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Diet-induced obesity (DIO) is associated with a defect of the orosensory detection of dietary lipids in rodents. This dysfunction is not anecdotic since it might worsen the negative effects of obesity by promoting the overconsumption of energy-dense foods. Previous studies have highlighted a progressive devaluation of reward value of lipid stimuli due to a desensitization of dopaminergic brain areas in DIO mice. Paradoxically, the putative deleterious impact of obesity on peripheral fat detection by the gustatory papillae remains poorly documented. Using a whole transcriptomic investigation of the circumvallate papillae (CVP), an analysis of CVP genes involved in fat taste transduction and signaling along the day, and two bottle choice tests, we have found that (i) CVP, known to house the most taste buds in the oral cavity, displays a genic circadian rhythm, (ii) DIO reduces the oscillation of key genes involved both in the circadian clock and lipid detection/signaling, and (iii) the gene invalidation of the clock gene Rev-Erbα does not significantly affect fat preference despite an oily solution intake slightly lower than littermate controls. Taken together these data bring the first demonstration that the gustatory function is under control of a peripheral clock in mammals, as already reported in fly and suggest that a disturbance of this rhythmicity might contribute to the lower fatty taste acuity found in obese mice.

Optic nerve sheath fenestration is a surgical procedure for the treatment of many optic neuropathies. The authors developed an experimental model carried out on healthy adult rabbits in order to study the morphological consequences of an iatrogenic meningeal 'breach' in optic nerve axons, macroglia, and meninges corresponding to optic nerve fenestration. The fibrous scar which developed at the level of the fenestration was accompanied by glial hypertrophy, along with meningeal laminae which were stuck together. There was no axonal loss, but there were reactive astrocytes with gliofilament bundles. These morphological data assisted the authors in building up hypotheses which partly explain the acknowledged efficiency of this procedure for specific optic neuropathies.

Background: Conjunctival provocation tests (CPTs) are used for assessing the efficacy of antiallergic treatments, but their reproducibility is not well characterized. A study was carried out to assess the reproducibility of CPTs and the release of mediators during CPTs. Methods: Both eyes of 30 grass-pollen-allergic patients were challenged with threefold increasing concentrations of a standardized orchard grass pollen extract. The positivity of the CPT was assessed by a cumulative symptom score. The release of mediators was examined by means of histamine (radioimmunoassay), prostaglandin D 2 and leukotrienes C 4 and D 4 (enzyme immunoassay). Results: There was a significant correlation between the concentrations of allergen inducing a positive CPT in both eyes ( p 2 , 11 of 19 for leukotrienes C 4 and D 4 and 15 of 18 for histamine. The correlations between the levels of mediators released during diluent and allergen challenges in both eyes were significant for prostaglandin D 2 (diluent and allergen challenges) and leukotrienes C 4 and D 4 (allergen challenge). Conclusion: Considering the whole group of patients, CPT is reproducible in both eyes, but the results are less satisfactory when patients are examined individually.

Summary Erythrocyte deformability and aggregability, fibrinogen plasma level, and hematocrit were measured in patients with primary open-angle glaucoma and in age-matched control subjects. Only one parameter, red blood cell rigidity, as evaluated by the Hanss filtration technique, was found significantly elevated in glaucoma patients. This erythrocyte abnormality, which corroborates previous data on blood viscosity, could be an important factor in the pathogenesis of optic nerve damage and could support the hypothesis of a primary oxidative stress in glaucoma.

