings of nicotine-elicited DA cell activation. We designed lentiviral re-expression vectors to achieve targeted re-expression of wild-type or mutant α5 in the VTA, in general, or in DA neurons exclusively. Our results establish a crucial role for α5*-nAChRs in DAergic neurons. These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement. Finally, we demonstrate that a single-nucleotide polymorphism, the non-synonymous α5 variant rs16969968, frequent in many human populations, exhibits a partial loss of function of the protein in vivo. This leads to increased nicotine consumption in the self-administration paradigm. We thus define a critical link between a human predisposition marker, its expression in DA neurons and nicotine intake.

The results of seton drainage combined with anti-TNFα therapy for anal fistula in Crohn's disease.

AIM: Combined infliximab and sphincter-sparing surgery can be effective in perianal fistula associated with Crohn's disease (CD). This study aimed to assess the efficacy of local surgery combined with infliximab on sustained fistula closure and to identify predictive factors for response after this combined treatment. METHOD: Between 2000 and 2010, 81 patients with fistulising perianal CD were included in this observational study. Drainage with a loose seton was followed by infliximab therapy. The primary end-points were the rate of complete fistula closure and time required for this to occur. RESULTS: The fistula was complex in 71 (88%) of the 81 patients. Local proctological surgery was carried out in 77 (95%), including seton drainage in 62 (80.5%) of these. This was continued for a median duration of 3.8 months and the patient then received infliximab therapy. The median follow-up after treatment was 64 months (2-263). Initial complete closure of the fistula occurred in 71 (88%) cases at a median interval of 12.4 months (1-147) from the start of treatment. Recurrence was observed in 29 (41%) patients at a median interval of 38.5 months (2-48) from the start of treatment. They were treated again with combined treatment with successful closure in 19 (65.5%) patients. The total rate of closure of the fistula was 75.3%. Female gender, anal stenosis, rectovaginal and complex fistula formation were factors independently associated with failure of combined treatment. CONCLUSION: Seton drainage for several months combined with infliximab therapy is effective in closing the fistula in 75% of patients with complex perianal fistula formation associated with CD.

Co-activation of VTA DA and GABA neurons mediates nicotine reinforcement.

Smoking is the most important preventable cause of mortality and morbidity worldwide. This nicotine addiction is mediated through the nicotinic acetylcholine receptor (nAChR), expressed on most neurons, and also many other organs in the body. Even within the ventral tegmental area (VTA), the key brain area responsible for the reinforcing properties of all drugs of abuse, nicotine acts on several different cell types and afferents. Identifying the precise action of nicotine on this microcircuit, in vivo, is important to understand reinforcement, and finally to develop efficient smoking cessation treatments. We used a novel lentiviral system to re-express exclusively high-affinity nAChRs on either dopaminergic (DAergic) or γ-aminobutyric acid-releasing (GABAergic) neurons, or both, in the VTA. Using in vivo electrophysiology, we show that, contrary to widely accepted models, the activation of GABA neurons in the VTA plays a crucial role in the control of nicotine-elicited DAergic activity. Our results demonstrate that both positive and negative motivational values are transmitted through the dopamine (DA) neuron, but that the concerted activity of DA and GABA systems is necessary for the reinforcing actions of nicotine through burst firing of DA neurons. This work identifies the GABAergic interneuron as a potential target for smoking cessation drug development.

[New medical device hospital assessment: what kind of clinical data?]. / Évaluation des DM innovants au sein des hôpitaux : avec quelles données cliniques ?

INTRODUCTION: Since 2003, the AP-HP medical devices committee (CODIMS) assess the therapeutic relevance of innovated medical device (MD) for the French AP-HP hospitals' group. To accomplish this task, the CODIMS asks manufacturers to bring out clinical arguments to justify the use of their MD in hospital. This work analyses retrospectively after 8years, all assessed MD until March 2011 and the scientific quality of the clinical data submitted by manufacturers to the CODIMS to purchase their MD. METHOD: All MD were classed according to their certification's level (I, IIa, IIb, III, DMIA). The quality of available clinical studies (CS) provided by manufacturers for each case was assessed and classed according to five clinical relevance levels based on the evidence-based medecine standards (1-2: high methodology; 3-5: low methodology). RESULTS: One hundred and three MD files (80 % of class IIb and III MD) were analysed by the CODIMS (630CS). Our results highlight the lack of relevance of files that are provided to assess innovated MD: 29 files without any CS; concerning class IIb (32DMS, 221CS) and III (50, 342CS) MD, only 6 % of CS presented a correct clinical relevance level. And the situation did not get better during this assessment period. DISCUSSION/CONCLUSION: The CODIMS deplore the poor clinical relevance of files provided to assess MD (wrong comparator, inappropriate ends-points, insufficient follow-up to assess long-term security, small population studied). Future legislative developments for MD assessment are expected to improve this situation.

