A Novel IFITM5 Variant Associated with Phenotype of Osteoporosis with Calvarial Doughnut Lesions: A Case Report.

Osteogenesis imperfecta (OI) and other decreased bone density disorders comprise a heterogeneous group of heritable diseases with skeletal fragility. Recently, it was discovered that mutations in SGMS2, encoding sphingomyelin synthetase 2, result in aberrant sphingomyelin metabolism and lead to a novel form of OI termed osteoporosis with calvarial doughnut lesions (OP-CDL) with moderate to severe skeletal fragility and variable cranial hyperostotic lesions. This study describes a Japanese family with the skeletal phenotype of OP-CDL. The affected individuals have moderately severe, childhood-onset skeletal fragility with multiple long-bone fractures, scoliosis and bone deformities. In addition, they exhibit multiple CDLs or calvarial bumps with central radiolucency and peripheral radiopacity. However, SGMS2 sequencing was normal. Instead, whole-exome sequencing identified a novel IFITM5 missense mutation c.143A>G (p.N48S) (classified as a VUS by ACMG). IFITM5 encodes an osteoblast-restricted protein BRIL and a recurrent c.-14C>T mutation in its 5' UTR region results in OI type V, a distinctive subtype of OI associated with hyperplastic callus formation and ossification of the interosseous membranes. The patients described here have a phenotype clearly different from OI type V and with hyperostotic cranial lesions, feature previously unreported in association with IFITM5. Our findings expand the genetic spectrum of OP-CDL, indicate diverse phenotypic consequences of pathogenic IFITM5 variants, and imply an important role for BRIL in cranial skeletogenesis.

Report of second case and clinical and molecular characterization of Eiken syndrome.

We report a boy with Eiken syndrome caused by a homozygous missense variant in Parathyroid hormone 1 receptor (PTH1R) c.103G > A [p.(Glu35Lys)]. Eiken syndrome is a very rare skeletal dysplasia due to bi-allelic variants in PTH1R. Only one affected family has been known to-date. The hallmarks include delayed ossification of bone including the epiphyses, pubic symphysis, and primary ossification centers of the short tubular bones, coarse bone trabeculae, and modeling abnormalities. The phenotype being described here recapitulates the delayed ossification and modeling abnormalities of Eiken syndrome. In addition, supernumerary epiphyses of the tubular bones of the hands and primary failure of eruption of teeth were observed in our proband. This report characterizes Eiken syndrome and confirms that bi-allelic hypomorphic variants in PTH1R are probably to cause this condition.

Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502.

BACKGROUND: While adjuvant chemotherapy is preferable for high-risk colon cancer, treatment duration is controversial. Oral uracil and tegafur (UFT)/leucovorin (LV) is widely used as a standard adjuvant chemotherapy for colon cancer in Japan. We conducted a phase III trial to investigate the optimal duration of adjuvant chemotherapy for stage IIB/III colon cancer. PATIENTS AND METHODS: Patients with curatively resected stage IIB/III colon cancer were eligible for enrollment in this trial. Patients were registered within 6 weeks after surgery and were randomly assigned to receive UFT/LV for 28 of 35 days for 6 months in the control group or for 5 consecutive days per week for 18 months in the study group. The primary end point was the disease-free survival (DFS), and the secondary end points were overall survival (OS) and safety. RESULT: A total of 1071 patients were registered from 233 centers. A statistically significant difference in DFS was not observed between the study group and the control group; the 5-year DFS was 69% in the study group and 69% in the control group. The 5-year OS was 85% in the study group and 85% in the control group. CONCLUSION: Eighteen-month treatment with UFT/LV did not improve DFS or OS compared with 6-month UFT/LV treatment in patients with stage IIB/III colon cancer. The important finding from this study is that not 18 months but 6 months of treatment is enough for postoperative UFT/LV for stage IIB/III colon cancer. CLINICAL TRIAL NUMBER: UMIN-CTR C000000245.

