Novel missense mutations in PNPLA2 causing late onset and clinical heterogeneity of neutral lipid storage disease with myopathy in three siblings

Neutral lipid storage disease with myopathy (NLSD-M) is a rare autosomal recessive disorder characterised by an abnormal accumulation of triacylglycerol into cytoplasmic lipid droplets (LDs). NLSD-M patients are mainly affected by progressive myopathy, cardiomyopathy and hepatomegaly. Mutations in the PNPLA2 gene cause variable phenotypes of NLSD-M. PNPLA2 codes for adipose triglyceride lipase (ATGL), an enzyme that hydrolyses fatty acids from triacylglycerol. This report outlines the clinical and genetic findings in a NLSD-M Italian family with three affected members. In our patients, we identified two novel PNPLA2 missense mutations (p.L56R and p.I193F). Functional data analysis demonstrated that these mutations caused the production of ATGL proteins able to bind to LDs, but with decreased lipase activity. The oldest brother, at the age of 38, had weakness and atrophy of the right upper arm and kyphosis. Now he is 61 years old and is unable to raise arms in the horizontal position. The second brother, from the age of 44, had exercise intolerance, cramps and pain in lower limbs. He is currently 50 years old and has an asymmetric distal amyotrophy. One of the two sisters, 58 years old, presents the same PNPLA2 mutations, but she is still oligo-symptomatic on neuromuscular examination with slight triceps muscle involvement. She suffered from diabetes and liver steatosis. This NLSD-M family shows a wide range of intra-familial phenotypic variability in subjects carrying the same mutations, both in terms of target-organs and in terms of rate of disease progression

A systematic review about work-related problems incurred by agricultural pilots

This study assesses qualitative information from primary studies on the work-related problems incurred by agricultural pilots. The aim is to shed light on what is known about these problems, which were resolved and what are the research gaps that can drive future studies to minimize accident events. In order to achieve it, a systematic review was conducted, using computerized search engines to gather primary studies on this topic, and extract qualitative information. Two different approaches were identified, those reporting data on a single work-related problem and those reporting data on existing problems in 'total work-environment', where the problems are considered as small parts of a whole. There remains a clear need for assisting these professionals, especially concerning the problems poorly addressed in the primary studies, such as organizational, informational and psychosocial factors as well as the factors that have not yet been discussed, such as education and training

Novel missense mutations in PNPLA2 causing late onset and clinical heterogeneity of neutral lipid storage disease with myopathy in three siblings

Neutral lipid storage disease with myopathy (NLSD-M) is a rare autosomal recessive disorder characterised by an abnormal accumulation of triacylglycerol into cytoplasmic lipid droplets (LDs). NLSD-M patients are mainly affected by progressive myopathy, cardiomyopathy and hepatomegaly. Mutations in the PNPLA2 gene cause variable phenotypes of NLSD-M. PNPLA2 codes for adipose triglyceride lipase (ATGL), an enzyme that hydrolyses fatty acids from triacylglycerol. This report outlines the clinical and genetic findings in a NLSD-M Italian family with three affected members. In our patients, we identified two novel PNPLA2 missense mutations (p.L56R and p.I193F). Functional data analysis demonstrated that these mutations caused the production of ATGL proteins able to bind to LDs, but with decreased lipase activity. The oldest brother, at the age of 38, had weakness and atrophy of the right upper arm and kyphosis. Now he is 61. years old and is unable to raise arms in the horizontal position. The second brother, from the age of 44, had exercise intolerance, cramps and pain in lower limbs. He is currently 50. years old and has an asymmetric distal amyotrophy. One of the two sisters, 58. years old, presents the same PNPLA2 mutations, but she is still oligo-symptomatic on neuromuscular examination with slight triceps muscle involvement. She suffered from diabetes and liver steatosis. This NLSD-M family shows a wide range of intra-familial phenotypic variability in subjects carrying the same mutations, both in terms of target-organs and in terms of rate of disease progression

ALMA reveals the molecular gas properties of five star-forming galaxies across the main sequence at 3

