Lowe syndrome

Lowe syndrome (the oculocerebrorenal syndrome of Lowe, OCRL) is a multisystem disorder characterised by anomalies affecting the eye, the nervous system and the kidney. It is a uncommon, panethnic, X-linked disease, with estimated prevalence in the general population of approximately 1 in 500,000. Bilateral cataract and severe hypotonia are present at birth. In the subsequent weeks or months, a proximal renal tubulopathy (Fanconi-type) becomes evident and the ocular picture may be complicated by glaucoma and cheloids. Psychomotor retardation is evident in childhood, while behavioural problems prevail and renal complications arise in adolescence. The mutation of the gene OCRL1 localized at Xq26.1, coding for the enzyme phosphatidylinositol (4,5) bisphosphate 5 phosphatase, PtdIns (4,5)P2, in the trans-Golgi network is responsible for the disease. Both enzymatic and molecular testing are available for confirmation of the diagnosis and for prenatal detection of the disease. The treatment includes: cataract extraction, glaucoma control, physical and speech therapy, use of drugs to address behavioural problems, and correction of the tubular acidosis and the bone disease with the use of bicarbonate, phosphate, potassium and water. Life span rarely exceeds 40 years

Correction to: The genetic architecture of Plakophilin 2 cardiomyopathy

PURPOSE: The genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function. METHODS: We assess the gene-wide and regional association of truncating and missense variants in PKP2 with arrhythmogenic cardiomyopathy (ACM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) specifically. A discovery data set compares genetic testing requisitions to gnomAD. Validation is performed in a rigorously phenotyped definite ARVC cohort and non-ACM individuals in the Geisinger MyCode cohort. RESULTS: The etiologic fraction (EF) of ACM-related diagnoses from truncating variants in PKP2 is significant (0.85 [0.80,0.88], p < 2 × 10-16), increases for ARVC specifically (EF = 0.96 [0.94,0.97], p < 2 × 10-16), and is highest in definite ARVC versus non-ACM individuals (EF = 1.00 [1.00,1.00], p < 2 × 10-16). Regions of missense variation enriched for ACM probands include known functional domains and the C-terminus, which was not previously known to contain a functional domain. No regional enrichment was identified for truncating variants. CONCLUSION: This multicohort evaluation of the genetic architecture of PKP2 demonstrates the specificity of PKP2 truncating variants for ARVC within the ACM disease spectrum. We identify the PKP2 C-terminus as a potential functional domain and find that truncating variants likely cause disease irrespective of transcript position

The genetic architecture of Plakophilin 2 cardiomyopathy

PURPOSE: The genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function. METHODS: We assess the gene-wide and regional association of truncating and missense variants in PKP2 with arrhythmogenic cardiomyopathy (ACM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) specifically. A discovery data set compares genetic testing requisitions to gnomAD. Validation is performed in a rigorously phenotyped definite ARVC cohort and non-ACM individuals in the Geisinger MyCode cohort. RESULTS: The etiologic fraction (EF) of ACM-related diagnoses from truncating variants in PKP2 is significant (0.85 [0.80,0.88], p < 2 × 10-16), increases for ARVC specifically (EF = 0.96 [0.94,0.97], p < 2 × 10-16), and is highest in definite ARVC versus non-ACM individuals (EF = 1.00 [1.00,1.00], p < 2 × 10-16). Regions of missense variation enriched for ACM probands include known functional domains and the C-terminus, which was not previously known to contain a functional domain. No regional enrichment was identified for truncating variants. CONCLUSION: This multicohort evaluation of the genetic architecture of PKP2 demonstrates the specificity of PKP2 truncating variants for ARVC within the ACM disease spectrum. We identify the PKP2 C-terminus as a potential functional domain and find that truncating variants likely cause disease irrespective of transcript position

Aggregation of αSynuclein promotes progressive in vivo neurotoxicity in adult rat dopaminergic neurons

Fibrillar αSynuclein is the major constituent of Lewy bodies and Lewy neurites, the protein deposits characteristic for Parkinson’s disease (PD). Multiplications of the αSynuclein gene, as well as point mutations cause familial PD. However, the exact role of αSynuclein in neurodegeneration remains uncertain. Recent research in invertebrates has suggested that oligomeric rather than fibrillizing αSynuclein mediates neurotoxicity. To investigate the impact of αSynuclein aggregation on the progression of neurodegeneration, we expressed variants with different fibrillation propensities in the rat substantia nigra (SN) by means of recombinant adeno-associated viral (AAV) vectors. The formation of proteinase K-resistant αSynuclein aggregates was correlated to the loss of nigral dopaminergic (DA) neurons and striatal fibers. Expression of two prefibrillar, structure-based design mutants of αSynuclein (i.e., A56P and A30P/A56P/A76P) resulted in less aggregate formation in nigral DA neurons as compared to human wild-type (WT) or the inherited A30P mutation. However, only the αSynuclein variants capable of forming fibrils (WT/A30P), but not the oligomeric αSynuclein species induced a sustained progressive loss of adult nigral DA neurons. These results demonstrate that divergent modes of αSynuclein neurotoxicity exist in invertebrate and mammalian DA neurons in vivo and suggest that fibrillation of αSynuclein promotes the progressive degeneration of nigral DA neurons as found in PD patients

Drone aggregation behavior in the social wasp Vespula germanica (Hymenoptera: Vespidae): Effect of kinship and density

