Daylight photodynamic therapy with methyl aminolevulinate cream as a convenient, similarly effective, nearly painless alternative to conventional photodynamic therapy in actinic keratosis treatment: a randomized controlled trial.

BACKGROUND: Daylight photodynamic therapy (DL-PDT) of actinic keratosis (AK) has shown preliminary efficacy and safety results comparable to conventional photodynamic therapy (c-PDT), using methyl aminolevulinate (MAL) cream. OBJECTIVES: To demonstrate the efficacy and safety of DL-PDT vs. c-PDT in treating mild facial/scalp AK. MATERIALS AND METHODS: This 24-week randomized, controlled, investigator-blinded, multicentre, intra-individual efficacy (non-inferiority) and safety (superiority regarding pain) study enrolled 100 subjects. AKs on the face/scalp were treated once, with DL-PDT on one side and c-PDT on the contralateral side. Primary end points for DL-PDT at week 12 were efficacy [non-inferiority regarding complete lesion response (mild AK)] and safety (superiority regarding subject's assessment of pain). Lesions with complete response 12 weeks after one treatment session were followed until week 24. The safety evaluation included incidence of adverse events. Subject satisfaction was classified using a questionnaire. RESULTS: At week 12, the complete lesion response rate with DL-PDT was non-inferior to c-PDT (89·2% vs. 92·8%, respectively; 95% confidence interval -6·8 to -0·3), confirmed by intention-to-treat analysis. Additionally, regardless of the treatment used, 96% of mild lesions were maintained in complete response 24 weeks after the PDT session. For DL-PDT, subject-reported pain was significantly lower (0·8 vs. 5·7, respectively; P < 0·001), with better tolerability and significantly higher subject satisfaction regarding convenience and outcome. CONCLUSIONS: Daylight-mediated PDT was not inferior in efficacy to Metvix c-PDT (mild AK response rate), better tolerated, nearly painless and more convenient for patients.

STOP proteins are responsible for the high degree of microtubule stabilization observed in neuronal cells.

Neuronal differentiation and function require extensive stabilization of the microtubule cytoskeleton. Neurons contain a large proportion of microtubules that resist the cold and depolymerizing drugs and exhibit slow subunit turnover. The origin of this stabilization is unclear. Here we have examined the role of STOP, a calmodulin-regulated protein previously isolated from cold-stable brain microtubules. We find that neuronal cells express increasing levels of STOP and of STOP variants during differentiation. These STOP proteins are associated with a large proportion of microtubules in neuronal cells, and are concentrated on cold-stable, drug-resistant, and long-lived polymers. STOP inhibition abolishes microtubule cold and drug stability in established neurites and impairs neurite formation. Thus, STOP proteins are responsible for microtubule stabilization in neurons, and are apparently required for normal neurite formation.

[Progression of nerve fiber layer defects in retrobulbar optic neuritis by the macular ganglion cell complex]. / Évolution des déficits des fibres optiques dans les névrites optiques rétrobulbaires par le complexe ganglionnaire maculaire.