International audienceWe present the detection of CO(5-4) with S/N> 7 - 13 and a lower CO transition with S/N > 3 (CO(4-3) for 4 galaxies, and CO(3-2) for one) with ALMA in band 3 and 4 in five main sequence star-forming galaxies with stellar masses 3-6x10^10 M/M_sun at 3 < z < 3.5. We find a good correlation between the total far-infrared luminosity LFIR and the luminosity of the CO(5-4) transition L'CO(5-4), where L'CO(5-4) increases with SFR, indicating that CO(5-4) is a good tracer of the obscured SFR in these galaxies. The two galaxies that lie closer to the star-forming main sequence have CO SLED slopes that are comparable to other star-forming populations, such as local SMGs and BzK star-forming galaxies; the three objects with higher specific star formation rates (sSFR) have far steeper CO SLEDs, which possibly indicates a more concentrated episode of star formation. By exploiting the CO SLED slopes to extrapolate the luminosity of the CO(1-0) transition, and using a classical conversion factor for main sequence galaxies of alpha_CO = 3.8 M_sun(K km s^-1 pc^-2)^-1, we find that these galaxies are very gas rich, with molecular gas fractions between 60 and 80%, and quite long depletion times, between 0.2 and 1 Gyr. Finally, we obtain dynamical masses that are comparable with the sum of stellar and gas mass (at least for four out of five galaxies), allowing us to put a first constraint on the alpha_CO parameter for main sequence galaxies at an unprecedented redshift

Citron Kinase Deficiency Leads to Chromosomal Instability and TP53-Sensitive Microcephaly

Mutations in citron (CIT), leading to loss or inactivation of the citron kinase protein (CITK), cause primary microcephaly in humans and rodents, associated with cytokinesis failure and apoptosis in neural progenitors. We show that CITK loss induces DNA damage accumulation and chromosomal instability in both mammals and Drosophila. CITK-deficient cells display "spontaneous" DNA damage, increased sensitivity to ionizing radiation, and defective recovery from radiation-induced DNA lesions. In CITK-deficient cells, DNA double-strand breaks increase independently of cytokinesis failure. Recruitment of RAD51 to DNA damage foci is compromised by CITK loss, and CITK physically interacts with RAD51, suggesting an involvement of CITK in homologous recombination. Consistent with this scenario, in doubly CitK and Trp53 mutant mice, neural progenitor cell death is dramatically reduced; moreover, clinical and neuroanatomical phenotypes are remarkably improved. Our results underscore a crucial role of CIT in the maintenance of genomic integrity during brain development

Citron Kinase Deficiency Leads to Chromosomal Instability and TP53-Sensitive Microcephaly

Mutations in citron (CIT), leading to loss or inactivation of the citron kinase protein (CITK), cause primary microcephaly in humans and rodents, associated with cytokinesis failure and apoptosis in neural progenitors. We show that CITK loss induces DNA damage accumulation and chromosomal instability in both mammals and Drosophila. CITK-deficient cells display “spontaneous” DNA damage, increased sensitivity to ionizing radiation, and defective recovery from radiation-induced DNA lesions. In CITK-deficient cells, DNA double-strand breaks increase independently of cytokinesis failure. Recruitment of RAD51 to DNA damage foci is compromised by CITK loss, and CITK physically interacts with RAD51, suggesting an involvement of CITK in homologous recombination. Consistent with this scenario, in doubly CitK and Trp53 mutant mice, neural progenitor cell death is dramatically reduced; moreover, clinical and neuroanatomical phenotypes are remarkably improved. Our results underscore a crucial role of CIT in the maintenance of genomic integrity during brain development

Evaluation of the pharmacological activity of Pfaffia paniculata (Martius) Kuntze

