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BACKGROUND: Type 2 diabetes in young people is an aggressive disease with a greater risk of complications leading to increased morbidity and mortality during the most productive years of life. Prevalence in the UK and globally is rising yet experience in managing this condition is limited. There are no consensus guidelines in the UK for the assessment and management of paediatric type 2 diabetes. METHODS: Multidisciplinary professionals from The Association of Children's Diabetes Clinicians (ACDC) and the National Type 2 Diabetes Working Group reviewed the evidence base and made recommendations using the Grading Of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. RESULTS AND DISCUSSION: Young people with type 2 diabetes should be managed within a paediatric diabetes team with close working with adult diabetes specialists, primary care and other paediatric specialties. Diagnosis of diabetes type can be challenging with many overlapping features. Diabetes antibodies may be needed to aid diagnosis. Co-morbidities and complications are frequently present at diagnosis and should be managed holistically. Lifestyle change and metformin are the mainstay of early treatment, with some needing additional basal insulin. GLP1 agonists should be used as second-line agents once early ketosis and symptoms are controlled. Glycaemic control improves microvascular but not cardiovascular risk. Reduction in excess adiposity, smoking prevention, increased physical activity and reduction of hypertension and dyslipidaemia are essential to reduce major adverse cardiovascular events. CONCLUSIONS: This evidence-based guideline aims to provide a practical approach in managing this condition in the UK.
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Diabetes Mellitus Tipo 2 , Metformina , Adulto , Humanos , Criança , Adolescente , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/terapia , Comorbidade , Obesidade , Reino Unido/epidemiologiaRESUMO
PURPOSE: The objective of this study is to determine primary survival endpoints in women with recurrent and metastatic endometrial carcinoma (RMEC) treated with progestins. METHODS: A retrospective chart review was conducted at The Ottawa Hospital using electronic medical records. Inclusion criteria were a diagnosis of RMEC between 2000 and 2019, endometrioid histology, and ≥one line of progestin treatment. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: Of 2342 cases reviewed, 74 met inclusion criteria. Sixty-six (88.0%) patients received megestrol acetate and 9 (12.0%) received a progestin alternative. The distribution of tumors by grade was: 1: 25 (33.3%), 2: 30 (40.0%), and 3: 20 (26.7%). The PFS and OS for the entire study sample was 14.3 months (95% CI 6.2-17.9) and 23.3 months (14.8-36.8), respectively. The PFS for patients with Grade 1-2 RMEC was 15.7 months (8.0, 19.5), compared to 5.0 months (3.0, 23.0) with Grade 3 disease. The OS for patients with Grade 1-2 versus Grade 3, was 25.9 months (15.3, 40.3) versus 12.5 months (5.7, 35.9), respectively. Thirty-four (45.9%) and 40 (54.1%) patients were treated with 0 and ≥1 line of chemotherapy. The PFS for chemotherapy-naïve patients was 17.9 months (14.3, 27.0), versus 6.2 months (3.9, 14.8) following ≥1 line of treatment. The OS was 29.1 months (17.9, 61.1) for chemotherapy-naïve patients versus 23.0 months (10.5, 37.6) for patients previously exposed. CONCLUSIONS: This real-world data on RMEC suggests there is a role for progestins in select subgroups of women. The PFS for chemotherapy-naïve patients was 17.9 months (14.3, 27.0), versus 6.2 months (3.9, 14.8) following ≥1 line of treatment. The OS was 29.1 months (17.9, 61.1) for chemotherapy-OS was 29.1 months (17.9, 61.1) for chemotherapy-naïve patients versus 23.0 months (10.5, 37.6) for patients previously exposed.
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Neoplasias do Endométrio , Progestinas , Humanos , Feminino , Progestinas/uso terapêutico , Estudos Retrospectivos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias do Endométrio/patologia , Acetato de Megestrol/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
We report the case of a patient who failed to meet tracheal extubation criteria due to low tidal volumes from suspected buffalo chest, which is a single pleural space physiology. This presentation followed the resection of a large pleural mass in a 59-year-old woman with a history of exercise-induced asthma, hypertension and tumour-related chronic respiratory failure. Creation of a pleuro-pleural communication during the resection of this large, unilateral pleural mass led to bilateral pneumothoraces and contributed to patients inability to generate negative inspiratory force leading to failure to meet extubation criteria. Buffalo chest may be more prevalent than suspected and should be a differential diagnosis for low tidal volumes with spontaneous ventilation following thoracic surgery. It can be differentiated from other causes of decreased tidal volume using clinical examination, ultrasound and radiography. Bilateral chest tube placement can be considered to expedite pneumothorax resolution and tracheal extubation.
