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OBJECTIVE: To investigate the efficacy and safety of aceneuramic acid extended-release (Ace-ER), a treatment intended to replace deficient sialic acid, in patients with GNE myopathy. METHODS: UX001-CL301 was a phase 3, double-blind, placebo-controlled, randomized, international study evaluating the efficacy and safety of Ace-ER in patients with GNE myopathy. Participants who could walk ≥200 meters in a 6-minute walk test at screening were randomized 1:1, and stratified by sex, to receive Ace-ER 6 g/d or placebo for 48 weeks and assessed every 8 weeks. The primary endpoint was change in muscle strength over 48 weeks measured by upper extremity composite (UEC) score. Key secondary endpoints included change in lower extremity composite (LEC) score, knee extensor strength, and GNE myopathy-Functional Activity Scale (GNEM-FAS) mobility domain score. Safety assessments included adverse events (AEs), vital signs, and clinical laboratory results. RESULTS: Eighty-nine patients were randomized (Ace-ER n = 45; placebo n = 44). Change from baseline to week 48 for UEC score between treatments did not differ (least square mean [LSM] Ace-ER -2.25 kg vs placebo -2.99 kg; LSM difference confidence interval [CI] 0.74 [-1.61 to 3.09]; p = 0.5387). At week 48, there was no significant difference between treatments for the change in key secondary endpoints: LEC LSM difference (CI) -1.49 (-5.83 to 2.86); knee extension strength -0.40 (-2.38 to 1.58); and GNEM-FAS mobility domain score -0.72 (-2.01 to 0.57). Gastrointestinal events were the most common AEs. CONCLUSIONS: Ace-ER was not superior to placebo in improving muscle strength and function in patients with GNE myopathy. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with GNE myopathy, Ace-ER does not improve muscle strength compared to placebo.
BACKGROUND: X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia. METHODS: In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705. FINDINGS: Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved. INTERPRETATION: Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy. FUNDING: Ultragenyx Pharmaceutical and Kyowa Kirin International.
AssuntosAnticorpos Monoclonais/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Estatura , Criança , Desenvolvimento Infantil , Pré-Escolar , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Feminino , Humanos , Lactente , Masculino , Índice de Gravidade de Doença , Resultado do Tratamento
The Rickets Severity Score (RSS) was used to evaluate X-linked hypophosphatemic rickets (XLH), a genetic disorder mediated by increased circulating FGF23. The reliability of the RSS was assessed using data from a randomized, phase 2 clinical trial that evaluated the effects of burosumab, a fully human anti-FGF23 monoclonal antibody, in 52 children with XLH ages 5 to 12â¯years. Bilateral knee and wrist radiographs were obtained at baseline, week 40, and week 64. We evaluated the relationships of the RSS to the Radiographic Global Impression of Change (RGI-C), serum alkaline phosphatase (ALP), height Z-score, 6-minute walk test (6MWT) percent predicted, and the Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument (POSNA-PODCI). The RSS showed moderate-to-substantial inter-rater reliability (weighted kappa, 0.45-0.65; Pearson correlation coefficient (r), 0.83-0.89) and substantial intra-rater reliability (weighted Kappa, 0.66; râ¯=â¯0.91). Baseline RSS correlated with serum ALP (râ¯=â¯0.47). Baseline RSS identified two subgroups (higher [RSS ≥1.5] and lower RSS [RSS <1.5]) that discriminated between subjects with greater and lesser rachitic disease. Higher RSS was associated with more severe clinical features, including impaired growth (Z-score, -2.12 vs -1.44) and walking ability (6MWT percent predicted, 77% vs 86%), more severe self-reported pain (29.9 [more severe] vs 45.3 [less severe]) and less physical function (29.6 [more severe] vs 40.9 [less severe]). During burosumab treatment, greater reductions in RSS corresponded to higher RGI-C global scores (râ¯=â¯-0.65). Improvements in RSS correlated with decreased serum ALP (râ¯=â¯0.47). These results show the reliability of the RSS in XLH, and demonstrate that higher RSS values are associated with greater biochemical, clinical, and functional impairments in children with XLH.
BACKGROUND: Children with X-linked hypophosphataemia have high concentrations of circulating phosphatonin fibroblast growth factor 23 (FGF23), which causes renal phosphate wasting and hypophosphataemia, rickets, skeletal deformities, and growth impairment. Burosumab, a human monoclonal antibody against FGF23, improves phosphate homoeostasis and rickets in children aged 5-12 years with X-linked hypophosphataemia. We aimed to assess the safety and efficacy of burosumab in younger children with X-linked hypophosphataemia. METHODS: In this open-label, phase 2 trial at three hospitals in the USA, children (aged 1-4 years) with X-linked hypophosphataemia received burosumab (0·8 mg/kg) via subcutaneous injection every 2 weeks for 64 weeks. The dose was increased to 1·2 mg/kg if two consecutive pre-dose serum phosphorus concentrations were below 1·03 mmol/L (3·2 mg/dL), serum phosphorus had increased by less than 0·16 mmol/L (<0·5 mg/dL) from baseline, and a dose of burosumab had not been missed. Participants could continue to receive burosumab for up to an additional 96 weeks during the extension period. Key inclusion criteria were age 1-4 years at the time of informed consent; fasting serum phosphorus concentration of less than 0·97 mmol/L (3·0 mg/dL); serum creatinine 8·8-35·4 µmol/L (0·1-0·4 mg/dL); radiographic evidence of rickets (at least five participants were required to have a Thacher Rickets Severity Score of ≥1·5 at the knee); and a confirmed PHEX mutation or a variant of unknown significance in the patient or direct relative also affected with X-linked hypophosphataemia. Conventional therapy was stopped upon enrolment. The coprimary endpoints were safety and change from baseline to week 40 in fasting serum phosphorus concentrations. Changes in rickets severity from baseline to weeks 40 and 64 (assessed radiographically using Thacher Rickets Severity Score and an adaptation of the Radiographic Global Impression of Change), and recumbent length or standing height, were key secondary outcomes. This trial is registered with ClinicalTrials.gov, number NCT02750618, and is ongoing. FINDINGS: Between May 16, 2016, and June 10, 2016, we enrolled 13 children with X-linked hypophosphataemia. All 13 children completed 64 weeks of treatment and were included in the efficacy and safety analysis; none exceeded 70 weeks of treatment at the time of analysis. Serum phosphorus least squares mean increase from baseline to week 40 of treatment was 0·31 mmol/L (SE 0·04; 95% CI 0·24-0·39; 0·96 mg/dL [SE 0·12]; p<0·0001). All patients had at least one adverse event. 14 treatment-related adverse events, mostly injection site reactions, occurred in five children. One serious adverse event considered unrelated to treatment (tooth abscess) occurred in a child with a history of tooth abscess. All other adverse events were mild to moderate, except a severe food allergy considered unrelated to treatment. No instances of nephrocalcinosis or noteworthy changes in the results of a standard safety chemistry panel emerged. Total Thacher Rickets Severity Score decreased by a least squares mean of -1·7 (SE 0·1; p<0·0001) from baseline to week 40 and by -2·0 (SE 0·1; p<0·0001) by week 64. The Radiographic Global Impression of Change score also indicated significant improvement, with a least squares mean score of +2·3 (SE 0·1) at week 40 and +2·2 (0·1) at week 64 (both p<0·0001). Mean length or standing height Z score was maintained from baseline to week 64. INTERPRETATION: Burosumab had a favourable safety profile, increased serum phosphorus, and improved rickets and prevented early declines in growth in children aged 1-4 years with X-linked hypophosphataemia. These findings could substantially alter the treatment of young children with X-linked hypophosphataemia. FUNDING: Ultragenyx Pharmaceutical and Kyowa Kirin International.
BACKGROUND: X-linked hypophosphatemia (XLH) is a rare genetic disorder characterized by renal phosphate wasting and defective bone mineralization. Symptoms include bone pain, joint pain, stiffness, and fatigue. Published evidence regarding the patient experience of XLH is sparse and no XLH-specific outcome measures have been validated. OBJECTIVES: To understand the symptoms, impacts, and patient experience of XLH and to evaluate the face and content validity of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®) and the Brief Pain Inventory Short Form (BPI-SF) for use as end points in XLH clinical trials. METHODS: Face-to-face, qualitative, semistructured interviews were conducted with 18 adults with XLH in the United States using concept elicitation and cognitive debriefing techniques. Open-ended questioning elicited spontaneous concepts focusing on XLH-associated symptoms and functional limitations. Cognitive debriefing of the WOMAC® and BPI-SF assessed the relevance and patient understanding of item wording, recall period, and response options. RESULTS: Various distinct symptom concepts were elicited including pain symptoms, dental symptoms, sensory symptoms, tiredness/fatigue symptoms, and musculoskeletal symptoms. Participants reported experiencing significant bone and joint pain, stiffness, mobility limitations, and an impact on their ability to work. Cognitive interviewing found both instruments to be relevant and well understood by most patients. CONCLUSIONS: The interviews generated rich, qualitative insights into the patient experience of XLH. Cognitive debriefing of the BPI-SF and WOMAC® supported their value as XLH clinical trial end points. Future research will assess the psychometric properties of these instruments for use in the XLH population.
