Intermediate and premutation FMR1 alleles in women with occult primary ovarian insufficiency.

OBJECTIVE: To compare the prevalence of intermediate and premutation FMR1 alleles in women with occult primary ovarian insufficiency (oPOI) and in controls. DESIGN: Observational study. SETTING: Division of Infertility and Service of Genetic Medicine, Geneva University Hospitals. PATIENT(S): The study group consisted of 27 infertile women with oPOI referred by infertility specialists for FMR1 testing in 2005-6 because of unexplained poor response to controlled ovarian hyperstimulation or altered hormonal profiles. The control group consisted of 32 women undergoing genetic testing for conditions unrelated to mental retardation or ovarian function. The DNA samples were anonymized. INTERVENTION(S): In the study group, data were collected concerning reproductive/family history, hormonal markers, possible fertility treatment outcomes, and results of karyotype and FMR1 testing. In the control group, FMR1 gene testing was done. The only clinical data available in controls were sex and indication for genetic testing. MAIN OUTCOME MEASURE(S): Distribution of FMR1 alleles. RESULT(S): Six (22%) of 27 women with oPOI had FMR1 alleles of >40 repeats (intermediate to premutation range), compared with one (3%) of 32 controls. CONCLUSION(S): These results suggest that women with oPOI might be at risk of carrying alleles in the intermediate and premutation range.

Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis.

OBJECTIVE: To evaluate the safety and efficacy of 2 doses of dexamethasone intravitreal implant (DEX implant) for treatment of noninfectious intermediate or posterior uveitis. METHODS: In this 26-week trial, eyes with noninfectious intermediate or posterior uveitis were randomized to a single treatment with a 0.7-mg DEX implant (n = 77), 0.35-mg DEX implant (n = 76), or sham procedure (n = 76). MAIN OUTCOME MEASURE: The main outcome measure was the proportion of eyes with a vitreous haze score of 0 at week 8. RESULTS: The proportion of eyes with a vitreous haze score of 0 at week 8 was 47% with the 0.7-mg DEX implant, 36% with the 0.35-mg DEX implant, and 12% with the sham (P < .001); this benefit persisted through week 26. A gain of 15 or more letters from baseline best-corrected visual acuity was seen in significantly more eyes in the DEX implant groups than the sham group at all study visits. The percentage of eyes with intraocular pressure of 25 mm Hg or more peaked at 7.1% for the 0.7-mg DEX implant, 8.7% for the 0.35-mg DEX implant, and 4.2% for the sham (P > .05 at any visit). The incidence of cataract reported in the phakic eyes was 9 of 62 (15%) with the 0.7-mg DEX implant, 6 of 51 (12%) with the 0.35-mg DEX implant, and 4 of 55 (7%) with the sham (P > .05). CONCLUSIONS: In patients with noninfectious intermediate or posterior uveitis, a single DEX implant significantly improved intraocular inflammation and visual acuity persisting for 6 months. Application to Clinical Practice Dexamethasone intravitreal implant may be used safely and effectively for treatment of intermediate and posterior uveitis. Trial Registration clinicaltrials.gov Identifier: NCT00333814.

Developmental changes in the heavy subunit of neurofilaments in the corpus callosum of the cat.

In the corpus callosum of the cat, the heavy subunit of neurofilaments (NFH) can be demonstrated with the monoclonal antibody NE14, as early as P11, not at P3, and only in a few axons. At P18-19 and more markedly at P29, many more callosal axons have become positive to NE14 and this is similar to what is found in the adult. In contrast, callosal axons become positive to the neurofilament antibody SMI-32 only between P29 and P39 and remain positive in the adult. Treatment with alkaline phosphatase prevents axonal staining with NE14, but results in SMI-32 staining of a few callosal axons as early as P11, but not at P3. Between P11 and P19 the number of axons stained with SMI-32 after alkaline phosphatase treatment increases, in parallel with that of axons stained with NE14. Thus NE14 appears to recognize a phosphorylated form of NFH, while SMI-32 appears to recognize an epitope of NFH which is either masked by phosphate or inaccessible until between P29 and P39, unless the tissue is treated with alkaline phosphatase. These two forms of NFH appear towards the end of the period of massive developmental elimination of callosal axons. They are also synchronous with changes in the spacing of neurofilaments quantified in a separate ultrastructural study. These cytoskeletal changes may terminate the juvenile-labile state of callosal axons and allow further axial growth of the axon.

