A new in vitro method to predict in vivo photoprotection of skin hyperpigmentation induced by visible light.

BACKGROUND: Ultraviolet radiation is the main cause of skin pigmentation, but more recently visible light has been shown to be an important contributor especially in melano-competent subjects. Photoprotection from visible light can improve several hyperpigmentation disorders. Recently, a visible light photoprotection assessment method has been proposed based on in vivo pigmentation; the visible light photoprotection factor (VL-PF) is determined by assessment of the change in colorimetry parameter ITA over several days measured using a chromameter. Although in vivo methods remain the most representative of real life, in vitro methods are more suited to screening sunscreen formulations. OBJECTIVE: The aim of this study was to evaluate the correlation between in vivo and in vitro methods in assessing protection against visible light induced pigmentation. METHODS: We first analysed the in vitro protective properties of the 10 commercially available sunscreens using transmission measurements in the visible spectrum. Then, we performed a monocentric, double-blind, randomized controlled study with intra-individual comparisons in 20 healthy subjects and measure the VL-PF in vivo of those sunscreens. The correlation between the VL-PF and the percentage of blocked light was evaluated using the coefficient of determination R2 . RESULTS: A strong significant correlation was demonstrated between in vivo visible light protection factor and in vitro transmittance measurements, with the highest correlation factor at 420 nm and in the spectrum covering from 400 to 469 nm. CONCLUSION: Transmittance measurements were found to be a good predictive tool to evaluate sunscreen visible light photoprotection efficacy and could be used to select formulations for final in vivo testing.

Reversal of neuromuscular blockade with sugammadex during continuous administration of anaesthetic agents: a double-blind randomised crossover study using the bispectral index.

Sugammadex, a specific reversal agent for steroidal neuromuscular blocking drugs, has on occasion been reported to be associated with clinical signs of awakening. We performed a study to systematically search for an increase in bispectral index values and signs of awakening in patients maintained under general anaesthesia following sugammadex administration. Patients, scheduled to receive general anaesthesia with neuromuscular blockade, were included in this double-blind randomised crossover study. After surgery was completed, and while the train-of-four ratio was zero, intravenous anaesthesia was continued with the aim of maintaining the bispectral index in the range of 40-60. Patients then received either sugammadex 4 mg.kg-1 or saline. In cases of incomplete reversal of neuromuscular blockade after 5 min, patients received the other drug. Bispectral index and train-of-four monitoring were recorded every minute and clinical signs of awakening noted. Fifty-one patients completed the study. Median (IQR [range]) bispectral index values increased after sugammadex administration from 49 (43-53 [38-64]) to 63 (53-80 [45-97]) (p < 0.01) with an increase of ≥ 20 in 22 patients; 14 (27%) patients had clinical signs of awakening. Saline had no effect on bispectral index values, clinical signs of awakening or degree of neuromuscular blockade. This study confirms that reversal of neuromuscular blockade with sugammadex may be associated with clinical signs of awakening despite maintenance of anaesthesia. Intravenous anaesthesia should be maintained until complete recovery of muscle function is achieved, especially when sugammadex is administered.

Comparison of conventional plating, PMA-qPCR, and flow cytometry for the determination of viable enterotoxigenic Escherichia coli along a gastrointestinal in vitro model.

Recent technological advances for bacterial viability assessment using molecular methods or flow cytometry can provide meaningful interest for the demarcation between live and dead microorganisms. Nonetheless, these methods have been scarcely applied to foodborne pathogens and never for directly assessing their viability within the human digestive environment. The purpose of this study was to compare two methods based on membrane integrity (propidium monoazide (PMA) q-PCR and Live/Dead flow cytometry) and the classical plate-count method to determine the viability of a common foodborne pathogen, enterotoxigenic Escherichia coli (ETEC), during its transit trough simulated human gastrointestinal environment. Viable ETEC counts in the gastric and small intestinal compartments of the gastrointestinal TIM model indicated a consensus between the three tested methods (PMA-qPCR, flow cytometry, and plate counts). In a further step, flow cytometry analysis appeared as the preferred method to elucidate ETEC physiological states in the in vitro digestive environment by discriminating four subpopulations, while PMA-qPCR can only distinguish two. The defined viable/altered ETEC population was found during all in vitro digestions, but mainly in the gastric compartment. Being able to discriminate the particular physiological states of pathogenic microorganisms in the digestive environment is of high interest, because if some cells are not observable on culture media, they might keep their ability to express virulence functions.