AssuntosRaquitismo Hipofosfatêmico Familiar/psicologia , Satisfação do Paciente , Adulto , Feminino , Humanos , Entrevistas como Assunto/métodos , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Psicometria/instrumentação , Psicometria/métodos , Pesquisa Qualitativa , Índice de Gravidade de Doença
BACKGROUND: X-linked hypophosphatemia is characterized by increased secretion of fibroblast growth factor 23 (FGF-23), which leads to hypophosphatemia and consequently rickets, osteomalacia, and skeletal deformities. We investigated burosumab, a monoclonal antibody that targets FGF-23, in patients with X-linked hypophosphatemia. METHODS: In an open-label, phase 2 trial, we randomly assigned 52 children with X-linked hypophosphatemia, in a 1:1 ratio, to receive subcutaneous burosumab either every 2 weeks or every 4 weeks; the dose was adjusted to achieve a serum phosphorus level at the low end of the normal range. The primary end point was the change from baseline to weeks 40 and 64 in the Thacher rickets severity total score (ranging from 0 to 10, with higher scores indicating greater disease severity). In addition, the Radiographic Global Impression of Change was used to evaluate rachitic changes from baseline to week 40 and to week 64. Additional end points were changes in pharmacodynamic markers, linear growth, physical ability, and patient-reported outcomes and the incidence of adverse events. RESULTS: The mean Thacher rickets severity total score decreased from 1.9 at baseline to 0.8 at week 40 with every-2-week dosing and from 1.7 at baseline to 1.1 at week 40 with every-4-week dosing (P<0.001 for both comparisons); these improvements persisted at week 64. The mean serum phosphorus level increased after the first dose in both groups, and more than half the patients in both groups had levels within the normal range (3.2 to 6.1 mg per deciliter [1.0 to 2.0 mmol per liter]) by week 6. Stable serum phosphorus levels were maintained through week 64 with every-2-week dosing. Renal tubular phosphate reabsorption increased from baseline in both groups, with an overall mean increase of 0.98 mg per deciliter (0.32 mmol per liter). The mean dose of burosumab at week 40 was 0.98 mg per kilogram of body weight with every-2-week dosing and 1.50 mg per kilogram with every-4-week dosing. Across both groups, the mean serum alkaline phosphatase level decreased from 459 U per liter at baseline to 369 U per liter at week 64. The mean standing-height z score increased in both groups, with greater improvement seen at all time points with every-2-week dosing (an increase from baseline of 0.19 at week 64) than with every-4-week dosing (an increase from baseline of 0.12 at week 64). Physical ability improved and pain decreased. Nearly all the adverse events were mild or moderate in severity. CONCLUSIONS: In children with X-linked hypophosphatemia, treatment with burosumab improved renal tubular phosphate reabsorption, serum phosphorus levels, linear growth, and physical function and reduced pain and the severity of rickets. (Funded by Ultragenyx Pharmaceutical and Kyowa Hakko Kirin; ClinicalTrials.gov number, NCT02163577 ; EudraCT number, 2014-000406-35 ).
AssuntosAnticorpos Monoclonais/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Fosfatase Alcalina/sangue , Criança , Pré-Escolar , Raquitismo Hipofosfatêmico Familiar/metabolismo , Raquitismo Hipofosfatêmico Familiar/fisiopatologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Crescimento/efeitos dos fármacos , Humanos , Túbulos Renais/metabolismo , Articulação do Joelho/diagnóstico por imagem , Masculino , Manejo da Dor , Fósforo/sangue , Radiografia , Índice de Gravidade de Doença
GNE myopathy is a rare distal myopathy, caused by mutations in the GNE gene, affecting sialic acid synthesis. Clinical presentation varies from asymptomatic early stage patients to severely debilitating forms. This first report describes clinical presentations and severity of the disease, using data of 150 patients collected via the on-line, patient-reported registry component of the GNE Myopathy Disease Monitoring Program (GNEM-DMP). Disease progression was prospectively analysed, over a 2-year period, using the GNE myopathy functional activity scale (GNEM-FAS). The average annual rates of decline in function were estimated at -9.6% and -3.2% in ambulant and non-ambulant patients respectively. 4.3% of participants became non-ambulant within one year. The mean time from onset to required use of a wheelchair was 11.9 years. Mean delay of genetic diagnosis from symptom onset was 5.2 years. Mutation specific analysis demonstrated genotype-phenotype relationships; i.e. p.Ala662Val may be associated with a more severe phenotype, compared to p.Val727Met. Patients with compound heterozygous mutation in epimerase and kinase domain appeared to have a more severe phenotype compared to patients with both mutations located within one domain. Acknowledging the limitations of the study, these findings suggest that the severity of the GNE mutations affects disease severity. The GNEM-DMP is a useful data collection tool, prospectively measuring the progression of GNE myopathy, which could play an important role in translational and clinical research and further understanding of genotype-phenotype correlations.
AIM: GNE myopathy, a rare, severe, progressive myopathy, presents with lower extremity distal muscle weakness. The GNE myopathy functional activity scale (GNEM-FAS) evaluates the impact of GNE myopathy on functioning in adults. This paper presents the psychometric validation of the GNEM-FAS. PATIENTS & METHODS: Validation of the GNEM-FAS was performed using data from a randomized, double-blind, placebo-controlled Phase-II study (n = 46). RESULTS: Domain score distributions were acceptable. Moderate inter-item correlations (typical range, 0.40-0.70), strong item convergent and discriminant validity and high internal consistency reliability (α = 0.88-0.92) supported the instrument structure. Test-retest reliability was strong (ICC range: 0.87-0.95). Scale scores distinguished among subjects with differing disease severity (p < 0.05). CONCLUSION: This study provides preliminary evidence of the GNEM-FAS as a valid, reliable assessment.
OBJECTIVE: To characterize the pattern and extent of muscle weakness and impact on physical functioning in adults with GNEM. METHODS: Strength and function were assessed in GNEM subjects (n = 47) using hand-held dynamometry, manual muscle testing, upper and lower extremity functional capacity tests, and the GNEM-Functional Activity Scale (GNEM-FAS). RESULTS: Profound upper and lower muscle weakness was measured using hand-held dynamometry in a characteristic pattern, previously described. Functional tests and clinician-reported outcomes demonstrated the consequence of muscle weakness on physical functioning. CONCLUSIONS: The characteristic pattern of upper and lower muscle weakness associated with GNEM and the resulting functional limitations can be reliably measured using these clinical outcome assessments of muscle strength and function.
AssuntosForça Muscular/genética , Debilidade Muscular/etiologia , Músculo Esquelético/fisiopatologia , Miosite de Corpos de Inclusão/congênito , Adolescente , Adulto , Idoso , Feminino , Humanos , Extremidade Inferior/fisiopatologia , Masculino , Pessoa de Meia-Idade , Atividade Motora/genética , Miosite de Corpos de Inclusão/complicações , Miosite de Corpos de Inclusão/genética , Ácido N-Acetilneuramínico/genética , Adulto Jovem
GNE myopathy (GNEM), also known as hereditary inclusion body myopathy (HIBM), is a late- onset, progressive myopathy caused by mutations in the GNE gene encoding the enzyme responsible for the first regulated step in the biosynthesis of sialic acid (SA). The disease is characterized by distal muscle weakness in both the lower and upper extremities, with the quadriceps muscle relatively spared until the late stages of disease. To explore the role of SA synthesis in the disease, we conducted a comprehensive and systematic analysis of both free and total SA levels in a large cohort of GNEM patients and a mouse model. A sensitive LC/MS/MS assay was developed to quantify SA in serum and muscle homogenates. Mean serum free SA level was 0.166 µg/mL in patients and 18% lower (p<0.001) than that of age-matched control samples (0.203 µg/mL). In biopsies obtained from patients, mean free SA levels of different muscles ranged from 0.046-0.075 µg/µmol Cr and were markedly lower by 72-85% (p<0.001) than free SA from normal controls. Free SA was shown to constitute a small fraction (3-7%) of the total SA pool in muscle tissue. Differences in mean total SA levels in muscle from patients compared with normal controls were less distinct and more variable between different muscles, suggesting a small subset of sialylation targets could be responsible for the pathogenesis of GNEM. Normal quadriceps had significantly lower levels of free SA (reduced by 39%) and total SA (reduced by 53%) compared to normal gastrocnemius. A lower SA requirement for quadriceps may be linked to the reported quadriceps sparing in GNEM. Analysis of SA levels in GneM743T/M743T mutant mice corroborated the human study results. These results show that serum and muscle free SA is severely reduced in GNEM, which is consistent with the biochemical defect in SA synthesis associated with GNE mutations. These results therefore support the approach of reversing SA depletion as a potential treatment for GNEM patients.
