NR2E3 mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP).

NR2E3, also called photoreceptor-specific nuclear receptor (PNR), is a transcription factor of the nuclear hormone receptor superfamily whose expression is uniquely restricted to photoreceptors. There, its physiological activity is essential for proper rod and cone photoreceptor development and maintenance. Thirty-two different mutations in NR2E3 have been identified in either homozygous or compound heterozygous state in the recessively inherited enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), and clumped pigmentary retinal degeneration (CPRD). The clinical phenotype common to all these patients is night blindness, rudimental or absent rod function, and hyperfunction of the "blue" S-cones. A single p.G56R mutation is inherited in a dominant manner and causes retinitis pigmentosa (RP). We have established a new locus-specific database for NR2E3 (www.LOVD.nl/eye), containing all reported mutations, polymorphisms, and unclassified sequence variants, including novel ones. A high proportion of mutations are located in the evolutionarily-conserved DNA-binding domains (DBDs) and ligand-binding domains (LBDs) of NR2E3. Based on homology modeling of these NR2E3 domains, we propose a structural localization of mutated residues. The high variability of clinical phenotypes observed in patients affected by NR2E3-linked retinal degenerations may be caused by different disease mechanisms, including absence of DNA-binding, altered interactions with transcriptional coregulators, and differential activity of modifier genes.

Phenotypic consequences of copy number variation: insights from Smith-Magenis and Potocki-Lupski syndrome mouse models.

A large fraction of genome variation between individuals is comprised of submicroscopic copy number variation of genomic DNA segments. We assessed the relative contribution of structural changes and gene dosage alterations on phenotypic outcomes with mouse models of Smith-Magenis and Potocki-Lupski syndromes. We phenotyped mice with 1n (Deletion/+), 2n (+/+), 3n (Duplication/+), and balanced 2n compound heterozygous (Deletion/Duplication) copies of the same region. Parallel to the observations made in humans, such variation in gene copy number was sufficient to generate phenotypic consequences: in a number of cases diametrically opposing phenotypes were associated with gain versus loss of gene content. Surprisingly, some neurobehavioral traits were not rescued by restoration of the normal gene copy number. Transcriptome profiling showed that a highly significant propensity of transcriptional changes map to the engineered interval in the five assessed tissues. A statistically significant overrepresentation of the genes mapping to the entire length of the engineered chromosome was also found in the top-ranked differentially expressed genes in the mice containing rearranged chromosomes, regardless of the nature of the rearrangement, an observation robust across different cell lineages of the central nervous system. Our data indicate that a structural change at a given position of the human genome may affect not only locus and adjacent gene expression but also "genome regulation." Furthermore, structural change can cause the same perturbation in particular pathways regardless of gene dosage. Thus, the presence of a genomic structural change, as well as gene dosage imbalance, contributes to the ultimate phenotype.

Choline-PET in prostate cancer management: The point of view of the radiation oncologist.

Among PET radiotracers, FDG seems to be quite accepted as an accurate oncology diagnostic tool, frequently helpful also in the evaluation of treatment response and in radiation therapy treatment planning for several cancer sites. To the contrary, the reliability of Choline as a tracer for prostate cancer (PC) still remains an object of debate for clinicians, including radiation oncologists. This review focuses on the available data about the potential impact of Choline-PET in the daily clinical practice of radiation oncologists managing PC patients. In summary, routine Choline-PET is not indicated for initial local T staging, but it seems better than conventional imaging for nodal staging and for all patients with suspected metastases. In these settings, Choline-PET showed the potential to change patient management. A critical limit remains spatial resolution, limiting the accuracy and reliability for small lesions. After a PSA rise, the problem of the trigger PSA value remains crucial. Indeed, the overall detection rate of Choline-PET is significantly increased when the trigger PSA, or the doubling time, increases, but higher PSA levels are often a sign of metastatic spread, a contraindication for potentially curable local treatments such as radiation therapy. Even if several published data seem to be promising, the current role of PET in treatment planning in PC patients to be irradiated still remains under investigation. Based on available literature data, all these issues are addressed and discussed in this review.

Immunological abnormalities of acquired immunodeficiency syndrome and related disorders in patients from Rio de Janeiro, Brazil

The immunoloical profile of acquired immunodeficiency syndrome (AIDS) and chronic lymphadenopathy syndrome (CLAS) in 15 and 11 Brazilian patients, respectively, was studied. The AIDS patients showed reduced percentage of total T (CD3) and T-helper-inducer (CD4) lymphocytes, relative increase in numbers of T-suppressor-cytotoxic (CD8) cells and a marked inversion of T-helper-inducer/suppressor-cytotoxic (CD4/CD8) ratio. Lymphoproliferative responses to PHA, ConA, PPD and PWM were diminished. Hypergamaglobulinemia and high levels of circulating immune complexes were also found. The CLAS patients also showed important immunological alterations, but not so intense as those with AIDS. These data seems to be similar to those observed in other parts of the world.