INTRODUCTION: Recent studies with SD OCT had shown early axonal damage to the macular ganglion cell complex (which consists of the three innermost layers of the retina: Inner Plexiform Layer [IPL], Ganglion Cell Layer [GCL], Retinal Nerve Fibre layer [RNFL]) in optic nerve pathology. Retrobulbar optic neuritis (RBON), occurring frequently in demyelinating diseases, leads to atrophy of the optic nerve fibers at the level of the ganglion cell axons, previously described in the literature. The goal of this study is to evaluate the progression of optic nerve fiber defects and macular ganglion cell complex defects with the SPECTRALIS OCT via a reproducible method by calculating a mean thickness in each quadrant after an episode of retrobulbar optic neuritis. METHODS: This is a prospective monocentric observational study including 8 patients at the Clermont-Ferrand university medical center. All patients underwent ocular examination with macular and disc OCT analysis and a Goldmann visual field at the time of inclusion (onset or recurrence of RBON), at 3 months and at 6 months. RESULTS: Patients were 40-years-old on average at the time of inclusion. After 6 months of follow-up, there was progression of the atrophy of the macular ganglion cell complex in the affected eye on (11.5% or 11µm) predominantly inferonasally (13.9% or 16µm) and superonasally (12.9% or 14µm) while the other eye remained stable. The decrease in thickness occurred mainly in the most internal 3 layers of the retina. On average, the loss in thickness of the peripapillary RNFL was predominantly inferotemporal (24.9% or 39µm) and superotemporal (21.8% or 28µm). DISCUSSION: In 3 months of progression, the loss of optic nerve fibers is already seen on macular and disc OCT after an episode of RBON, especially in inferior quadrants in spite of the improvement in the Goldmann visual field and visual acuity. Segmentation by quadrant was used here to compare the progression of the defect by region compared to the fovea in a global and reproducible way. The loss of thickness, predominantly inferonasally and superonasally, appears to correspond to the temporal loss on optic nerve OCT according to the literature. CONCLUSION: The follow-up of these patients with retrobulbar neuritis is important as shown by the possibility of relapse, especially in multiple sclerosis. Monitoring of the macular ganglion cell complex by a global method of calculation could contribute to the detection and localization of early damage after an episode of retrobulbar neuritis. This could possibly lead to a discussion of treatment modification or increased surveillance in cases of early detection of nerve fiber atrophy, or to showing the importance of monitoring, since monitoring of RBON is not standardized.

[Descemet's membrane endothelial keratoplasty (DMEK): Analysis of a variation in Descemet's endothelial graft preparation]. / Greffes endothéliales par Descemet membrane endothelial keratoplasty (DMEK) : analyse d'une variante de découpe du greffon endothélio-descemétique.

INTRODUCTION: Descemet's membrane endothelial keratoplasty (DMEK) can replace just the corneal endothelium and respect the natural corneal anatomy. Currently, the technique of endothelial graft preparation remains manual and non-standardized. PURPOSE: To report anatomic and functional results after DMEK, and compare two techniques of graft preparation. METHODS: Single-center retrospective study, including 64 eyes of 64 patients undergoing DMEK, from September 2014 to February 2016 at Clermont-Ferrand University Medical Center. The "classic" preparation was used in 44 patients (group 1) and the "variant" preparation was used in 20 patients (group 2). An analysis of functional parameters (visual acuity), anatomy (pachymetry, corneal edema, endothelial cell count) and keratometry (sphere, cylinder, mean keratometry) was performed during the first postoperative year. RESULTS: The mean follow-up was 10.0±2.5 months. The average preparation time was 12.3±8.1minutes, with 14.4±8.8 in group 1 versus 7.8±3.0 in group 2 (P<0.001). At six months, the best corrected distance visual acuity was significantly better in group 1 with an acuity of 0.28±0.28 LogMAR in group 1 and 0.37±0.30 LogMAR in group 2 (P<0.01). The best corrected near visual acuity was also better in group 1 at 6 months, with an acuity of 0.29±0.24 LogMAR (P<0.001) in group 1 and 0.37±0.28 LogMAR in group 2 (P=0.02). Improvement in visual acuity was continuous for the 2 groups. At 6 months, endothelial cell loss was greater in group 1 than in group 2, but the difference was not significant (P=0.44). Central corneal thickness was similar between the 2 groups. Finally, no change in keratometry parameters was found between preoperative data and 6 months in each group or between the two groups. CONCLUSION: DMEK led to an improvement in all parameters as well as rapid visual rehabilitation. The new variation in preparation saved a considerable amount of time without decreasing graft survival or postoperative results.

Visceral leishmaniosis in HIV-positive patients: primary infection, reactivation and latent infection. Impact of the CD4+ T-lymphocyte counts.

