Search

From November 2018 through February 2019, person-to-person transmission of Andes virus (ANDV) hantavirus pulmonary syndrome occurred in Chubut Province, Argentina, and resulted in 34 confirmed infections and 11 deaths. Understanding the genomic, epidemiologic, and clinical characteristics of person-to-person transmission of ANDV is crucial to designing effective interventions.Clinical and epidemiologic information was obtained by means of patient report and from public health centers. Serologic testing, contact-tracing, and next-generation sequencing were used to identify ANDV infection as the cause of this outbreak of hantavirus pulmonary syndrome and to reconstruct person-to-person transmission events.After a single introduction of ANDV from a rodent reservoir into the human population, transmission was driven by 3 symptomatic persons who attended crowded social events. After 18 cases were confirmed, public health officials enforced isolation of persons with confirmed cases and self-quarantine of possible contacts; these measures most likely curtailed further spread. The median reproductive number (the number of secondary cases caused by an infected person during the infectious period) was 2.12 before the control measures were enforced and decreased to 0.96 after the measures were implemented. Full genome sequencing of the ANDV strain involved in this outbreak was performed with specimens from 27 patients and showed that the strain that was present (Epuyén/18-19) was similar to the causative strain (Epilink/96) in the first known person-to-person transmission of hantavirus pulmonary syndrome caused by ANDV, which occurred in El Bolsón, Argentina, in 1996. Clinical investigations involving patients with ANDV hantavirus pulmonary syndrome in this outbreak revealed that patients with a high viral load and liver injury were more likely than other patients to spread infection. Disease severity, genomic diversity, age, and time spent in the hospital had no clear association with secondary transmission.Among patients with ANDV hantavirus pulmonary syndrome, high viral titers in combination with attendance at massive social gatherings or extensive contact among persons were associated with a higher likelihood of transmission. (Funded by the Ministerio de Salud y Desarrollo Social de la Nación Argentina and others.).

Involuntary moaning has been reported in sporadic cases of neurodegenerative diseases. A five-generation Hispanic family with eight members exhibiting involuntary moaning, most of whom with isolated moaning in the absence of any additional neurological disorder carried a missense variant in the NEFH gene segregating in the family.

We report a case of Argentine hemorrhagic fever diagnosed in a woman in Belgium who traveled from a disease-endemic area. Patient management included supportive care and combination therapy with ribavirin and favipiravir. Of 137 potential contacts, including friends, relatives, and healthcare and laboratory workers, none showed development of clinical symptoms of this disease., info:eu-repo/semantics/published

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected at least 180 million people since its identification as the cause of the current COVID-19 pandemic. The rapid pace of vaccine development has resulted in multiple vaccines already in use worldwide. The contemporaneous emergence of SARS-CoV-2 ‘variants of concern’ (VOC) across diverse geographic locales underscores the need to monitor the efficacy of vaccines being administered globally. All WHO designated VOC carry spike (S) polymorphisms thought to enable escape from neutralizing antibodies. Here, we characterize the neutralizing activity of post-Sputnik V vaccination sera against the ensemble of S mutations present in alpha (B.1.1.7) and beta (B.1.351) VOC. Using de novo generated replication-competent vesicular stomatitis virus expressing various SARS-CoV-2-S in place of VSV-G (rcVSV-CoV2-S), coupled with a clonal 293T-ACE2 + TMPRSS2 + cell line optimized for highly efficient S-mediated infection, we determine that only 1 out of 12 post-vaccination serum samples shows effective neutralization (IC90) of rcVSV-CoV2-S: B.1.351 at full serum strength. The same set of sera efficiently neutralize S from B.1.1.7 and exhibit only moderately reduced activity against S carrying the E484K substitution alone. Taken together, our data suggest that control of some emergent SARS-CoV-2 variants may benefit from updated vaccines., Here, the authors characterize the neutralization capacity of post-Sputnik V vaccination sera against SARS-CoV-2 variants of concern B.1.1.7 (alpha) and B.1.351 (beta), showing the latter to exhibit resistance to neutralization in vitro.

