Human VDAC pseudogenes: an emerging role for VDAC1P8 pseudogene in acute myeloid leukemia.

BACKGROUND: Voltage-dependent anion selective channels (VDACs) are the most abundant mitochondrial outer membrane proteins, encoded in mammals by three genes, VDAC1, 2 and 3, mostly ubiquitously expressed. As 'mitochondrial gatekeepers', VDACs control organelle and cell metabolism and are involved in many diseases. Despite the presence of numerous VDAC pseudogenes in the human genome, their significance and possible role in VDAC protein expression has not yet been considered. RESULTS: We investigated the relevance of processed pseudogenes of human VDAC genes, both in physiological and in pathological contexts. Using high-throughput tools and querying many genomic and transcriptomic databases, we show that some VDAC pseudogenes are transcribed in specific tissues and pathological contexts. The obtained experimental data confirm an association of the VDAC1P8 pseudogene with acute myeloid leukemia (AML). CONCLUSIONS: Our in-silico comparative analysis between the VDAC1 gene and its VDAC1P8 pseudogene, together with experimental data produced in AML cellular models, indicate a specific over-expression of the VDAC1P8 pseudogene in AML, correlated with a downregulation of the parental VDAC1 gene.

A dynamic web-based decision aid to improve informed choice in organised breast cancer screening. A pragmatic randomised trial in Italy.

BACKGROUND: Improving the quality of information and communication is a priority in organised breast cancer screening and an ethical duty. Programmes must offer the information each woman is looking for, promoting informed decision-making. This study aimed to develop and evaluate a web-based dynamic decision aid (DA). METHODS: A pragmatic randomised trial carried out in six regional organised screening programmes recruited women at the first invitation receiving DA or a web-based standard brochure (SB). The primary outcome was informed choice measured on knowledge, attitudes, and intentions. Follow-up period: 7-10 days. Secondary outcomes included participation rate, satisfaction, decisional conflict, and acceptability of DA. RESULTS: Two thousand one hundred and nineteen women were randomised and 1001 completed the study. Respectively, 43.9% and 36.9% in the DA and SB reached the informed choice. The DA gave a 13-point higher proportion of women aware about overdiagnosis compared to SB (38.3% versus 25.2%, p < 0.0001). The percentage of women attending screening was the same: 84% versus 83%. Decisional conflict was significantly lower in the DA group (14.4%) than in the SB group (19.3%). CONCLUSION: DA increases informed choice. Complete information including the pros, cons, controversies, and overdiagnosis-overtreatment issues boost a woman's knowledge without reducing the rate of actual screening participation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number NCT03097653.

Seizures and EEG pattern in the 22q13.3 deletion syndrome: clinical report of six Italian cases.

PURPOSE: The 22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome, is a rare genetic disorder characterized by hypotonia, severely impaired development of speech and language, autistic-like behaviour, and minor dysmorphic features. Neurologic problems may include seizures of different types, such as febrile, generalized tonic-clonic, focal, and absence seizures. No peculiar EEG features have been associated with 22q13 deletion syndrome to date. In order to verify if a peculiar clinical and EEG pattern is present in 22q13.3 deletion syndrome, we studied six Italian patients with this chromosome abnormality. METHOD: Array CGH analysis was carried out in the six subjects (1 male, 5 females, age range 11-30 years, median 19.5). They underwent a complete general and neurologic examinations. The EEG study consisted of at least one awake and one nap-sleep video-EEG recordings and evaluation of other EEGs performed elsewhere. RESULTS: Three subjects suffered from myoclonic or generalized tonic-clonic seizures with a rather benign course; all showed multifocal paroxysmal abnormalities on EEG recording, predominant over the frontal-temporal regions, activated during sleep. CONCLUSION: 22q13.3 deletion syndrome seems to be associated, at least in a subgroup of patients, with a peculiar clinical and EEG pattern, characterized by a childhood epilepsy with a rather benign evolution and with multifocal paroxysmal EEG abnormalities activated by sleep.

Definition of minimal duplicated region encompassing the XIAP and STAG2 genes in the Xq25 microduplication syndrome.