Efficacy and toxicity of (chemo)radiotherapy for primary subglottic cancer.

BACKGROUND AND PURPOSE: Primary subglottic cancer is a rare malignancy. We investigated the efficacy and toxicity of radiotherapy for subglottic cancer. PATIENTS AND METHODS: Nineteen patients with primary squamous cell carcinoma of the subglottis received radiotherapy, 14 of whom also underwent chemotherapy. Of the 19 patients, 15 received definitive radiotherapy to the gross tumors with total doses of 70-70.2 Gy in 35-39 fractions, and 4 underwent preoperative radiotherapy with total doses of 37.8-55.8 Gy in 21-31 fractions, followed by total laryngectomy. RESULTS: Of the 19 patients, 5 developed local progression and 2 developed distant metastasis at the median follow-up period of 5 years. The 5-year local control and disease-free rates were 74 and 63%, respectively. Three patients died of tumor progression, and the 5-year overall and disease-free survival rates were 80 and 63%, respectively. Regarding acute toxicities, transient mucositis and dermatitis of grade 3 or lower were observed in all patients, but there were no late toxicities of grade 3 or higher. CONCLUSION: Radiotherapy is a safe and effective treatment for patients with primary squamous cell carcinoma of the subglottis. The use of chemotherapy together with radiotherapy may enhance treatment efficacy and contribute to larynx preservation through good local control.

Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease.

Camurati-Engelmann disease (CED, MIM 131300) is an autosomal dominant, progressive diaphyseal dysplasia characterized by hyperosteosis and sclerosis of the diaphyses of long bones. We recently assigned the CED locus to an interval between D19S422 and D19S606 at chromosome 19q13.1-q13.3, which two other groups confirmed. As the human transforming growth factor-1 gene (TGFB1) is located within this interval, we considered it a candidate gene for CED.

Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.

BACKGROUND: Mutations in TRPV4, a gene that encodes a Ca(2+) permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear. OBJECTIVES AND METHODS: To examine TRPV4 mutation spectrum and phenotype-genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands. RESULTS: TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations. CONCLUSION: The TRPV4 mutation spectrum in MD and SMDK, which showed genotype-phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.

Natural parasitism in fruit fly (Diptera: Tephritidae) and interaction with wild hosts surrounding apple orchards adjacent to Atlantic Forest fragments in Paraná State, Brazil.

The South American fruit fly, Anastrepha fraterculus (Wiedemann, 1830) (Diptera: Tephritidae), is an important pest in the subtropical region of Brazil. This insect has tritrophic relation between wild fruits and parasitoids and is associated with apple (Malus domestica Borkh.) orchards adjacent to the Atlantic Forest in Paraná. We thus investigated the degree of infestation of the fruit fly and natural parasitism in wild and cultivated fruits surrounding apple orchards. For this purpose, we collected fruits of Acca sellowiana (Berg.) Burret, Campomanesia xanthocarpa (Mart), Eugenia uniflora L., Eugenia pyriformis Cambessèdes, Psidium cattleianum Sabine, Psidium guajava (L.), Annona neosericea Rainer and Eriobotrya japonica (Thumb) in apple orchards adjacent to the Atlantic Forest located in Campo do Tenente, Lapa and Porto Amazonas counties. In total, we collected 18,289 fruits during four growing years. The occurrence of A. fraterculus depends on the susceptible period of apple fruits. A. sellowiana and P. cattleianum were considered primary fruit fly multipliers and P. guajava was secondary, all occurring after the apple harvest (IS period). The group of parasitoids with A. fraterculus was Aganaspis pelleranoi (Brèthes, 1924) (Hymenoptera: Figitidae), Opius bellus (Gahan, 1930), Doryctobracon areolatus (Szépligeti, 1911) and Doryctobracon brasiliensis (Szépligeti, 1911) (Hymenoptera: Braconidae) all of which are first records in the Atlantic Forest in Paraná. First record of O. bellus occurring in the State of Paraná, as well as, first record of the tritrophic association between host plant A. neosericea, parasitoids D. areolatus and O. bellus and fruit fly A. fraterculus. The host P. cattleianum stood out among the Myrtaceae species in regard to the high diversity of parasitoid species (81% of parasitoids). The total number of Figitidae species (76.5%) was higher than that of Braconidae species. The influence of climatic events in southern Brazil on wild fruit production should be further studied to understand the association of A. fraterculus with the tritrophic relationship.

Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases.

BACKGROUND: Schneckenbecken dysplasia (SBD) is an autosomal recessive lethal skeletal dysplasia that is classified into the severe spondylodysplastic dysplasias (SSDD) group in the international nosology for skeletal dysplasias. The radiological hallmark of SBD is the snail-like configuration of the hypoplastic iliac bone. SLC35D1 (solute carrier-35D1) is a nucleotide-sugar transporter involved in proteoglycan synthesis. Recently, based on human and mouse genetic studies, we showed that loss-of-function mutations of the SLC35D1 gene (SLC35D1) cause SBD. OBJECT: To explore further the range of SLC35D1 mutations in SBD and elucidate whether SLC35D1 mutations cause other skeletal dysplasias that belong to the SSDD group. METHODS AND RESULTS: We searched for SLC35D1 mutations in five families with SBD and 15 patients with other SSDD group diseases, including achodrogenesis type 1A, spondylometaphyseal dysplasia Sedaghatian type and fibrochondrogenesis. We identified four novel mutations, c.319C>T (p.R107X), IVS4+3A>G, a 4959-bp deletion causing the removal of exon 7 (p.R178fsX15), and c.193A>C (p. T65P), in three SBD families. Exon trapping assay showed IVS4+3A>G caused skipping of exon 4 and a frameshift (p.L109fsX18). Yeast complementation assay showed the T65P mutant protein lost the transporter activity of nucleotide sugars. Therefore, all these mutations result in loss of function. No SLC35D1 mutations were identified in all patients with other SSDD group diseases. CONCLUSION: Our findings suggest that SLC35D1 loss-of-function mutations result consistently in SBD and are exclusive to SBD.

Faunistic analyses of fruit fly species (Diptera: Tephritidae) in orchards surrounded by Atlantic Forest fragments in the metropolitan region of Curitiba, Paraná state, Brazil.

The objective of this trial was to characterize the assemblage structure of fruit flies (Diptera: Tephritidae) by determining the diversity and faunal indices. Fruit flies were collected for ten years between 2003 and 2015 in six municipalities of the Metropolitan Region of Curitiba, Paraná. The orchards were divided into three crop protection strategies: organic, conventional, and integrated pest management. The characteristic of each community was determined using the Shannon-Wiener, Margalef, and Pielou's indexes. The frequency, constancy, and dominance indexes were also determined. Biological material was analyzed using the explanatory variables: site, crop, plant protection strategy, and susceptibility period. A total of 8,089 fruit flies were collected, of which 4,681 were females. The species Anastrepha daciformis Bezzi, A. dissimilis Stone, A. distincta Greene and A. pickeli Lima were recorded for the first time in Paraná State, the occurrence of three other species was recorded for the first time in the Metropolitan Region of Curitiba (A. montei Lima, A. obliqua Macquart, and A. sororcula Zucchi), in addition A. fraterculus (Wiedemann), A. grandis (Macquart) and Ceratitis capitata (Wiedemann). A. fraterculus accounted for 98.5% of the collected species. Only A. fraterculus and A. sororcula were found in fruits. Fruit flies occurred predominantly in peach trees cultivated under organic conditions. The Shannon index indicated that the municipality of Cerro Azul had the highest diversity and richness whereas apple orchards had the lowest diversity. Crops cultivated under organic conditions exhibited the highest diversity whereas those cultivated under conventional conditions had the highest evenness index. The largest specimens number was collected during the period of crop susceptibility.