Background: Gam-COVID-Vac, also known as SPUTNIK V, is the first COVID-19 vaccine registered, has emergency use authorization in 70 nations, and has been administered to millions worldwide. However, there are very few peer-reviewed studies describing its effects. As independent reports begin to be published, a more accurate picture regarding safety and effectiveness could accelerate approval by the WHO. Methods: An ELISA that detects anti-SARS-CoV-2-spike-RBD IgG was used, in both transversal and longitudinal studies, to analyze humoral immune responses in 602 healthcare workers who received SPUTNIK V between December 2020 and July 2021.Findings: Seroconversion was detected in 97% of individuals after 28 days post-vaccination (dpv). Anti-RBD titers began to decrease after 60 dpv, but remained detectable in 94% of volunteers at 90 dpv. At 180 dpv, anti-RDB titers persisted in 31% of volunteers. Previous SARS-CoV-2 infection triggered increased immune response to the first dose, and increased neutralization activity against different variants of concern. The second dose in previously infected individuals further increased anti-RBD titers, even after 90 dpv. However, not all individuals with previous infection responded equally, as only those with basal titers above a certain threshold showed robust responses. Time elapsed between COVID-19 diagnosis and vaccination did not influence titers elicited. Interpretation: Data presented herein provides essential knowledge regarding the kinetics of antibodies induced by SPUTNIK V up to six months after immunization, and suggests that when considering one-dose vaccination policies for individuals with previous SARS-CoV-2 infection, serological studies to determine basal titers may be important, independent of when diagnosis occurred. Funding Statement: This research was supported by the Ministry of Public Health of Tucuman (Argentina), Argentinean Research Council-CONICET (PIP 722 and 806), Argentinean Research Agency-MINCYT grants (PICT-2018-3379 and PICT2018-02989), National University of Tucuman (PIUNT-UNT D644/1 and D624), and Florencio Fiorini Foundation. Declaration of Interests: B. L. is a named inventor on a patent filed by the Icahn School of Medicine which includes the 293T-ACE2-TMPRSS2 (F8-2) cells used for the virus neutralization assay. All other have nothing to declare. Ethics Approval Statement: Protocols were approved by the regional ethics research boards (Ex. N° 3929-410-P-2020), following the Declaration of Helsinki. Personal data from all volunteers were encrypted. Eligibility criteria were age between 18 to 60 years without any COVID-19 symptoms at the time of vaccination. Individuals provided a signed informed consent to be included in the database of the present study.

Antibodies are the most used technological tool in histochemistry. However, even with monoclonal antibodies, their standardization is difficult due to variation of biological systems as well as to variability due to the affinity and amplification of the signal arising from secondary peroxidase detection systems. In this article we combined two synthetic molecules to facilitate the standardization of a detection protocol of protein markers in histological sections. The first molecule was an aptamer, a 50-base single-stranded DNA fragment, which recognizes a PTEN tumor suppressor. The second molecule used was also another single stranded 18-base aptamer DNA fragment, which forms a quadruplex structure guanine box. This G-quadruplex recognizes and attaches a molecule of hemin, increasing the catalytic capacity for the hydrogen peroxide. Our results show how the correct structural design of DNA combining an aptamer together with the peroxidase-like DNAzyme allows to detect proteins in histological sections. This tool offers the standardization of the detection of prognostic markers in cancer, in quality and quantity, due to its synthetic nature and its 1:1 antigen:enzyme ratio. This is the first time that reproducible results have been presented in histological sections staining a cancer marker using a single-stranded DNA molecule with dual function.

Huntington disease (HD) is a devastating monogenic autosomal dominant disorder. HD is caused by a CAG expansion in exon 1 of the gene coding for huntingtin, placed in the short arm of chromosome 4. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. Here, we review some of the currently known functions of the wild-type huntingtin protein and discuss the deleterious effects that arise from the expansion of the CAG repeats, which are translated into an abnormally long polyglutamine tract. Also, we present a modern view on the molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. The main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as autophagy, impaired mitochondrial biogenesis, lysosomal dysfunction, organelle and protein transport, inflammation, oxidative stress, and transcription factor modulation. However, other unraveling mechanisms are still unknown. This practical and brief review summarizes some of the currently known functions of the wild-type huntingtin protein and the recent findings related to the mechanisms involved in HD pathogenesis.

Background Gam-COVID-Vac (SPUTNIK V) has been granted emergency use authorization in 70 nations and has been administered to millions worldwide. However, there are very few peer-reviewed studies describing its effects. Independent reports regarding safety and effectiveness could accelerate the final approval by the WHO. We aimed to study the long-term humoral immune response in naive and previously infected volunteers who received SPUTNIK V. Methods Humoral immune responses, assayed by anti-SARS-CoV-2-spike-RBD IgG ELISA and neutralization assays, were measured in 602 healthcare workers at 0, 14, 28, 60 and 180 days after receiving SPUTNIK V between December 2020 and July 2021 in Tucuman, Argentina. Findings Seroconversion was detected in 97% of individuals after 28 days post-vaccination (dpv) (N = 405). Anti-RBD titers began to decrease after 60 dpv (N = 328), but remained detectable in 94% at 90 dpv (N = 224). At 180 dpv, anti-RDB titers persisted in 31% (N = 146). Previous infection triggered an increased immune response to the first dose and increased neutralization activity against variants of concern (VOC). Second doses in previously infected individuals further increased titers, even 90 dpv (N = 75). Basal antibody titers had more influence on post-vaccination anti-RBD responses than the time elapsed between diagnosis and vaccination (N = 274). Interpretation Data presented herein provides essential knowledge regarding the kinetics of antibodies induced by SPUTNIK V up to six months after immunization, and suggests that when considering one-dose vaccination policies for individuals with previous SARS-CoV-2 infection, serological studies to determine basal titers may be important, independent of when diagnosis occurred. Funding Tucuman Public Health System (SIPROSA), Argentinean National Research Council (CONICET), National University of Tucuman (UNT).