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Respiratory outcomes in Mucopolysaccharidosis Type I (MPS I), have mainly focused on upper airway obstruction, with the evolution of the restrictive lung disease being poorly documented. We report the long-term pulmonary function outcomes and examine the potential factors affecting these in 2 cohorts of MPS I patients, those who have undergone Haematopoietic Stem Cell Transplantation (HSCT) and those treated with Enzyme Replacement Therapy (ERT). The results were stratified using the American Thoracic Society (ATS) guidelines. 66 patients, capable of adequately performing testing, were identified by a retrospective case note review, 46 transplanted (45 Hurler, 1 Non-Hurler) and 20 having ERT (17 Non-Hurler and 3 Hurler diagnosed too late for HSCT). 5 patients died; 4 in the ERT group including the 3 Hurler patients. Overall 14% of patients required respiratory support (non-invasive ventilation (NIV) or supplemental oxygen)) at the end of follow up. Median length of follow-up was 12.2 (range = 4.9-32) years post HSCT and 14.34 (range = 3.89-20.4) years on ERT. All patients had restrictive lung disease. Cobb angle and male sex were significantly associated with more severe outcomes in the HSCT cohort, with 49% having severe to very severe disease. In the 17 Non-Hurler ERT treated patients there was no variable predictive of severity of disease with 59% having severe to very severe disease. During the course of follow up 67% of the HSCT cohort had no change or improved pulmonary function as did 52% of the ERT patients. However, direct comparison between therapeutic modalities was not possible. This initial evidence would suggest that a degree of restrictive lung disease is present in all treated paediatrically diagnosed MPS I and is still a significant cause of morbidity, though further stratification incorporating diffusing capacity for carbon monoxide (DLCO) is needed.
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Obstrução das Vias Respiratórias/terapia , Pneumopatias Obstrutivas/terapia , Mucopolissacaridose I/terapia , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Obstrução das Vias Respiratórias/complicações , Obstrução das Vias Respiratórias/epidemiologia , Obstrução das Vias Respiratórias/patologia , Monóxido de Carbono/metabolismo , Criança , Pré-Escolar , Terapia de Reposição de Enzimas , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Pneumopatias Obstrutivas/complicações , Pneumopatias Obstrutivas/epidemiologia , Pneumopatias Obstrutivas/patologia , Masculino , Pessoa de Meia-Idade , Mucopolissacaridose I/complicações , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose I/patologia , Adulto JovemRESUMO
Tumour necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising anti-tumour agent that induces apoptosis of malignant cells through activation of death receptors. Death receptor agonistic antibodies are in clinical trials as TRAIL-mimetics, however, along with TRAIL monotherapy, there is limited efficacy due to the rapid emergence of TRAIL resistance, or due to existing TRAIL-insensitive disease. TRAIL-sensitisers, which enhance TRAIL activity or overcome TRAIL resistance, may facilitate death receptor agonists as viable anti-tumour strategies. In this study we demonstrate that the nuclear export inhibitor Leptomycin B, is a potent in vitro TRAIL-sensitiser in osteosarcoma cell lines. Leptomycin B works synergistically with both TRAIL and death receptor 5 agonistic antibodies to induce apoptosis in TRAIL sensitive cell lines. Further, Leptomycin B sensitises TRAIL-insensitive cell lines to TRAIL and death receptor agonistic antibody mediated apoptosis. We also confirmed that aldehyde dehydrogenase (ALDH) positive cells are not resistant to the apoptotic effects of TRAIL and Leptomycin B, an important observation since ALDH positive cells can have enhanced tumorigenicity and are implicated in disease recurrence and metastasis. The nuclear export pathway in combination with death receptor agonists, is a potential therapeutic strategy in osteosarcoma and warrants further research on clinically relevant selective inhibitors of nuclear export.