Natural parasitism in fruit fly (Diptera: Tephritidae) and interaction with wild hosts surrounding apple orchards adjacent to Atlantic Forest fragments in Paraná State, Brazil / Parasitismo natural de mosca-das-frutas (Diptera: Tephritidae) e interação com hospedeiros silvestres em pomares de macieira adjacentes a fragmentos de Mata Atlântica no Estado do Paraná, Brasil

The South American fruit fly, Anastrepha fraterculus (Wiedemann, 1830) (Diptera: Tephritidae), is an important pest in the subtropical region of Brazil. This insect has tritrophic relation between wild fruits and parasitoids and is associated with apple (Malus domestica Borkh.) orchards adjacent to the Atlantic Forest in Paraná. We thus investigated the degree of infestation of the fruit fly and natural parasitism in wild and cultivated fruits surrounding apple orchards. For this purpose, we collected fruits of Acca sellowiana (Berg.) Burret, Campomanesia xanthocarpa (Mart), Eugenia uniflora L., Eugenia pyriformis Cambessèdes, Psidium cattleianum Sabine, Psidium guajava (L.), Annona neosericea Rainer and Eriobotrya japonica (Thumb) in apple orchards adjacent to the Atlantic Forest located in Campo do Tenente, Lapa and Porto Amazonas counties. In total, we collected 18,289 fruits during four growing years. The occurrence of A. fraterculus depends on the susceptible period of apple fruits. A. sellowiana and P. cattleianum were considered primary fruit fly multipliers and P. guajava was secondary, all occurring after the apple harvest (IS period). The group of parasitoids with A. fraterculus was Aganaspis pelleranoi (Brèthes, 1924) (Hymenoptera: Figitidae), Opius bellus (Gahan, 1930), Doryctobracon areolatus (Szépligeti, 1911) and Doryctobracon brasiliensis (Szépligeti, 1911) (Hymenoptera: Braconidae) all of which are first records in the Atlantic Forest in Paraná. First record of O. bellus occurring in the State of Paraná, as well as, first record of the tritrophic association between host plant A. neosericea, parasitoids D. areolatus and O. bellus and fruit fly A. fraterculus. The host P. cattleianum stood out among the Myrtaceae species in regard to the high diversity of parasitoid species (81% of parasitoids). The total number of Figitidae species (76.5%) was higher [...].

Mosca-das-frutas sul-americana, Anastrepha fraterculus (Wiedemann, 1830) (Diptera: Tephritidae), é uma importante praga da região subtropical do Brasil. Este inseto tem relação tritrófico entre frutos silvestres e parasitoides e está associado a pomares de macieiras (Malus domestica Borkh.) adjacentes à Mata Atlântica no Paraná. Assim, investigamos o grau de infestação da mosca-das-frutas e o parasitismo natural em frutas silvestres e cultivadas ao redor de pomares de maçã. Para tanto, foram coletados frutos de Acca sellowiana (Berg.) Burret, Campomanesia xanthocarpa (Mart), Eugenia uniflora L., Eugenia pyriformis Cambessèdes, Psidium cattleianum Sabine, Psidium guajava (L.), Annona neosericea Rainer e Eriobotrya japonica (Thumb) em pomares de maçã adjacentes à Mata Atlântica localizados nos municípios de Campo do Tenente, Lapa e Porto Amazonas. No total, coletamos 18.289 frutos durante quatro anos de cultivo. A ocorrência de A. fraterculus depende do período de suscetibilidade dos frutos da maçã. A. sellowiana e P. cattleianum foram considerados multiplicadores primários de mosca-das-frutas e P. guajava foi secundário, todos ocorrendo após a colheita da maçã (período IS). Os parasitóides a associados a A. fraterculus foram Aganaspis pelleranoi (Brèthes, 1924) (Hymenoptera: Figitidae), Opius bellus (Gahan, 1930), Doryctobracon areolatus (Szépligeti, 1911) e Doryctobracon brasiliensis (Szépligeti, 1911) (Hymenoptera: Braconidae), todos os quais são primeiros registros na Mata Atlântica no Paraná. Primeiro registro de O. bellus ocorrendo no Estado do Paraná, assim como, primeiro registro da associação tritrófica entre o hospedeiro A. neosericea, parasitoides D. areolatus e O. bellus e mosca-das-frutas A. fraterculus. O hospedeiro P. cattleianum se destacou entre as espécies de Myrtaceae pela alta diversidade de parasitóides associados (81% dos parasitóides). O número total de espécies de Figitidae (76,5%) foi superior [...].