A correction to this article has been published and is linked from the HTML version of this article.

Mutations in Leucine Repeat Rich Kinase 2 (LRRK2), primarily located in codons G2019 and R1441, represent the most common genetic cause of Parkinson’s disease in European-derived populations. However, little is known about the frequency of these mutations in Latin American populations. In addition, a prior study suggested that a LRRK2 polymorphism (p.Q1111H) specific to Latino and Amerindian populations might be a risk factor for Parkinson’s disease, but this finding requires replication. We screened 1734 Parkinson’s disease patients and 1097 controls enrolled in the Latin American Research Consortium on the Genetics of Parkinson’s disease (LARGE-PD), which includes sites in Argentina, Brazil, Colombia, Ecuador, Peru, and Uruguay. Genotypes were determined by TaqMan assay (p.G2019S and p.Q1111H) or by sequencing of exon 31 (p.R1441C/G/H/S). Admixture proportion was determined using a panel of 29 ancestry informative markers. We identified a total of 29 Parkinson’s disease patients (1.7%) who carried p.G2019S and the frequency ranged from 0.2% in Peru to 4.2% in Uruguay. Only two Parkinson’s disease patients carried p.R1441G and one patient carried p.R1441C. There was no significant difference in the frequency of p.Q1111H in patients (3.8%) compared to controls (3.1%; OR 1.02, p = 0.873). The frequency of LRRK2-p.G2019S varied greatly between different Latin American countries and was directly correlated with the amount of European ancestry observed. p.R1441G is rare in Latin America despite the large genetic contribution made by settlers from Spain, where the mutation is relatively common., Genetic risk: Uncovering ethnic-specific mutations A new study reveals the frequency of Leucine-Rich Repeat Kinase 2 (LRRK2) mutations associated with Parkinson’s disease (PD) in Latin Americans. Ignacio F. Mata at the University of Washington and the VA Puget Sound Health Care System, Seattle, USA, and colleagues from six South American countries have screened the largest cohort of Latino PD patients ever assembled (1739) and 1104 healthy controls for LRRK2 mutations that are known to cause PD in European-derived populations. They found that the p.G2019S missense mutation was the most common, although its frequency varied greatly between countries and was directly correlated with European ancestry. In contrast, the p.R1441G mutation which is common in Spain is rare in Latin America. Further analyses of this cohort will help to further characterize the genetic profile of PD patients in Latin America and contribute to the development of personalized medicines.

Autosomal‐dominant progressive external ophthalmoplegia type 1 (adPEO1) is characterized by slowly progressive ophthalmoplegia. It can be caused by mutations in different genes, including the mitochondrial DNA polymerase γ (POLG), which results in heterogeneous clinical phenotypes associated with progressive external ophthalmoplegia, including myoclonic epilepsy,1 parkinsonism,2 and ataxia3 (Table 1). Other additional features may include premature ovarian failure and hypogonadism.2 POLG mutations causing adPEO1 can have both autosomal‐dominant or ‐recessive inheritance traits.4 Dystonia has been observed in patients with POLG mutations,5-7 however, to our knowledge, not in adPEO1. Here, we describe the first adPEO1 patient attributed to a POLG mutation showing dystonia as the presenting and core clinical feature. Fil: Rossi, Malco Damián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina Fil: Medina Escobar, Alex. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina Fil: Radrizzani Helguera, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología; Argentina Fil: Tenembaum, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Perandones, Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”; Argentina Fil: Merello, Marcelo Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by an excessive prenatal and postnatal growth, macrosomia, macroglossia, and hemihyperplasia. The molecular basis of this syndrome is complex and heterogeneous, involving genes located at 11p15.5. BWS is correlated with assisted reproductive techniques. BWS in individuals born following assisted reproductive techniques has been found to occur four to nine times higher compared to children with to BWS born after spontaneous conception. Here, we report a series of 187 patients with to BWS born either after assisted reproductive techniques or conceived naturally. Eighty-eight percent of BWS patients born via assisted reproductive techniques had hypomethylation of KCNQ1OT1:TSS-DMR in comparison with 49% for patients with BWS conceived naturally. None of the patients with BWS born via assisted reproductive techniques had hypermethylation of H19/IGF2:IG-DMR, neither CDKN1 C mutations nor patUPD11. We did not find differences in the frequency of multi-locus imprinting disturbances between groups. Patients with BWS born via assisted reproductive techniques had an increased frequency of advanced bone age, congenital heart disease, and decreased frequency of earlobe anomalies but these differences may be explained by the different molecular background compared to those with BWS and spontaneous fertilization. We conclude there is a correlation of the molecular etiology of BWS with the type of conception. © 2016 Wiley Periodicals, Inc.

