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In higher plants, Zn nutritional imbalance can affect growth, physiology and response to stress, with effect variable depending on host-pathogen interaction. Mechanisms through which Zn operates are not yet well known. The hormone salicylic acid (SA) can affect plant ion uptake, transport and defence responses. Thus, in this study the impact of Zn imbalance and SA co-supply on severity of infection with the necrotrophic fungal pathogen B. cinerea or the biotroph G. cichoracearum was assessed in A. thaliana Col-0. Spectrophotometric assays for pigments and malondialdehyde (MDA) content as a marker of lipid peroxidation, plant defensin 1.2 gene expression by semi-quantitative PCR, callose visualization by fluorescence microscopy and diseases evaluation by macro- and microscopic observations were carried out. Zinc plant concentration varied with the supplied dose. In comparison with the control, Zn-deficit or Zn-excess led to reduced chlorophyll content and PDF 1.2 transcripts induction. In Zn-deficient plants, where MDA increased, also the susceptibility to B. cinerea increased, whereas MDA decreased in G. cichoracearum. Zinc excess increased susceptibility to both pathogens. Co-administration of SA positively affected MDA level, callose deposition, PDF 1.2 transcripts and plant response to the two pathogens. The increased susceptibility to B. cinerea in both Zn-deficient and Zn-excess plants could be related to lack of induction of PDF 1.2 transcripts; oxidative stress could explain higher susceptibility to the necrotroph and lower susceptibility to the biotroph in Zn-deficient plants. This research shows that an appropriate evaluation of Zn supply according to the prevalent stress factor is desirable for plants.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Botrytis/metabolismo , Ciclopentanos , Regulação da Expressão Gênica de Plantas , Estilo de Vida , Oxilipinas , Doenças das Plantas , Ácido Salicílico , ZincoRESUMO
Congenital pseudoarthrosis of the tibia (CPT) is a rare disease characterised by the onset of bone anomalies or fractures, leading to deformities in paediatric patients. The aetiology of this pathology is unknown. The main theories include the presence of hamartomatous tissue related to Neurofibromatosis type 1, vascularisation deficit of the periosteum and alterations in the numbers and functions of the osteoblasts and osteoclasts in loco. Surgical treatment generally requires multiple operations during the patient's childhood and adolescence. The best outcomes seem to occur when using intramedullary nailing, vascularised fibular transplant and external fixation with the Ilizarov technique. The purpose of this paper is to evaluate the effectiveness of in-situ injections of Bone Marrow Aspirate Concentrate (BMAC) as an adjuvant therapy for congenital pseudoarthrosis of the tibia in patients treated with external fixation and that of radiographic healing over time compared to external fixation treatment alone. We performed a retrospective review of clinical and radiographic records of patients affected by CPT and treated in the Paediatric Orthopaedics and Traumatology Department of the Gaetano Pini Orthopaedic Institute with in-situ injections of bone marrow aspirate concentrate (BMAC) on the pseudoarthrosis site, in addition to pseudoarthrosis site excision and application of circular external fixator frame in compression (Group A). The time needed to reach the radiological consolidation of the resection site was recorded and compared to that needed for patients treated with only pseudoarthrosis site excision and application of circular external fixator frame in compression (Group B). There is a statistically relevant improvement of healing time in patients affected by congenital pseudoarthrosis of the tibia treated with external fixation and bone marrow aspirate concentrate compared to patients affected by the same pathology treated with external fixation only. Injection of MSC in the pseudoarthrosis site after focus removal in combination with circular external fixation achieves faster bone healing compared with external fixation only, and the lower refracture percentage may be associated with the better quality and structure of the new bone. However, it would be desirable to have a longer followup to determine if the results of the BMC as adjuvant therapy will hold up over time.