OBJECTIVE: To discriminate cases of visceral leishmaniosis (VL) following a primary infection from cases originating in a reactivation of a latent Leishmania infection and to assess the impact of CD4+ T-cell counts on the occurrence of VL in patients with HIV disease. METHODS: We searched by Western blotting for the presence of Leishmania infantum-specific antibodies in the sera of 236 HIV-positive patients. We performed a follow-up of antileishmanial serology and analysed the evolution of the CD4+ T-cell counts for 14 HIV-positive VL patients and for 18 HIV-positive Leishmania-seropositive patients without VL. RESULTS: This study (1) showed that the VL disease/Leishmania infection ratio in HIV-positive individuals is high (1 : 10); (2) discriminated between a primary Leishmania infection (five patients who converted from Leishmania-seronegative to Leishmania-seropositive) and a reactivation of a latent infection (seven patients); (3) showed that HIV-positive individuals with dramatically low CD4+ T-cell counts maintained or generated a specific antileishmanial antibody production; (4) demonstrated that the primary-VL appeared at significantly higher (P = 0.028) CD4+ T-cell levels than the reactivation-VL; (5) documented the existence of HIV-positive Leishmania-seropositive individuals who despite a severe and prolonged immunosuppression did not develop VL (eight of 18). CONCLUSION: Our data stress the utility of the follow-up by Western blotting for an early diagnosis of VL, and therefore an early treatment, for HIV-positive patients living in endemic areas. They suggest that in a latent Leishmania infection supplementary control mechanism(s) might operate in addition to the T-cell-mediated response, and provide a further example of non-appearance of an opportunistic infection despite a severe reduction in CD4+ T cells.

[Risk reduction and intravenous drug use abstinence in patients with HIV infection. The SEROCO group]. / Réduction des risques et arrêt de la prise de drogues intraveineuses chez des sujets infectés par le VIH. Groupe SEROCO.

BACKGROUND: Little is known about the complex stepwise process of giving up intravenous (i.v.) drugs. However, HIV risk reduction programs directed towards i.v. drug users have been accused by some opponents to encourage users to continue. In order to better assess the relationships between risk reduction and abstinence, we studied factors associated with abstinence in HIV-infected patients using i.v. drugs at enrollment in the SEROCO cohort (1988-1994). METHODS: 63 HIV-infected patients injecting i.v. drugs at enrollment were followed-up every 6 months with a clinical examination and a questionnaire concerning sexual and drugs practices since last consultation. Abstinence was defined as non injecting for at least 6 months. The 30 patients who became abstinent during a follow-up period of 3 years were compared to the 33 remaining. RESULTS: Abstinence during follow-up was not related to age at inclusion, duration of i.v. drug use, gender or marital status. However, patients who became abstinent were more likely to have a professional activity at inclusion than the remaining (70% vs 42%, p = 0.03). Before knowledge of HIV infection, frequency of injections, needle sharing and use of condoms did not differ between the 2 groups. During follow-up, behavioural changes occurred in the two groups, but were more marked in those who lately became abstinent. These latter were more likely to always inject with new needles/syringes (57% vs 18%, p = 0.003), and to use condoms with HIV-negative partners or of unknown status (73% vs 39%, p = 0.06). Professional activity and systematic use of new needles/syringes remained independently associated with abstinence in multivariate analysis. CONCLUSION: In this cohort, abstinence appeared as a stepwise process in which risk reduction preceded abstinence. This confirms that risk reduction programs do not work against those messages aimed at stopping i.v. drug use. Since this analysis selected particular subjects, enrolled in a cohort of HIV-infected patients, results should be confirmed in other samples of i.v. drugs users.