We report the case of a male patient from an Ashkenazi Jewish ethnic group with a history of midline defects (congenital heart disease, high-arched palate and bifid uvula). At the age of 46 years, he came to our center complaining of resting tremor, and a neurological examination concluded Parkinson?s disease. As a part of his approach, genetic evaluation was performed. Fluorescence in-situ hybridization (FISH) confirmed a mosaicism of a 22q deletion in 24% of the analyzed blood cells. Also, immunohistochemical studies were performed on samples from the minor salivary glands using a SNCA antibody. Intense SNCA immunoreactive profiles were obtained for cells from the salivary glands of the patient. This is, to our knowledge, the first description of the association of amosaicism of a 22q11.2 microdeletion syndrome with Parkinson?s disease. Our findings suggest that, before excluding the involvement of the 22q11.2 deletion in the etiology of early-onset PD cases, the spectrum of evaluations should be extended to include more sensitive FISH analysis and immunohistochemical studies. The pathogenesis of early-onset PD in patients with 22q11.2 deletion syndrome remains unknown but, if elucidated, it may contribute to understanding the etiology of PD and ultimately to preventionand treatment strategies. Fil: Perandones, Claudia. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán"; Argentina Fil: Farini, Veronica Lujan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina Fil: Pellene, L. A. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Sáenz Farret, Michel. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Cuevas, S. M. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Micheli, Federico. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Radrizzani Helguera, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente; Argentina

To the Editor: We have read with great interest the review published in your journal titled "Hypothesis: Somatic Mosaicism and Parkinson Disease (Exp Neurobiol. 2014 Dec;23:271-276)," which discusses the "potential" existence of mosaicisms in Parkinson's disease. We find it essential to clarify some concepts that we consider inadequate/incorrect because they are presented as a new hypothesis when in fact our group has already published two papers including cases reporting the presence of Mosaicisms of Alpha-Synuclein rearrangements associated to Early Onset Parkinson Disease (EOPD) cases [1,2]. The paper by Han-Joon Kim and Beom S. Jeon published in Dec. 2014 speculates about the possibility that "a somatic mutation affecting cells in the central nervous system, including substantia nigra dopaminergic neurons could lead to the development of PD through the same pathomechanisms of genetic PD even in the absence of a germ-line mutation". Furthermore, the manuscript mentions in two sections (in its abstract and in section "PD and somatic mosaicism") that "The study of somatic mosaicism in Parkinson disease (PD) is only in its infancy, and a case with somatic mutation has not yet been described." In our first paper, available online as early as May 2014 [1], we described the clinical phenotype and the genetic and immunohistochemical findings in two unrelated cases with early-onset PD due to Alpha-Synuclein (SNCA) mosaicism. Although Fluorescent In- Situ Hybridization (FISH) results indicated few or no rearrangements (i.e. ≤4 FISH probe signals in >20% of interphase cells scored) in peripheral leucocytes from either case, 75% of oral mucosal cells showed triplication and duplication of SNCA in case 1 and 43% showed duplication in case 2. This duplication occurs in the original chromosome (Fig. 1). Fig. 1 FISH analysis for Alpha-Synuclein gene. Panel A presents an interphase of a lymphocyte showing the presence of three DNA regions hybridized with probes obtained from BAC (Bacterial Artificial Chromosomes) containing the Alpha-Synuclein gene. Panel B, ... In the "Testing the hypothesis" section, Han-Joon Kim and Beom S. Jeon [3], present the need to investigate other tissues other than peripheral blood lymphocytes. They suggest evaluating oral mucosa cells, something that was conducted and described for the first time by us in our above-mentioned paper. Our paper also describes the technique used to identify the ectodermal origin of the buccal mucosa cells evaluated in both patients (for further details, see Fig. 2 in [1]). Fig. 2 Immunohistochemical assays for the detection of alpha-synuclein protein. The figure shows the section of a salivary gland dyed with red fluorescence for neurofilament protein (A), the fluorescent DAPI with the genomic DNA in cell nuclei appears in blue ... The authors Han-Joon Kim and Beom S. Jeon [3], also suggest evaluating salivary gland cells in order to increase the chance of finding somatic mosaicisms in PD. In connection with this suggestion, we consider it relevant to point out that our publication included the evaluation of cells from a biopsy of a minor salivary gland, but with the purpose of evaluating the presence of immunoreactive augment as a consequence of an increase in the alpha-synuclein protein (immunohistochemical assays), rather than to detect rearrangements of the Alpha-Synuclein gene. We decided not to use minor salivary gland cells to evaluate gene rearrangements taking into account that salivary glands have a mixed endodermal-ectodermal embryological origin. It is also worth pointing out that, in patients with Alpha-Synuclein mosaicisms, the studies performed on samples from the minor salivary glands using a rabbit polyclonal SNCA antibody [4] showed intense SNCA immunoreactive profiles (Fig. 2). We agree with the authors' statement concerning the fact that the technology used in the detection of mosaicisms is key. However, we consider it relevant to stress that precisely one of the techniques suggested by the authors, "High Resolution Melting PCR" based on the findings of Prourakis et al. [5], is not the most suitable for detection of Copy-Number Variations (CNVs). We would like to mention that the de novo mutation rate for CNV can be two to four orders of magnitude higher than for Single Nucleotide Variations (SNVs) [6], with CNVs arising in mitosis, explaining the increasing evidence for CNV mosaicisms in healthy humans, including the brain. In our experience, the mosaicism of CNVs in SNCA is one of the most important targets when searching for PD somatic mosaicism. Therefore, in our paper we postulate that techniques such as FISH (low cost, high reproducibility, possibility to perform individual tests cell by cell) should be taken into account at present, at least until single cell sequencing becomes optimized and generally available. In conclusion, somatic mosaicism has already been confirmed as an etiological factor for Parkinson's disease. In our experience, the keys for detection of somatic mosaicism in PD are: a) Diagnostic suspicion based on the clinical characteristics of patients who present autonomic dysfunction and cognitive impairment in addition to EOPD b) The evaluation of multiple tissues of ectodermal origin that are accessible in patients c) The use of techniques that guarantee individual cell analysis as well as the detection of low-level mosaicisms. Given all of the above, we deem the publication of this letter important in order to shed some light about the existence of somatic mosaicisms as a relevant (although relatively unexplored) etiologic mechanism, not only in PD but in other neurological diseases.