Natural parasitism in fruit fly (Diptera: Tephritidae) and interaction with wild hosts surrounding apple orchards adjacent to Atlantic Forest fragments in Paraná State, Brazil

Abstract The South American fruit fly, Anastrepha fraterculus (Wiedemann, 1830) (Diptera: Tephritidae), is an important pest in the subtropical region of Brazil. This insect has tritrophic relation between wild fruits and parasitoids and is associated with apple (Malus domestica Borkh.) orchards adjacent to the Atlantic Forest in Paraná. We thus investigated the degree of infestation of the fruit fly and natural parasitism in wild and cultivated fruits surrounding apple orchards. For this purpose, we collected fruits of Acca sellowiana (Berg.) Burret, Campomanesia xanthocarpa (Mart), Eugenia uniflora L., Eugenia pyriformis Cambessèdes, Psidium cattleianum Sabine, Psidium guajava (L.), Annona neosericea Rainer and Eriobotrya japonica (Thumb) in apple orchards adjacent to the Atlantic Forest located in Campo do Tenente, Lapa and Porto Amazonas counties. In total, we collected 18,289 fruits during four growing years. The occurrence of A. fraterculus depends on the susceptible period of apple fruits. A. sellowiana and P. cattleianum were considered primary fruit fly multipliers and P. guajava was secondary, all occurring after the apple harvest (IS period). The group of parasitoids with A. fraterculus was Aganaspis pelleranoi (Brèthes, 1924) (Hymenoptera: Figitidae), Opius bellus (Gahan, 1930), Doryctobracon areolatus (Szépligeti, 1911) and Doryctobracon brasiliensis (Szépligeti, 1911) (Hymenoptera: Braconidae) all of which are first records in the Atlantic Forest in Paraná. First record of O. bellus occurring in the State of Paraná, as well as, first record of the tritrophic association between host plant A. neosericea, parasitoids D. areolatus and O. bellus and fruit fly A. fraterculus. The host P. cattleianum stood out among the Myrtaceae species in regard to the high diversity of parasitoid species (81% of parasitoids). The total number of Figitidae species (76.5%) was higher than that of Braconidae species. The influence of climatic events in southern Brazil on wild fruit production should be further studied to understand the association of A. fraterculus with the tritrophic relationship.