AssuntosMiopatias Distais/metabolismo , Músculo Esquelético/metabolismo , Ácido N-Acetilneuramínico/deficiência , Adolescente , Adulto , Idoso , Animais , Biomarcadores , Biópsia , Cromatografia Líquida , Modelos Animais de Doenças , Miopatias Distais/sangue , Miopatias Distais/patologia , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Ácido N-Acetilneuramínico/sangue , Espectrometria de Massas em Tandem , Adulto Jovem
BACKGROUND: GNE Myopathy (GNEM) is a progressive adult-onset myopathy likely caused by deficiency of sialic acid (SA) biosynthesis. OBJECTIVE: Evaluate the safety and efficacy of SA (delivered by aceneuramic acid extended-release [Ace-ER]) as treatment for GNEM. METHODS: A Phase 2, randomized, double-blind, placebo-controlled study evaluating Ace-ER 3âg/day or 6âg/day versus placebo was conducted in GNEM subjects (nâ=â47). After the first 24 weeks, placebo subjects crossed over to 3âg/day or 6âg/day for 24 additional weeks (dose pre-assigned during initial randomization). Assessments included serum SA, muscle strength by dynamometry, functional assessments, clinician- and patient-reported outcomes, and safety. RESULTS: Dose-dependent increases in serum SA levels were observed. Supplementation with Ace-ER resulted in maintenance of muscle strength in an upper extremity composite (UEC) score at 6âg/day compared with placebo at Week 24 (LS mean difference +2.33âkg, pâ=â0.040), and larger in a pre-specified subgroup able to walk ≥200âm at Screening (+3.10âkg, pâ=â0.040). After cross-over, a combined 6âg/day group showed significantly better UEC strength than a combined 3âg/day group (+3.46âkg, pâ=â0.0031). A similar dose-dependent response was demonstrated within the lower extremity composite score, but was not significant (+1.06âkg, pâ=â0.61). The GNEM-Functional Activity Scale demonstrated a trend improvement in UE function and mobility in a combined 6âg/day group compared with a combined 3âg/day group. Patients receiving Ace-ER tablets had predominantly mild-to-moderate AEs and no serious adverse events. CONCLUSIONS: This is the first clinical study to provide evidence that supplementation with SA delivered by Ace-ER may stabilize muscle strength in individuals with GNEM and initiating treatment earlier in the disease course may lead to better outcomes.
AssuntosMiopatias Distais/tratamento farmacológico , Ácido N-Acetilneuramínico/farmacologia , Avaliação de Resultados (Cuidados de Saúde) , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácido N-Acetilneuramínico/administração & dosagem , Ácido N-Acetilneuramínico/efeitos adversos , Adulto Jovem
Well-defined and reliable clinical outcome assessments are essential for determining whether a drug provides clinically meaningful treatment benefit for patients. In 2015, FDA convened a workshop, "Assessing Neurocognitive Outcomes in Inborn Errors of Metabolism." Topics covered included special challenges of clinical studies of inborn errors of metabolism (IEMs) and other rare diseases; complexities of identifying treatment effects in the context of the dynamic processes of child development and disease progression; and the importance of natural history studies. Clinicians, parents/caregivers, and participants from industry, academia, and government discussed factors to consider when developing measures to assess treatment outcomes, as well as tools and methods that may contribute to standardizing measures. Many issues examined are relevant to the broader field of rare diseases in addition to specifics of IEMs.
AssuntosTestes de Estado Mental e Demência/normas , Erros Inatos do Metabolismo/tratamento farmacológico , Avaliação de Resultados (Cuidados de Saúde) , Doenças Raras/tratamento farmacológico , Cuidadores , Criança , Desenvolvimento Infantil , Ensaios Clínicos como Assunto , Progressão da Doença , Humanos , National Institutes of Health (U.S.) , Pais , Tecnologia de Sensoriamento Remoto , Estados Unidos , United States Food and Drug Administration
BACKGROUND: Hypophosphatasia results from mutations in the gene for the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Inorganic pyrophosphate accumulates extracellularly, leading to rickets or osteomalacia. Severely affected babies often die from respiratory insufficiency due to progressive chest deformity or have persistent bone disease. There is no approved medical therapy. ENB-0040 is a bone-targeted, recombinant human TNSALP that prevents the manifestations of hypophosphatasia in Tnsalp knockout mice. METHODS: We enrolled infants and young children with life-threatening or debilitating perinatal or infantile hypophosphatasia in a multinational, open-label study of treatment with ENB-0040. The primary objective was the healing of rickets, as assessed by means of radiographic scales. Motor and cognitive development, respiratory function, and safety were evaluated, as well as the pharmacokinetics and pharmacodynamics of ENB-0040. RESULTS: Of the 11 patients recruited, 10 completed 6 months of therapy; 9 completed 1 year. Healing of rickets at 6 months in 9 patients was accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSALP substrates inorganic pyrophosphate and pyridoxal 5'-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti-ENB-0040 antibodies developed in four patients, with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment. CONCLUSIONS: ENB-0040, an enzyme-replacement therapy, was associated with improved findings on skeletal radiographs and improved pulmonary and physical function in infants and young children with life-threatening hypophosphatasia. (Funded by Enobia Pharma and Shriners Hospitals for Children; ClinicalTrials.gov number, NCT00744042.).
AssuntosFosfatase Alcalina/uso terapêutico , Terapia de Reposição de Enzimas , Hipofosfatasia/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Raquitismo/tratamento farmacológico , Fosfatase Alcalina/administração & dosagem , Fosfatase Alcalina/farmacologia , Disponibilidade Biológica , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Pré-Escolar , Terapia de Reposição de Enzimas/efeitos adversos , Feminino , Humanos , Hipofosfatasia/complicações , Imunoglobulina G/administração & dosagem , Imunoglobulina G/farmacologia , Lactente , Recém-Nascido , Infusões Intravenosas , Injeções Subcutâneas/efeitos adversos , Masculino , Radiografia , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/farmacologia , Raquitismo/diagnóstico por imagem , Raquitismo/etiologia , Resultado do Tratamento
BACKGROUND: Pompe's disease is a metabolic myopathy caused by a deficiency of acid alpha glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Late-onset Pompe's disease is characterized by progressive muscle weakness and loss of respiratory function, leading to early death. We conducted a randomized, placebo-controlled trial of alglucosidase alfa, a recombinant human GAA, for the treatment of late-onset Pompe's disease. METHODS: Ninety patients who were 8 years of age or older, ambulatory, and free of invasive ventilation were randomly assigned to receive biweekly intravenous alglucosidase alfa (20 mg per kilogram of body weight) or placebo for 78 weeks at eight centers in the United States and Europe. The two primary end points were distance walked during a 6-minute walk test and percentage of predicted forced vital capacity (FVC). RESULTS: At 78 weeks, the estimated mean changes from baseline in the primary end points favored alglucosidase alfa (an increase of 28.1+/-13.1 m on the 6-minute walk test and an absolute increase of 3.4+/-1.2 percentage points in FVC; P=0.03 and P=0.006, respectively). Similar proportions of patients in the two groups had adverse events, serious adverse events, and infusion-associated reactions; events that occurred only in patients who received the active study drug included anaphylactic reactions and infusion-associated reactions of urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure (each of which occurred in 5 to 8% of the patients). CONCLUSIONS: In this study population, treatment with alglucosidase alfa was associated with improved walking distance and stabilization of pulmonary function over an 18-month period. (ClinicalTrials.gov number, NCT00158600.)
AssuntosDoença de Depósito de Glicogênio Tipo II/tratamento farmacológico , alfa-Glucosidases/uso terapêutico , Adolescente , Adulto , Idade de Início , Idoso , Análise de Variância , Criança , Hipersensibilidade a Drogas/etiologia , Feminino , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Humanos , Imunoglobulina G/sangue , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Capacidade Vital/efeitos dos fármacos , Caminhada , Adulto Jovem , alfa-Glucosidases/efeitos adversos , alfa-Glucosidases/imunologia
PURPOSE: A clinical trial was conducted to evaluate the safety and efficacy of alglucosidase alfa in infants and children with advanced Pompe disease. METHODS: Open-label, multicenter study of IV alglucosidase alfa treatment in 21 infants 3-43 months old (median 13 months) with minimal acid alpha-glucosidase activity and abnormal left ventricular mass index by echocardiography. Patients received IV alglucosidase alfa every 2 weeks for up to 168 weeks (median 120 weeks). Survival results were compared with an untreated reference cohort. RESULTS: At study end, 71% (15/21) of patients were alive and 44% (7/16) of invasive-ventilator free patients remained so. Compared with the untreated reference cohort, alglucosidase alfa reduced the risk of death by 79% (P < 0.001) and the risk of invasive ventilation by 58% (P = 0.02). Left ventricular mass index improved or remained normal in all patients evaluated beyond 12 weeks; 62% (13/21) achieved new motor milestones. Five patients were walking independently at the end of the study and 86% (18/21) gained functional independence skills. Overall, 52% (11/21) of patients experienced infusion-associated reactions; 95% (19/20) developed IgG antibodies to recombinant human lysosomal acid alpha-glucosidase; no patients withdrew from the study because of safety concerns. CONCLUSIONS: In this population of infants with advanced disease, biweekly infusions with alglucosidase alfa prolonged survival and invasive ventilation-free survival. Treatment also improved indices of cardiomyopathy, motor skills, and functional independence.