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Pseudoartrose , Fraturas da Tíbia , Medula Óssea , Humanos , Pseudoartrose/congênito , Pseudoartrose/cirurgia , Estudos Retrospectivos , Tíbia/diagnóstico por imagem , Tíbia/cirurgia , Fraturas da Tíbia/diagnóstico por imagem , Fraturas da Tíbia/cirurgia , Resultado do TratamentoRESUMO
INTRODUCTION: Femoral shaft fractures are the commonest major pediatric fractures. For generations, traction and casting were the standard method of treatment for children. However, over the past two decades there has been growing recognition of the advantages of fixation and rapid mobilization. METHODS: A prospective multicenter study was conducted at four Italian centers of reference for pediatric fractures (January 2005 to December 2014). The study involved 62 patients of both sexes, between 6 and 14 years of age, with closed femoral shaft fractures. The aim was to find out more about the short-term complications of titanium elastic nailing in diaphyseal femur fractures in children in order to reduce them. RESULTS: The commonest complication observed in our study was pain at the nail entry point (24.19%) due to a local inflammatory reaction. After 1 year, 3.22% had limbs of different lengths. Proximal migration occurred in 1.61% of cases. DISCUSSION: Over the last two decades, the treatment of femoral shaft fractures in pediatric patients has developed to include internal fixation using Titanium Elastic Nails (TEN). We only observed a few complications in our study, most of which were minor and associated with the surgical technique employed, particularly during the initial phase of the surgeon's learning curve. CONCLUSIONS: TEN are an excellent internal fixation system if used by an expert surgeon and have a very low rate of complications. None of them produced permanent damage in the patients. In older children weighing more than 50 kg, alternative techniques such as subtrochanteric nailing, plates, or external fixation are advisable.
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Diáfises/cirurgia , Fraturas do Fêmur/cirurgia , Complicações Pós-Operatórias/cirurgia , Adolescente , Pinos Ortopédicos , Criança , Diáfises/lesões , Feminino , Fraturas do Fêmur/fisiopatologia , Fixação Intramedular de Fraturas , Humanos , Masculino , Complicações Pós-Operatórias/fisiopatologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Selenium (Se) is a trace element necessary for both human and livestock nutrition. To increase Se human intake, soil Se fertilizations were performed but the fate of the added Se remains unclear. The present research aims to: (1) determine the influence of Se fertilization on the fractionation of Se in soil; (2) assess the influence of water availability on the distribution of soil Se chemical fractions; and (3) monitor the Se content in soil, leachates and plants. To reach these goals, 200â¯g Se ha-1 was applied to soil as sodium selenite in maize crops under two irrigation regimes, and the Se content in plant, soil chemical fractions and leachates were analyzed. Se application increased the total Se content of the soil, specifically it increased the Se content of the soluble, exchangeable and organic fractions with more pronounced effect in the soils with higher water availability. These differences disappeared over time likely due to the Se loss through volatilization. The hypothesis of Se volatilization is confirmed by the absence of both leachates during the maize growing season and differences among the treatments of Se content in sub-soil samples. Also, although the Se treated plants showed higher Se content than the untreated ones, overall <1% of the added Se was assimilated by plants. Hence, this study demonstrated that the addition of selenite to the soil increased the Se contents of the plants, but the Se does not accumulate in the soil because it is likely lost via volatilization. Further, leaching of Se into groundwater is avoided due to its association with both the soil organic matter and positively charged binding sites of soil, and due to its loss via volatilization. Therefore, soil Se fertilization could increase the nutritional value of plants without consequences on the environment.
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Fertilizantes/análise , Selenito de Sódio/metabolismo , Solo/química , Água/análise , Zea mays/metabolismo , Selênio/metabolismoRESUMO
INTRODUCTION: Pegvaliase is a recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL) enzyme under investigation for treatment of adult phenylketonuria (PKU). This manuscript describes results of a randomized discontinuation trial (RDT) designed to evaluate the effects of pegvaliase treatment on blood phenylalanine (Phe) and neuropsychiatric outcomes in adults with PKU. METHODS: PRISM-2 is a 4-part, Phase 3 study that enrolled adults with PKU receiving pegvaliase treatment (initiated in a prior Phase 2 or Phase 3 study). The RDT, Part 2 of PRISM-2, was an 8-week trial that evaluated change in blood Phe concentrations, neuropsychiatric and neurocognitive measures, and safety outcomes in PRISM-2 participants who had achieved at least a 20% blood Phe reduction from pre-treatment baseline with pegvaliase treatment. Participants were randomized 2:1 to either continue pegvaliase (20â¯mg/day or 40â¯mg/day) or switch to matching placebo. RESULTS: The pooled pegvaliase group enrolled 66 participants and each placebo group enrolled 14 participants. The primary endpoint of change in blood Phe concentration from RDT entry to RDT Week 8 was met with clinically meaningful and statistically significant differences between the pegvaliase and placebo groups. Mean (SD) blood Phe at the beginning of the RDT when all participants were receiving pegvaliase was 563.9⯵M (504.6) in the group assigned to the 20â¯mg/day placebo group (nâ¯=â¯14), 508.2⯵M (363.7) in those assigned to the 40â¯mg/day placebo group (nâ¯=â¯14), and 503.9⯵M (520.3) in those assigned to continue pegvaliase treatment (nâ¯=â¯58). At Week 8 of the RDT, the least squares mean change (95% confidence interval) in blood Phe was 949.8⯵M (760.4 to 1139.1) for the 20â¯mg/day placebo group and 664.8⯵M (465.5 to 864.1) for the 40â¯mg/day placebo group in comparison to 26.5⯵M (-68.3 to 121.3) for the pooled (20â¯mg/day and 40â¯mg/day) pegvaliase group (Pâ¯<â¯0.0001 for pooled pegvaliase group vs each placebo group). Adverse events (AEs) were usually lower in the pooled placebo group when compared to the pooled pegvaliase group. The most common AEs for the pooled pegvaliase and pooled placebo groups were arthralgia (13.6% and 10.3%, respectively), headache (12.1% and 24.1%), anxiety (10.6% and 6.9%), fatigue (10.6% and 10.3%), and upper respiratory tract infection (1.5% and 17.2%). CONCLUSION: Mean blood Phe reduction was sustained in the pegvaliase group, while placebo groups had mean blood Phe concentration increase toward pre-treatment baseline levels. Results from this study confirmed the efficacy of pegvaliase in maintaining reduced blood Phe concentrations with a manageable safety profile for most participants.