Typical Xq25 duplications are large and associated with heterogeneous phenotypes. Recently, small duplications involving this genomic region and encompassing the GRIA3 and STAG2 genes have been reported. These Xq25 microduplications are associated with a recognizable syndrome including intellectual disability and distinctive facial appearance. We report on Xq25 microduplications in two unrelated families identified by array comparative genomic hybridization. In both families, the genomic imbalances segregated with the disease in male individuals, while the phenotypes of the heterozygous females appeared to be modulated by their X-inactivation pattern. These rearrangements of about 600 kb involved only three genes: THOC2, XIAP, and STAG2. Further characterization by FISH analyses showed tandem duplication in the Xq25 locus of these genes. These data refine the Xq25 candidate region, identifying a minimal duplicated region of about 270 kb encompassing the XIAP and STAG2 genes. We discuss the function of the genes in the rearrangements and their involvement in the pathogenesis of this disorder.

Increased FGF3 and FGF4 gene dosage is a risk factor for craniosynostosis.

Interstitial duplications involving chromosome 11q have rarely been reported in the literature and mainly represent large, cytogenetically detectable rearrangements associated with a wide and variable spectrum of neurodevelopmental disorders. We report on a patient affected by intellectual disability, craniosynostosis, and microcephaly. Array-CGH analysis identified a de novo 290 kb interstitial duplication of chromosome 11q13.3 including the FGF3 and FGF4 genes. Clinical comparison of our patient with those previously reported with overlapping 11q duplications allows us to define the minimal duplicated region associated with craniosynostosis and strongly supports the hypothesis that the constitutional increased dosage of the FGF3 and FGF4 genes is a risk factor for craniosynostosis in humans.

Intragenic ILRAPL1 deletion in a male patient with intellectual disability, mild dysmorphic signs, deafness, and behavioral problems.

Intellectual disability affects approximately 2% of the population, with affected males outnumbering affected female, partly due to disturbances involving X-linked genes. To date >90 genes associated with X-linked intellectual disability have been identified and, among these, IL1RAPL1 (interleukin 1 receptor accessory protein-like 1), was first described and mapped to Xp21.3-22.1 in 1999. Intragenic deletions of IL1RAPL1, only rarely identified, have mostly been associated with nonspecific intellectual disability (IDX) and autism spectrum disorder. Array-CGH analysis performed in our patient with intellectual disability, mild dysmorphic signs and changes in behavior identified a 285 Kb deletion in chromosome Xp21.3-21.2, with breakpoints lying in IL1RAPL1 gene intron 2 and intron 3. This is the first patient reported in literature with deletion of only exon 3 of IL1RAPL1 gene. Our patient also exhibits bilateral progressive neurosensorial deafness, which has not been previously associated with IL1RAPL1 mutations.

Occurrence of anti-Toxoplasma gondii antibodies in cattle and pigs slaughtered, State of Rio de Janeiro.

This study aimed to estimate the occurrence of anti-Toxoplasma gondii antibodies by means of the Indirect Immunufluorescent Antibody Assay (IFAT) in cattle and pigs from slaughterhouses in two municipalities in the State of Rio de Janeiro. IgG anti-T. gondii antibodies was found in 1.96% (9/459) of the cattle and 7.64% (31/406) of the pigs, without any positive association (p > 0.05) with risk factors for transmission and seropositivity. Taking the cutoff point of IFAT ³ 1:64, titers of 64 and 256 were detected, suggesting chronic infection. Despite the low prevalence rates found for cattle and pigs, these indicated environmental contamination in the municipalities investigated, biosafety failures at the technified pig farm evaluated and the possibility of human and animal infection through eating raw or undercooked meat from these animals.

Occurrence of anti-Toxoplasma gondii antibodies in cattle and pigs slaughtered, State of Rio de Janeiro / Ocorrência de anticorpos anti-Toxoplasma gondii em bovinos e suínos abatidos, Estado do Rio de Janeiro

This study aimed to estimate the occurrence of anti-Toxoplasma gondii antibodies by means of the Indirect Immunufluorescent Antibody Assay (IFAT) in cattle and pigs from slaughterhouses in two municipalities in the State of Rio de Janeiro. IgG anti-T. gondii antibodies was found in 1.96 percent (9/459) of the cattle and 7.64 percent (31/406) of the pigs, without any positive association (p > 0.05) with risk factors for transmission and seropositivity. Taking the cutoff point of IFAT ³ 1:64, titers of 64 and 256 were detected, suggesting chronic infection. Despite the low prevalence rates found for cattle and pigs, these indicated environmental contamination in the municipalities investigated, biosafety failures at the technified pig farm evaluated and the possibility of human and animal infection through eating raw or undercooked meat from these animals.