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Antibióticos Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Ácidos Graxos Insaturados/farmacologia , Humanos , Osteossarcoma/metabolismoRESUMO
PURPOSE: This study examines the long-term outcomes of paediatric Morquio (MPS IVA) patients undergoing cervical spine surgery and evaluates the factors that impacting this. METHODS: A retrospective review was performed on all MPS IVA patients undergoing cervical spine surgery, since the introduction of standardised neuroradiological screening. The impact of preoperative neurological status, growth, genotype and radiological status on outcome is assessed, whilst long-term surgical, radiological and neurological outcomes are documented. RESULTS: Twenty-six of the eighty-two MPS IVA patients (31%) reviewed underwent cervical spine surgery at a median age of 6.1 years (range, 1.45 to 15.24). Preoperatively, cord signal change was seen in 11 patients with 5 being myelopathic; however, 6 clinically manifesting patients had no overt cord signal change. Postoperatively, none of the 14 preoperatively clinically asymptomatic patients followed long term progressed neurologically during a median follow-up of 77.5 months (range = 18-161). Of the ten preoperatively clinically symptomatic patients who were followed up for the same duration, seven continued to deteriorate, two initially improved and one remained stable. Radiological follow-up performed for a median duration of 7 years (range = 0.5-16) has shown a degree of stenosis at the level immediately caudal to the termination of the graft in 76% of patients, though only one has become clinically symptomatic and required revision. CONCLUSIONS: Once clinically elicitable neurological signs become evident in patients with MPS IVA, they tend to progress despite surgical intervention. Referring clinicians should also not be falsely reassured by the lack of T2 spinal cord signal change but should consider surgical intervention in the face of new clinical symptomology or radiological signs of progressive canal stenosis or instability.
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Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Mucopolissacaridose IV/diagnóstico por imagem , Mucopolissacaridose IV/cirurgia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
STUDY QUESTION: Is human endometrial leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) gene expression limited to the postulated epithelial stem cell niche, stratum basalis glands, and is it hormonally regulated? SUMMARY ANSWER: LGR5 expressing cells are not limited to the postulated stem cell niche but LGR5 expression is hormonally regulated. WHAT IS KNOWN ALREADY: The human endometrium is a highly regenerative tissue; however, endometrial epithelial stem cell markers are yet to be confirmed. LGR5 is a marker of stem cells in various epithelia. STUDY DESIGN, SIZE, DURATION: The study was conducted at a University Research Institute. Endometrial samples from 50 healthy women undergoing benign gynaecological surgery with no endometrial pathology at the Liverpool Women's hospital were included and analysed in the following six sub-categories; proliferative, secretory phases of menstrual cycle, postmenopausal, those using oral and local progestagens and samples for in vitro explant culture. PARTICIPANTS/MATERIALS, SETTING, METHODS: In this study, we used the gold standard method, in situ hybridisation (ISH) along with qPCR and a systems biology approach to study the location of LGR5 gene expression in full thickness human endometrium and Fallopian tubes. The progesterone regulation of endometrial LGR5 was examined in vivo and in short-term cultured endometrial tissue explants in vitro. LGR5 expression was correlated with epithelial proliferation (Ki67), and expression of previously reported epithelia progenitor markers (SOX9 and SSEA-1) immunohistochemistry (IHC). MAIN RESULTS AND THE ROLE OF CHANCE: LGR5 gene expression was significantly higher in the endometrial luminal epithelium than in all other epithelial compartments in the healthy human endometrium, including the endometrial stratum basalis (P < 0.05). The strongest SSEA-1 and SOX9 staining was observed in the stratum basalis glands, but the general trend of SOX9 and SSEA-1 expression followed the same cyclical pattern of expression as LGR5. Stratum functionalis epithelial Ki67-LI and LGR5 expression levels correlated significantly (r = 0.74, P = 0.01), however, they did not correlate in luminal and stratum basalis epithelium (r = 0.5 and 0.13, respectively). Endometrial LGR5 demonstrates a dynamic spatiotemporal expression pattern, suggesting hormonal regulation. Oral and local progestogens significantly reduced endometrial LGR5 mRNA levels compared with women not on hormonal treatment (P < 0.01). Our data were in agreement with in silico analysis of published endometrial microarrays. LARGE SCALE DATA: We did not generate our own large scale data but interrogated publically available large scale data sets. LIMITATIONS, REASONS FOR CAUTION: In the absence of reliable antibodies for human LGR5 protein and validated lineage markers for the various epithelial populations that potentially exist within the endometrium, our study does not formally characterise or examine the functional ability of the resident LGR5+ cells as multipotent. WIDER IMPLICATIONS OF THE FINDINGS: These data will facilitate future lineage tracing studies in the human endometrial epithelium; to identify the location of stem cells and further complement the in vitro functional studies, to confirm if the LGR5 expressing epithelial cells indeed represent the epithelial stem cell population. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by funding from the Wellbeing of Women project grant (RTF510) and Cancer Research UK (A14895). None of the authors have any conflicts of interest to disclose.