PIP: Few prospective studies have described the stepwise process of giving up intravenous drug (IV) use. In an effort to deepen the understanding of the relationship between risk reduction related to IV drug use and giving up such drug use, the authors studied factors associated with IV drug abstinence among HIV-infected patients using IV drugs at their enrollment in the multicenter French cohort SEROCO between 1988 and 1994. 63 HIV-infected patients injecting IV drugs at enrollment were followed clinically every 6 months and with a questionnaire on their sexual practices and drug use since their most recent consultations. The termination of drug use was defined as not using drugs for a period of at least 6 months. The 30 subjects who gave up IV drug use over the 3-year follow-up were compared to the 33 subjects who continued using IV drugs. Those who gave up IV drugs were more likely to be professionally active at enrollment than those who kept injecting, they more often used during the follow-up period new injection materials for each injection, and more often used condoms with HIV-negative partners and those of unknown serostatus. The abandonment of IV drug use in this study followed a stepwise process in which the reduction of risks preceded the eventual cessation of drug use.

[Platypnea-orthodeoxia syndrome: a rare cause of severe hypoxemia]. / Syndrome de platypnée-orthodéoxie: une cause rare d'hypoxémie sévère.

INTRODUCTION: The platypnea-orthodeoxia syndrome (PO) includes: (i) a dyspnea increasing with orthostatism and decreasing in supine position, (ii) wide positional range in arterial oxygen saturation with tachycardia, (iii) and hypoxemia refractory to oxygen therapy. This syndrome is usually related to a cardiac right-left shunt, and rarely to a pulmonary shunt. OBSERVATION: We report a case of a patient presenting with a post-lung infection dyspnea associated with severe hypoxemia and shunt effect at blood gas. Contrast-enhanced CT-scan showed no pulmonary embolism. PO syndrome was suspected given the transcutaneous blood oxygen saturation variation from 90% in supine position to 60% in standing position, tachycardia, and absence of response to the intensive oxygen therapy. CONCLUSION: This syndrome should be known by physicians as a possible differential diagnose for refractory dyspnea to oxygen since effective treatment is available.

[Paclitaxel-bevacizumab is a possible alternative as salvage chemotherapy in advanced non-small cell bronchial carcinoma]. / L'association paclitaxel-bevacizumab est une alternative intéressante dans le traitement des cancers bronchopulmonaires non épidermoïdes avancés en troisième ligne et plus.

INTRODUCTION: Bevacizumab is recommended in first line chemotherapy for advanced non-squamous non-small cell lung cancer (NSCLC). Paclitaxel is a doublet drug also widely used in cisplatin-based regimens. Paclitaxel plus bevacizumab is a standard regimen as first line treatment of metastatic breast cancer. Since there is no guideline for third line treatment of NSCLC, some oncology units use paclitaxel-bevacizumab in some NSCLC patient after relapse of the second line. The aim of this study was to assess retrospectively the feasibility and efficacy of this treatment option in stage IV NSCLC. METHODS: Patients who had received the combination of paclitaxel (80 to 90 mg/m(2) in a weekly schedule) and bevacizumab (7.5 to 15 mg/kg every 21 days) in the thoracic oncology departments of two university hospitals in the Rhone-Alpes Department were retrospectively reviewed. RESULTS: Twelve patients underwent this treatment. Their mean age was 56 years and their performance status was less or equal to 1 in 50 % of the cases. The chemotherapy was given as fifth line in 67 % of the patients and 67 % were antiangiogenic naïve. They received a mean of 6 courses. The overall response rate was 33 % and the disease control rate 66 %. Median progression-free survival was 5.1 months (95 %CI 1.0-9.1). Ten patients (82 %) experienced toxicity, the majority grade 1 to 2 events, and only one a grade 3 event (febrile neutropenia). There were no severe bleeding episodes. CONCLUSION: Combined paclitaxel-bevacizumab chemotherapy seems feasible in patients with NSCLC. The toxicity profile is acceptable. This regimen should be evaluated in further prospective studies.

[Severe pneumonia due to cytomegalovirus in chronic obstructive pulmonary disease]. / Pneumopathies sévères à Cytomégalovirus et broncho-pneumopathie chronique obstructive.