Inbreeding can have negative consequences on population viability because of the reduced fitness of the progeny. In general, most species have developed mechanisms to minimize inbreeding such as dispersal and kin avoidance behavior. In the eusocial Hymenoptera, related individuals typically share a common nest and have relatively short mating periods, this could lead to inbreeding, and because of their single?locus complementary sex determination system, it may generate diploid males that could result in infertile triploid progeny representing a cost for the colony. Vespula germanica, is an eusocial wasp that has invaded many parts of the world, despite likely facing a reduced genetic pool during the arrival phases. We ask whether male wasp display specific aggregation behavior that favors genetic diversity, key to reduce inbreeding. Through a set of laboratory experiments, we investigated the effects of drone nestmateship and density on the aggregation behavior of V. germanica drones. We show that drones avoid aggregating with their nestmates at all densities while non-nestmates are avoided only at high densities. This suggests that lek genetic diversity and density could be regulated through drone behavior and in the long run minimize inbreeding favoring invasion success.Fil: Masciocchi, Maité. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Patagonia Norte. Estación Experimental Agropecuaria San Carlos de Bariloche. Instituto de Investigaciones Forestales y Agropecuarias Bariloche. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigaciones Forestales y Agropecuarias Bariloche; ArgentinaFil: Angeletti, Bárbara. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Patagonia Norte. Estación Experimental Agropecuaria San Carlos de Bariloche. Instituto de Investigaciones Forestales y Agropecuarias Bariloche. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigaciones Forestales y Agropecuarias Bariloche; ArgentinaFil: Corley, Juan Carlos. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Patagonia Norte. Estación Experimental Agropecuaria San Carlos de Bariloche. Instituto de Investigaciones Forestales y Agropecuarias Bariloche. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigaciones Forestales y Agropecuarias Bariloche; ArgentinaFil: Martinez Von Ellrichshausen, Andres Santiago. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Patagonia Norte. Estación Experimental Agropecuaria San Carlos de Bariloche. Instituto de Investigaciones Forestales y Agropecuarias Bariloche. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigaciones Forestales y Agropecuarias Bariloche; Argentin

Multivariate modeling of chromium-induced oxidative stress and biochemical changes in plants of Pistia stratiotes L.

Biochemical changes in the plants of Pistia stratiotes L., a free floating macrophyte exposed to different concentrations of hexavalent chromium (0, 10, 40, 60, 80 and 160 μM) for 48, 96 and 144 h were studied. Chromium-induced oxidative stress in macrophyte was investigated using the multivariate modeling approaches. Cluster analysis rendered two fairly distinct clusters (roots and shoots) of similar characteristics in terms of their biochemical responses. Discriminant analysis identified ascorbate peroxidase (APX) as discriminating variable between the root and shoot tissues. Principal components analysis results suggested that malondialdehyde (MDA), superoxide dismutase (SOD), APX, non-protein thiols (NP-SH), cysteine, ascorbic acid, and Cr-accumulation are dominant in root tissues, whereas, protein and guaiacol peroxidase (GPX) in shoots of the plant. Discriminant partial least squares analysis results further confirmed that MDA, SOD, NP-SH, cysteine, GPX, APX, ascorbic acid and Cr-accumulation dominated in the root tissues, while protein in the shoot. Three-way analysis helped in visualizing simultaneous influence of metal concentration and exposure duration on biochemical variables in plant tissues. The multivariate approaches, thus, allowed for the interpretation of the induced biochemical changes in the plant tissues exposed to chromium, which otherwise using the conventional approaches is difficult

Irish general practitioner attitudes toward decriminalisation and medical use of cannabis: results from a national survey.

BACKGROUND: Governmental debate in Ireland on the de facto decriminalisation of cannabis and legalisation for medical use is ongoing. A cannabis-based medicinal product (Sativex®) has recently been granted market authorisation in Ireland. This unique study aimed to investigate Irish general practitioner (GP) attitudes toward decriminalisation of cannabis and assess levels of support for use of cannabis for therapeutic purposes (CTP). METHODS: General practitioners in the Irish College of General Practitioner (ICGP) database were invited to complete an online survey. Anonymous data yielded descriptive statistics (frequencies, percentages) to summarise participant demographic information and agreement with attitudinal statements. Chi-square tests and multi-nominal logistic regression were included. RESULTS: The response rate was 15% (n = 565) which is similar to other Irish national GP attitudinal surveys. Over half of Irish GPs did not support the decriminalisation of cannabis (56.8%). In terms of gender, a significantly higher proportion of males compared with females (40.6 vs. 15%; p < 0.0001) agreed or strongly agreed with this drug policy approach. A higher percentage of GPs with advanced addiction specialist training (level 2) agreed/strongly agreed that cannabis should be decriminalised (54.1 vs. 31.5%; p = 0.021). Over 80% of both genders supported the view that cannabis use has a significant effect on patients' mental health and increases the risk of schizophrenia (77.3%). Over half of Irish GPs supported the legalisation of cannabis for medical use (58.6%). A higher percentage of those who were level 1-trained (trained in addiction treatment but not to an advanced level) agreed/strongly agreed cannabis should be legalised for medical use (p = 0.003). Over 60% agreed that cannabis can have a role in palliative care, pain management and treatment of multiple sclerosis (MS). In the regression response predicator analysis, females were 66.2% less likely to agree that cannabis should be decriminalised, 42.5% less likely to agree that cannabis should be legalised for medical use and 59.8 and 37.6% less likely to agree that cannabis has a role in palliative care and in the treatment of multiple sclerosis (respectively) than males. CONCLUSIONS: The majority of Irish GPs do not support the present Irish governmental drug policy of decriminalisation of cannabis but do support the legalisation of cannabis for therapeutic purposes. Male GPs and those with higher levels of addiction training are more likely to support a more liberal drug policy approach to cannabis for personal use. A clear majority of GPs expressed significant concerns regarding both the mental and physical health risks of cannabis use. Ongoing research into the health and other effects of drug policy changes on cannabis use is required