Etalonnage de trois épreuves de recognition continue : Effets de l'âge, du sexe et du niveau socio-professionnel sur les mesures de discrimination et de biais de réponse. [Standardization of three continuous recognition test forms - Effects of age, sex and socio-economic level on measurements of discrimination and response bias.]

Nous présontons l'étalonnage d'un test mnésique de recognition dans un échantillon de 180 adultes francophones de la Suisse Romande. Le test comprend trois formes utilisant un matériel verbal (mots) ou non verbal (visages ou paysages). Une attention particulière est accordée à l'âge dans la présentation des résultats. Celui-ci affecte plus précocement et plus intensément la performance aux formes non verbales qu'à la forme verbale du test. Il induit également une importante augmentation du nombre de fausses reconnaissances pour les formes non verbales.

Association of urethral toxicity with dose exposure in combined high-dose-rate brachytherapy and intensity-modulated radiation therapy in intermediate- and high-risk prostate cancer.

INTRODUCTION: To report acute and late toxicities in patients with intermediate- and high-risk prostate cancer treated with combined high-dose-rate brachytherapy (HDR-B) and intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS: From March 2003 to September 2005, 64 men were treated with a single implant HDR-B with 21 Gy given in three fractions, followed by 50 Gy IMRT along with organ tracking. Median age was 66.1 years, and risk of recurrence was intermediate in 47% of the patients or high in 53% of the patients. Androgen deprivation therapy was received by 69% of the patients. Toxicity was scored according to the CTCAE version 3.0. Median follow-up was 3.1 years. RESULTS: Acute grade 3 genitourinary (GU) toxicity was observed in 7.8% of the patients, and late grades 3 and 4 GU toxicity was observed in 10.9% and 1.6% of the patients. Acute grade 3 gastrointestinal (GI) toxicity was experienced by 1.6% of the patients, and late grade 3 GI toxicity was absent. The urethral V(120) (urethral volume receiving &gt; or =120% of the prescribed HDR-B dose) was associated with acute (P=.047) and late &gt; or = grade 2 GU toxicities (P=.049). CONCLUSIONS: Late grades 3 and 4GU toxicity occurred in 10.9% and 1.6% of the patients after HDR-B followed by IMRT in association with the irradiated urethral volume. The impact of V(120) on GU toxicity should be validated in further studies.

Acute toxicity of curative radiotherapy for intermediate risk localized prostate cancer in the EORTC trial 22991

Introduction: EORTC trial 22991 randomly assessed the addition of concomitant and adjuvant short-term hormonal therapy to curative conformal/intensity-modulated radiotherapy (RT) for intermediate risk localized prostate cancer. We report the acute toxicity (assessed weekly during RT) for the organs at risk (genito-urinary (GU) and gastro-intestinal (GI)) in relation to radiation parameters. Material and Methods: Eligibility criteria were age _80 years, PSA _ 50 ng/ml, N0M0 and either tumour stage cT2a (1997 UICC TNM) or cT1b-c combined with PSA_10 ng/ml and/or Gleason score _7. We report toxicity for all eligible patients who received the planned RT with documented acute toxicity (CTCAEv.2) and RT-quality assurance parameters. The RT dose (70 Gy, 74 Gy or 78 Gy) and technique (3DCRT vs IRMT) were per institution choice, the randomization was stratified for institution. Statistical significance was set at 0.05. (ClinicalTrials.gov: NCT00021450) Results: Of 819 randomized patients, 28 were excluded from the analysis (3 with <60 Gy RT, 25 with missing information). Of the 791 analysed patients, 652 (82.4%) were treated with 3D-CRT, 139 with IMRT. In the 3DCRT group, 195 patients (29.9%) were treated with a total prescribed dose of 70 Gy; 376 (57.7%) with 74 Gy and 81 (12.4%) with 78 Gy. In the IMRT group, 28 (20.1%) were treated to a total dose of 74 Gy and 111 (79.9%) with 78 Gy. Overall, only 7 of 791 patients (0.9%) had grade 3 GI toxicity during RT: diarrhea (N = 6), rectal bleeding (N = 1) and proctitis (N = 1). Fifty patients (6.3%) had grade 3 GU toxicity: urinary frequency (N = 38, 4.6%), dysuria (N = 14, 1.7%), urinary retention (N = 11, 1.3%), urinary incontinence (N = 2) and hematuria (N = 1). No grade 4 toxicity was reported. Hormonal treatment did not influence the risk of side effects (p>0.05). The risk of grade _2 GI toxicity significantly correlated to D50%-rectum (p = 0.004) with a cut-of value of 44 Gy. The risk of grade _2 GU toxicity was moderately affected by Dmax-bladder (p = 0.051). Overall, only 14 patients (1.8%) had residual grade 3 toxicities one month after RT. Conclusion: 3D-CRT and IMRT up to 78 Gy is well tolerated. Dmaxbladder and D50%-rectum were related to the risk of grade_2 GU and GI toxicity, respectively. IMRT lowered D50% rectum and Dmax-bladder. An irradiated volume >400 cc for 3D-RT and a dose of 78 Gy, even for IMRT, negatively affected those parameters and increased the risk for toxicity.