Summary: Purpose: To evaluate the effects on vision in patients receiving lamotrigine (LTG) monotherapy. Methods: Twenty-four consecutive patients taking LTG for partial seizures were referred for a routine ophthalmologic examination including visual acuity testing, tonometry, slit lamp, and fundus examination. Automated kinetic perimetry, electrooculogram (EOG), and electroretinogram were performed after informed consent was obtained. Results: In 18 patients finally included, the clinical ophthalmologic examination showed no abnormality. Four patients complained of blurring; among them, one patient had a visual field constriction in both eyes, which, however, was of unclear clinical significance (poor compliance) and a reduced light/dark ratio of the electrooculogram. One other patient with blurred vision had a reduced EOG, but the visual field was normal. Two patients had a reduced EOG but no visual symptoms. Considering the whole group of patients receiving LTG therapy, the light/dark ratio of the EOG was reduced in a dose-dependent fashion (p < 0.0001). The electroretinogram was normal in all patients. Conclusions: No irreversible visual field impairment in patients treated with LTG was encountered, although a dosedependent retinal toxicity may have been present. The exact cellular mechanism of the electrophysiologic changes in patients taking LTG remain to be explained. Key Words: Lamotrigine—Visual field constriction—Retinal pigment epithelium—Electrooculogram—γ -Aminobutyric acid. Lamotrigine (LTG) is an antiepileptic drug (AED) effective against both partial and generalized seizures, including generalized absence seizures. Among the documented side effects, visual blurring is reported by 23% of the patients treated with LTG (1). Although it is highly improbable that these visual symptoms are all related to a measurable dysfunction, they have never been precisely evaluated by a complete visual, clinical, and electrophysiologic investigation in patients treated with the drug. One published case exists of visual field constriction in a child treated with LTG and valproate (VPA) (2). The only established cellular mechanism of LTG is a sodium-current block (3), a mechanism in common with phenytoin (PHT) and carbamazepine (CBZ) (4). However, different from LTG, PHT and CBZ are ineffective against absence seizures and have never been associated with visual field constriction. Therefore it has been advocated that LTG may have as-yet-uncharacterized cellular actions, which could combine with its sodium channel‐ blocking actions (5). Among other effects, there appears

Amyloid deposits with Arg124 mutated TGFBI protein have been identified in autosomal dominant blinding corneal dystrophies. We assessed in vitro the mechanisms determining TGFBI protein amyloid transformation involving mutations of Arg124. Eight peptides synthesized following the TGFBI protein sequence, centered on codon Arg124 holding the previously reported amyloidogenic mutations and the respective controls were studied. Cys124 and His124 mutated peptide preparations contained significantly higher amounts of amyloid than the native peptide. Blocking the SH group of Cys124 and deleting the first four NH2-terminal amino acids including Val112-Val113 resulted in a decrease in amyloid fibril formation while deletion of the nine CONH2-terminal residues increased amyloid fibril concentration. Fourrier transformed-infrared spectroscopy analysis of the different peptide solutions showed an increase in beta-pleated sheet structures in those with enhanced amyloid yielding. We designed a peptide (BB1) likely to counteract the role of Val112-Val113 in amyloid fibril formation. Incubation of Cys124 peptide with BB1 indeed resulted in a 35% inhibition of amyloid fibril formation. Our results are in keeping with the clinical observations of Arg124 mutation-linked amyloidosis and show the importance of Val112-Val113, disulfide and hydrogen bonding in increasing the beta-pleated conformation and amyloid formation. These findings shed new light on the molecular mechanisms of TGFBI protein amyloidogenesis and encourage further research on the use of specifically designed peptides as putative therapeutic agents for these disabling diseases.

To study the modifications undergone by the macroglial cells after meningeal breach of the optic nerve in the rabbit, without optic neuropathy.The optic nerve sheath fenestration technique carried out in humans was adapted to rabbit without axonal injury in the optic nerve. The effects of meningeal fenestration on glial cells were examined by immunocytochemical procedures (day 15) using the antibodies against two astrocyte markers: glial fibrillary acidic protein (GFAP) and vimentin. Proliferation of glial cells was evaluated with single 5-bromodeoxyuridine (BrdU) labeling or double GFAP and BrdU labelings. Qualitative data on glial cells were evaluated with the electron microscope.Optic nerve sheath fenestration on healthy adult rabbits resulted in a decrease of volume of the subarachnoid space located at the level of the meningeal scar, with a significant increase of the optic nerve area. The meninges presented a fibrous scar. In the optic nerve parenchyma, astrocytes appeared hypertrophic in the vicinity of the fenestration. The whole nerve contains numerous BrdU-labeled mitotic cells, a number of which double-labeled for both BrdU and GFAP belong to the astrocyte line. There was no loss of optic nerve axons.The inflammation produced by the surgical breach of the peri-optic meningeal sheaths induces a significant reactivity, including proliferation of astrocytes in the optic nerve. Reactive astrocytes may interact positively with axons and may modify the extracellular environment in the optic nerve.