Resumo Mosca-das-frutas sul-americana, Anastrepha fraterculus (Wiedemann, 1830) (Diptera: Tephritidae), é uma importante praga da região subtropical do Brasil. Este inseto tem relação tritrófico entre frutos silvestres e parasitoides e está associado a pomares de macieiras (Malus domestica Borkh.) adjacentes à Mata Atlântica no Paraná. Assim, investigamos o grau de infestação da mosca-das-frutas e o parasitismo natural em frutas silvestres e cultivadas ao redor de pomares de maçã. Para tanto, foram coletados frutos de Acca sellowiana (Berg.) Burret, Campomanesia xanthocarpa (Mart), Eugenia uniflora L., Eugenia pyriformis Cambessèdes, Psidium cattleianum Sabine, Psidium guajava (L.), Annona neosericea Rainer e Eriobotrya japonica (Thumb) em pomares de maçã adjacentes à Mata Atlântica localizados nos municípios de Campo do Tenente, Lapa e Porto Amazonas. No total, coletamos 18.289 frutos durante quatro anos de cultivo. A ocorrência de A. fraterculus depende do período de suscetibilidade dos frutos da maçã. A. sellowiana e P. cattleianum foram considerados multiplicadores primários de mosca-das-frutas e P. guajava foi secundário, todos ocorrendo após a colheita da maçã (período IS). Os parasitóides a associados a A. fraterculus foram Aganaspis pelleranoi (Brèthes, 1924) (Hymenoptera: Figitidae), Opius bellus (Gahan, 1930), Doryctobracon areolatus (Szépligeti, 1911) e Doryctobracon brasiliensis (Szépligeti, 1911) (Hymenoptera: Braconidae), todos os quais são primeiros registros na Mata Atlântica no Paraná. Primeiro registro de O. bellus ocorrendo no Estado do Paraná, assim como, primeiro registro da associação tritrófica entre o hospedeiro A. neosericea, parasitoides D. areolatus e O. bellus e mosca-das-frutas A. fraterculus. O hospedeiro P. cattleianum se destacou entre as espécies de Myrtaceae pela alta diversidade de parasitóides associados (81% dos parasitóides). O número total de espécies de Figitidae (76,5%) foi superior ao de espécies de Braconidae. A influência de eventos climáticos no sul do Brasil na produção de frutas silvestres deve ser mais estudada para entender a associação de A. fraterculus com a relação tritrófica.

Natural parasitism in fruit fly (Diptera: Tephritidae) and interaction with wild hosts surrounding apple orchards adjacent to Atlantic Forest fragments in Paraná State, Brazil / Parasitismo natural de mosca-das-frutas (Diptera: Tephritidae) e interação com hospedeiros silvestres em pomares de macieira adjacentes a fragmentos de Mata Atlântica no Estado do Paraná, Brasil

Abstract The South American fruit fly, Anastrepha fraterculus (Wiedemann, 1830) (Diptera: Tephritidae), is an important pest in the subtropical region of Brazil. This insect has tritrophic relation between wild fruits and parasitoids and is associated with apple (Malus domestica Borkh.) orchards adjacent to the Atlantic Forest in Paraná. We thus investigated the degree of infestation of the fruit fly and natural parasitism in wild and cultivated fruits surrounding apple orchards. For this purpose, we collected fruits of Acca sellowiana (Berg.) Burret, Campomanesia xanthocarpa (Mart), Eugenia uniflora L., Eugenia pyriformis Cambessèdes, Psidium cattleianum Sabine, Psidium guajava (L.), Annona neosericea Rainer and Eriobotrya japonica (Thumb) in apple orchards adjacent to the Atlantic Forest located in Campo do Tenente, Lapa and Porto Amazonas counties. In total, we collected 18,289 fruits during four growing years. The occurrence of A. fraterculus depends on the susceptible period of apple fruits. A. sellowiana and P. cattleianum were considered primary fruit fly multipliers and P. guajava was secondary, all occurring after the apple harvest (IS period). The group of parasitoids with A. fraterculus was Aganaspis pelleranoi (Brèthes, 1924) (Hymenoptera: Figitidae), Opius bellus (Gahan, 1930), Doryctobracon areolatus (Szépligeti, 1911) and Doryctobracon brasiliensis (Szépligeti, 1911) (Hymenoptera: Braconidae) all of which are first records in the Atlantic Forest in Paraná. First record of O. bellus occurring in the State of Paraná, as well as, first record of the tritrophic association between host plant A. neosericea, parasitoids D. areolatus and O. bellus and fruit fly A. fraterculus. The host P. cattleianum stood out among the Myrtaceae species in regard to the high diversity of parasitoid species (81% of parasitoids). The total number of Figitidae species (76.5%) was higher than that of Braconidae species. The influence of climatic events in southern Brazil on wild fruit production should be further studied to understand the association of A. fraterculus with the tritrophic relationship.