Anti-infectious properties of the probiotic Saccharomyces cerevisiae CNCM I-3856 on enterotoxigenic E. coli (ETEC) strain H10407.

Enterotoxigenic Escherichia coli (ETEC) are major food-borne pathogens responsible for traveler's diarrhea. The production of adhesins and the secretion of enterotoxins constitute the major virulence traits of the bacteria. Treatments are mainly symptomatic and can involve antibiotherapy. However, given the rise of antibiotic resistance worldwide, there is an urgent need for the development of new preventive strategies for the control of ETEC infections. Among them, a promising approach is the use of probiotics. The aim of this study was to investigate, using complementary in vitro and in vivo approaches, the inhibitory potential of the yeast Saccharomyces cerevisiae CNCM I-3856 against the human ETEC reference strain H10407. In conventional culture media, S. cerevisiae significantly reduced ETEC growth and toxin production. The yeast also inhibited bacterial adhesion to mucin-agar and intestinal Caco-2/TC7 cells in a dose-dependent manner. Lastly, pre-treatment with S. cerevisiae inhibited interleukin-8 production by ETEC-infected intestinal cells. In streptomycin-treated mice, the probiotic yeast decreased bacterial colonization, mainly in the ileum, the main site of ETEC pathogenesis. For the first time, this study shows that the probiotic yeast S. cerevisiae CNCM I-3856 can exert an anti-infectious activity against a human ETEC strain through a multi-targeted approach, including inhibition of bacterial growth and toxin production, reduction of bacterial adhesion to mucins and intestinal epithelial cells, and suppression of ETEC-induced inflammation. Interestingly, the highest activity was obtained with a prophylactic treatment. Further studies will aim to assess the effect of the yeast on ETEC survival and virulence under human simulated digestive conditions.

Prevalence of HIV-1 drug resistance in treated patients with viral load >50 copies/mL: a 2014 French nationwide study.

Background: Surveillance of HIV-1 resistance in treated patients with a detectable viral load (VL) is important to monitor, in order to assess the risk of spread of resistant viruses and to determine the proportion of patients who need new antiretroviral drugs with minimal cross-resistance. Methods: The HIV-1 protease and reverse transcriptase (RT) and integrase genes were sequenced in plasma samples from 782 consecutive patients on failing antiretroviral regimens, seen in 37 specialized centres in 2014. The genotyping results were interpreted using the ANRS v24 algorithm. Prevalence rates were compared with those obtained during a similar survey conducted in 2009. Results: The protease and RT sequences were obtained in 566 patients, and the integrase sequence in 382 patients. Sequencing was successful in 60%, 78%, 78% and 87% of patients with VLs of 51-200, 201-500, 501-1000 and >1000 copies/mL, respectively. Resistance to at least one antiretroviral drug was detected in 56.3% of samples. Respectively, 3.9%, 8.7%, 1.5% and 3.4% of patients harboured viruses that were resistant to any NRTI, NNRTI, PI and integrase inhibitor (INI). Resistance rates were lower in 2014 than in 2009. Resistance was detected in 48.5% of samples from patients with a VL between 51 and 200 copies/mL. Conclusion: In France in 2014, 90.0% of patients in AIDS care centres were receiving antiretroviral drugs and 12.0% of them had VLs >50 copies/mL. Therefore, this study suggests that 6.7% of treated patients in France might transmit resistant strains. Resistance testing may be warranted in all treated patients with VL > 50 copies/mL.

Noninvasive proteome analysis of psoriatic stratum corneum reflects pathophysiological pathways and is useful for drug profiling.