Patients with congenital stationary night blindness enjoy normal daytime vision, which is mediated by cone photoreceptors, but are blind when ambient light is so dim that a normal individual would utilize only rod photoreceptors to see without colour discrimination. The disease is genetically heterogeneous. One form of dominantly inherited congenital night blindness is eponymously named ‘Nougaret’ because pedigree analysis reveals that the disease originated in Jean Nougaret (1637–1719), a butcher who lived in Vendemian in southern France1–6. Here we report that his affected descendants carry a missense mutation in the gene encoding the a subunit of rod transducin — the G-protein that couples rhodopsin to cGMP-phosphodiesterase in the phototransduction cascade. Based on these results, rod transducin joins rhodopsin7,8 and the β subunit of rod cGMP-phosphodiesterase9 to become the third component of the rod phototransduction cascade where a defect is implicated as a cause of stationary night blindness. Interestingly, the amino acid residue in transducin affected by the Nougaret mutation is in the position homologous to that affected by the oncogenic mutation originally reported in p21ras, a distant relative in the G-protein superfamily.

PURPOSE. Retinitis punctata albescens (RPA) is an infrequently occurring form of autosomal recessive (and rarely dominant) retinal dystrophy featuring early-onset severe night blindness and tiny, dotlike, white deposits in the fundus. RPA is associated mostly with mutations in RLBP1 and occasionally in RHO, RDS, and RDH5. In this study, mutations were sought in RLBP1, which encodes the retinol binding protein CRALBP in patients with typical RPA. METHODS. Clinical investigation included funduscopy, visual field testing, electroretinogram recording, and adaptometry. The 7 coding exons (3-9) of RLBP1 and the 15th (last) exon of ABDH2 were PCR amplified and sequenced. Long-distance PCR and cloning of genomic DNA were performed to characterize the deletion. RESULTS. The study involved a 24-year-old Moroccan patient with typical RPA, born of first-cousin parents. He carried a 7.36-kb homozygous deletion encompassing the last 3 exons of RLBP1 (7, 8, and 9) and part of the intergenic region between RLBP1 and ABHD2, which lies downstream of RLBP1. This deletion abolishes the retinal binding site of CRALBP. The telomeric breakpoint of the deletion (in RLBP1 intron 6) is embedded in an Alu element, whereas the centromeric breakpoint (in the intergenic region) lies between two Alu elements placed in the opposite orientation. CONCLUSIONS. Because of the high density of Alu elements in RLBP1, a systematic search should be made for deletions in this gene when one or both alleles lack point mutations, in the case of RPA or flecked retinal dystrophy.

Background Recently, a mutation (Gly38Asp) was identified in the α subunit of rod transducin in members of the Nougaret pedigree affected with dominantly inherited stationary night blindness. Objective To evaluate retinal function in patients with the Gly38Asp gene defect. Design Ocular examinations, including specialized measures of rod and cone function. Setting A clinical research facility in Boston, Mass. Patients A father (aged 48 years) and son (aged 25 years) with the Gly38Asp mutation. Main Outcome Measures Psychophysical thresholds to white and narrowband lights and full-field electroretinographic (ERG) responses. Results Both patients showed dark-adapted thresholds to white light that were elevated approximately 2 log-units across the retina. Spectral sensitivity testing revealed thresholds that seemed to be governed mostly by rods. Although both patients' dark-adapted ERG responses to a dim blue flash were nondetectable, their dark-adapted ERGs to a white flash showed an a-wave with cone and rod components and a b-wave amplitude larger than what could have been generated by cone function alone. Rod ERGs to bright blue flashes had subnormal, but detectable, amplitudes that seemed to result from a profound reduction in sensitivity. The patients also showed loss of a cone subcomponent in the dark-adapted response to a red flash. The abnormal dark-adapted ERG responses of the patients could be simulated in the ERG responses of normal subjects tested with blue, white, and red flashes presented in the presence of a mesopic background. Conclusions Although the Nougaret form of stationary night blindness has been cited as a prototype of absent rod function with normal cone function, our findings, based on the genealogically and genotypically documented descendants of Jean Nougaret, show that rod function is present, although subnormal, and that there is slight impairment of cone function. The data also suggest that these abnormalities can be simulated by light-adapting the normal retina, compatible with the proposal that the rod transducin encoded by the mutant gene is constitutively active and that the night blindness results from partial desensitization of rods caused by the constitutive activity.