Este trabalho objetivou estimar a ocorrência de anticorpos anti-Toxoplasma gondii por meio da Reação de Imunofluorescência Indireta (RIFI) em bovinos e suínos de abatedouros de dois municípios do Estado do Rio de Janeiro. Anticorpos IgG anti-T. gondii foram encontrados em 1,96 por cento (9/459) dos bovinos e em 7,64 por cento (31/406) dos suínos, sem associação positiva (p > 0,05) em relação aos fatores de risco de transmissão e a soropositividade. Considerando-se o ponto de corte (RIFI ³ 1:64), foram detectados os títulos de 64 e 256, sugestivos de infecção crônica. Apesar de baixas, as prevalências encontradas para bovinos e suínos indicaram contaminação ambiental nos municípios avaliados, falhas na biossegurança da granja tecnificada de suínos e a possibilidade de infecção humana e animal pela ingestão da carne crua ou mal passada desses animais.

Soroepidemiologia da toxoplasmose em caprinos e ovinos de três municípios do estado do Rio de Janeiro / Seroepidemiology of toxoplasmosis in goats and sheep from three counties of Rio de Janeiro state, Brazil

A toxoplasmose é uma zoonose de ampla distribuição mundial, causada pelo Toxoplasma gondii. O estudo da prevalência desta infecção em animais produtores de carne e leite é de interesse à saúde pública, devido ao fato desses produtos oriundos de animais infectados serem importantes vias de transmissão para o homem, quando consumidos in natura. Além disso, há o aspecto econômico, uma vez que pode causar aborto, retardo no crescimento e animais debilitados, levando prejuízos ao pecuarista. Este trabalho objetivou estimar a soroprevalência da infecção por T. gondii, por meio da reação de imunofluorescência indireta (RIFI) em caprinos e ovinos de três municípios do estado do Rio de Janeiro, provenientes de 10 propriedades. A prevalência de anticorpos IgG anti-T.gondii foi de 29,12 por cento (60/206) nos caprinos e de 38,05 por cento (137/360) nos ovinos, sendo observada nessa última espécie associação (p<0,05) entre sexo (fêmeas), idade adulta, sistema de criação extensivo, dieta de pastagem e água de beber de açude com a soropositividade. Os títulos variaram de 64 a 256, podendo ser sugestivos de infecção crônica. Melhorias nas técnicas de criação podem reduzir as fontes de infecção por T. gondii nos rebanhos.

Toxoplasmosis is a worldwide zoonosis caused by Toxoplasma gondii. Epidemiological surveys of T. gondii infection among livestock have great economical importance since this infection may cause abortion, growth retardation and neonatal mortality, with significant losses to breeders. In regard of public health, human infection can be acquired by ingestion of meat or milk in natura from infected livestock. The aim of this study was to assess the toxoplasmosis seroprevalence by indirect immunofluorescence antibody test (IFAT) in goats and sheep, in three counties of Rio de Janeiro state, from 10 different farms. The seroprevalences of anti-T.gondii IgG antibodies were 29.12 percent (60/206) in goats and 38.05 percent (137/360) in sheep, with titers ranging from 64 to 256, suggesting chronic infection. Association of each of the following epidemiological factors: female gender, adult age, extensive management system, grazing pasture and drinking lake water with seropositivity was observed only in sheep (p<0.05). Improvement in breeding conditions may reduce the sources of infection in herds.

The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype.