AssuntosDoença de Depósito de Glicogênio Tipo II/tratamento farmacológico , alfa-Glucosidases/uso terapêutico , Estatura , Peso Corporal , Pré-Escolar , Tosse/induzido quimicamente , Ecocardiografia , Ensaio de Imunoadsorção Enzimática , Feminino , Glicogênio/metabolismo , Doença de Depósito de Glicogênio Tipo II/metabolismo , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Humanos , Imunoglobulina G/sangue , Lactente , Estimativa de Kaplan-Meier , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Dermatopatias/induzido quimicamente , Fatores de Tempo , Resultado do Tratamento , alfa-Glucosidases/efeitos adversos , alfa-Glucosidases/imunologia
The objective of this 12-month study was to describe the clinical features of late-onset Pompe disease and identify appropriate outcome measures for use in clinical trials. Assessments included quantitative muscle testing (QMT), functional activities (FAA), 6-min walk test (6MWT), and pulmonary function testing (PFT). Percent predicted values indicated quantifiable upper and lower extremity weakness, impaired walking ability, and respiratory muscle weakness. Significant declines in arm and leg strength and pulmonary function were observed during the study period. The outcome measures were demonstrated to be safe and reliable. Symptom duration was identified as the best predictor of the extent of skeletal and respiratory muscle weakness.
AssuntosDoença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Debilidade Muscular/diagnóstico , Debilidade Muscular/fisiopatologia , Paralisia Respiratória/diagnóstico , Paralisia Respiratória/fisiopatologia , Adulto , Idade de Início , Idoso , Biomarcadores/análise , Doença Crônica/terapia , Estudos de Coortes , Avaliação da Deficiência , Progressão da Doença , Feminino , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Músculo Esquelético/fisiopatologia , Valor Preditivo dos Testes , Estudos Prospectivos , Músculos Respiratórios/fisiopatologia , Índice de Gravidade de Doença
The enzymatic defect in Pompe disease is insufficient lysosomal acid alpha-glucosidase (GAA) activity which leads to lysosomal glycogen accumulation. We recently introduced a simple and reliable method to measure GAA activity in dried blood spots using Acarbose, a highly selective alpha-glucosidase inhibitor, to eliminate isoenzyme interference. Here we demonstrate that this method efficiently detects late-onset Pompe patients who are frequently misdiagnosed by conventional methods due to residual GAA activity in other tissue types.
AssuntosDoença de Depósito de Glicogênio Tipo II/diagnóstico , alfa-Glucosidases/sangue , Acarbose/farmacologia , Adulto , Coleta de Amostras Sanguíneas/métodos , Células Cultivadas , Fibroblastos/enzimologia , Fluorometria/métodos , Inibidores de Glicosídeo Hidrolases , Humanos , Himecromona/análogos & derivados , Himecromona/metabolismo , Isoenzimas/sangue , Especificidade por Substrato
The purpose of this article is threefold: (1) to describe the development, reliability, and validity of a revised physical performance measure for individuals with mucopolysaccharidosis type I (MPS I); (2) to standardize the test on a normal sample; and (3) to compare results from a selected sample of individuals with MPS I with age-based centiles. The MPS Physical Performance Measure (MPS-PPM) is composed of eight timed functional tasks (FT-8) and two endurance tasks with a modified Energy Expenditure Index for comfortable walking (CW) and fast walking (FW) speeds. Age norms were derived from a convenience sample of 150 typically developing children and adolescents (75 males, 75 females; mean age 11y 2mo [SD 4y 5mo]; range 5-22y). Using a Rasch model for speed tests and confirmatory factor analysis, we established the unidimensionality of the FT-8. Interrater reliability of the FT-8 (intraclass correlation [ICC]=0.98) and test-retest reliability of the FT-8 (ICC=0.96), CW (ICC=0.91), and FW (ICC=0.83) were good. Results of the age-based profiles in 10 individuals with MPS I (five males, five females; mean age 14y 2mo [SD 7y 6mo]; range 6-29y) indicate that the amount of time needed to perform functional tasks is severely affected by the disease, and most individuals were at or below the fifth centile for their age. The patterns of limitations in endurance were more varied. These results suggest the utility of using this revised MPS-PPM to identify the extent of limitation in age-expected physical performance. Implications for using the MPS-PPM for monitoring physical performance changes during clinical interventions are discussed.
AssuntosAvaliação da Deficiência , Teste de Esforço/métodos , Destreza Motora , Mucopolissacaridose I/diagnóstico , Resistência Física , Atividades Cotidianas , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Determinação de Ponto Final , Metabolismo Energético , Análise Fatorial , Feminino , Humanos , Masculino , Mucopolissacaridose I/complicações , Mucopolissacaridose I/terapia , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Caminhada
PURPOSE: The purposes of this article are to describe the pathology, medical implications, and typical impairments of individuals with various lysosomal storage diseases (LSDs), summarize results of recent clinical trials on medical interventions relevant to physical therapy practice, report new advances in functional measurement, and suggest a framework for physical therapy management and intervention. SUMMARY OF KEY POINTS: Medical and surgical interventions are enabling individuals with LSDs to not only survive but to improve their daily functioning and quality of life. This is likely to become an increasing area of emphasis in pediatric physical therapy, as the intervention emphasis for some individuals will shift from maintenance to restorative programs. RECOMMENDATIONS: We recommend that pediatric physical therapists become familiar with new LSD therapeutics, play a major role in evaluating impairment and functional limitation changes in individuals with LSDs, and become knowledgeable about the indications and precautions for restorative physical therapy programs.
AssuntosDoenças por Armazenamento dos Lisossomos/reabilitação , Fisioterapia , Papel Profissional , Pessoal Técnico de Saúde , Administração de Caso , Criança , Crianças com Deficiência/reabilitação , Humanos , Doenças por Armazenamento dos Lisossomos/classificação , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/reabilitação , Desempenho Psicomotor
The purpose of this article is to demonstrate: (1) the accuracy and (2) the reduction in amount of time and effort in assessing physical functioning (self-care and mobility domains) of children and adolescents using computer-adaptive testing (CAT). A CAT algorithm selects questions directly tailored to the child's ability level, based on previous responses. Using a CAT algorithm, a simulation study was used to determine the number of items necessary to approximate the score of a full-length assessment. We built simulated CAT (5-, 10-, 15-, and 20-item versions) for self-care and mobility domains and tested their accuracy in a normative sample (n=373; 190 males, 183 females; mean age 6y 11mo [SD 4y 2m], range 4mo to 14y 11mo) and a sample of children and adolescents with Pompe disease (n=26; 21 males, 5 females; mean age 6y 1mo [SD 3y 10mo], range 5mo to 14y 10mo). Results indicated that comparable score estimates (based on computer simulations) to the full-length tests can be achieved in a 20-item CAT version for all age ranges and for normative and clinical samples. No more than 13 to 16% of the items in the full-length tests were needed for any one administration. These results support further consideration of using CAT programs for accurate and efficient clinical assessments of physical functioning.


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Enjoy a wonderfully developed over-sized north facing rear patio that has extended patio spaces to enjoy mountain view to the east and mature landscaping. Large front patio to enjoy friendly neighborhood interaction or red sky sunsets! This light and airy two bedroom, two bath home with a private den is move-in ready! Large, spacious kitchen has an over sized island for entertaining and a charming breakfast nook -- all are open to the great room. Separate entertaining space includes either formal dining or additional living room. En suite master bedroom is open and airy with a large bay window, and huge custom closet and well-designed master bathroom. Extended garage with built-in storage. There is room in this budget for your own updates!
From gatehome, proceed to first four way stoop; go straight and take a right at cypress canyon (1st right), right on mahogany gulch to the house on right.
Green Valley NorthEast Green Valley
Quail Creek
Quail Creek CC

subset: commoncrawl


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Written by keith
19 Apr 2011
bill and tom the allotment men part 1
- 2 Comments
- 6019 Views
2 minute read
hi last year trying to be green liz and myself took on an allotment, liz is now 29 slim size 10 keeps herself fit sorry iff your a big boob guy shes not for you shes 34b. last year the two old guys doing the two allotments to our left in there 60's or seventies were very helpfull to us with advice. but they couldnt hide there obvious thoughts of liz with blatant stares.
during the warmer days of which there were not that many last year liz would wear a tight top and shorts. I often joked that the two guys would be disappearing into there sheds for a wank and it was well known allotment sheds were full of porno mags for rainy days. at first she shrugged it off but then after a while asked do you really think they still read porn and wank.to which i replied keep bending over like that and i bet hes got a hard on and laughed.
this seemed to awaken something in her as she would talk while we were in bed asking iff i thought they wanked over her and my reply of i wouldnt be suprised only seemed to give her a girlish giggle and almost excitement in her voice. while we were there her thong might slip into view above one type of shorts she would wear. i didnt tell her bill on the next allotment had been having a good stare untill we got home. to my surprise she said i know it happens with them thats why i put them on, she laughed and asked do you think he had a play.
well nothing other than flirting/teasing happened last year. a few weeks back we started going again for this year and bill and tom seemed pleased to see we were going to have another go. the weather picked up and we went about our tasks. Last week i was working nights, so i took liz to a pub where we sat outside having a drink and meal she drank abit of wine and i was going home to bed said she would go and do a bit at the allotment and to have some fresh air. i dropped her off then went home to bed. i heard her come in and rush upstairs to the bathroom and in the shower as i need the toilet wakeing up after a couple of pints i went for a pee i was rather taken aback by liz's red bottom and i meen red as she heard me walk in she quickly turned round and her face coloured up to match. to avoid making this to long ill make this part one


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Meet Theon
Theon is very active when it comes to playtime & loves a good cuddle.