BACKGROUND: Protein expression is disturbed in the psoriatic stratum corneum (SC). Noninvasive methods for the description of pathophysiological changes and drug profiling in psoriasis are desirable. OBJECTIVES: Undertake large-scale noninvasive protein expression studies in psoriatic SC to identify biomarkers of pathophysiological processes and use them for drug profiling. METHODS: Psoriatic SC was harvested through repetitive tape-stripping. Nonlesional and lesional SC, as well as vehicle-treated and drug-treated lesional SC samples were collected. Protein extracts from nonlesional and lesional skin biopsies were used for comparison. Calcipotriol-betamethasone (CB) was used as a reference medication. Proteins extracted from pooled tape strips were quantified using mass spectrometry (MS), Western blotting, enzyme-linked immunosorbent assay and Luminex technologies. RESULTS: MS-based methods identified 140 proteins differentially expressed in psoriatic SC. Epidermis development, glycolysis, regulation of apoptosis, cytoskeleton organization and peptide cross-linking were modulated, all reflecting perturbed epidermal differentiation. Using antibody-based techniques, increased levels of sICAM1, of CXCL1- and CXCL8-attracting neutrophils, of CXCL10- and CCL4-attracting T helper (Th) 1 cells, and of CCL2- and CCL4-attracting monocytes and dendritic cells were observed. Quantification of the Th1 and Th17 markers tumour necrosis factor, interleukin (IL) 12B, IL17A and IL17F in lesional SC was successful, while the Th2 cytokines IL4, IL5 and IL13, not involved in the disease process, were not detected. The pruritic cytokine IL31 was detected in lesional SC. CXCL1, CXCL8, CXCL10 and sICAM were used to investigate disease remission, ranking three topical treatments according to their known clinical efficacy. CONCLUSIONS: Protein biomarker quantification in psoriatic SC detects key pathophysiological mechanisms and enables noninvasive drug profiling in translational medicine settings.

Enhanced vasoconstrictor potency of the fixed combination calcipotriol plus betamethasone dipropionate in an innovative aerosol foam formulation vs. other corticosteroid psoriasis treatments.

BACKGROUND: An aerosol foam formulation of fixed combination calcipotriol 50 µg/g (Cal) and betamethasone 0.5 mg/g (as dipropionate; BD) has been developed for psoriasis vulgaris treatment. OBJECTIVE: To compare Cal/BD aerosol foam pharmacodynamic activity with Cal/BD ointment and with other topical corticosteroids of different potencies by assessing vasoconstrictor potential. METHODS: A Phase I, single-centre, investigator-blinded, vehicle-controlled, intra-individual comparison vasoconstriction study. Healthy volunteers received a single application on selected sites of: Cal/BD aerosol foam, clobetasol propionate 0.5 mg/g cream (CP; very potent), Cal/BD ointment (potent), fluocinolone acetonide 0.25 mg/g ointment (FA; moderately potent), BD aerosol foam and aerosol foam vehicle. A seventh untreated site acted as a negative control. Skin blanching was assessed by visual (primary response criterion) and colorimetric a* and L* measurements (secondary criteria), and was analysed over time (6-32 h post-application). RESULTS: Thirty-five healthy volunteers were included. All active treatments led to significantly greater skin blanching than control. By visual assessment, skin blanching with Cal/BD aerosol foam was significantly less compared with CP cream [mean AUC0-32 2560 vs. 3831; mean difference = -1272; 95% confidence interval (CI): -1598, -945; P < 0.001], similar to BD aerosol foam (mean AUC0-32 2560 vs. 2595; mean difference = -35; 95% CI: -362, 292; P = 0.83) and significantly greater than Cal/BD ointment (mean AUC0-32 2560 vs. 2008; mean difference = 552; 95% CI: 225, 878; P = 0.001) and FA ointment (mean AUC0-32 2560 vs. 1981; mean difference = 578; 95% CI: 251, 905; P < 0.001). Colorimetric assessments a* and L* also indicated significantly reduced skin blanching with Cal/BD aerosol foam compared with CP cream. No adverse events (AEs) were reported. CONCLUSION: Cal/BD aerosol foam can be considered a more potent formulation than Cal/BD ointment and the moderately potent FA ointment, but less potent than the very potent corticosteroid, CP cream.