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Fenilalanina Amônia-Liase/uso terapêutico , Fenilalanina/sangue , Fenilcetonúrias/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Adolescente , Adulto , Proteínas Alimentares , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenilalanina Amônia-Liase/administração & dosagem , Fenilalanina Amônia-Liase/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Adulto JovemRESUMO
Non-union (or pseudoarthrosis) is defined as a fracture that fails to consolidate after 6 months from the trauma. Current conservative treatments consist of biological (i.e. with calcium, Vitamin D) and mechanical stimulation. Moreover, surgical approaches include the use of endomidollar nail osteosynthesis, compression plates that are often associated with bone grafts. External fixation is a valid surgical alternative especially in case of septic non-unions. Indeed, compression-distraction osteosynthesis results in a significant improvement in bone vascularisation and exerts a powerful osteoinductive stimulus on the non-union site. In this review, we will describe a cohort of patients affected by low-grade septic non-unions and treated with external fixation.
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Despite remarkable progress in identifying causal genes for many types of genetic lipodystrophies in the last decade, the molecular basis of many extremely rare lipodystrophy patients with distinctive phenotypes remains unclear. We conducted whole exome sequencing of the parents and probands from six pedigrees with neonatal onset of generalized loss of subcutaneous fat with additional distinctive phenotypic features and report de novo heterozygous null mutations, c.424C>T (p.Q142*) and c.479_480delTT (p.F160*), in CAV1 in a 7-year-old male and a 3-year-old female of European origin, respectively. Both the patients had generalized fat loss, thin mottled skin and progeroid features at birth. The male patient had cataracts requiring extraction at age 30 months and the female patient had pulmonary arterial hypertension. Dermal fibroblasts of the female patient revealed negligible CAV1 immunofluorescence staining compared to control but there were no differences in the number and morphology of caveolae upon electron microscopy examination. Based upon the similarities in the clinical features of these two patients, previous reports of CAV1 mutations in patients with lipodystrophies and pulmonary hypertension, and similar features seen in CAV1 null mice, we conclude that these variants are the most likely cause of one subtype of neonatal onset generalized lipodystrophy syndrome.
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Caveolina 1/genética , Exoma/genética , Heterozigoto , Lipodistrofia/genética , Mutação , Células Cultivadas , Feminino , Humanos , Recém-Nascido , Masculino , LinhagemRESUMO
PURPOSE: The purpose of this study is to conduct a comparative analysis of the suspected adverse drug reactions (ADRs) associated with intravitreal bevacizumab, ranibizumab and pegaptanib in the WHO database in order to have a real-life information on these drugs, which now is only based on data coming from clinical trials. METHODS: ADR reports for intravitreal use of bevacizumab, ranibizumab and pegaptanib from January 2002 to December 2012 were selected from the WHO-VigiBase. Reporting odds ratio (ROR) with confidence interval of 95 % and p value was calculated. The analysis was performed for drug-reaction pairs. The Medical Dictionary for Regulatory Activities (MedDRA) terminology for ADRs was used. RESULTS: The analysis was performed on 3180 reports corresponding to 7753 drug-reaction pairs. Significant RORs for endophthalmitis and uveitis (1.90, 95 % confidence interval (CI) 1.48-2.43, and 10.62, 6.62-17.05, respectively) were retrieved for bevacizumab, and cerebrovascular accident and myocardial infarction produced significant ROR (1.54, 1.14-2.10 and 1.73, 1.18-2.53, respectively) for ranibizumab. Pegaptanib was significantly associated with visual impairment (1.98, 1.12-3.5, p = 0.02), nausea (3.29, 1.57-6.86, p < 0.001), vomiting (2.91, 1.2-7.07, p = 0.01) and drug hypersensitivity (8.75, 3.1-24.66, p < 0.001). CONCLUSIONS: Our data showed an elevated disproportionality for cardiovascular ADRs in patients treated with ranibizumab and for infective ocular reactions in those treated with bevacizumab. No relevant safety issues were identified for pegaptanib. These findings suggest bevacizumab as a suitable choice for AMD therapy due to its effectiveness similar to that of ranibizumab, its favourable safety profile and for its lower cost.