Anp32e/Cpd1, a member of the acidic nuclear phosphoprotein (Anp)32 family, is characterized by the presence of an amino terminal domain containing four leucine-rich repeats and a carboxyl-terminal low-compositional complexity acidic region. In previous studies performed to understand the biological role of Anp32e/Cpd1, we showed a predominant presence of Anp32e/Cpd1 in the nucleus. However, when Anp32e/Cpd1 is in the cytoplasm, it co-localizes spatially with protein phosphatase 2A (PP2A) near cell membranes, far from the synapses. In the present work, we show that Anp32e/Cpd1 is also present as a membrane-bound 74/76-kDa protein with a widespread distribution in the brain. We reveal that the expression, synthesis and half-life of this high-molecular-weight form of Anp32e/Cpd1 are spatially and temporally correlated with the cerebellar synaptogenesis period. We demonstrate that synaptic Anp32e/Cpd1 co-localizes, interacts and inhibits PP2A activity, and that phosphorylation of Anp32/Cpd1 is required for the Anp32e-PP2A interaction. Also, subcellular localization was shown with electronic microscopy. Finally, we examine Anp32e/Cpd1 and PP2A distribution in two ataxic mutant models, weaver and staggerer, and show that their co-localization in Purkinje cell dendrites depends on parallel fibre/Purkinje cell contacts. Based on these observations, we propose that Anp32e/Cpd1 mediates synaptogenesis process by modulating PP2A activity.

Objective The purpose of this investigation was to study the social environment of families of children with different types of nonsyndromic oral clefts (OC) and to compare these groups with a control population of families of children without clefts. Design The study compared three nonsyndromic oral cleft groups and the control group using the Moos Family Environment Scale, which examines cohesion, expressiveness, conflict, independence, achievement-orientation, intellectual-cultural orientation, active-recreational orientation, moral-religious emphasis, organization, and control. Setting All parents of children with nonsyndromic oral clefts from a large craniofacial clinic in Buenos Aires, Argentina, were identified and were enrolled in this study between June 2000 and August 2001. Control families were ascertained from the pediatrics service of a hospital located in the vicinity of the craniofacial clinic. Participants One hundred and sixty-five parents were selected, based on having a child with nonsyndromic unilateral cleft lip with or without cleft palate (UCL/P), bilateral cleft lip with or without cleft palate (BCL/P), or isolated cleft palate (ICP). One hundred and eighty control parents with no family history of congenital anomalies were selected, as well. Results There was no major difference in the social environment of families of children with different types of nonsyndromic oral clefts. When compared with families in the control group, families of children with nonsyndromic oral clefts scored better in all three subdimensions of family relationship, revealed a high level of independence, and showed better structure and organization than control families did; however, families of children with nonsyndromic oral clefts reported participating in fewer recreational activities. Conclusions Overall, families of children with nonsyndromic oral clefts displayed a good social environment. Efforts should be focused to involve them in recreational activities.

The D216H polymorphism (rs1801968) in TOR1A has been suggested as a risk factor for developing primary dystonia in German subjects not carrying the deletion c.904-906delGAG (∆GAG). However, this association could not be confirmed in other populations with different ethnic backgrounds. The purpose of this study is to evaluate the D216H polymorphism in an Argentinean cohort of 40 patients with primary dystonia and 200 unrelated control subjects. The authors could observe a significantly higher frequency of the H216 variant in dystonic patients lacking ∆GAG as compared with controls.

The PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor gene codifies a lipid inositol 3′-phosphatase that negatively regulates cell survival mediated by the phosphatidyl inositol 3′ kinase (PIP3-kinase)–protein kinase B/Akt signaling pathway. Recently, PIP3-kinase was involved in axon polarization, but PTEN functions in dendrites are uncertain. Using amino-terminal antibodies against the catalytic domain, we found a 34 kDa fragment of PTEN protein detected only in mouse brain tissue, present in neuron dendrites and spines of cerebral cortex, cerebellum, hippocampus and olfactory bulb. The PTEN-fragment reaches the synaptic fraction with a positive temporal correlation with synaptic stabilization in postnatal cerebellum and brain. In the weaver mutant mice, PTEN was absent only in the Purkinje cells dendrites that cannot receive the granule cells synaptic input. Furthermore, the activated p-Akt/PKB was present in axons but not in dendrites of mature neuron cells. P-Akt was also altered by the weaver mutation maintaining the inverse correlation with the PTEN-fragment in Purkinje cell dendrites. In contrast, the expression of this fragment was not affected by the staggerer mutation. Together, these results suggest that synaptogenesis is a necessary process for polarization in PIP3 pathway mediated by the PTEN catalytic-fragment into dendrites of CNS neurons.

In genetics, the term mosaicism describes the situation in which groups of cells have a different genetic composition to other cells in an organism. Somatic gene rearrangements due to multiplication or deletion of genes (copy number variation) and/or sections of chromosomes can lead to mosaicism. The presence of multiple copies of the alpha-synuclein gene (SNCA) is known to be associated with Parkinson´s disease (PD) and the severity of symptoms increases with the number of copies of the gene [1]. While the features of PD associated with duplication of SNCA are usually (but not always) typical of the condition [2] and [3], patients with triplicate copies have atypical features, including rapidly evolving symptoms, severe cognitive impairment, limited response to levodopa, more severe symptoms of dementia and more frequent urinary incontinence [2]. A lack of studies of mosaicism in PD illustrates that the prevalence and mechanism of these rearrangements have not yet been elucidated. Fil: Perandones, Claudia. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Giugni, J. C.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Calvo, D. S.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Raina, G. B.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: De Jorge Lopez, L.. Universidad de Barcelona. Hospital Duran I Reynals. Instituto de Investigación Biomédica de Bellvitge; España Fil: Volpini, Victor. Universidad de Barcelona. Hospital Duran I Reynals. Instituto de Investigación Biomédica de Bellvitge; España Fil: Zabetian, Cyrus P.. University of Washington; Estados Unidos Fil: Mata, Ignacio F.. University of Washington; Estados Unidos Fil: Caputo, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; Argentina Fil: Corach, Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; Argentina Fil: Radrizzani Helguera, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de San Martín; Argentina Fil: Micheli, Federico Eduardo. Universidad de Buenos Aires. Facultad de Medicina; Argentina

Huntington’s disease (HD) is an autosomal dominant, progressive neurodegenerative disorder with a clinical spectrum that includes chorea, incoordination, cognitive decline, and behavioral difficulties. The underlying genetic defect responsible for the disease is the expansion of a CAG repeat in the huntingtin (HTT) gene. This repeat is unstable and its length is inversely correlated with the age at onset of the disease. Despite its widespread distribution, mutant HTT causes neurodegeneration, which occurs preferentially in the striatum and deeper layers of the cortex. Mechanisms implicated in HD include those relevant to DNA repair, transcriptional and translational modulation of expanded trinucleotide repeats (including somatic expansion), mitochondria and energy homeostasis, vesicular trafficking dynamics, oligomerization of mHTT (chaperone biology), autophagy, epigenetic mechanisms, and synaptic signaling. Notably, not all the effects of mutant HTT are cell autonomous. The present review focuses on the molecular pathogenesis of HD and the current state of therapeutic development for the treatment of HD. We review the preclinical and clinical development molecular therapies targeting HTT expression and the modulation of biological mechanisms thought to contribute to disease pathogenesis via novel therapeutic agents.

Several regulated mRNAs were detected by applying differential display to the mouse cerebellum during postnatal development. One cDNA fragment, referred to as CPD1 (GenBank U89345), was characterized and cloned. Northern blots showed maximum mRNA expression at postnatal day seven (P7). The mRNA encodes a protein of 260 amino acids. In situ RT-PCR showed that CPD1 is expressed mainly in granule cells and faintly in Purkinje cells. Polyclonal rabbit antibodies and oligobodies (oligonucleotide-based synthetic antibodies) revealed a protein of 34 kDa in Western blots. Immunohistochemistry showed not only marked nuclear staining but also mild cytoplasmic localization. Granule cells undergoing active division (P4) showed very little expression of CPD1 protein, which increases from P7 to P17. CPD1, affinity-purified using a chemically synthesized oligobody inhibits the activity of protein phosphatase PP2A but not protein phosphatase PP1. Differentiated PC12 cells also showed nuclear and cytoplasmic localization. Interestingly, maximal cytoplasmic CPD1/PP2A colocalization was observed near cell membrane regions that are far from growing neurites, and on growing cones. These results suggest that CPD1 might have an important role in cerebellar development.