Narrative enhancement and cognitive therapy (NECT) to improve social functioning in people with serious mental illness: study protocol for a stepped-wedge cluster randomized controlled trial.

BACKGROUND: Self-stigma is highly prevalent in serious mental illness (SMI) and is associated with poorer clinical and functional outcomes. Narrative enhancement and cognitive therapy (NECT) is a group-based intervention combining psychoeducation, cognitive restructuring and story-telling exercises to reduce self-stigma and its impact on recovery-related outcomes. Despite evidence of its effectiveness on self-stigma in schizophrenia-related disorders, it is unclear whether NECT can impact social functioning. METHODS: This is a 12-centre stepped-wedge cluster randomized controlled trial of NECT effectiveness on social functioning in SMI, compared to treatment as usual. One hundred and twenty participants diagnosed with schizophrenia, bipolar disorder or borderline personality disorder will be recruited across the 12 sites. The 12 centres participating to the study will be randomized into two groups: one group (group 1) receiving the intervention at the beginning of the study (T0) and one group (group 2) being a control group for the first 6 months and receiving the intervention after (T1). Outcomes will be compared in both groups at T0 and T1, and 6-month and 12-month outcomes for groups 1 and 2 will be measured without a control group at T2 (to evaluate the stability of the effects over time). Evaluations will be conducted by assessors blind to treatment allocation. The primary outcome is personal and social performance compared across randomization groups. Secondary outcomes include self-stigma, self-esteem, wellbeing, quality of life, illness severity, depressive symptoms and personal recovery. DISCUSSION: NECT is a promising intervention for reducing self-stigma and improving recovery-related outcomes in SMI. If shown to be effective in this trial, it is likely that NECT will be implemented in psychiatric rehabilitation services with subsequent implications for routine clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT03972735 . Trial registration date 31 May 2019.

Clinical evidence of benefits of a dietary supplement containing probiotic and carotenoids on ultraviolet-induced skin damage.

BACKGROUND: Lactobacillus johnsonii (La1) has been reported to protect skin immune system homeostasis following ultraviolet (UV) exposure. OBJECTIVES: To assess the effects of a dietary supplement (DS) combining La1 and nutritional doses of carotenoids on early UV-induced skin damage. METHODS: Three clinical trials (CT1, CT2, CT3) were performed using different UV sources: nonextreme UV with a high UVA irradiance (UV-DL, CT1), extreme simulated solar radiation (UV-SSR, CT2) and natural sunlight (CT3). All three clinical trials were carried out in healthy women over 18 years of age with skin type II-IV. In CT1, early markers of UV-induced skin damage were assessed using histology and immunohistochemistry. In CT2, the minimal erythemal dose (MED) was determined by clinical evaluation and by chromametry. Chromametry was also used to evaluate skin colour. Dermatologists' and subjects' assessments were compiled in CT3. RESULTS: A 10-week DS intake prevented the UV-DL-induced decrease in Langerhans cell density and the increase in factor XIIIa+ type I dermal dendrocytes while it reduced dermal inflammatory cells. Clinical and instrumental MED rose by 20% and 19%, respectively, and skin colour was intensified, as shown by the increase in the ΔE* parameter. The efficacy of DS was confirmed by dermatologists and subjects under real conditions of use. CONCLUSIONS: Nutritional supplementation combining a specific probiotic (La1) and nutritional doses of carotenoids reduced early UV-induced skin damage caused by simulated or natural sun exposure in a large panel of subjects (n=139). This latter result might suggest that DS intake could have a beneficial influence on the long-term effects of UV exposure and more specifically on skin photoageing.

[CyberKnife and neoadjuvant chemotherapy for breast tumors: preliminary results]. / CyberKnife et chimiothérapie néoadjuvante pour les tumeurs du sein localement évoluées : résultats préliminaires.