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Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Aptâmeros de Nucleotídeos/efeitos adversos , Bevacizumab , Feminino , Humanos , Injeções Intravítreas , Degeneração Macular/tratamento farmacológico , Masculino , Ranibizumab , Organização Mundial da SaúdeAssuntos
Torção do Cordão Espermático/diagnóstico , Torção do Cordão Espermático/cirurgia , Adulto , Emergências , Seguimentos , Humanos , Masculino , Exame Físico/métodos , Medição de Risco , Resultado do Tratamento , Ultrassonografia Doppler , Procedimentos Cirúrgicos Urogenitais/métodos , Adulto JovemRESUMO
Recent advances in high-resolution, rapid, in situ microanalytical techniques present numerous opportunities for the analytical community, provided accurately characterized reference materials are available. Here, we present multicollector thermal ionization mass spectrometry (MC-TIMS) and multicollector inductively coupled plasma mass spectrometry (MC-ICP-MS) uranium and thorium concentration and isotopic data obtained by isotope dilution for a suite of newly available Chinese Geological Standard Glasses (CGSG) designed for microanalysis. These glasses exhibit a range of compositions including basalt, syenite, andesite, and a soil. Uranium concentrations for these glasses range from â¼2 to 14 µg g(-1), Th/U weight ratios range from â¼4 to 6, (234)U/(238)U activity ratios range from 0.93 to 1.02, and (230)Th/(238)U activity ratios range from 0.98 to 1.12. Uranium and thorium concentration and isotopic data are also presented for a rhyolitic obsidian from Macusani, SE Peru (macusanite). This glass can also be used as a rhyolitic reference material, has a very low Th/U weight ratio (around 0.077), and is approximately in (238)U-(234)U-(230)Th secular equilibrium. The U-Th concentration data agree with but are significantly more precise than those previously measured. U-Th concentration and isotopic data agree within estimated errors for the two measurement techniques, providing validation of the two methods. The large (238)U-(234)U-(230)Th disequilibria for some of the glasses, along with the wide range in their chemical compositions and Th/U ratios should provide useful reference points for the U-series analytical community.
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BACKGROUND: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, with a long half-life. Tivozanib has demonstrated clinical activity and acceptable tolerability in renal cell carcinoma (RCC). This phase Ib study determined the recommended phase II dose (RP2D) and evaluated the safety and clinical activity of tivozanib plus temsirolimus, a mammalian target of rapamycin inhibitor. PATIENTS AND METHODS: Patients with advanced RCC were administered open-label tivozanib 0.5, 1.0 or 1.5mg/d orally (3 weeks on/1 week off) and temsirolimus 15 or 25 mg/week intravenously in a 3+3 dose-escalation design and subsequent expansion cohort. RESULTS: Of 27 patients treated, 20 patients had received ≥ 1 prior VEGF-targeted therapy. No dose-limiting toxicities occurred; the RP2D was determined to be tivozanib 1.5mg/d plus temsirolimus 25mg/week. Combination of tivozanib plus temsirolimus demonstrated acceptable tolerability and suggested no synergistic toxicity. The most common grade ≤ 3 adverse events were fatigue and thrombocytopenia (15% each). One patient each required dose reduction of tivozanib or temsirolimus due to an adverse event. Confirmed partial responses and stable disease were achieved at 23% and 68%, respectively. Pharmacokinetic analyses may suggest lack of an interaction between tivozanib and temsirolimus. CONCLUSIONS: In this small phase Ib study, tivozanib and temsirolimus were safely combined at the fully recommended dose and schedule of both agents. The observed clinical activity and manageable toxicity profile of this combination warrant further exploration in patients with RCC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Administração Intravenosa , Administração Oral , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/mortalidade , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/enzimologia , Neoplasias Renais/mortalidade , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Quinolinas/administração & dosagem , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Fatores de Tempo , Resultado do TratamentoRESUMO
The serum- and glucocorticoid-regulated kinase (Sgk1) is essential for hormonal regulation of epithelial sodium channel-mediated sodium transport and is involved in the transduction of growth factor-dependent cell survival and proliferation signals. Growing evidence now points to Sgk1 as a key element in the development and/or progression of human cancer. To gain insight into the mechanisms through which Sgk1 regulates cell proliferation, we adopted a proteomic approach to identify up- or downregulated proteins after Sgk1-specific RNA silencing. Among several proteins, the abundance of which was found to be up- or downregulated upon Sgk1 silencing, we focused our attention of RAN-binding protein 1 (RANBP1), a major effector of the GTPase RAN. We report that Sgk1-dependent regulation of RANBP1 has functional consequences on both mitotic microtubule activity and taxol sensitivity of cancer cells.