Resumo Mosca-das-frutas sul-americana, Anastrepha fraterculus (Wiedemann, 1830) (Diptera: Tephritidae), é uma importante praga da região subtropical do Brasil. Este inseto tem relação tritrófico entre frutos silvestres e parasitoides e está associado a pomares de macieiras (Malus domestica Borkh.) adjacentes à Mata Atlântica no Paraná. Assim, investigamos o grau de infestação da mosca-das-frutas e o parasitismo natural em frutas silvestres e cultivadas ao redor de pomares de maçã. Para tanto, foram coletados frutos de Acca sellowiana (Berg.) Burret, Campomanesia xanthocarpa (Mart), Eugenia uniflora L., Eugenia pyriformis Cambessèdes, Psidium cattleianum Sabine, Psidium guajava (L.), Annona neosericea Rainer e Eriobotrya japonica (Thumb) em pomares de maçã adjacentes à Mata Atlântica localizados nos municípios de Campo do Tenente, Lapa e Porto Amazonas. No total, coletamos 18.289 frutos durante quatro anos de cultivo. A ocorrência de A. fraterculus depende do período de suscetibilidade dos frutos da maçã. A. sellowiana e P. cattleianum foram considerados multiplicadores primários de mosca-das-frutas e P. guajava foi secundário, todos ocorrendo após a colheita da maçã (período IS). Os parasitóides a associados a A. fraterculus foram Aganaspis pelleranoi (Brèthes, 1924) (Hymenoptera: Figitidae), Opius bellus (Gahan, 1930), Doryctobracon areolatus (Szépligeti, 1911) e Doryctobracon brasiliensis (Szépligeti, 1911) (Hymenoptera: Braconidae), todos os quais são primeiros registros na Mata Atlântica no Paraná. Primeiro registro de O. bellus ocorrendo no Estado do Paraná, assim como, primeiro registro da associação tritrófica entre o hospedeiro A. neosericea, parasitoides D. areolatus e O. bellus e mosca-das-frutas A. fraterculus. O hospedeiro P. cattleianum se destacou entre as espécies de Myrtaceae pela alta diversidade de parasitóides associados (81% dos parasitóides). O número total de espécies de Figitidae (76,5%) foi superior ao de espécies de Braconidae. A influência de eventos climáticos no sul do Brasil na produção de frutas silvestres deve ser mais estudada para entender a associação de A. fraterculus com a relação tritrófica.

Isolation of entomopathogenic nematodes in an apple orchard in Southern Brazil and its virulence to Anastrepha fraterculus (Diptera: Tephritidae) larvae, under laboratory conditions.

Entomopathogenic nematodes (EPNs) are a promising alternative to integrated control in many fruit pests. Few studies were made on the relationship of Anastrepha fraterculus natural population with native EPNs population and other biotic and abiotic factors. The aim of this work was to verify the occurrence of endemic nematodes in an apple orchard, concerning environmental conditions and technical procedure, and access isolates virulence to A. fraterculus larvae. The experiment was conducted during a year taking monthly soil samples from an apple orchard, with and without fallen fruits just above the soil. Samples were baited with Tenebrium molitor and A. fraterculus larvae in laboratory. Canopy and fallen fruits were sampled to access the pest infestation. Seventy three EPN isolates were captured, in 23.2% soil samples, more with T. molitor than with A. fraterculus baits. From the 20 isolates tested against A. fraterculus, only five were pathogenic, and they were identified as Oscheius sp. The nematodes were captured during all seasons in a similar frequency. Soil and weather conditions, presence of fruit over the orchard soil, and A. fraterculus pupae in the fruits had no significant influence on the capture. As a conclusion, nematodes of the genera Oscheius are found in an apple orchard of Porto Amazonas constantly along the year, independently of fluctuations in A. fraterculus population, climate conditions and presence of fruit over the soil. Some of the isolates are pathogenic to A. fraterculus.

Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.