UNLABELLED: Severe pneumonia due to cytomegalovirus in chronic obstructive pulmonary disease. INTRODUCTION: We describe two cases of immunocompetent patients with chronic obstructive pulmonary disease (COPD) who developed severe cytomegalovirus (CMV) pneumonia. The clinical and radiological context and CMV replication in broncho-alveolar lavage suggested a diagnosis of CMV pneumonia. CASE HISTORIES: We report two cases in patients with moderate chronic obstructive pulmonary disease not treated with long-term steroid therapy who developed bilateral pneumonia with hypoxaemia. The only pathogen identified was CMV with replication of the virus in the broncho-alveolar lavage. Investigation failed to detect any associated immune deficiency. CONCLUSION: Severe cytomegalovirus pneumonia could be encouraged by the existence of chronic obstructive pulmonary disease due to local inflammatory changes.

Myelin basic protein functions as a microtubule stabilizing protein in differentiated oligodendrocytes.

Myelin basic protein (MBP) is an oligodendrocyte-specific protein essential for oligodendrocyte morphogenesis at late stages of cell differentiation. There is evidence that the morphogenetic function of MBP is mediated by MBP interaction with the cytoskeleton. Thus, an MBP/cytoplasmic microtubule association has been reported, and MBP has Ca(2+)/calmodulin-regulated microtubule cold-stabilizing activity in vitro. However, the unambiguous demonstration of a microtubule-stabilizing activity for MBP in cells has been difficult because oligodendrocytes contain variants of STOP (stable tubule only polypeptide) proteins, which are responsible for microtubule cold stability in different cell types. Herein, we have used genetic mouse models and RNA interference to assay independently the microtubule cold-stabilizing activities of MBP and of STOP in developing oligodendrocytes. In wild-type oligodendrocytes, microtubules were cold stable throughout maturation, which is consistent with the presence of STOP proteins from early stages of differentiation. In contrast, in oligodendrocytes from STOP-deficient mice, microtubules were cold labile in the absence of MBP expression or when MBP expression was restricted to the cell body and became stable in fully differentiated oligodendrocytes, where MBP is expressed in cell extensions. The suppression of MBP by RNA interference in STOP-deficient oligodendrocytes suppressed microtubule cold stability. Additionally, STOP suppression in oligodendrocytes derived from shiverer mice that lack MBP led to the complete suppression of microtubule cold stability at all stages of cell differentiation. These results demonstrate that both STOP and MBP function as microtubule-stabilizing proteins in differentiating oligodendrocytes and could be important for the morphogenetic function of MBP.

STOP proteins.

Microtubules assembled from pure tubulin in vitro are labile, rapidly depolymerized upon exposure to the cold. In contrast, in a number of cell types, cytoplasmic microtubules are stable, resistant to prolonged cold exposure. During the past years, the molecular basis of this microtubule stabilization in cells has been elucidated. Cold stability is due to polymer association with different variants of a calmodulin-regulated protein, STOP protein. The dynamic and hence the physiological consequences of STOP association with microtubules vary in different tissues. In neurons, STOP seems almost permanently associated with microtubules. STOP is apparently a major determinant of microtubule turnover in such cells and is required for normal neuronal differentiation. In cycling cells, only minor amounts of STOP are associated with interphase microtubules and STOP does not measurably affects microtubule dynamics. However, STOP is associated with mitotic microtubules in the spindle. Recent results indicate that such an association could be vital for meiosis and for the long-term fidelity of the mitotic process.

A mutation in a Rhodobacter capsulatus gene encoding an integration host factor-like protein impairs in vivo hydrogenase expression.