Volcanic debris avalanche deposits of the upper Maronne valley (Cantal Volcano, France): evidence for contrasted formation and transport mechanisms

The deposits of two volcanic debris avalanches (VDA I and II) that occur in the upper Maronne valley, northwest sector of Cantal Volcano, France, were studied to establish their mechanisms of formation, transport and deposition. These two volcanic debris avalanches that clearly differ with regard to their structures, textures and extensions, exemplify the wide spectrum of events associated with large-scale sector collapse. VDA I is voluminous (similar to1 km(3) in the upper Maronne valley) and widespread. The deposits comprise two distinct facies: the block facies that forms the intermediate and upper part of the unit and the mixed facies that crops out essentially at the base of the unit. The block facies consists of more or less brecciated lava, block-and-ash-flow breccia and pumice-flow tuff megablocks set in breccias resulting from block disaggregation. Mixing and differential movements are almost absent in this part of the VDA. The mixed facies consists of breccias rich in fine particles that originate from block disagregation, as well as being picked up from the substratum during movement. Mixing and differential movements are predominant in this zone. Analysis of fractures on lava megablocks suggests that shear stress during the initial sliding is the principal cause of fracture. These data strongly indicate that VDA I is purely gravitational and argue for a model in which the initial sliding mass transforms into a flow due to differential in situ fragmentation caused by the shear stress. VDA II is restricted to low-topography areas. Its volume, in the studied area, is about 0.3 km(3). The deposits consist of brecciated, rounded blocks and megablocks set in a fine-grained matrix composed essentially of volcanic glass. This unit is stratified, with a massive layer that contains all the megablocks at the base and in the intermediate part, and in the upper part a normally graded layer that contains only blocks <1 m in size. The different lithologies present are totally mixed. These observations suggest that VDA II may be of the Bezymianny-type and that it underwent a flow transformation from a turbulent to a stratified flow consisting of a basal hyperconcentrated laminar body overlain by a dilute layer. (C) 2000 Elsevier Science B.V. All rights reserved.

Early intervention for conversion disorder: neurologists and psychiatrists working together

It has been shown that for the reaction catalyzed by "biodegradative" L-threonine dehydratase from E. coli strains K-12 and 980 in 0.5 M phosphate-carbonate buffer, pH 8.4 and pH 9.5, the plots of initial reaction rate (v) versus the initial substrate concentration ([S]0 are characterized by several inflection points, i. e. an intermediate plateau. The plot of v versus the allosteric activator (AMP) concentration have very complicated shapes: there are several inflection points, and also the maximum at L-threonine concentration equal to 3-10(2) and 5-10(-2) M. High AMP concentrations inhibit the enzyme at high substrate concentrations. The reduced glutathion dose not influence the enzyme and does not alter the activating effect of AMP. On the basis of the data obtained it is proposed that the substrate and AMP shift the equilibrium between multiple oligomeric enzyme forms differing in catalytic activity and kinetic manifestations of allosteric interactions between the active and allosteric AMP-binding sites towards polymerization. Thus, the functioning the enzyme under study is discussed in the frames of the model of dissociating regulatory enzymes with multiple intermediate oligomeric forms.