Mutations in the LRRK2 gene are the most common genetic cause of Parkinson’s disease, with frequencies displaying a high degree of population-specificity. Although more than 100 coding substitutions have been identified, only seven have been proven to be highly penetrant pathogenic mutations. Studies however are lacking in non-white populations. Recently, Lrrk2 p.Q1111H (rs78365431) was identified in two affected Hispanic brothers and absent in 386 non-Hispanic white healthy controls. We therefore screened this variant in 1460 individuals (1150 PD patients and 310 healthy controls) from 4 Latin American countries (Peru, Chile, Uruguay and Argentina). In our case-control series from Peru and Chile we observed an increased frequency of Lrrk2 p.Q1111H in patients (7.9%) compared to controls (5.4%) although the difference did not reach significance (OR 1.38; p = 0.10). In addition, the frequency of Lrrk2 p.Q1111H varied greatly between populations and further screening in a set of pure Amerindian and pure Spanish controls suggested that this variant likely originated in an Amerindian population. Further studies in other Latin American populations are warranted to assess its role as a risk factor for Parkinson’s disease. Screening in Parkinson’s disease patients from under-represented populations will increase our understanding of the role of LRRK2 variants in disease risk worldwide.

DBS is an established therapy for advanced PD [1] and has been reported to be efficacious in a few patients with monogenic parkinsonisms such as LRRK2, Parkin, and PINK1 [2–6]. By contrast, knowledge about the outcome of DBS in patients with SNCA mutations is scarce, since only one case has been reported to date [7]. We now report the case of a 26-year-old male with Parkinson’s disease due to mosaicism of alpha-synuclein duplication, who has successfully undergone GPi-DBS. The patient, who has no family history of PD, developed PD at the age of 18. He initially presented dystonic posturing and tremor in his left foot. Within a few months, this had progressed to micrographia, bradykinesia and resting tremor in his upper left limb. He subsequently developed mild autonomic failure, and mild cognitive decline, as well as behavior disorders (rage episodes, panic attacks, and hallucinations). He initially showed good response to dopamine agonists, but after a short period levodopa was needed to obtain satisfactory motor control. He also developed impulse control disorders secondary to treatment with dopamine agonists, resulting in punding behaviors (e.g., disassembling guitars, computers and his car). FISH was conducted using rhodamine-labeled SNCA probes at 4q22.1 (BAC RP11-614o7, 151 kb) and 4q21.3 [BAC-RP11-711j3, 192 kb (control)]. Results indicated few or no rearrangements (i.e., B4 FISH probe signals in [20 % of interphase cells scored) [6] in peripheral leucocytes from the patient, but 43 % of oral mucosa cells showed duplication of SNCA gene. No exon dosage rearrangements were detected in SNCA or other relevant PD genes using MLPA technique. Mutations in PINK1, PARK2, and DJ were not found and were excluded as causes for the patient’s symptoms. Further description of the ancestral origin, genetic tests and immunohistochemical findings of this patient can be found in Perandones et al. [8]. As he rapidly showed disabling motor fluctuations and severe peak-dose dyskinesias refractory to pharmacological strategies, the patient was proposed for DBS. The target chosen was the globus pallidus internus (GPi) based on the dyskinesias that affected his quality of life and the fact that he already presented mild cognitive impairment as demonstrated in the preoperative neuropsychological examination. A quadripolar brain electrode (model 3387, Medtronic) was implanted stereotactically with microregistration technique in each GPi and fixed with the Stimloc system. Magnetic resonance imaging was performed in stereotactic conditions; the images were processed with WinNeus program to identify coordinates for both GPi. The electrodes were connected to a pulse generator (Activa RC; Medtronic). C. Perandones N. Araoz Olivos G. B. Raina L. A. Pellene J. C. Giugni D. S. Calvo F. E. Micheli (&) Parkinson’s Disease and Movement Disorders Program, Hospital de Clinicas, University of Buenos Aires, Ciudad Autonoma de Buenos Aires, Juncal 1695 Piso 5 J, Zip Code 1062, C1120AAR Buenos Aires, Argentina e-mail: fmicheli@fibertel.com.ar