A gene capable of encoding a protein sharing 45% identical amino acids with the alpha subunit of the integration host factor (IHF) of Escherichia coli was isolated from the photosynthetic bacterium Rhodobacter capsulatus strain B10 by complementation of a hydrogenase-deficient (Hup-) mutant, IR4. A DNA fragment of 274 base pairs containing an IHF binding consensus sequence, isolated from the promoter region of the hydrogenase structural genes (hupSL), was shown by gel retardation assays to bind the IHF protein from E. coli. The product of the R. capsulatus gene was shown to bind specifically to the 274-base-pair DNA fragment from the hupSL promoter. By analogy to the E. coli himA gene, which encodes the alpha subunit of IHF, the gene complementing the IR4 mutant was named himA of R. capsulatus. The wild-type himA gene, cloned in plasmid pBO2, was introduced into the IR4 strain and shown to restore, in trans, hydrogenase activity and autotrophic growth in the mutant. In IR4, a C----T transition mutation had replaced Arg-8 by Cys-8. Gel mobility shifts of the 274-base-pair DNA fragment, not observed with the himA gene product of IR4, were restored with extracts from IR4(pBO2) cells, containing the himA gene on the recombinant plasmid pBO2.

Astrocytes and oligodendrocytes express different STOP protein isoforms.

Many cell types contain subpopulations of microtubules that resist depolymerizing conditions, such as exposure to cold or to the drug nocodazole. This stabilization is due mainly to polymer association with STOP proteins. In mouse, neurons express two major variants of these proteins, N-STOP and E-STOP (120 kDa and 79 kDa, respectively), whereas fibroblasts express F-STOP (42 kDa) and two minor variants of 48 and 89 kDa. N- and E-STOP induce microtubule resistance to both cold and nocodazole exposure, whereas F-STOP confers microtubule stability only to the cold. Here, we investigated the expression of STOP proteins in oligodendrocytes and astrocytes in culture. We found that STOP proteins were expressed in precursor cells, in immature and mature oligodendrocytes, and in astrocytes. We found that oligodendrocytes express a major STOP variant of 89 kDa, which we called O-STOP, and two minor variants of 42 and 48 kDa. The STOP variants expressed by oligodendrocytes induce microtubule resistance to the cold and to nocodazole. For astrocytes, we found the expression of two STOP variants of 42 and 48 kDa and a new STOP isoform of 60 kDa, which we called A-STOP. The STOP variants expressed by astrocytes induce microtubule resistance to the cold but not to nocodazole, as fibroblast variants. In conclusion, astrocytes and oligodendrocytes express different isoforms of STOP protein, which show different microtubule-stabilizing capacities.

Identification of novel bifunctional calmodulin-binding and microtubule-stabilizing motifs in STOP proteins.

Although microtubules are intrinsically labile tubulin assemblies, many cell types contain stable polymers, resisting depolymerizing conditions such as exposure to the cold or the drug nocodazole. This microtubule stabilization is largely due to polymer association with STOP proteins. There are several STOP variants, some with capacity to induce microtubule resistance to both the cold and nocodazole, others with microtubule cold stabilizing activity only. These microtubule-stabilizing effects of STOP proteins are inhibited by calmodulin and we now demonstrate that they are determined by two distinct kinds of repeated modular sequences (Mn and Mc), both containing a calmodulin-binding peptide, but displaying different microtubule stabilizing activities. Mn modules induce microtubule resistance to both the cold and nocodazole when expressed in cells. Mc modules, which correspond to the STOP central repeats, have microtubule cold stabilizing activity only. Mouse neuronal STOPs, which induce both cold and drug resistance in cellular microtubules, contain three Mn modules and four Mc modules. Compared with neuronal STOPs, the non-neuronal F-STOP lacks multiple Mn modules and this corresponds with an inability to induce nocodazole resistance. STOP modules represent novel bifunctional calmodulin-binding and microtubule-stabilizing sequences that may be essential for the generation of the different patterns of microtubule stabilization observed in cells.

Genomic structure and chromosomal mapping of the mouse STOP gene (Mtap6).