Ginger & white with half a moustache tells him apart from his brother.
He loves lazing in the sunshine by the window & having pets and smooches.
Plays with his toys & tunnels & wrestles his siblings along with his foster carers resident cats.
Loves his food, litter trained
Would prefer Theon & Tyrion are adopted together as they have bonded.
Theon is ready and waiting to meet his new furever family.
Theon has been in foster care since 30 October 2019, for 1 month
- male
- 20 July 2019
- 4 months and 2 weeks
- Ginger & White
- $200
- Mt Druitt Area
- 30 October 2019
Would you like to adopt Theon?
- Anita
- 0400 206 532
- 0400 206 532
- Send enquiry email - preferred
NSW Rehoming Organisation Number: R251000023
To find out more information about Theon, or to organise to see him, please contact his foster carer above. Alternatively use our contact form
Our animals are rescued from various pounds and shelters and placed in Foster Care until a permanent home can be found. Our Foster Carers are located throughout Sydney, Australia.
Animals in our Care
These animals have been rescued from various pounds and shelters by volunteer Foster Carers who provide the animal with a safe haven until they can be permanently rehomed. They are located throughout Sydney, Australia.
Please note that descriptions of breed, age and size are given in good faith and are based on assessment of the animal's features, together with veterinary opinion. We cannot guarantee the age and breed of any animal listed.
All dogs and cats listed come desexed, vaccinated, wormed, microchipped and heartworm tested.
Also have a look at our Cats in Care pages for more cats available for adoption.


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Recently we at ShipCompliant hosted a webinar to review the latest updates in the ongoing saga of the Illinois qui tam cases. We were excited to be joined by Steve Gross of the Wine Institute, along with Adam Beckerink and Michael Wynne of Reed Smith LLP, who are representing the Wine Institute in its suit against the Illinois Department of Revenue and the Illinois Attorney General. While many interesting points were brought up in the webinar, we noted a few major take aways we wanted to highlight.
To quickly rehash what is going on in the Qui Tam cases, an Illinois attorney, Stephen Diamond, has filed lawsuits against at least 132 wineries since last December, accusing them of failing to pay tax on shipping and handling charges for deliveries made into Illinois. (Qui Tam essentially means that a party can stand in the king's shoes, and sue on behalf of the government–and receive a share of any bounty raised.) Under Illinois' tax rules, there are certain situations where tax on the freight is due; these are when the freight charges are "inseparable" from the cost of the product itself (according to a 2009 Illinois Supreme Court case, Kean v. Wal-Mart). However, Adam and Michael, under the direction of the Wine Institute, have been seeking to get Qui Tam cases dismissed, arguing that the wineries had properly separated freight charges from the cost of the wine.
To this effect, they have received Private Letter Rulings, on behalf of two of their winery clients, from the Illinois Department of Revenue, which provided a general definition of what "inseparable" means. While a private letter ruling cannot control how a judge will rule on a case or be relied on by a party that did not request the ruling, it does indicate how the relevant government body would view the law. The Private Letter Rulings they received highlighted three requirements in order for the shipping charges incurred by Illinois customers to be considered separate:
- Shipping charges must be stated separately from the cost of the wine.
- There must be an option to pick up the wine at the winery (even for non-Illinois wineries).
- The price of the wine cannot change depending on whether the wine is shipped to the customer or picked up onsite.
When all three of these conditions are in place, then tax on the shipping charges is not required. If a winery can document that it had these conditions in place when Diamond made his purchase (he had to have bought wine to show that the winery wasn't levying the tax), then it has a good basis for dismissal of its case.
However, there is an important double-edge to this provision. Just as a winery needn't pay a tax on freight if these conditions are in place, a winery may be subject to a potential lawsuit if these conditions are in place and is still assessing a tax on freight. This charge would arise out of Illinois' consumer protection rules, under which a consumer would accuse the winery of overcharging them. (This was the basis of the Kean trial, where the plaintiff accused Wal-Mart of improperly charging tax on shipping; but there the Illinois Supreme Court said that the absence of a pick up option meant that Wal-Mart was correct in charging the tax.)
So our big take away from the webinar is that a winery can set up their shop to avoid having to pay tax on freight. It would do so by implementing the three requirements listed above. But, if a winery did follow this system, it should also make sure it is not charging a tax on freight. Or it might be sued by its customers (a good chance it may still be Stephen Diamond).
If you are a ShipCompliant user, you must do this by logging into your account, and changing your settings. Simply go to the Tax Preference page here, and uncheck the box that indicates Illinois Tax Freight. If you are not a ShipCompliant user, you will have to arrange this through your existing system.
It is also notable that wineries that offered a pick-up option can argue to dismiss their case. While none have yet been successful, the Illinois Attorney General has indicated this is an argument that has particular sway.
If you'd like to learn more about this situation, check out the resources here. As always, feel free to contact us at email@example.com.


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Book: Mellon Andrew W «Development of the United States Capital. Addresses delivered in the auditorium of the United States Chamber of Commerce Building, Washington, D. C., at... of the national capital. April 25-26, 1929»
Серия: "-"
Книга представляет собой репринтное издание. Несмотря на то, что была проведена серьезная работа по восстановлению первоначального качества издания, на некоторых страницах могут обнаружиться небольшие "огрехи" :помарки, кляксы и т. п.
Издательство: "Книга по Требованию" (2011)
Купить за 686 руб в My-shop
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Mellon, Andrew W.
▪ American financier and politician
in full Andrew William Mellon
born March 24, 1855, Pittsburgh, Pa., U.S.
died Aug. 26, 1937, Southampton, N.Y.
American financier, philanthropist, and secretary of the Treasury (1921–32) who reformed the tax structure of the U.S. government in the 1920s. His benefactions made possible the building of the National Gallery of Art in Washington, D.C.
After completing his studies at Western University (now the University of Pittsburgh), Mellon entered his father's banking house in 1874 and proved so capable that in 1882 his father transferred the bank's ownership to him. In the next three decades Mellon built up a financial-industrial empire by supplying capital for Pittsburgh-based corporations to expand in such fields as aluminum, steel, oil, coal, coke, and synthetic abrasives. Mellon's keen judgment of new technologies and potentially successful firms and entrepreneurs enabled him to help found the Aluminum Company of America (Alcoa) and the Gulf Oil Company. In alliance with Henry Clay Frick (Frick, Henry Clay), he helped found the Union Steel Company, which later merged with United States Steel Corporation. He and Frick were also the principal organizers (in 1889) of the Union Trust Company, which became Mellon's principal financial instrument and acquired his family's bank. By the early 1920s Mellon had become one of the richest men in the United States.
Mellon was appointed to head the U.S. Treasury by President Warren G. Harding in 1921. In discussions concerning reduction of the national debt, which totaled $24,000,000,000 in 1920 as a result of World War I expenditures, Mellon held that continuance of the high wartime tax rates would discourage business expansion and hence reduce revenue. He also advocated reduction of the surtax rates on incomes. Largely through his efforts Congress repealed the excess-profits tax and gradually lowered the income tax rate until in 1926 the maximum surtax was reduced from 50 to 20 percent. Further reductions in tax rates were later made; by June 30, 1928, the national debt had fallen to $17,604,000,000. As chairman ex officio of the World War I foreign debt commission, Mellon also played a prominent part in formulating U.S. policy concerning the funding of war debts owed to the United States by foreign governments. Mellon's policies helped stimulate the American economic boom of the 1920s, and he continued to head the Treasury under presidents Calvin Coolidge and Herbert Hoover. His popularity declined after the Great Depression began in 1929, however, and in 1932 he resigned to serve as U.S. ambassador to England for a year.
One of the nation's foremost art collectors, Mellon gave a collection valued at $25,000,000 to the U.S. government in 1937. Among other paintings, it contained Raphael's "Alba Madonna," 23 Rembrandts, and 6 Vermeers. Mellon donated $15,000,000 to build the National Gallery of Art, opened in 1941, to house the collection.
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Источник: Mellon, Andrew W.