Alterations in neurofilament protein immunoreactivity in human hippocampal neurons related to normal aging and Alzheimer's disease.

The distribution of immunoreactivity for the neurofilament triplet class of intermediate filament proteins was examined in the hippocampus of young, adult and elderly control cases and compared to that of Alzheimer's disease cases. In a similar fashion to non-human mammalian species, pyramidal neurons in the CA1 region showed a very low degree of neurofilament triplet immunoreactivity in the three younger control cases examined. However, in the other control cases of 49 years of age and older, many CA1 pyramidal neurons showed elevated neurofilament immunoreactivity. In the Alzheimer's disease cases, most of the surviving CA1 neurons showed intense labeling for the neurofilament triplet proteins, with many of these neurons giving off abnormal "sprouting" processes. Double labeling demonstrated that many of these neurons contained tangle-like or granular material that was immunoreactive for abnormal forms of tau and stained with thioflavine S, indicating that these neurons are in a transitional degenerative stage. An antibody to phosphorylated neurofilament proteins labeled a subset of neurofibrillary tangles in the Alzheimer's disease cases. However, following formic acid pre-treatment, the number of neurofibrillary tangles showing phosphorylated neurofilament protein immunoreactivity increased, with double labeling confirming that all of the tau-immunoreactive neurofibrillary tangles were also immunoreactive for phosphorylated neurofilament proteins. Immunoblotting demonstrated that there was a proportionately greater amount of the neurofilament triplet subunit proteins in hippocampal tissue from Alzheimer's disease cases as compared to controls. These results indicate that there are changes in the cytoskeleton of CA1 neurons associated with age which are likely to involve an increase in the level of neurofilament proteins and may be a predisposing factor contributing towards their high degree of vulnerability in degenerative conditions such as Alzheimer's disease. The cellular factors affecting hippocampal neurons during aging may be potentiated in Alzheimer's disease to result in even higher levels of intracellular neurofilament proteins and the progressive alterations of neurofilaments and other cytoskeletal proteins that finally results in neurofibrillary tangle formation and cellular degeneration.

Persisting atypical and cystic forms of Borrelia burgdorferi and local inflammation in Lyme neuroborreliosis

BACKGROUND: The long latent stage seen in syphilis, followed by chronic central nervous system infection and inflammation, can be explained by the persistence of atypical cystic and granular forms of Treponema pallidum. We investigated whether a similar situation may occur in Lyme neuroborreliosis. METHOD: Atypical forms of Borrelia burgdorferi spirochetes were induced exposing cultures of Borrelia burgdorferi (strains B31 and ADB1) to such unfavorable conditions as osmotic and heat shock, and exposure to the binding agents Thioflavin S and Congo red. We also analyzed whether these forms may be induced in vitro, following infection of primary chicken and rat neurons, as well as rat and human astrocytes. We further analyzed whether atypical forms similar to those induced in vitro may also occur in vivo, in brains of three patients with Lyme neuroborreliosis. We used immunohistochemical methods to detect evidence of neuroinflammation in the form of reactive microglia and astrocytes. RESULTS: Under these conditions we observed atypical cystic, rolled and granular forms of these spirochetes. We characterized these abnormal forms by histochemical, immunohistochemical, dark field and atomic force microscopy (AFM) methods. The atypical and cystic forms found in the brains of three patients with neuropathologically confirmed Lyme neuroborreliosis were identical to those induced in vitro. We also observed nuclear fragmentation of the infected astrocytes using the TUNEL method. Abundant HLA-DR positive microglia and GFAP positive reactive astrocytes were present in the cerebral cortex. CONCLUSION: The results indicate that atypical extra- and intracellular pleomorphic and cystic forms of Borrelia burgdorferi and local neuroinflammation occur in the brain in chronic Lyme neuroborreliosis. The persistence of these more resistant spirochete forms, and their intracellular location in neurons and glial cells, may explain the long latent stage and persistence of Borrelia infection. The results also suggest that Borrelia burgdorferi may induce cellular dysfunction and apoptosis. The detection and recognition of atypical, cystic and granular forms in infected tissues is essential for the diagnosis and the treatment as they can occur in the absence of the typical spiral Borrelia form.