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Carcinoma/genética , Carcinoma/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Imediatamente Precoces/metabolismo , Proteínas Nucleares/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transcrição Gênica , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Paclitaxel/farmacologia , Fosforilação , Proteômica , Interferência de RNA , Fator de Transcrição Sp1/metabolismoRESUMO
Androgen levels during critical periods of testicular development may be involved in the aetiology of testicular germ cell tumours (TGCT). We evaluated the roles of adolescent and early adult life correlates of androgen exposure and TGCT in a hospital-based case-control study. TGCT cases (n=187) and controls (n=148), matched on age, race and state of residence, participated in the study. Unconditional logistic regression was used to estimate associations between TGCT and male pattern baldness, severe acne, markers of puberty onset and body size. Cases were significantly less likely to report hair loss than controls [odds ratio (OR): 0.6; 95% confidence interval (CI): 0.4, 1.0]. Amount of hair loss, increasing age at onset and increasing rate of loss were all inversely associated with TGCT (rate of hair loss: p-trend=0.03; age at onset: p-trend=0.03; amount of hair loss: p-trend=0.01). History of severe acne was inversely associated with TGCT (OR: 0.5; 95% CI: 0.3, 0.9) and height was positively associated with TGCT (p-trend=0.02). Increased endogenous androgen levels during puberty and early adulthood may be associated with a decreased risk of TGCT. Additional studies of endogenous hormone levels during puberty and early adult life are warranted, especially studies evaluating the role of androgen synthesis, metabolism and uptake.
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Acne Vulgar/epidemiologia , Alopecia/epidemiologia , Neoplasias Embrionárias de Células Germinativas/epidemiologia , Neoplasias Testiculares/epidemiologia , Adolescente , Adulto , Idade de Início , Androgênios/sangue , Estudos de Casos e Controles , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Testículo/embriologia , Testículo/patologiaRESUMO
AIM: NYHA classification divides into four classes. Although subjective and lacking of standardization, NYHA class II is in clinical practice often further subgrouped in IIA and IIB, where IIA class can be defined as dyspnea after running or climbing ≥ 2 ramps of stairs, and IIB class as dyspnea after fast walking or climbing 2 ramps of stairs. Validation of NYHA IIA and IIB sub-grouping was performed with left ventricular dysfunction questionnaire (LVD-36) results and echocardiographic left ventricular ejection fraction. METHODS: The study includes a total of 127 patients with both systolic and diastolic heart failure (mean age 65 ± 17, range 38-85 years). Sixteen patients were in NYHA class I, 81 patients in NYHA class II (45 in class IIA and 36 in class IIB) and 30 in class III. RESULTS: In class IIA patients' mean age was 64 ± 9 years, LVD-36 score 31.79 ± 14.06, EF 43 ± 10% (P = ns, P<0.001 and P=ns, respectively, vs. class I patients). In class IIB patients' mean age was 67 ± 10 years, LVD-36 score 48.90 ± 15.51, EF 39 ± 12% (P = ns, P < 0.0001 and P = ns, respectively, vs. IIA patients). In class III patients' mean age was 65 ± 11 years, LVD-36 score 65.17 ± 16.35, EF 32.77 ± 12.91% (P = ns, P < 0.01 and P = ns, respectively, compared with class IIB). CONCLUSION: NYHA class II sub-grouping appears an accurate method of classification and could represent a further useful tool in monitoring functional capacity of heart failure patients. NYHA class II sub-grouping correlates well with patients functional impairment and can therefore be implemented as an accurate method to better characterize heart failure patients.