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Latest Updates
December 12, 2019
Driver's License office in Fargo temporarily moved to new location
Beginning Monday, December 16, Fargo driver's license services will be moved to a temporary location at Village West Mall at 4101 13th Ave. S in Fargo while a renovation project takes place at the permanent driver's license office on 38th Street S. The temporary move will allow for less disruptions in service for customers in Fargo.Read More
December 8, 2019
Travel Alert extended to southeastern North Dakota
The North Dakota Department of Transportation (NDDOT) along with the North Dakota Highway Patrol (NDHP) have extended the Travel Alert to southeastern North Dakota due to heavy snow creating reduced visibility and slippery roads. Cities included in the Travel Alert are Jamestown, Valley City, Fargo, Casselton, Wahpeton, and surrounding areas. A Travel Alert means conditions are such that motorists can still travel in these areas, but should be advised of rapidly changing conditions. Motorists are encouraged to wear seat belts, reduce speed, and drive according to the conditions Read More
December 1, 2019
No Travel Advised LIFTED for south central and northeastern North Dakota
The North Dakota Department of Transportation (NDDOT) along with the North Dakota Highway Patrol (NDHP) have LIFTED the No Travel Advisory for south-central and northeastern North Dakota. All travelers are encouraged to monitor road conditions as weather conditions occur and use caution while traveling.Read More


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|"Andor Molnar (JIRA)" <j...@apache.org>
|[jira] [Commented] (ZOOKEEPER-3404) BouncyCastle upgrade to 1.61 might cause flaky test issues
|Mon, 27 May 2019 21:22:00 GMT
[ https://issues.apache.org/jira/browse/ZOOKEEPER-3404?page=com.atlassian.jira.plugin.system.issuetabpanels:comment-tabpanel&focusedCommentId=16849213#comment-16849213 ] Andor Molnar commented on ZOOKEEPER-3404: ----------------------------------------- Similar with Java 13: [https://builds.apache.org/view/S-Z/view/ZooKeeper/job/ZooKeeper-trunk-java13/94/testReport/org.apache.zookeeper.server.quorum/QuorumSSLTest/history/] and Java 12: [https://builds.apache.org/view/S-Z/view/ZooKeeper/job/ZooKeeper-trunk-java12/77/] Looks like the patch has doubled the test execution time and sometimes it's just not able to finish within the timeout. > BouncyCastle upgrade to 1.61 might cause flaky test issues > ---------------------------------------------------------- > > Key: ZOOKEEPER-3404 > URL: https://issues.apache.org/jira/browse/ZOOKEEPER-3404 > Project: ZooKeeper > Issue Type: Bug > Components: tests > Affects Versions: 3.6.0 > Reporter: Andor Molnar > Priority: Major > Labels: pull-request-available > Time Spent: 20m > Remaining Estimate: 0h > > I've seen a lot of test timeout errors with QuorumSSL tests since I upgraded master to BouncyCastle 1.61 due to a Java 9 warning. The warning has been reported by [~eolivelli] which we tried to solve by the upgrade, but the warning message is still present so I don't see any harm in downgrading to the previous version. > The timeout errors are very frequent with recent Java versions (11+) and quite rare with Java 8. > I think it's worth a try to downgrade and see if tests will be in a better shape. -- This message was sent by Atlassian JIRA (v7.6.3#76005)
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By Penny North-Lewis
Liver ailment is a frequent and lengthening challenge during the global, besides the fact that little is released on how differing types and levels of liver disorder impact the body's skill to address medicines."Drugs and the Liver" is designed to help practitioners in making pragmatic offerings for his or her sufferers. It goals to: allow the practitioner to evaluate liver functionality utilizing biochemical markers, different checks, symptoms, indicators and sickness wisdom; determine which pharmacokinetic and pharmacodynamic parameters of a drug usually are tormented by types of liver affliction; and view the impression of a drug's unwanted side effects on a sufferer with liver disease.This useful consultant covers historical past details on liver functionality, the rules of drug use in liver affliction and incorporates a portion of labored examples of frequently asked questions. it is going to be necessary to medical pharmacists and a person making medication offerings in sufferers with liver impairment.
Read or Download Drugs and the Liver: A Guide to Drug Handling in Liver Dysfunction PDF
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Sample text
A bile salt-independent process. Bile acid metabolism and transport The bile acid molecule is composed of two distinct components: a steroid nucleus and an aliphatic side chain. The two principal primary bile acids (cholanoic acids), cholic acid and chenodeoxycholic acid, are synthesised from cholesterol in the liver. More than 99% of bile acids are conjugated before being secreted by the hepatocytes, allowing them to interact with other molecules within bile, and preventing them from being precipitated in the acidic environment of the small intestine.
A variety of proteins are constructed in the liver using amino acids (Aa) as their basic building blocks. Amino acids are categorised as 'essential' and 'non-essential', the former being a requirement of dietary intake as they cannot be constructed in vivo, whereas the latter can be synthesised hepatically. The essential amino acids are further categorised as branched-chain amino acids (BCAA; leucine, valine, isoleucine) or aromatic amino acids (AAA; phenylalanine, tyrosine, methionine) according to their structure.
It is characterised synthesised by the liver to by panacinar emphysema of the lungs, and limit the plasma circulation cirrhosis hepatitis in the young, progressing in some to of important proteases cirrhosis, and culminating in hepatocellular carcinoma in 2–3% Host defence against Complement C3, C5a, B, D, I and P There are 16 components of the complement system, which is divided into the classic and infectious and inflammatory levels are all reduced in hepatitis alternative pathways and cirrhosis processes Haptoglobin levels are raised with A haemoglobin-binding α2- Haptoglobin is synthesised in the globulin that targets aged liver and its levels are diminished in inflammatory and infective processes.


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Published at Saturday, 10 August 2019. Coloring Pages. By Jeanne Villain.
Coloring pages can also be a good way to make money if you are free landscape artist. If you can reproduce any character from cartoons or fairy tales, you can draw sketches of them and sell them, either online, either to a library store that can sell them and give you a part of the profit. You can also say that some people use the sketches as they are, black and white, without coloring them. The printable ones can also be used to make stickers and such. One disadvantage of printable pages in general is that they need paper, and as we know paper is made out of trees, and the planet needs trees to survive, but a good thing is that paper can also be recycled. In the near future, we'll probably see more and more online coloring pages, but the feeling won't be the same though.
May be you might be full-time professional or may be a businessman or an educator or a parent, everyone is determined to give something interesting and appealing to his or her kids, after his or her school work. If you are interested to provide some printable pages to your kids – those were created in order to be colored. Thanks to the available services that are provided by the internet, you can teach your kids or pupils how to use the online coloring because this online activity may increase their creativity levels for good. The online coloring is the perfect educational entertainment and it will greatly enrich your child's own artistic view.
We have yet to discuss the benefit that your child will be learning about the different colors as they color their pages. And the more exposure your child has to coloring, the more they will learn about the typical colors of objects, and they will begin to choose specific colors for specific items, such as red apples, or green leaves. And, as they grow older, you will also begin to see that they will color animals the color that they truly are. This may seem obvious to somebody who has known their colors since they can remember, but you had to learn it at some point and this is a great way for your child to learn theirs.
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is backordered and will ship as soon as it is back in stock.
'Live life in the clouds' is engraved on this scenic charm in sterling silver. The design is decorated on the front with billowing white enamel clouds, a pastel enamel sky and silver hot air balloons in flight, all encircled with sparkling stones.


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Household Asset Holding Diversification in Australia
34 Pages Posted: 12 Jul 2014
There are 2 versions of this paper
Household Asset Holding Diversification in Australia
Household Asset‐Holding Diversification in Australia
We explore asset holding diversification by Australian households, in particular, the household asset diversification participation decision (whether or not to diversify at all) is jointly estimated with the decision of how much to diversify. In so doing, recent literature on the modelling of proportions is combined with the growing body of research concerning household financial decision making. Our findings are consistent with the participation of households operating in diverse financial markets being constrained by ineffective information conduits, influencing the decision of whether or not to diversify. We further find that short term concerns over job security or health are associated with less participation in, as well as a lower extent of, asset holding diversification.
Keywords: job insecurity, asset allocation, asset diversification, household finance, employment, Zero-Inflated Beta
JEL Classification: J3, J7
Suggested Citation: Suggested Citation


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Modernize your space with the Sauder Woodworking Studio RTA Boutique Backless Counter Stool, which is designed with a round seat made from engineered wood and supported by a sturdy metal frame. It has a solid ash dowel footrest along with an overlapping base. The combination of white and natural tones creates a fashionable look that offers loads of styling versatility. And, this stool is designed with discreet footing to protect your surfaces.
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Fashion & Beauty consultant, Jijiglam has every reason to walk us through the path she deem fashionably right! This week on her www.jijiglam.com, she tells us a story about her red asymmetric flare trouser and 80s leopard shirt with a puff shoulders – an interesting piece, we must confess! To get the full gist, visit her page to enjoy the harmony.
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Shows like a model! Fantastic and spacious (1403 sq feet) 2 BR, 2 BA condo in the heart of Annapolis. Open floor plan, gleaming hardwood flooring, gourmet kitchen with granite counters, stainless appliances. Large spacious bedrooms on opposite sides of units, 2 walk-in closets. Two deeded parking spaces, elevator and extra storage. Walk everywhere! Option to purchase furnished if desired!
View of marina and boats.~ Ready to relax and watch the boats go by?~ This one is for you.~ Neutral paint, carpet, 2 bedrooms, 2 bath, open living room and dining room.~ Updated kitchen and baths, wood burning fireplace.~ Granite counters, SS appliances.~ Amenities include 24/7 security, 2 pools, tennis courts, private sandy beach and walking paths.~ Water taxi to Historic Annapolis or dine at~ Sam's Waterfront Cafe on site.