Results of isolated ulnar shaft shortening osteotomy in the treatment of idiopathic ulnocarpal impaction syndrome.

The objective of this study was to evaluate the results of isolated ulnar shaft shortening osteotomy (USSO) in the treatment of idiopathic ulnocarpal impingement syndrome. This was a two-center retrospective study. All patients older than 18 years who underwent isolated USSO for idiopathic ulnocarpal impingement syndrome between 2006 and 2016 were included. The outcome measures were: patient satisfaction, decrease in pain intensity, change in occupation, QuickDASH and PRWE functional scores, secondary palliative surgery suggesting failure of the ulnar shaft shortening osteotomy, and postoperative ulnar variance. The main complications were analyzed. Thirty-one patients were included. Twenty-six (84%) were satisfied with the procedure. At an average follow-up of 62 months, there was no secondary palliative surgery. Mean pain intensity on VAS was 7/10 (range, 2-10) and 1.7/10 (range, 0-6) preoperatively and postoperatively, respectively, for a mean decrease of 5.3 ± 2.6 points; this decrease was statistically significant (p < 0.001). None of the manual workers had to alter their work. Mean postoperative QuickDASH score was 19.6/100 (range, 0-79.55) and mean postoperative PRWE score was 23/100 (range, 1-85). Mean postoperative ulnar variance was -0.5 mm. As for complications, 61% of patients (n = 19/31) had discomfort related to the plate; 9.7% (n = 3/31) had distal radioulnar osteoarthritis; 4% (n = 1/19) had a fracture after hardware removal; 13% (n = 4/31) had non-union. Despite a high rate of complications, the study confirmed the effectiveness, in terms of pain, of isolated USSO in the treatment of idiopathic ulnocarpal impingement syndrome. LEVEL OF EVIDENCE: IV; retrospective cohort.

[Virological diagnosis of anterior herpetic ocular disease on tear sample: A simple and non-invasive technique]. / Diagnostic virologique des atteintes oculaires herpétiques antérieures sur prélèvement lacrymal : une technique simple et non invasive.

INTRODUCTION: Virological diagnosis of anterior ocular herpetic disease (AOHD) is essential for the management of these often-chronic pathologies that may require long-term therapy. PCR has become the gold standard, but the type of sampling (tears, corneal scraping, aqueous tap) has not been standardized. In this study, we studied the technique of tear sampling for the diagnosis of AOHD. MATERIALS AND METHOD: We retrospectively analyzed the medical files of patients with a positive tear sample (Schirmer strip) for herpes simplex 1 virus (HSV-1) in the Department of Ophthalmology of Paris-Saclay Bicêtre Hospital between January 2018 and December 2020. We studied the clinical and virological characteristics (viral loads) of these cases of proven AOHD. RESULTS: Thirty-six samples (33 patients) were included: 12 epithelial keratitis, 9 stromal HSK with ulceration, 5 uveitis, 4 stromal HSK without ulceration, 3 blepharitis, 1 endothelial HSK, 1 neurotrophic keratitis, and 1 conjunctivitis. The mean viral load was 3.9×105 copies/mL. Viral load was higher in cases of corneal ulceration (5.2×105±9.4×105 versus 1.2×102±1.7×102 copies/mL, P<1×10-4). There was no significant difference between primary episodes and relapses. CONCLUSION: Tear sampling using Schirmer strips is a simple, non-invasive method that can be useful for the virological diagnosis of various clinical forms of AOHD.

Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors.

Worldwide, 100 million people are expected to die this century from the consequences of nicotine addiction, but nicotine is also known to enhance cognitive performance. Identifying the molecular mechanisms involved in nicotine reinforcement and cognition is a priority and requires the development of new in vivo experimental paradigms. The ventral tegmental area (VTA) of the midbrain is thought to mediate the reinforcement properties of many drugs of abuse. Here we specifically re-expressed the beta2-subunit of the nicotinic acetylcholine receptor (nAChR) by stereotaxically injecting a lentiviral vector into the VTA of mice carrying beta2-subunit deletions. We demonstrate the efficient re-expression of electrophysiologically responsive, ligand-binding nicotinic acetylcholine receptors in dopamine-containing neurons of the VTA, together with the recovery of nicotine-elicited dopamine release and nicotine self-administration. We also quantified exploratory behaviours of the mice, and showed that beta2-subunit re-expression restored slow exploratory behaviour (a measure of cognitive function) to wild-type levels, but did not affect fast navigation behaviour. We thus demonstrate the sufficient role of the VTA in both nicotine reinforcement and endogenous cholinergic regulation of cognitive functions.

Multistep thermodesorption coupled with molecular analyses as a quick, easy and environmentally friendly way to measure PAH availability in contaminated soils.