Anp32e/Cpd1, a member of the acidic nuclear phosphoprotein (Anp)32 family, is characterized by the presence of an amino terminal domain containing four leucine-rich repeats and a carboxyl-terminal low-compositional complexity acidic region. In previous studies performed to understand the biological role of Anp32e/Cpd1, we showed a predominant presence of Anp32e/Cpd1 in the nucleus. However, when Anp32e/Cpd1 is in the cytoplasm, it co-localizes spatially with protein phosphatase 2A (PP2A) near cell membranes, far from the synapses. In the present work, we show that Anp32e/Cpd1 is also present as a membrane-bound 74/76-kDa protein with a widespread distribution in the brain. We reveal that the expression, synthesis and half-life of this high-molecular-weight form of Anp32e/Cpd1 are spatially and temporally correlated with the cerebellar synaptogenesis period. We demonstrate that synaptic Anp32e/Cpd1 co-localizes, interacts and inhibits PP2A activity, and that phosphorylation of Anp32/Cpd1 is required for the Anp32e-PP2A interaction. Also, subcellular localization was shown with electronic microscopy. Finally, we examine Anp32e/Cpd1 and PP2A distribution in two ataxic mutant models, weaver and staggerer, and show that their co-localization in Purkinje cell dendrites depends on parallel fibre/Purkinje cell contacts. Based on these observations, we propose that Anp32e/Cpd1 mediates synaptogenesis process by modulating PP2A activity.

We studied chromosomal abnormalities in arrested embryos produced by assisted reproductive technology with fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH) in order to determine the best technique for evaluating chromosomal aneusomies to be implemented in different situations. We examined individual blastomeres from arrested embryos by FISH and arrested whole embryos by CGH. All of the 10 FISH-analyzed embryos gave results, while only 7 of the 30 embryos analyzed by CGH were usable. Fifteen of the 17 embryos were chromosomally abnormal. CGH provided more accurate data for arrested embryos; however, FISH is the technique of choice for screening in preimplantation genetic diagnosis, because the results can be obtained within a day, while the embryos are still in culture.

Results from a genome-wide screen of 10 multiplex families ascertained through probands with nonsyndromic cleft lip with or without cleft palate (CL/P) in Mexico, Argentina, and the United States yielded suggestive evidence of linkage to chromosomes 2, 6, 17 and 18. Fine mapping excluded all regions except chromosome 2. Subsequent analysis was performed on the original 10 families plus an additional 16 families using 31 markers on chromosome 2. This analysis showed intriguing evidence of linkage to 2q (Zlr=2.26, empirical P-value=0.028 in a chromosome-wide analysis). Transmission disequilibrium tests also revealed evidence of linkage and disequilibrium for two markers in this region (D2S168 and D2S1400 with P-values=0.022 and 0.006, respectively). A subset of these 26 families provided additional evidence for a susceptibility gene for CL/P on 2q, suggesting that further studies of genes in this region are warranted.

Objective To investigate the attitudes of Argentine parents of children with nonsyndromic oral clefts with respect to prenatal diagnosis, termination of pregnancy, and reproduction and to assess the variables that might influence their responses. Design One hundred and sixty-five parents of children with oral clefts, ascertained from a craniofacial clinic in the suburbs of Buenos Aires, answered a 151-item semistructured questionnaire. The questionnaire included sections covering sociodemographic information, level of religiousness, characteristics of the child's cleft, parental perception of their child's cleft, pregnancy history, recurrence risk, access to health care, attitudes in regard to abortion, and family environment. Results Most parents (60%) believe their child's cleft is not a serious condition. None of the respondents would terminate a pregnancy because the ultrasound reveals an oral cleft. Similarly, very few (6.1%) would terminate the pregnancy if there were an early diagnosis of Down syndrome. Half of the respondents believe that abortion should not be an option for any couple expecting a child. Conclusions Most respondents do not perceive oral clefts as a severe condition. Parents would not choose to terminate the pregnancy over delivery of such an affected newborn. Copyright © 2003 John Wiley & Sons, Ltd.

We report on a 13 year old boy with microcephaly, sloping forehead, prominent nose, scoliosis, and flexion contractures involving the elbows and knees. The patient showed severe mental and growth retardation. Since birth and up to the present he has suffered from multiple and varied infections. Immunological studies showed a marked decrease in leucocyte chemotaxis. Clinical and laboratory findings confirm the similarity of this case to the two brothers described by Say et al. We have not found any descriptions of similar patients. The purpose of this paper is to contribute to the phenotypic delineation of this syndrome and to highlight the need for immunological investigation in patients with multiple congenital malformations.

PTEN is a critical gene involved in the regulation of many cellular processes. The product of this gene has dual phosphatase activity and is able to dephosphorylate the 5′ end of the phosphatidylinositol (3,4,5)-trisphosphate. Within the cellular nucleus, this protein has been associated with regulation of the expression of many genes, although the mechanism of this regulation remains unclear. In this paper, two specific oligonucleotide aptamers were developed and selected, using the SELEX procedure, according to their ability to detect the PTEN protein in different subcellular compartments of neurons. While one aptamer was able to detect PTEN in the nucleus, the other recognized PTEN in the cytoplasm. The recognition pattern of PTEN by both aptamers was confirmed using antibodies in western blots of the proteins purified from mouse cerebellar homogenates and subcellular fractions. Additionally, we demonstrated that the two aptamers recognized different epitopes of the target peptide. The results presented here could not be fully explained by the canonical phosphatase structure of PTEN, suggesting the existence of different conformations of phosphatase in the nucleus and the cytoplasm.