Six submicroscopic deletions comprising chromosome band 2q23.1 in patients with severe mental retardation (MR), short stature, microcephaly and epilepsy have been reported, suggesting that haploinsufficiency of one or more genes in the 2q23.1 region might be responsible for the common phenotypic features in these patients. In this study, we report the molecular and clinical characterisation of nine new 2q23.1 deletion patients and a clinical update on two previously reported patients. All patients were mentally retarded with pronounced speech delay and additional abnormalities including short stature, seizures, microcephaly and coarse facies. The majority of cases presented with stereotypic repetitive behaviour, a disturbed sleep pattern and a broad-based gait. These features led to the initial clinical impression of Angelman, Rett or Smith-Magenis syndromes in several patients. The overlapping 2q23.1 deletion region in all 15 patients comprises only one gene, namely, MBD5. Interestingly, MBD5 is a member of the methyl CpG-binding domain protein family, which also comprises MECP2, mutated in Rett's syndrome. Another gene in the 2q23.1 region, EPC2, was deleted in 12 patients who had a broader phenotype than those with a deletion of MBD5 only. EPC2 is a member of the polycomb protein family, involved in heterochromatin formation and might be involved in causing MR. Patients with a 2q23.1 microdeletion present with a variable phenotype and the diagnosis should be considered in mentally retarded children with coarse facies, seizures, disturbed sleeping patterns and additional specific behavioural problems.

15q13.3 microdeletions increase risk of idiopathic generalized epilepsy.

We identified 15q13.3 microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with idiopathic generalized epilepsy (IGE), which were not detected in 3,699 controls (joint P = 5.32 x 10(-8)). Most deletion carriers showed common IGE syndromes without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia. Our results indicate that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified to date.

Avaliação da reatividade cruzada entre antígenos de Leishmania spp e Trypanosoma cruzi na resposta sorológica de cães pela técnica de imunofluorescência indireta (RIFI) / Cross reaction evaluation of Leishmania spp and Trypanosoma cruzi antigens in dogs’ serologic response by indirect immunofluorescence test (IIF)

A leishmaniose visceral (LV) é uma zoonose causada por protozoários do gênero Leishmania. O cão é o principal reservatório do parasito, especialmente em áreas urbanas. A Reação de Imunofluorescência Indireta (RIFI) é comumente empregada para o diagnóstico da leishmaniose visceral canina (LVC), baseada na detecção de anticorpos contra o parasito. Entretanto, reações cruzadas com Trypanosoma cruzi podem ocorrer à sorologia. Com o objetivo de avaliar as reações cruzadas entre os antígenos de Leishmania spp. e de T.cruzi, foram colhidas 150 amostras de sangue de cães positivos para LVC em inquérito epidemiológico e os soros foram testados pela RIFI. Os cães foram submetidos à eutanásia no Centro de Controle de Zoonoses de Bauru (SP), área endêmica para LV. Outras 150 amostrasde sangue de cães foram colhidas em Botucatu (SP), área não endêmica para LV, e os soros foram também testados pela RIFI. Os soros de cães procedentes de Bauru resultaram positivos, tanto para Leishmania spp. quanto para T.cruzi, demonstrando uma grande incidência de reações cruzadas, reforçando a necessidade da confirmação diagnóstica por outras técnicas. As amostras de soros de cães procedentes de Botucatu (SP), pela técnica de RIFI, demonstraram baixa prevalência de resultados positivos para Leishmania spp. e para T.cruzi. Entretanto,apesar do reduzido número de resultados positivos à sorologia para ambos parasitos, a investigação sorológica e epidemiológica para LVe doença de Chagas em cães de Botucatu deve ser mantida, considerando a importância do cão como reservatório doméstico no contexto destas zoonoses.

Visceral Leishmaniasis (VL) is a zoonosis caused by Leishmania spp. protozoa. Dog is the main parasite’s reservoir, especially in urban areas. Indirect Immunofluorescent Antibody Test (IFAT) is commonly used for canine visceral leishmaniasis (CVL) diagnosis, by detection of antibodies against the parasite. However, Trypanosoma cruzi (T.cruzi) cross reactions can occur in serological diagnosis. In order to evaluate the occurrence of cross reactions between antigens of Leishmania spp. and T.cruzi, 150 blood samples of CVL epidemiological inquiry positive dogs were collected and sera were tested by IFAT. Dogs were culled at Zoonosis Control Center of Bauru (SP), an endemic area for VL. Another 150 dogs’ blood samples were collected in Botucatu (SP), a non endemic area for LV, and será were also tested by IFAT. Serum samples of dogs from Bauru were positive, both for Leishmania spp. and for T. cruzi, showing high cross-reactions incidence, reinforcing the need of diagnosis confirmation by other tests. Serum samples of dogs from Botucatu demonstrated low prevalence of positive results by IFAT, both for Leishmania spp. and T.cruzi. However, despite the low number of positive serological results for these parasites, the epidemiological and serological investigation for LV and Chagas disease in dogs from Botucatu must be kept, considering the importance of dog as domestic reservoir for both parasites.