PURPOSE: CyberKnife((R)) (CK) allows stereotaxic irradiation for thoracic tumor thanks to a tracking system which potential is known for lung tumors. This technique has never been used to treat breast tumors but may have a real potential. PATIENTS AND METHOD: In order to define the interest of treating breast tumors with CK, we have conducted a phase I study with a dose escalation, adding CK to neoadjuvant chemotherapy in view of allowing conservative treatment for patients that will not have surgery in first intent. Neoadjuvant chemotherapy includes six cures, including three of docetaxel and three of FEC. CK treatment is made during the second cure of chemotherapy. Two dose levels are delivered in three fractions: 19.5 and 22.5Gy. Surgery is performed six to eight weeks after the last cure. The primary objective is to define tolerance of stereotactic irradiation concomitant with neoadjuvant chemotherapy for breast tumors. Skin toxicity is the limiting criterion of the study. The secondary objectives are both histological response and quality of surgery. Here, we are presenting the preliminary results of the 2-dose level. This study participates in the French national grant called Programme hospitalier de recherche clinique (PHRC). RESULTS: No skin toxicity of grade I or more have been find. Surgery was performed as conventional and there was no complication. Pathology exams found one complete response, one lymphangitis and one partial response. CONCLUSION: These preliminary results seem to be promising but need to be confirmed. We carry on the dose escalation study.

Vasoconstrictor potency of fixed-dose combination calcipotriol (50 µg/g) and betamethasone dipropionate (0.5 mg/g) cutaneous foam versus other topical corticosteroids used to treat psoriasis vulgaris.

Background: It is important to determine the vasoconstrictor potencies of topical corticosteroids used to treat psoriasis to ensure appropriate clinical use. Objective: To compare the vasoconstrictive potencies of fixed-dose combination calcipotriol (50 µg/g) and betamethasone dipropionate (0.5 mg/g) (Cal/BD) cutaneous foam with other topical corticosteroids. Methods: In this Phase I, single-center, healthy volunteer study, Cal/BD foam, clobetasol propionate 0.05% cream (CP; very potent), BD 0.05% ointment (potent), mometasone furoate 0.1% cream (MF; potent), hydrocortisone-17-butyrate 0.1% ointment (HB; moderately potent), and foam vehicle were applied, then removed after 16 h. Skin blanching was visually assessed 2 h later (scale of 0-4). Results: Thirty-six volunteers were randomized. Skin blanching with Cal/BD foam (median [range], 2.00 [0.75-3.00]) was significantly lower than CP cream (3.00 [1.75-4.00]; p < .001), was not significantly different from BD ointment (1.75 [0.75-3.00]; p = .30) and MF cream (2.00 [1.00-3.75]; p = .22), and was significantly greater than HB ointment (1.25 [0.50-3.00]; p < .001) and vehicle (0 [0-0.50]; p < .001). There were no local tolerability reactions or adverse events. Conclusions: The corticosteroid potency of Cal/BD foam was not significantly different from BD ointment and MF cream, significantly stronger than HB ointment, but weaker than CP cream in healthy volunteers.

Breast cancer screening in France: results of the EDIFICE survey.

BACKGROUND: The EDIFICE survey aimed to investigate the compliance of the general population to the screening tests available in France for the 4 most common cancers: breast, colorectal, prostate and lung. Implementation of breast cancer screening has been generalized in France since 2003: women aged between 50 and 74 years are systematically invited to perform a mammography every second year. Results pertaining to breast cancer are reported hereafter. METHODS: This nationwide observational survey was carried out in France from 18 January to 2 February 2005 among representative samples of 773 women aged between 40 and 75 years and 600 general practitioners (GPs). Information collected included socio-demographic characteristics, attitude towards cancer screening and actual experience of cancer screening, as well as GPs' practice regarding screening. The precision of the results is +/- 4.3% for a 95% confidence interval. RESULTS: Among the 507 participating women aged between 50 and 74 years, 92.5% (469/507) had undergone at least one mammography: 54.6% (256/469) underwent this test on their own initiative and 44.6% (209/469) of women performed it in the framework of a systematic screening plan. Most women participating in the systematic screening (89.0% i.e. 186/209) had a mammography within the last dating from less than 2 years versus 73.8% (189/256) of those who performed it outside the screening program (Chi(2) test; p<0.01). Interestingly, 422 women (61.9% i.e. 422/682 women aged between 40-75 years with at least one mammography) had performed a mammography before the recommended age for screening. There was a significant correlation (p = 0.009) between the existence of a first mammography before 50 years of age and subsequent screening on women's own initiative (54.6% of 469 screened women). Main reasons for not performing the screening test every second year (77 women aged between 50-74 years) included: feeling unconcerned and/or unmotivated (p = 0.0001), no cancer anxiety (p = 0.020) and no recommendation by the GP (p = 0.015); Of the 600 participating GPs, 68.6% (412/600) systematically recommended a mammography to their patients. GPs' perceptions of the reasons for women's avoidance of the screening test were unwillingness to be aware of mammography results (44.4% - 266/600) and the belief that mammography was painful (52.5% - 315/600). CONCLUSION: The main result of the EDIFICE survey is the high rate of women's attendance at mammography screening. The EDIFICE survey pointed out that systematic and organized screening played a major role in the regularity of screening tests for breast cancer every second year. GPs and gynaecologist are key actors in heightening public awareness.