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Endométrio/metabolismo , Células Epiteliais/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Endométrio/citologia , Células Epiteliais/citologia , Tubas Uterinas/metabolismo , Feminino , Expressão Gênica , Humanos , Menstruação/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Intragastric Balloons are a temporary, reversible and safer option compared to bariatric surgery to promote significant weight loss, leading to improved metabolic outcomes. However, due to subsequent weight regain, alternative procedures are now preferred in adults. In adolescents, more amenable to lifestyle change, balloons may be an alternative to less reversible procedures. Our aim was to assess the tolerability and efficacy of the intragastric balloon in severely obese adolescents and the impact of associated weight loss on biomedical outcomes (glucose metabolism, blood pressure, lipid profiles) and bone density. A 2-year cohort study of 12 adolescents (BMI >3.5 s.d., Tanner stage >4) following 6 months intragastric balloon placement was carried out. Subjects underwent anthropometry, oral glucose tolerance test, and DEXA scans at 0, 6 and 24 months. The results showed clinically relevant improvements in blood pressure, insulin: glucose metabolism, liver function and sleep apnoea at 6 months. Changes were not sustained at 2 years though some parameters (Diastolic BP, HBA1c, insulin AUC) demonstrated longer-term improvement despite weight regain. Despite weight loss, bone mass accrual showed age appropriate increases. In conclusion, the intragastric balloon was safe, well tolerated and effective in supporting short-term weight loss and clinically relevant improvement in obesity-related complications, which resolved in some individuals. Benefits were not sustained in the majority at 2 years.
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Balão Gástrico , Obesidade Mórbida , Adolescente , Pressão Sanguínea , Índice de Massa Corporal , Estudos de Viabilidade , Feminino , Humanos , Hipertensão/complicações , Masculino , Obesidade Mórbida/complicações , Obesidade Mórbida/fisiopatologia , Obesidade Mórbida/cirurgia , Resultado do Tratamento , Redução de PesoRESUMO
Patients may exhibit risky bone health behaviors. In a large pragmatic clinical trial, we tested whether a tailored patient activation DXA result letter accompanied by a bone health brochure led to smoking and excessive drinking cessations. The intervention did not, however, alter these risky bone health behaviors. INTRODUCTION: Besides dual-energy x-ray absorptiometry (DXA) screening and pharmacotherapy when indicated, beneficial bone health behaviors including proper calcium and vitamin D intake and weight-bearing and muscle-strengthening exercise should be encouraged. Similarly, risky bone health behaviors like smoking and excessive drinking should be discouraged. We examined whether a direct-to-patient activation intervention led to smoking and excessive drinking cessations. METHODS: The Patient Activation after DXA Result Notification (PAADRN) pragmatic clinical trial enrolled 7749 patients between February 2012 and August 2014. Interviews occurred at baseline and 12 and 52 weeks later. Intervention subjects were mailed an individually tailored DXA results letter accompanied by a bone health educational brochure 4 weeks post-DXA. Usual care subjects were not sent these materials. Smoking and excessive drinking were assessed by self-report at each interview. Intention-to-treat linear probability models were used. RESULTS: Mean age was 66.6 years, 83.8% were women, and 75.3% were Non-Hispanic-Whites. Smoking was reported at baseline by 7.6% of the intervention group vs. 7.7% of the usual care group (p = 0.873). Excessive drinking was reported at baseline by 6.5% of the intervention group vs. 6.5% of the usual care group (p = 0.968). Intention-to-treat analyses indicated no significant differences between the intervention vs. usual care groups at either 12 or 52 weeks post-DXA (all p values ≥ 0.346). CONCLUSION: An individually tailored DXA result letter accompanied by an educational brochure did not lead to smoking or excessive drinking cessations in patients who received DXA. TRIAL REGISTRATION: clinicaltrials.gov identifier NCT01507662.