Soroepidemiologia da infecção por Toxoplasma gondii em animais de produção e em funcionários de abatedouros e propriedades rurais do Estado do Rio de Janeiro / Soroepidemiology of Toxoplasma gondii infection in livestock and workers from slaughterhouses and farms of Rio de Janeiro State

A toxoplasmose é uma zoonose de ampla distribuição mundial, causada pelo Toxoplasma Gondii, um protozoário coccídio intracelular obrigatório, que pode infectar o homen e outros animais de sangue quente, sendo os felídeos os hospedeiros definitivos do parasito. O estudo da prevalência de T. gondii em animais de produção é de grande importância para a saúde pública, por ser a carne e leite desses animais importantes vias de transmissão para o homem, além do aspecto econômico, uma vez que pode causar aborto, retardo no crescimento e animais debilitados, levando prejuízos ao pecuarista. Sendo assim, este trabalho teve como objetivo estimar a soroprevalência da infecção por T. gondii, por meio da reação de imunofluorescência indireta (RIF), em animais de produção (bovinos, suínos, caprinos e ovinos) e em funcionários de abatedouros e propriedades rurais, em três regiões geográficas distintas do Estado do Rio de Janeiro, visando contribuir para o estudo da cadeia epidemiológica e avaliando os fatores de risco associados à infecção toxoplásmica. Foram coletados amostras de sangue de 1431 animais das quatro espécies estudadas e de 51 funcionários, contactantes ou não das carcaças dos animais abatidos, com aplicação de um questionário, que contemplava as principais variáveis epidemiológicas, tanto para os animais como para os seres humanos. Obteve-se uma prevalência de anticorpos IgG anti-T. gondii em 1,95por cento (9/459) dos bovinos, 7,64por cento (31/406) dos suínos, 29,12por cento (60/206) dos caprinos e 38,05por cento (137/360) dos ovinos, sendo observada nessa última espécie associação entre sexo (fêmeas), idade adulta, sistema de criação extensivo, dieta de pastagem e água de beber de açude com a soropositividade. Anticorpos IgG anti-T. gondii foram detectados em 79,31por cento (23/29) dos indivíduos do grupo funcionários e em 59,10por cento (13/22) dos indivíduos do grupo controle, não sendo observada diferença estatisticamente significativa entre dois grupos...

Bilateral periventricular nodular heterotopia and lissencephaly in an infant with unbalanced t(12;17)(q24.31; p13.3) translocation.

Periventricular nodular heterotopia and Miller-Dieker syndrome are two different disorders of brain development. Miller-Dieker syndrome exhibits classical lissencephaly and is related to defects in the lissencephaly gene (LIS1). Periventricular nodular heterotopia is characterized by aggregates of grey matter adjacent to the lateral ventricle and is mainly linked to mutations in the Filamin A (FLNA) gene. We describe a male infant presenting with facial dysmorphisms resembling those of Miller-Dieker syndrome, neuromotor delay, and drug - resistant infantile spasms. Magnetic resonance imaging of the brain showed periventricular nodular heterotopia overlaid by classical lissencephaly with complete agyria. Cytogenetic and molecular investigations detected a maternally inherited unbalanced translocation involving chromosome arms 17p and 12q. This resulted in partial monosomy of 17p13.3-->pter and partial trisomy of 12q24.3-->qter. No mutation was found in the FLNA gene. The patient died at the age of 22 months from respiratory insufficiency during an infection of the lower respiratory tract. Our observation extends the list of the overlying cortical malformations associated with periventricular nodular heterotopia. It remains to be established whether this peculiar neuronal migration disorder represents a phenotype totally linked to 17q13.3 deletion or results from a combination of gene defects at 17q13.3 and 12q24.3.