We read with interest the study by Seitz et al, 1 which was published in the August 1996 issue of theArchives. Apart from the slight mismatch concerning products and companies in the "Subjects and Methods" section, we want to focus on the results and their interpretation with reference to the difference observed between white and nonwhite volunteers. The authors underlined the fact that a racial difference has not been reported on sensitivity of the cornea. Nevertheless, Millodot 2 has already emphazised the difference between whites and blacks. Similarly, he underlined the variation of corneal sensitivity according to the color of the eye. 2,3 With white volunteers, blue eyes are on average twice as sensitive as brown eyes. These data were reviewed by Martin and Safran 4 in 1988, and they mentioned that such a difference could be dependent on the amount of neuromelanin in areas of the central nervous

Some obese subjects overeat lipid-rich foods. The origin of this eating behavior is unknown. We have here tested the hypothesis that these subjects could be characterized by an impaired fatty taste sensitivity linked to a change in the gustatory papillae microbial and salivary environment. The composition of microbiota and saliva surrounding the circumvallate papillae was analyzed in combination with the orosensory lipid detection threshold in normal weight (NW) and obese (O) adults. Microbial architecture was similar to what was known in feces, but with an increased frequency of Proteobacteria. No difference in the orosensory sensitivity to lipids and composition of oral microbiota and saliva was observed between NW and O subjects. By contrast, specific bacterial and salivary signatures were found in lipid non-tasters, irrespectively of BMI. A multivariate approach highlighted that the salivary flow, lysozyme activity, total antioxidant capacity and TM7 bacterial family discriminated between tasters and non-tasters. Subgroup analysis of obese tasters (OT) versus obese non-tasters (ONT) identified specific bacterial metabolic pathways (i.e. phosphotransferase and simple sugar transport systems) as being higher in ONT. Altogether with the identification of a set of significant salivary variables, our study suggests that an “obese tongue” phenotype is associated with decreased orosensory sensitivity to lipids in some obese subjects.

International audience; Implication of the long-chain fatty acid (LCFA) receptor GPR120, also termed free fatty acid receptor 4 (FFAR4), in the taste-guided preference for lipids is a matter of debate. To further unravel the role of GPR120 in the "taste of fat", the present study was conducted on GPR120-null mice and their wild-type littermates. Using a combination of morphological (i.e. immunohistochemical staining of circumvallate papillae - CVP), behavioral (i.e. two-bottle preference tests, licking tests and conditioned taste aversion) and functional studies (i.e. calcium imaging in freshly isolated taste bud cells - TBC), we show that absence of GPR120 in oral cavity was not associated with changes in i) the gross anatomy of CVP, ii) the LCFA-mediated increases in [Ca2+]i, iii) the preference for oily and LCFA solutions and iv) the conditioned avoidance of LCFA solutions. In contrast, the rise in [Ca2+]i triggered by grifolic acid (GA), a specific GPR120 agonist, was dramatically curtailed when GPR120 gene was lacking. Taken together these data demonstrate that activation of lingual GPR120 and preference for fat are disconnected, suggesting that GPR120 expressed in TBC is not absolutely required for the oral fat detection in the mouse.