Whether it is for risk assessment or for remediation purpose, contaminant availability in polluted soils is a key parameter to determine. Two methods were recently standardized for the estimation of the environmental available fraction of non-polar organics but, in some cases, their application on real historically contaminated soils does not provide satisfactory results. The present study aimed at proposing an alternative method for the estimation of PAH availability in soils, based on analytical thermal desorption and molecular analyses with the hypothesis that the binding strength between PAH and the solid matrix is linked to the desorption temperature. This hypothesis was validated by comparing the thermodesorption molecular distribution of different contaminated soils and of their respective extractable organic matter. Then, comparing the thermodesorption profiles of each studied PAH to the efficiency of biological and chemical remediation treatments through principal component analysis allowed obtaining the desorption temperature corresponding to PAH fractions available towards both treatments. This method was proven to effectively estimate the PAH fraction available towards biological (microbial incubation) and chemical (KMnO4 oxidation) treatments and present multiple advantages such as being fast, easy to execute and solvent free.

[Fluoroquinolones use at the Saint-Louis Hospital: investigations before and after diffusion of recommendations and interventions of the anti-infectious referent]. / Prescription des fluoroquinolones à l'hôpital Saint-Louis: enquête avant et après diffusion de recommandations et interventions du référent anti-infectieux.

OBJECTIVE: The increase of bacterial resistance and of fluoroquinolones consumption led to set up an action plan in order to improve the use of fluoroquinolones. METHODS: Two audits "on a given day" in February 2005 (before action) and January 2007 (after action) allowed evaluating the effects of several interventions: restitution of the results from the first audit and antibiotics counselling by an infectious diseases expert, conception and diffusion of local recommendations and follow-up of antibiotic consumption. RESULTS: The prevalence of the fluoroquinolones' prescriptions was 49/503 hospitalized patients in 2005 (1st audit) and 30/482 in 2007 (2nd audit). Global conformity to the recommendations was 47% in 2005 and 40% in 2007. The number of inappropriate indications remained stable between 2005 (12, 25%) and 2007 (10, 33%) with a reduction in the use of fluoroquinolones for empirical treatments: 74% in 2005 and 50% in 2007. The use of the intravenous route decreased from 45% in 2005 to 27% in 2007. Consumption of antibiotics and fluoroquinolones decreased by 7% and 30% between 2005 and 2007 respectively. CONCLUSION: The interventions allowed to decrease the use of fluoroquinolones in empirical treatments and to limit the use of the intravenous route. The impact on the fluoroquinolones and antibiotics consumption has been demonstrated. However, the proportion of inappropriate indications remained unchanged. The impact of the fluoroquinolones consumption decrease on the bacterial resistance will be the next step of our action.

Efficacy, Tolerability, and Safety of Low-Volume Bowel Preparations for Patients with Inflammatory Bowel Diseases: The French Multicentre CLEAN Study.

BACKGROUND: Standard high-volume polyethylene glycol [PEG] bowel preparations [PEG-4L] are recommended for patients with inflammatory bowel disease [IBD] undergoing colonoscopy. However, low-volume preparations [≤2 L of active volume] are often used in clinical practice. The aim of this study was to evaluate the efficacy, tolerability, and safety of the various bowel preparations for patients with IBD, including low-volume preparations. METHODS: We conducted a French prospective multicentre observational study over a period of 1 month. Patients aged 18-75 years with IBD with an indication of colonoscopy independent of the study were enrolled. The choice of the preparation was left to the investigators, as per their usual protocol. The patients' characteristics, disease, and colonoscopy characteristics were recorded, and they were given self-reported questionnaires. RESULTS: Twenty-five public and private hospitals enrolled 278 patients. Among them, 46 had a disease flare and 41 had bowel stenoses. Bowel preparations for colonoscopy were as follows: 42% received PEG-2L, 29% received sodium picosulfate [Pico], 15% received PEG-4L, and 14% had other preparations. The preparation did not reach the Boston's score efficacy outcome in the PEG-4L group in 51.2% of the patients [p = 0.0011]. The preparation intake was complete for 59.5% in the PEG-4L group, compared with 82.9% in the PEG-2L group and 93.8% in the Pico group [p < 0.0001]. Tolerability, as assessed by the patients' VAS, was significantly better for both Pico and PEG-2L compared with PEG-4L, and better for Pico compared with PEG-2L [p = 0.008; p = 0.0003]. In multivariate analyses, low-volume preparations were independent factors of efficacy and tolerability. Adverse events occurred in 4.3% of the patients. CONCLUSIONS: Preparations with PEG-2L and Pico were equally safe, with better efficacy and tolerability outcomes compared with PEG-4L preparations. The best efficacy/tolerance/safety profile was achieved with the Pico preparation.