The microtubule associated protein STOP (Stable Tubule Only Polypeptide) is a calmodulin-regulated protein able to induce a high degree of microtubule stability. STOP is abundant in neurons which contain large subpopulations of stable microtubules. Genomic clones spanning 67 kb and encompassing the mouse STOP gene (Mtap6) have been isolated and characterized. These clones derive from a single gene mapping to the E2-F1 region of mouse chromosome 7. The gene is composed of 4 exons that exhibit conventional vertebrate splicing sequences. Transcription of the gene initiate at multiple sites in a 85 nucleotide region located 530 bases upstream the translation initiation codon. Accordingly, the 5' flanking region of the gene lacks a TATA box or an initiator element at usual position. The protein encoded by the mouse STOP gene (Mtap6) is composed of 906 amino acids and presents a 91% identities with the rat brain STOP.

Nonneuronal isoforms of STOP protein are responsible for microtubule cold stability in mammalian fibroblasts.

A number of cycling mammalian cells, such as NIH 3T3, contain abundant subsets of cold-stable microtubules. The origin of such microtubule stabilization in nonneuronal cells is unknown. We have previously described a neuronal protein, stable tubule-only polypeptide (STOP), that binds to microtubules and induces cold stability. We find that NIH 3T3 fibroblasts contain a major 42-kDa isoform of STOP (fibroblastic STOP, F-STOP). F-STOP contains the central repeats characteristic of brain STOP but shows extensive deletions of N- and C-terminal protein domains that are present in brain STOP. These deletions arise from differences in STOP RNA splicing. Despite such deletions, F-STOP has full microtubule stabilizing activity. F-STOP accumulates on cold-stable microtubules of interphase arrays and is present on stable microtubules within the mitotic spindle of NIH 3T3 cells. STOP inhibition by microinjection of affinity-purified STOP central repeat antibodies into NIH 3T3 cells abolishes both interphase and spindle microtubule cold stability. Similar results were obtained with Rat2 cells. These results show that STOP proteins have nonneuronal isoforms that are responsible for the microtubule cold stability observed in mammalian fibroblasts.

Cloning, expression, and properties of the microtubule-stabilizing protein STOP.

Nerve cells contain abundant subpopulations of cold-stable microtubules. We have previously isolated a calmodulin-regulated brain protein, STOP (stable tubule-only polypeptide), which reconstitutes microtubule cold stability when added to cold-labile microtubules in vitro. We have now cloned cDNA encoding STOP. We find that STOP is a 100.5-kDa protein with no homology to known proteins. The primary structure of STOP includes two distinct domains of repeated motifs. The central region of STOP contains 5 tandem repeats of 46 amino acids, 4 with 98% homology to the consensus sequence. The STOP C terminus contains 28 imperfect repeats of an 11-amino acid motif. STOP also contains a putative SH3-binding motif close to its N terminus. In vitro translated STOP binds to both microtubules and Ca2+-calmodulin. When STOP cDNA is expressed in cells that lack cold-stable microtubules, STOP associates with microtubules at 37 degrees C, and stabilizes microtubule networks, inducing cold stability, nocodazole resistance, and tubulin detyrosination on microtubules in transfected cells. We conclude that STOP must play an important role in the generation of microtubule cold stability and in the control of microtubule dynamics in brain.

[Use in hemodialysis and hemofiltration of CY 216 (Fraxiparine) administered via intravenous bolus in patients with acute and chronic renal insufficiency with and without hemorrhagic risk]. / Utilisation en hémodialyse et en hémofiltration du CY 216 (Fraxiparine) en bolus intraveineux, chez des patients insuffisants rénaux aigus et chroniques, avec et sans risque hémorragique.