O presente trabalho teve como objetivo investigar o efeito anti-inflamatório, antimicrobiano, antiprotozoário e possível ação sobre o sistema nervoso central (SNC) em ratos tratados com extrato hidroalcoólico de Pfaffia paniculata. Verificou-se atividade anti-inflamatória tanto in vivo, na dose de 100 mg/kg, como in vitro nas concentrações de 50 e 100 μg/mL. Porém, verificou-se efeito pró-inflamatório na dose de 200 mg/kg, pelo ensaio de pleurisia e de 200 μg/mL, pela quimiotaxia in vitro. Sugere-se potencial ação antimicrobiana frente a Staphylococcus aureus, nas concentrações de 250 e 500 mg/mL, com forma- ção de halo de inibição de 11 e 21 mm, respectivamente. Observou-se que o extrato de P. paniculata nas concentrações de 1, 10 e 50 μg/mL potencializou o crescimento de trofozoítos de Trichomonas vaginalis. Quanto aos ensaios sobre o SNC, verificou-se diminuição da ansiedade e aumento da atividade locomotora em animais tratados com doses de 125 e 250 mg/kg.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Dendritic Cells/Natural Killer Cross-Talk: A Novel Target for Human Immunodeficiency Virus Type-1 Protease Inhibitors

BACKGROUND: HIV-1 Protease Inhibitors, namely PIs, originally designed to inhibit HIV-1 aspartic protease, can modulate the immune response by mechanisms largely unknown, and independent from their activity on viral replication. Here, we analyzed the ability of PIs to interfere with differentiation program of monocytes toward dendritic cell (DCs) lineage, a key process in the inflammatory response. METHODOLOGY/PRINCIPAL FINDINGS: Monocytes from healthy donors were isolated and induced to differentiate in vitro in the presence or absence of saquinavir, ritonavir, nelfinavir, indinavir or amprenavir (sqv, rtv, nlfv, idv, apv, respectively). These drugs demonstrated a differential ability to sustain the generation of immature DCs (iDCs) with an altered phenotype, including low levels of CD1a, CD86, CD36 and CD209. DCs generated in the presence of rtv also failed to acquire the typical phenotype of mature DCs (mDCs), and secreted lower amounts of IL-12 and IL-15. Accordingly, these aberrant mDCs failed to support activation of autologous Natural Killer (NK) cells, and resulted highly susceptible to NK cell-mediated cytotoxicity. CONCLUSIONS/SIGNIFICANCE: Our findings uncover novel functional properties of PIs within the DC-NK cell cross-talk, unveiling the heterogeneous ability of members of this class drugs to drive the generation of atypical monocyte-derived DCs (MDDCs) showing an aberrant phenotype, a failure to respond appropriately to bacterial endotoxin, a weak ability to prime autologous NK cells, and a high susceptibility to NK cell killing. These unexpected properties might contribute to limit inflammation and viral spreading in HIV-1 infected patients under PIs treatment, and open novel therapeutical perspectives for this class drugs as immunomodulators in autoimmunity and cancer

Molecular, clinical, and muscle studies in myotonic dystrophy type 1 (DM1) associated with novel variant CCG expansions

We assessed clinical, molecular and muscle histopathological features in five unrelated Italian DM1 patients carrying novel variant pathological expansions containing CCG interruptions within the 3'-end of the CTG array at the DMPK locus, detected by bidirectional triplet primed PCR (TP-PCR) and sequencing. Three patients had a negative DM1 testing by routine long-range PCR; the other two patients were identified among 100 unrelated DM1 cases and re-evaluated to estimate the prevalence of variant expansions. The overall prevalence was 4.8&nbsp;% in our study cohort. There were no major clinical differences between variant and non-variant DM1 patients, except for cognitive involvement. Muscle RNA-FISH, immunofluorescence for MBNL1 and RT-PCR analysis documented the presence of ribonuclear inclusions, their co-localization with MBNL1, and an aberrant splicing pattern involved in DM1 pathogenesis, without any obvious differences between variant and non-variant DM1 patients. Therefore, this study shows that the CCG interruptions at the 3'-end of expanded DMPK alleles do not produce qualitative effects on the RNA-mediated toxic gain-of-function in DM1 muscle tissues. Finally, our results support the conclusion that different patterns of CCG interruptions within the CTG array could modulate the DM1 clinical phenotype, variably affecting the mutational dynamics of the variant repeat