Located in the desirable Eastport Peninsula. Walk to Shoppes, restaurants and marinas. Non-Flood zone, two units on property, main house uninhabited, second structure built 2005-6 Is a 2car insulated garage with work space and efficiency unit on the second level, each with their own security and heating/AC units. Metal roof, Hardy board frame construction. Walk to restaurants, privacy fence, plenty of off-street parking on desirable one way street. Garage efficiency in-law suit comes furnished and is available for immediate occupancy.*****Build to suit from your own plans or City approved and transferable SDRP plans for custom 3,180 sf custom home with additional sf in attic and full basement if desired. Rough in for elevator and designed to allow for 1st floor Master BR. Permitting process nearly complete including full construction plans, Grading Plan, front set back and roof height surveys for entire block. Structural engineering reports etc. All the heavy lifting has been completed.
Sold AS-IS. Priced below tax assessed value. Spacious interior with 4 bedrooms and garage has been converted to a large bonus room/optional 5th bedroom. Backs to trees offering privacy and wonderful screened porch in the rear.
Take a look inside this beautiful, modern style Baltimore townhome with 1 car garage! The entry level floor is finished with rec room and half bath for extra space to entertain or relax. The main level flows nicely with the living room and dining area where it is connected via the center kitchen.Baltimore's kitchen comes accentuated with granite counters and stainless steel appliances awaiting all of your culinary favorites. On the 3rd level you will find the Owners Suite, a 2nd bedroom also with an in-suite bathroom plus a convenient laundry area. The 4th level offers a 3rd Bedroom with full bath and a loft area perfect for an office or hang out space. Unwind from a long day and hang on the RoofTop Terrace. Located within a quaint community with gathering areas and fire pit! Photos similar while construction finishes
Beautifully updated and spacious home sited on a large lot on a lovely culdesac. Stylish yet utilitarian culinary kitchen with fabulous cabinetry and granite counter tops as well as stainless steel appliances. The kitchen opens onto the side yard, perfect for outdoor dining. Lower level family room with fireplace with walk out level to the back deck and relaxing hot tub. The family room works well for practicing your yoga or game tables. Perfect location with easy access to downtown Annapolis, shopping and restaurants. There is the added bonus of community amenities to include a pool and tennis courts. Welcome home!
Perfect set -up for one floor living and or room to grow with a fully unfinished basement. Nice size living room and 3 bedrooms & two baths. Hardwoods in 2 bedrooms and laminate flooring in living room. Big yard, close to downtown. Ready for your personal touches.
*This is a rare 4 bedroom floorplan. Modern cabinets, black granite counters, stainless steel appliances. Building has secure code entry. Condo conveys with additional storage unit in basement. Condo fee includes water/Sewer, Gas for cooking and Gas Heat, Master Insurance policy, Clubhouse, fitness center, pool, party room, billiards, office space, picnic areas, pier with access to boat slips. No front foot fee's. Location is Ideal!! The Annapolis water taxi service will pick you up right at the dock and deliver you to any number of locations throughout Eastport and the City Dock. SPA CREEK CONDOMINIUMS OFFERS: Facilities for canoe and kayak storage Clubhouse with swimming pool and sundeck, fitness center, locker rooms and lounge Walking pathways along the water and through lushly landscaped grounds Boat ramp & pier Gated waterfront lawn ADJACENT TO THE COMMUNITY IS THE TRUXTON PARK RECREATION CENTER WITH: Lighted tennis courts Swimming complex Playgrounds & FieldsA brand new, 80,000 sq. ft. public indoor recreation center featuring:- Three-court gymnasium- Rock-climbing wall- Indoor track- Fitness center- Indoor playground
WEST 141 BY BOZZUTO HOMES. Quick Delivery in incredible downtown Annapolis location! Turnkey one-bedroom in boutique building on coveted Inner West Street. Sunny plan features 9+ ft. ceilings, large windows, barn doors, walk-in closet plus all the features & finishes you expect from Bozzuto: wide plank floors, quartz counters, stainless steel appliances, subway tile backsplash, designer bath tile, washer/dryer & more. Condo fee only half of most in downtown. Bylaws allow owners to short-term lease - rare!
NEW IMPROVED PRICE!!! SOLD STRICTLY AS-IS. Adorable rancher on a quiet street situated on 1 acre! Restore this to the tranquil oasis! Near Sandy Point State Park and one exit from the Bay Bridge. Easy access to Naval Academy, Annapolis Mall, and DC! Great location for that secluded getaway! Don~t miss this wonderful opportunity!
Rare Severn House townhouse (only 10 in community!) with amazing water views of Back Creek. Private patio and 17x7' deck to enjoy the views! 30'Lx11'Wx5.5'D deeded boat slip conveys with property. Community pool & outdoor dining space right on the water, marina, & water taxi takes you from the community to downtown Annapolis. This community does not allow pets.
FIRST FLOOR MASTER IN ALMOST NEW HOME CONVENIENT TO EVERYTHING IN ANNAPOLIS! Main floor master suite w/ gorgeous master bathroom. Wake up every morning and sit on your deck as you enjoy the wildlife in your private, wooded backyard. All the major components have been updated/replaced in this gorgeous home. Fine details throughout such as crown molding & wainscoting. Brand new large kitchen w/ white shaker, soft closing cabinets & drawers, all new appliances, contrasting gray center island, & tons of storage. 2 story family room off kitchen w/ wood fireplace & 2 new sliding glass doors leads to deck & patio-perfect for entertaining! 1 of the 3 main floor bedrooms has floor to ceiling built in shelves-could be perfect for your home office! Fully finished basement w/ multiple rooms for endless possibilities-home gym...game room-the choice is yours! One of the rooms downstairs has a rough in for a wet bar-make it your home theater! 2 car attached garage! Brand new updates incl: roof, HVAC, water heater, water treatment system, carpet, all appliances & much more! Windfern Forest community has a private pier w/ slips on a first come first served basis included in your $400/year HOA. Community also has large gazebo, picnic tables & charcoal grills!
3057 Rundelac Road is a five-bedroom, all brick waterfront estate home located on Aberdeen Creek. The home is situated on two beautiful acres boasting a park-like landscaped yard surrounded by mature trees, an in-ground pool, and a private pier with deep water. Enjoy quick access to downtown Annapolis, shopping and dining, and major commute routes. The circular drive, featuring decorative brick and stonework, welcomes you with style. As you step into the grand two-story foyer, your eyes are drawn upward by the majestic double staircase. The ceiling is accented by the multi-tiered candlelight chandelier and ornate medallion. The formal living room on one side has beautiful hardwood floors, a wood-burning fireplace with black-marble surround, chair rail accent, crown molding, and tons of natural light. The formal dining room, with beautiful chandelier, offers a pellet stove to warm your gatherings. Through the foyer, the family room features an oversized wood-burning brick-surround fireplace; a breathtaking focal point of this space. There~s also updated lighting, hardwood floors, a wet bar and French doors leading to the waterside patio. The family room flows nicely into the gourmet kitchen with informal dining space and oversized center island with breakfast bar. Top-of-the-line finishes include updated white cabinetry, black quartz countertops, Jenn-air double wall ovens, a Subzero refrigerator, and a separate beverage fridge. Down the hall the two-story solarium has a soaring ceiling, fantastic natural light, and plantation shutters. The main level also includes a home office that could be used as a sixth bedroom, two full bathrooms, and a laundry room. Upstairs, the master suite, with gorgeous gas-fireplace, is located off the grand second floor landing. This oasis setting has a luxurious private bathroom with two vanities, jetted tub, separate tiled shower, and ample storage. Glass doors in both the bath and the bedroom lead to a private waterside balcony overlooking the yard, pool and patio. There are three additional bedrooms, all generous in size, with gracious closet space and their own built-in storage systems. One of these bedrooms has an ensuite bath and the other two share an updated hall bathroom. There is a huge bonus room that runs the length of the four-car garage, with two large closets, dormered windows and plenty of space for hobbies or play. The current owners are using it as a bedroom, but the size gives it lots of flexibility. An upstairs laundry room and a staircase to the whole house attic with natural light offer extra conveniences to the home. Outside you~ll find the beautiful stone patio overlooking the park-like backyard. A short path leads to the fully fenced in-ground pool and continues to the tree-lined stone path to the Aberdeen Creek waterfrontage. The private pier has two deep-water slips, one with a lift and a floating dock for easy entry and exit on a kayak or paddle board. Some of the features that you may not notice upon first glance are the solar panels hidden over the garage on the slate roof, the fence at the back of the property offering additional privacy, the very quiet location near the end of the cul-de-sac, the underground sprinkler system, and the side driveway leading to the oversized four-car garage. If you are ready for a home grand enough for entertaining and comfortable enough for your family, this home is ready for you! Call today for a private tour!
PENTHOUSE AT WEST 141 BY BOZZUTO HOMES. Fall 2019 Delivery. Overlooking West Street, spacious 2-bedroom/2 bath home boasts enormous private rooftop terrace with stunning city skyline views! Premium interior upgrades include wide plank hardwood floors & oversized designer bath tile. Peninsula kitchen fabulous closet space, separate owners tub & shower, washer/dryer. Must see! Includes 2 deeded garage spaces. Condo fee 1/2 of most downtown.