Cellulite and skin ageing: is there any interaction?

OBJECTIVE: This study aimed to identify the characteristics of cellulite in women of different age and to appreciate whether cellulite could interfere with skin ageing or not. METHODS: 94 Healthy females, divided into three age groups (21-30yrs; 31-40yrs; 51-60yrs) and two grade groups of cellulite (grade 2; grade 0 or control group), were investigated using non invasive techniques. The "orange peel appearance" was quantified by measuring the shadowed surfaces under low angle light. The biomechanichal properties were measured (extensibility-retractability-elasticity). The thicknesses of the skin structures were also evaluated using ultrasound. Echogenicity of the dermis was recorded and dermis density determined in two bands (superficial and low dermis). RESULTS: In grade 2, the shadowed surfaces are significantly different according to age; i.e. smaller and more numerous after age of 30; the total skin thickness including hypodermis is increased of about 30% irrespective to age, compared to control group. The biomechanical properties of the skin are significantly modified as age increases without any grade effect. In grade 2, retractability and elasticity parameters are altered from age 30 whilst only from age 50 in the control group. Echogenicities of the superficial and deep dermis also decrease from age 30 and become significantly lower than the ones of grade 0. CONCLUSION: Population with cellulite presents earlier skin ageing characteristics than the control population. Two sub-populations may exist: the under 30 age with large dimpled surfaces, normal biomechanical and density properties; and the over 30 age with smaller and numerous dimpled surfaces and already altered dermis properties. This premature skin ageing should be prevented accordingly.

Use of artesunate in non-malarial indications.

INTRODUCTION: Artesunate and other artemisinin derivatives are used in various infectious and non-infectious diseases. We aimed to analyze available data on artesunate and artemisinin derivatives activity in humans and their potential clinical benefits in non-malarial indications. MATERIAL AND METHODS: Literature review performed on PubMed and the Cochrane Library databases using the PRISMA method. We analyzed studies published in English from January 2008 to August 2017 using the same indicators of drug efficacy. RESULTS: We included 19 studies performed in humans (1 meta-analysis, 1 literature review, 4 randomized controlled trials, 3 prospective controlled trials, 3 prospective uncontrolled trials, 2 exploratory phase 1 or 2 trials, 1 case series, and 4 case reports). Artesunate and artemisinin derivatives demonstrated efficacy in the treatment of schistosomiasis in combination with praziquantel (P=0.003). Artesunate monotherapy was less effective than praziquantel alone (P<0.001) probably because its activity only affects the early stages of Schistosoma parasites. Artesunate monotherapy could be interesting as a chemoprophylactic drug against schistosomiasis (P<0.001). Findings seem promising but are still controversial in the treatment of multidrug-resistant CMV infections. Studies do not conclude on artesunate and artemisinin derivatives efficacy in the treatment of cervix, breast, colorectal, and lung cancers. CONCLUSION: Artesunate and artemisinin derivatives in combination with praziquantel were effective against schistosomiasis, and could be used as a chemoprophylactic drug alone. They could be interesting as anti-CMV and anti-tumor treatment. Additional trials in humans are required to assess the efficacy of artesunate and artemisinin derivatives in diseases other than malaria.

Performance of genotypic algorithms for predicting tropism for HIV-1 CRF01_AE recombinant.