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Consumo de Bebidas Alcoólicas/prevenção & controle , Comportamentos Relacionados com a Saúde , Conhecimentos, Atitudes e Prática em Saúde , Osteoporose/diagnóstico , Abandono do Hábito de Fumar/métodos , Absorciometria de Fóton , Idoso , Alabama , Correspondência como Assunto , Feminino , Georgia , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/psicologia , Fraturas por Osteoporose/prevenção & controle , Folhetos , Educação de Pacientes como Assunto/métodos , Abandono do Hábito de Fumar/estatística & dados numéricos , TemperançaRESUMO
BACKGROUND: Severe adolescent obesity (body mass index (BMI) >99.6th centile) is a significant public health challenge. Current non-invasive treatments, including community-based lifestyle interventions, are often of limited effectiveness in this population, with NICE guidelines suggesting the use of bariatric surgery as the last line of treatment. Health professionals are understandably reluctant to commission bariatric surgery and as an alternative, the use of an intra-gastric balloon as an adjunct to a lifestyle programme might offer a reversible, potentially safer and less invasive option. OBJECTIVES: Explore the use of an intra-gastric balloon as an adjunct to a lifestyle support programme, to promote weight loss in severely obese adolescents. Outcomes included weight loss, waist and hip measurements, psychosocial outcomes including health-related quality of life (HRQoL) and physical self perceptions, physical activity and cardiorespiratory fitness. METHOD: Non-randomised pilot study. RESULTS: Twelve severely obese adolescents (5 males, 7 females; mean age 15 years; BMI >3.5 s.d.; puberty stage 4 or more) and their families were recruited. Mean weight loss at 12 months (n=9) was 3.05 kg±14.69; d=0.002, P=0.550, and a BMI Z-score (n=12) change of 0.2 s.d.; d=0.7, P=0.002 was observed at 6 months with a large effect, but was not sustained at 12 months (mean change 0.1 s.d.; d=0.3, P=0.146). At 24 months (n=10), there was a weight gain from baseline of +9.9 kg±1.21 (d=0.4; P=0.433). Adolescent and parent HRQoL scores exceeded the minimal clinical important difference between baseline and 12 months for all domains but showed some decline at 24 months. CONCLUSION: An intra-gastric balloon as an adjunct to a lifestyle support programme represents a safe and well-tolerated treatment approach in severely obese adolescents, with short-term effects on weight change. Improvements in psychosocial health, physical activity and cardiorespiratory fitness were maintained at 12 months, with varying results at 24 months.
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Aptidão Cardiorrespiratória/fisiologia , Exercício Físico/fisiologia , Balão Gástrico , Obesidade Mórbida/terapia , Obesidade Infantil/terapia , Comportamento de Redução do Risco , Redução de Peso/fisiologia , Adolescente , Aptidão Cardiorrespiratória/psicologia , Inglaterra , Exercício Físico/psicologia , Feminino , Seguimentos , Humanos , Masculino , Obesidade Mórbida/epidemiologia , Obesidade Mórbida/fisiopatologia , Obesidade Mórbida/psicologia , Obesidade Infantil/epidemiologia , Obesidade Infantil/fisiopatologia , Obesidade Infantil/psicologia , Projetos Piloto , Qualidade de Vida , Fatores de Tempo , Resultado do TratamentoRESUMO
Palmoplantar pustulosis (PPP) is a chronic pustular dermatitis of the palms and soles, which is frequently associated with significant pruritus and pain, often limiting daily activities. We present the case of a 36-year-old man with severe PPP who had treatment failure with multiple medical therapies but showed marked improvement with high-dose rate brachytherapy. Brachytherapy has the advantage of providing a conformal dose distribution over complex curved surfaces, such as the foot and ankle. Our observations suggest that brachytherapy may be a well-tolerated treatment option for patients with severe, refractory PPP.