The skeletal ciliopathies are a heterogeneous group of disorders with a significant clinical and genetic variability and the main clinical features are thoracic hypoplasia and short tubular bones. To date, 25 genes have been identified in association with skeletal ciliopathies. Mutations in the KIAA0753 gene have recently been associated with Joubert syndrome (JBTS) and orofaciodigital (OFD) syndrome. We report biallelic pathogenic variants in KIAA0753 in four patients with short-rib type skeletal dysplasia. The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses. We demonstrate that KIAA0753 is expressed in normal fetal human growth plate and show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by our findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning.

SHOX haploinsufficiency and overdosage: impact of gonadal function status.

Since its discovery in 1997, knowledge about the SHOX gene has rapidly increased. In this review, we summarise clinical features and diagnostic and therapeutic implications in SHOX haploinsufficiency and overdosage. SHOX haploinsufficiency usually results in mesomelic short stature and Turner skeletal features, including Madelung deformity with puberty, in subjects with normal gonadal function. Thus, identification of early or mild signs of Madelung deformity is pivotal for the diagnosis, and gonadal suppression therapy may serve to mitigate the clinical features. By contrast, SHOX overdosage usually leads to long limbs and tall stature resulting from continued growth into the late teens in subjects with gonadal dysgenesis. Thus, the combination of tall stature and poor pubertal development is the key to diagnosis, and oestrogen therapy can help the prevention of unfavourably tall stature as well as the induction of sexual development. These findings, in conjunction with skeletal assessment in Turner syndrome and expression analysis during human embryogenesis, imply that SHOX functions as a repressor for growth plate fusion and skeletal maturation in the distal limbs and, thus, counteracts the skeletal maturing effects of oestrogens.

Skeletal features and growth patterns in 14 patients with haploinsufficiency of SHOX: implications for the development of Turner syndrome.

We report on clinical features in 14 Japanese patients (4 males and 10 females) with partial monosomy of the short arm pseudoautosomal region involving SHOX (n = 11) or total monosomy of the pseudoautosomal region with no involvement of disease genes on the sex-differential regions (n = 3). Skeletal assessment showed that three patients had no discernible skeletal abnormalities, one patient exhibited short 4th metacarpals and borderline cubitus valgus, and the remaining 10 patients had Madelung deformity and/or mesomelia characteristic of Léri-Weill dyschondrosteosis (LWD), together with short 4th metacarpals and/or cubitus valgus. Skeletal lesions were more severe in females and became obvious with age. Growth evaluation revealed that patients without LWD grew along by the -2 SD growth curve before puberty and showed a normal or exaggerated pubertal growth spurt, whereas those with LWD grew along by the standard growth curves before puberty but exhibited an attenuated pubertal growth spurt and resultant short stature. Maturational assessment indicated a tendency of relatively early maturation in patients with LWD. There was no correlation between the clinical phenotype and the deletion size. These findings suggest that haploinsufficiency of SHOX causes not only short stature but also Turner skeletal anomalies (such as short 4th metacarpals, cubitus valgus, and LWD) and that growth pattern is primarily dependent on the presence or absence of LWD. Because skeletal lesions have occurred in a female-dominant and age-influenced fashion, it is inferred that estrogens exert a maturational effect on skeletal tissues that are susceptible to premature fusion of growth plates because of haploinsufficiency of SHOX, facilitating the development of skeletal lesions.

Regulation of apoptosis by respiration: cytochrome c release by respiratory substrates.

Cytochrome c release from mitochondria is essential for apoptosis. Using human myelogenous leukemia ML-1a, its respiration-deficient and reconstituted cells, we demonstrated that respiratory function is essential for tumor necrosis factor-induced cytochrome c release. In a cell free system using mitochondrial fraction from ML-1a, initiation of respiration by substrates for complexes I, II, and III but not IV released cytochrome c, suggesting that reduction of coenzyme Q or complex III is essential for cytochrome c release. In the same system, disruption of mitochondrial outer membrane was neither enough nor the cause for cytochrome c release by succinate. These observations define an early pathway in which a change in respiration releases cytochrome c.