OBJECTIVES: There is no consensus about the performances of genotypic rules for predicting HIV-1 non-B subtype tropism. Three genotypic methods were compared for CRF01_AE HIV-1 tropism determination. METHODS: The V3 env region of 207 HIV-1 CRF01_AE and 178 B subtypes from 17 centers in France and 1 center in Switzerland was sequenced. Tropism was determined by Geno2Pheno algorithm with false positive rate (FPR) 5% or 10%, the 11/25 rule or the combined criteria of the 11/25, net charge rule and NXT/S mutations. RESULTS: Overall, 72.5%, 59.4%, 86.0%, 90.8% of the 207 HIV-1 CRF01_AE were R5-tropic viruses determined by Geno2pheno FPR5%, Geno2pheno FPR10%, the combined criteria and the 11/25 rule, respectively. A concordance of 82.6% was observed between Geno2pheno FPR5% and the combined criteria for CRF01_AE. The results were nearly similar for the comparison between Geno2pheno FPR5% and the 11/25 rule. More mismatches were observed when Geno2pheno was used with the FPR10%. Neither HIV viral load, nor current or nadir CD4 was associated with the discordance rate between the different algorithms. CONCLUSION: Geno2pheno predicted more X4-tropic viruses for this set of CRF01_AE sequences than the combined criteria or the 11/25 rule alone. For a conservative approach, Geno2pheno FPR5% seems to be a good compromise to predict CRF01_AE tropism.

Modulation of neuronal excitability by intracellular calcium buffering: from spiking to bursting.

We have investigated the detailed regulation of neuronal firing pattern by the cytosolic calcium buffering capacity using a combination of mathematical modeling and patch-clamp recording in acute slice. Theoretical results show that a high calcium buffer concentration alters the characteristic regular firing of cerebellar granule cells and that a transition to various modes of oscillations occurs, including bursting. Using bifurcation analysis, we show that this transition from spiking to bursting is a consequence of the major slowdown of calcium dynamics. Patch-clamp recordings on cerebellar granule cells loaded with a high concentration of the fast calcium buffer BAPTA (15 mM) reveal dramatic alterations in their excitability as compared to cells loaded with 0.15 mM BAPTA. In high calcium buffering conditions, granule cells exhibit all bursting behaviors predicted by the model whereas bursting is never observed in low buffering. These results suggest that cytosolic calcium buffering capacity can tightly modulate neuronal firing patterns leading to generation of complex patterns and therefore that calcium-binding proteins may play a critical role in the non-synaptic plasticity and information processing in the central nervous system.

Isolated mitral valve replacement with St. Jude medical prosthesis: long-term results: a follow-up of 19 years.

BACKGROUND: In this retrospective study, approximately 440 patients received mitral valve replacements with the St Jude Medical prosthesis. The last patient was operated on 10 years before the beginning of the follow-up. The extended follow-up was 19 years. METHODS AND RESULTS: Four hundred forty patients (sex ratio, 1.32 [men to women]; age, 60+/-11.4 years; age range, 7 to 75 years) were operated on from 1979 to 1987. All patients underwent isolated mitral valve replacement. Tricuspid plasty was the only associated procedure. The follow-up at 19 years was 98% complete. The overall actuarial survival rate was 63+/-3.3% at 19 years, and the actuarial survival rate (only valve related) was 83+/-2.7%. The operative mortality rate (0 to 30 days) was 4.09%. We found that 89.4% of the patients alive at 19 years were in NYHA class I/II. Multivariate analysis showed that age and sex were significantly correlated with valve-related mortality and that age, sex, NYHA class, and atrial fibrillation were significantly correlated with overall mortality. The linearized rates (percent patient-years) of thromboembolism, thrombosis, and hemorrhage were 0.69, 0.2, and 1, respectively. At 19 years, freedom from endocarditis and reoperation was 98.6+/-1% and 90+/-3%, respectively. CONCLUSIONS: In this study, the very-long-term results confirm the excellent durability of the St Jude Medical prosthesis in the mitral position and show the difficulty of adjusting the anticoagulation protocol, even after long-term treatment.