Superior outcome of women with stage I/II cutaneous melanoma: pooled analysis of four European Organisation for Research and Treatment of Cancer phase III trials.

PURPOSE: Several studies observed a female advantage in the prognosis of cutaneous melanoma, for which behavioral factors or an underlying biologic mechanism might be responsible. Using complete and reliable follow-up data from four phase III trials of the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group, we explored the female advantage across multiple end points and in relation to other important prognostic indicators. PATIENTS AND METHODS: Patients diagnosed with localized melanoma were included in EORTC adjuvant treatment trials 18832, 18871, 18952, and 18961 and randomly assigned during the period of 1984 to 2005. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs for women compared with men, adjusted for age, Breslow thickness, body site, ulceration, performed lymph node dissection, and treatment. RESULTS: A total of 2,672 patients with stage I/II melanoma were included. Women had a highly consistent and independent advantage in overall survival (adjusted HR, 0.70; 95% CI, 0.59 to 0.83), disease-specific survival (adjusted HR, 0.74; 95% CI, 0.62 to 0.88), time to lymph node metastasis (adjusted HR, 0.70; 95% CI, 0.51 to 0.96), and time to distant metastasis (adjusted HR, 0.69; 95% CI, 0.59 to 0.81). Subgroup analysis showed that the female advantage was consistent across all prognostic subgroups (with the possible exception of head and neck melanomas) and in pre- and postmenopausal age groups. CONCLUSION: Women have a consistent and independent relative advantage in all aspects of the progression of localized melanoma of approximately 30%, most likely caused by an underlying biologic sex difference.

Status epilepticus in fragile X syndrome.

Epilepsy is frequent in fragile X syndrome (FXS), the most common cause of inherited mental retardation. Status epilepticus (SE), however, seems exceptional in FXS, particularly as an initial epileptic manifestation. To our knowledge, SE was reported in only four FXS patients. We report the clinical features and electroencephalography (EEG) findings of five children with FXS, who presented with SE as their initial seizure.

An outbreak of american cutaneous leishmaniasis (Leishmania braziliensis braziliensis) in a periurban area of Rio de Janeiro city, Brazil: clinical and epidemiological studies

From July 1984 to September 1986, 105 cases of American cutaneous leishmaniasis were studied in a locality closely situated to an urbanized area of the city of Rio de Janeiro, Brazil. Settement in this area was established at least 20 years ago but the first cases were noted six months prior to the beginning of this study. Cases were almost exlusively cutaneous and ulcerated, with one to six months of evolution. Montenegro's skin tests were positive in all cases and anti-Leishmania antibodies were detected by indirect immunofluorescence test in 74.3% of the patients. Parasites were demonstrated in 69.5% of cases. Domestic animals were easily found infected; 32% of the examined dogs and 30.8% of the examined equines were positive to the presence of Leishmania in cutaneous ulcerated lesions. Parasite isolates from human, dog andequines were immunologically characterized and identified as L. b. braziliensis. 73,0% of the sandfly population were Lutzomyia intermedia mainly caught on human baits and on domestic animals. Our observations suggest that this is an area of recent established L. b. braziliensis infection and that transmission probably occurs indoors or outdoors close to the houses.

Zoonotic cutaneous leishmaniasis due to Leishmania (Viannia) braziliensis associated with domestic animals in Venezuela and Brazil

After outbreaks of cutaneous leishmaniasis in Solano State, Venezuela, 5% of the population had parasitized ulcers while after similar outbreaks in Mesquita, Rio de Janeiro State, Brazil, 9% had the disease. In these foci children, including some under six years of age, wre affected. There was no significant difference in the occurence of the disease according to sex or type of employment. In Solano, 3% of dogs and 28% of donkeys had parasitized lesions, while in Mesquita these indices were 19.8% and 30.8% respectively. The parasite from man, dogs and equines was identified as Leishmania (Viannia) braziliensis, by zymodeme and serodeme characterization. In these foci there is evidence suggesting that leishmaniasis is a zoonosis, possibly with equine and dogs as reservoirs, although both a wild enzootic cycle and the role of man as a source of infection can not be ruled out. Transmission is assumed to occur peridomestically by sandfly vectors such as Lutzomyia panamensis in Venezuela and Lutzomyia intermedia in Brazil. Information about the origin of these foci suggests that infected equines may be an important factor in the dissemination of the parasite in a peridomestic situation where these sandflies are abundant.