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Braquiterapia/métodos , Dermatoses do Pé/radioterapia , Dermatoses da Mão/radioterapia , Psoríase/radioterapia , Adulto , Humanos , Masculino , Resultado do TratamentoRESUMO
BACKGROUND: Dupuytren contracture (DC) is a fibrocontractile disease of the palms, affecting approximately 4% of the population, while psoriasis is an immune-mediated disease, affecting 2% of the population. Through clinical observation in our psoriasis clinic, we found an apparent increased prevalence of DC in patients with psoriasis compared with the general population. This has not previously been statistically verified in a clinical study. AIM: To evaluate the prevalence of DC in the full range of clinical psoriasis phenotypes. METHODS: In total, 98 patients with psoriasis attending our psoriasis clinic were examined for DC, based on predetermined criteria. In addition, 84 patients with DC, obtained from a specialist hand clinic, were assessed using a validated psoriasis questionnaire. We utilized Bayes theorem and bootstrap simulation to calculate the conditional prevalence of DC, then we used the results to compare the prevalence of DC between patients with psoriasis and a nonpsoriasis population. RESULTS: The percentage of patients with DC was 19.6% in the psoriasis population and 3.6% in the nonpsoriasis population. Development of DC showed a phenotypic predilection, with 39.1% of patients with predominantly palmoplantar involvement and 38.9% of patients with intertriginous psoriasis developing DC compared with 12.7% of patients with psoriasis who did not have these two phenotypical presentations. CONCLUSIONS: Our data show a positive correlation between psoriasis and DC. Patients with the palmoplantar phenotype of psoriasis were more likely to develop DC. By understanding this relationship, dermatologists may diagnose DC early in its onset in patients with psoriasis, prompting referral to hand surgeons when appropriate.
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Contratura de Dupuytren/epidemiologia , Psoríase/epidemiologia , Adulto , Idoso , Teorema de Bayes , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Distribuição por Sexo , Estados Unidos/epidemiologiaRESUMO
Rabies in dogs can be controlled through mass vaccination. Oral vaccination of domestic dogs would be useful in the developing world, where greater vaccination coverage is needed especially in inaccessible areas or places with large numbers of free-roaming dogs. From this perspective, recent research has focused on development of new recombinant vaccines that can be administered orally in a bait to be used as adjunct for parenteral vaccination. One such candidate, a recombinant canine adenovirus type 2 vaccine expressing the rabies virus glycoprotein (CAV2-RG), is considered a promising option for dogs, given host specificity and safety. To assess the potential use of this vaccine in domestic dog populations, we investigated the prevalence of antibodies against canine adenovirus type 2 in South African dogs. Blood was collected from 241 dogs from the Gauteng and KwaZulu-Natal provinces. Sampled dogs had not previously been vaccinated against canine adenovirus type 1 (CAV1) or canine adenovirus type 2 (CAV2). Animals from both provinces had a high percentage of seropositivity (45% and 62%), suggesting that CAV2 circulates extensively among domestic dog populations in South Africa. Given this finding, we evaluated the effect of pre-existing CAV-specific antibodies on the efficacy of the CAV2-RG vaccine delivered via the oral route in dogs. Purpose-bred Beagle dogs, which received prior vaccination against canine parvovirus, canine distemper virus and CAV, were immunized by oral administration of CAV2-RG. After rabies virus (RABV) infection all animals, except one vaccinated dog, developed rabies. This study demonstrated that pre-existing antibodies against CAV, such as naturally occurs in South African dogs, inhibits the development of neutralizing antibodies against RABV when immunized with a CAV-based rabies recombinant vaccine.