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Volume Sistólico/fisiologia , Disfunção Ventricular Esquerda/classificação , Disfunção Ventricular Esquerda/fisiopatologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Insuficiência Cardíaca/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Terminologia como Assunto , Ultrassonografia , Disfunção Ventricular Esquerda/diagnóstico por imagemRESUMO
Alpers disease is a mitochondrial depletion syndrome characterized by psychomotor retardation, intractable epilepsy, and liver failure. Polymerase gamma (POLG) gene mutations are a known cause of the disease. We describe a case in which a 14-month-old female presented with epilepsia partialis continua evolving into generalized status epilepticus. Treatment with multiple antiepileptic medications and the ketogenic diet eliminated her seizures, but she remained severely encephalopathic. Magnetic resonance imaging showed diffuse atrophy of gray-matter structures. She ultimately developed liver failure and died. Mitochondrial analysis revealed compound heterozygosity for 3 POLG gene mutations, 2 of which were previously unreported.
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DNA Polimerase Dirigida por DNA/genética , Esclerose Cerebral Difusa de Schilder/genética , Mutação/genética , DNA Polimerase gama , Esclerose Cerebral Difusa de Schilder/diagnóstico , Esclerose Cerebral Difusa de Schilder/fisiopatologia , Feminino , Heterozigoto , Humanos , Lactente , Imageamento por Ressonância Magnética , Músculo Esquelético/patologia , Músculo Esquelético/ultraestruturaRESUMO
NRXN1 is highly expressed in brain and has been shown recently to be associated with ASD, schizophrenia, cognitive and behavioral abnormalities, and alcohol and nicotine dependence. We present three families, in whom we identified intragenic rearrangements within NRXN1 using a clinical targeted oligonucleotide array CGH. An approximately 380 kb deletion was identified in a woman with Asperger syndrome, anxiety, and depression and in all four of her children affected with autism, anxiety, developmental delay, and speech delay but not in an unaffected child. An approximately 180 kb tandem duplication was found in a patient with autistic disorder and cognitive delays, and in his mother and younger brother who have speech delay. An approximately 330 kb tandem duplication was identified in a patient with autistic features. As predicted by conceptual translation, all three genomic rearrangements led to the premature truncation of NRXN1. Our data support previous observations that NRXN1 may be pathogenic in a wide variety of psychiatric diseases, including autism spectrum disorder, global developmental delay, anxiety, and depression.
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Moléculas de Adesão Celular Neuronais/genética , Transtornos Globais do Desenvolvimento Infantil/complicações , Transtornos Globais do Desenvolvimento Infantil/genética , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Rearranjo Gênico/genética , Transtornos do Desenvolvimento da Linguagem/complicações , Proteínas do Tecido Nervoso/genética , Adolescente , Adulto , Sequência de Aminoácidos , Sequência de Bases , Proteínas de Ligação ao Cálcio , Moléculas de Adesão Celular Neuronais/química , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Família , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/química , Moléculas de Adesão de Célula Nervosa , Linhagem , Reação em Cadeia da Polimerase , Gravidez , Análise de Sequência de DNARESUMO
In 2006, all clinical genetics practices in Northern New England (Vermont, New Hampshire, and Maine) formed a learning collaborative with the purpose of improving genetic health care and outcomes. This article describes the current status of this effort. The methodology is based on our own modifications of the Institute of Healthcare Improvement "Breakthrough Series" and the Northern New England Cystic Fibrosis Consortium. Because of similarities across practices and the availability of existing published practice parameters, the clinical genetics evaluation of the child with developmental delay or intellectual disability was chosen as the topic to be studied. The aim was to improve the rate of etiological diagnosis of those with developmental delays referred to each genetics center by improving the processes of care. Process and outcomes were evaluated. Four of five sites also evaluated the impact of array comparative genomic hybridization (a-CGH) laboratory testing of such patients. There was significant site-to-site variation in the rate of new diagnoses by a-CGH with the average new diagnosis rate of 11.8% (range 5.4-28.8%). Barriers to implementation of the process and outcome data collection and analysis were significant and related to time pressures, lack of personnel or staff to support this activity, and competing quality improvement initiatives at the institutional home of some genetics centers.