***PRICE LOWERED***SELLER WILL ENTERTAIN ALL OFFERS**Resort Style Community on the Chesapeake Bay. Amenities inc. 2 Swimming Pools, 4 Tennis Cts.,2 Fishing/Crabbing Piers, Kayak Launch ,Beach, On- Site Restaurant, Tiki Bar and Marina Unit has 2 BR(1 Master), 2 BA, Eat-in Kitchen and 2 Decks 1 of which has View of Open Space, Harbour and Marina. FP with custom surround, New Carpet through-out, State-of-the-Art Sliders and Crown Molding. Minutes to downtown Annapolis by Boat or Car. Owner/Agent.
PRICE ADJUSTMENT!!!!! RARE OPPORTUNITY to OWN in the HISTORIC DISTRICT! PARKING is NOT an issue when you can lease a one car garage space just steps away!! Prime location in the shadows of the MD State House. Restored Colonial showcasing carefully chosen and executed updates respecting period features. Original hardwoods mixed with trend setting plank flooring. Living Room sharing fireplace ambiance with continuing Dining/Kitchen areas. High-end quartz & stainless chefs Kitchen w/Wolf range. Sunroom spilling out to privacy fenced yard & patio. Sizable Master BR with revamped en suite modern clawfoot tub Bath. Finished lower level Rec Room for game tables, gym or home theater. Walk to crab cake eateries, boutiques, bistros & galleries! Embrace Chesapeake maritime heritage with A DASH OF OLD BAY! One car garage space available for$350.00/month
Don't miss this contemporary, light filled, custom home in Epping Forest! 3 bedrooms and 2.5 bathrooms in an efficient, open floor plan design that makes great use of space. Open the sliding glass door to the large deck and entertain among the trees. Cozy up in the colder months with the artfully designed wood burning fireplace. New kitchen, remodeled bathrooms, and countless cosmetic and utility improvements make this home turnkey. - Epping Forests boasts a community beach, marina, clubhouse (with food service), tennis and basketball courts, garden, park and chapel. This active community includes holiday parties, summer camp, swim team and social events. Not just a neighborhood~ a lifestyle!
Gorgeous renovation on this large 3 bedroom, 2.5 bath town home is Woods Landing. Walk into a freshly painted home with refinished hardwood floors and see the bright kitchen with new quartz counter-tops, an island, new stainless steel appliances, new tile flooring and back splash. The large separate dining space overlooks the family room with a wood burning fireplace. Enjoy evenings out on the rear deck. Upstairs, the grand master suite with cathedral ceilings has new hardwood flooring and a totally renovated master bath with a walk in closet and private deck. The basement is finished and ready for an entertainment room. The large utility room has a washer and dryer. The house has a new roof, windows, carpet, appliances, bathrooms and more! The community amenities include a park with a playground, dog park, tennis courts, basketball courts & nature trails. Water access, perfect location and great schools! There are 2 assigned parking spots right out front! Additional parking also available for guests.
Incredible colonial with water views of the Chesapeake Bay from every level situated in serenity on nearly an acre of landscaped grounds. A 10-foot deeded easement in the rear yard allows direct access to the Bay. Enjoy your own private retreat with the screened porch, large deck, fenced side yard, fruit trees, and beautiful sunrises and sunsets. The spacious interiors are accented by hardwood flooring and a fresh neutral color palette throughout. Kitchen offers corian counters, breakfast bar, and a pantry. Three sliding glass doors to the deck from the formal living room, dining room, and family room adjacent to the kitchen. Two wood-burning fireplaces. Expansive finished third floor bonus room with a rough-in and closets. Property Updates: Water heater, heat pump, portico, finished third floor, renovated baths, interior paint, and more! Benefit from being a short distance from Eastport, Downtown Annapolis, South River and water activities at Sandy Point and the Bay Bridge. Close proximity to the Eastern Shore and several marinas. Commuter routes including MD-665, US-50, I-97, and the scenic Cape St. Claire Road offer convenient access US Naval Academy, BWI Airport, and more. Outdoor recreation awaits you at Bay Head Park.
Stunning Custom-built private retreat in St. Margarets, tucked away on nearly 5.5 Acres surrounded by natural beauty, and within just 5 miles to downtown Annapolis!! The country club setting includes a saltwater pool, 9 hole Putting Green, Attached Guest House, 3 car garage and an inviting wrap around Deck with covered porch. A gracious circular driveway welcomes you into this true Entertainer's Modern Dream Home, where soaring ceilings and expansive light-filled windows greet you at every turn! The updated chef's kitchen opens to a spacious living area, featuring a fireplace, wet bar, and walkout onto Porch and expansive wrap around Deck overlooking the tranquil backyard oasis, saltwater pool and putting green. The main level also features an office with a fireplace, large formal living and dining areas, a gym/bonus room & "Summer" kitchen with full bath. The upper level boasts 3 en- suite bedrooms, including the sunny Master Suite complete with walls of windows, sitting areas, gas fireplace, double walk in closets and a luxe spa bath. The attached guest house has a separate entrance and is equipped with a full kitchen, 2 story great room, en- suite bedroom, separate security system and private screened Porch. Additional Features: Detached Oversized Shed with roll up garage door and Concrete Floors. Back Up Generator, Irrigation, Accent Exterior Lighting. This one truly has it all!
Open House:
Sunday, 12/22
This charming two bedroom, two bath cottage is on an oversized corner lot with water views in Arundel on the Bay, a private community on the Chesapeake Bay and Fishing Creek. Spend your days relaxing by the beach, watch gorgeous sunsets or launch your boat for a cruise or sail. Enjoy the community wine tasting events, movie night on the beach, fish from the pier or make new memories crabbing with the family. Great spot for watching the Blue Angels show off in the nearby Naval Academy. It is minutes to fabulous downtown Annapolis dining, shopping, Annapolis Harbour Center and nearby waterfront cafes. ~Famous folks had ties there including Frederick Douglass, Alex Haley, Martha Washington, Patrick Henry, Rep. Adam Clayton Powell, Todd Duncan-opera star of Porgy and Bess fame and Rep. Clarence Mitchell, Jr.~, as quoted in The Amazing Story of Arundel on the Bay, 1600s to Today book sold on Amazon! Come and make this part of your family history. Needs work but what a gem this will be once you make this your own.
Water-front property in Annapolis/Oyster Harbor. Inground indoor swimming pool. Bank owned unit. Needs work. Sold in as-is condition. Over 9900 finished sq ft per tax records, boat house and pier. Tons of possibilities.


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Basically you ll possess the ability to appear throughout
The alpha handbook reveals some new particulars on this system. Characters will obtain "physical levels" the way in which most MMO avid gamers are utilized to-by gaining knowledge points, which presently is only carried out by method of killing monsters."Skill ranks" are separate for each and every weapon type and therefore are raised by use in combat or crafting. equally ability ranks and actual physical safe wow gold quantities are capped at twenty to the alpha. We are not just provide last Fantasy XI gils, but on top of that update information and guides at major time.
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That evening, after having sex with Jennifer in my fort in the backyard, I had dinner with my other half Nancy. I had actually made my homemade ravioli, filled with crab, and also covered with a beautiful Béarnaise sauce. Unfortunately, we had an economical twenty buck Pinot Grigio to clean it down. Yet it was a wonderful meal paired with a fresh salad.
In the middle of supper, I found myself trembling and excused myself and bowel movement. Guilt wracked me like no other time when I had actually ripped off on my other half. It amazed me with the intensity as well as I spent time simply looking at my face in the mirror trying to find indicators of the regret that was consuming me. My typical face gazed back, but I was certain my eyes were a little larger than regular.
Jennifer had actually gone home soon after we had fooled around. I had actually gone within very pleased and also showered. I had a glass of scotch and went outside to have a smoke. I had searched for at Jennifer's home window and also located her grinning down at me, upper body exposed, and her gorgeous breasts pushed up against the home window glass. I had grinned and swung as well as really felt heat training course via me while looking at her stunning, tooth-filled smile. She swung as well as went away inside and after that the shame struck me once again.
I shrugged it off and rested confused drinking my scotch. The only time I had ever before really felt guilt similar to this desired the first time I had cheated on my better half with a service provider in New Zealand. This moment it was different. It was much more extreme and also weakened me physically.
Currently in my washroom checking out myself I searched for a way past it. I really did not recognize why it was happening. Thoughts of Jennifer kept flooding my mind. I might see her again, lying back with her legs spread out as well as holding her pussy lips open for me to see every one of her. She was so hot and so stunning. My dick rose in my trousers. I bore in mind the initial feeling of her breasts in my hands. So soft, so cozy, and also with her nipples so receptive as well as difficult versus my palms.
I remembered just how wet she was. It had actually been so long because I had really felt a female so wet for me. To have that effect on a woman is empowering. As well as I remembered her preference. So sweet, so great smelling. My mouth sprinkled and also I needed to taste her once again. I needed to plunge my dick back inside her as well as see her eyes illuminate in delight. I required to see those environment-friendly, eco-friendly eyes burning out right into mine from a beautiful face framed in lavish red hair.
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