The effectiveness and safety of CY 216 as anticoagulant for extracorporeal circulation were evaluated in 403 haemodialysis of haemofiltration sessions performed in 33 patients with chronic [24] or acute [9] renal failure; 149 of the sessions were carried at risk of haemorrhage. Initially CY 216 was administered as a bolus intravenous injection in doses of 7,500 anti-Xa Institut Choay units (AXa.IC.U) to patients under 50 kg, 15,000 AXa.IC.U to patients weighting between 50 and 80 kg and 22,500 AXa.IC.U to patients over 80 kg. Subsequently dosage was adjusted according to clinical results. With a median dose of 250 AXa.IC.U per kg, no haemorrhage was observed. Blood restitution was satisfactory in 84.6% of the cases, extracorporeal circulation was without clotting of fibrin deposit in 90% of the cases and the incidence of total coagulation was only 0.5%. Using CY 216 seems to be effective in preventing coagulation in the extracorporeal circuit and was well tolerated by all patients whether or not they were carried at risk of haemorrhage.

S18616, a highly potent spiroimidazoline agonist at alpha(2)-adrenoceptors: II. Influence on monoaminergic transmission, motor function, and anxiety in comparison with dexmedetomidine and clonidine.

The alpha(2)-adrenoceptor (AR) agonist, S18616 ((S)-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4,2'-(8'-chloro-1' , 2',3',4'-tetrahydronaphthalene)] accompanying article), suppressed electrical activity of adrenergic neurons in the locus ceruleus, an action reversed by the alpha(2)-AR antagonist, idazoxan, which itself enhanced their firing rate. Electrical activity of serotonergic neurons in the dorsal raphe nucleus was similarly suppressed, an action likewise blocked by idazoxan, which did not, itself, influence firing. In freely moving rats, S18616 decreased extracellular levels of norepinephrine (NE), serotonin (5-HT), and dopamine (DA) in frontal cortex and hippocampus. The selective alpha(2)- versus alpha(1)-AR antagonists, atipamezole and BRL-44408 (a preferential alpha(2A)-AR antagonist), elevated levels of NE and DA but not 5-HT. In their presence, the influence of S18616 on frontocortical levels of NE, DA, and 5-HT was blocked. In contrast, prazosin, a selective alpha(1)- versus alpha(2)-AR antagonist (which also preferentially blocks alpha(2B/2C)-ARs) dose dependently decreased levels of 5-HT, but not NE and DA, and failed to modify the actions of S18616. Ultrasonic vocalizations elicited by rats in an aversive environment were inhibited by S18616, which also suppressed aggressive and marble-burying behaviors in mice. Furthermore, S18616 (biphasically) enhanced punished responses in the Vogel conflict test and active social interaction tests in rats. At higher doses, S18616 displayed sedative/hypnotic properties. Both anxiolytic and motor actions of S18616 were inhibited by atipamezole and BRL-44408 but not prazosin. Dexmedetomidine mimicked the actions of S18616 at higher doses except for more potent sedative/hypnotic properties. Clonidine also mimicked S18616, but only at markedly higher doses. In conclusion, via activation of alpha(2)-ARs, S18616 potently inhibits corticolimbic adrenergic, serotonergic, and (frontocortical) dopaminergic transmission in parallel with the expression of its anxiolytic and sedative properties.

Role of fibrates and HMG-CoA reductase inhibitors in gallstone formation: epidemiological study in an unselected population.

Fibrate derivatives and HMG-CoA reductase inhibitors modify homeostasis of cholesterol. The aim of this study was to assess in an unselected population whether these hypolipidemic drugs are risk factors for cholelithiasis or, conversely, are protective agents. Both sexes, all socioeconomic categories, pregnant women, and cholecystectomized subjects were included. Clinical data collection and gallbladder ultrasonography were both carried out in a double-blind fashion. Fibrate derivatives were predominantly fenofibrate, HMG-CoA reductase inhibitors were simvastatin and pravastatin. On univariate analysis, age (>50 years), sex, and use of fibrates were found to be significantly related to the presence of cholelithiasis. Age, sex, and fibrate treatment remained independently correlated with the presence of gallstones on multivariate analysis. With fibrates, the relative risk for lithiasis was 1.7 (P = 0.04). The HMG-CoA reductase inhibitors were not associated with a protective effect on univariate analysis. Of the lipid-lowering drugs, only fibrate derivatives were found to increase the risk of gallstone formation.