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Adenovirus Caninos/imunologia , Anticorpos Antivirais/sangue , Doenças do Cão/prevenção & controle , Vacina Antirrábica/imunologia , Raiva/imunologia , Vacinas Sintéticas/imunologia , Adenovirus Caninos/genética , Administração Oral , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais/imunologia , Doenças do Cão/imunologia , Cães , Raiva/prevenção & controle , Raiva/veterinária , Vacina Antirrábica/administração & dosagem , Vacina Antirrábica/genética , Estudos Soroepidemiológicos , África do Sul , Resultado do Tratamento , Vacinas Sintéticas/administração & dosagemRESUMO
Anecdotal reports suggest that the currently approved dosing interval of agalsidase alfa (0.2 mg/kg/2 weeks) for Fabry disease treatment is too long. This randomised, double-blind, placebo-controlled, crossover study investigated three altered dosing intervals. 18 Fabry patients received three agalsidase alfa dosing schedules, each for four weeks (A: 0.2 mg/kg∗2 weeks, B: 0.1 mg/kg/week, C: 0.2 mg/kg/week). Health state, pain levels, sweat volume and latency and plasma and urinary globotriaosylceramide levels were recorded throughout the study. No significant differences were found among the schedules for the primary efficacy outcome of self-assessed health state, or for pain scores. A trend toward increased sweat volume on QSART testing, and reduced urine globotriaosylceramide concentration were seen with treatment schedule C. Agalsidase alfa was safe and well tolerated with all schedules. In conclusion, the primary analyses did not find weekly infusions of agalsidase alfa to be statistically better than the approved dosing schedule however the data indicates that further studies with more patients over a longer period are required to more accurately determine the optimum dose and schedule.
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Terapia de Reposição de Enzimas , Doença de Fabry/tratamento farmacológico , alfa-Galactosidase/uso terapêutico , Adulto , Idoso , Anticorpos/imunologia , Estudos Cross-Over , Doença de Fabry/diagnóstico , Feminino , Humanos , Isoenzimas/administração & dosagem , Isoenzimas/efeitos adversos , Isoenzimas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Resultado do Tratamento , alfa-Galactosidase/administração & dosagem , alfa-Galactosidase/efeitos adversos , alfa-Galactosidase/genética , alfa-Galactosidase/imunologia , alfa-Galactosidase/metabolismoRESUMO
BACKGROUND: Burkitt's lymphoma (BL) is an aggressive non-Hodgkin's lymphoma endemic to regions of Africa. Cases are thought to be typically found in low-lying, humid regions where malaria is rife. AIMS AND OBJECTIVES: To investigate the clinical characteristics of BL, its incidence and relationship with malarial incidence in Northwest (NW) Province, Cameroon. METHODS: Data on BL were collected from the three tertiary referral centres for BL treatment in NW Province, Cameroon. Data on malaria were collected from the Delegation of Public Health in Bamenda, NW Province. Data were collected between March and May 2010. RESULTS: 471 cases of BL were identified. The St Jude's stage of patients at presentation was as follows: stage I, 14.4% (43/299); stage II, 8.4% (25/299); stage III, 69.9% (209/299); stage IV, 7.4% (22/299). The incidences of BL per 100,000 children <15 years of age from 2005 to 2009 were as follows: 2005, 3.01 (29); 2006, 2.02 (20); 2007, 2.45 (25); 2008, 2.38 (25); 2009, 3.06 (33). The average incidence in NW Province was 2.58. In the Ndop plain, Ngo-Ketunjia, the incidences of BL were as follows: 2005, 10.3 (10); 2006, 3.00 (3); 2007, 1.95 (2); 2008, 2.84 (3); 2009, 4.60 (5). The average incidence was 4.54/100,000 children <15 years of age. Statistical analysis demonstrated a sinusoidal distribution of malaria cases throughout the year (P<0.00), with a peak incidence on 10 April. Conversely, no sinusoidal distribution of BL cases was demonstrated throughout the year (P = 0.09). CONCLUSION: No relationship was demonstrated between an acute malarial infection and BL. Significant clustering was found, with the low-lying Ndop plain of Ngo-Ketunjia having an incidence of BL nearly twice that elsewhere in the region. The study demonstrates that the incidence of BL in NW Province, Cameroon remains one of the highest documented in the world.
Assuntos
Linfoma de Burkitt/epidemiologia , Adolescente , Linfoma de Burkitt/patologia , Camarões/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Malária/complicações , Malária/epidemiologia , MasculinoRESUMO
Fifty-eight consecutive children with high-risk malignancies were treated with CY, and targeted topotecan followed by autologous hematopoietic cell transplantation (AHCT) in a phase I/II Institutional Review Board-approved study. Twelve participants enrolled in phase I; 5 received dose level 1 of topotecan 3 mg/m(2) per day, with subsequent doses targeted to total systemic exposure of 100±20 ng h/mL and CY 750 mg/m(2) per day. Seven participants received dose level 2. CY dose escalation to 1 g/m(2) per day was considered excessively toxic; one died from irreversible veno-occlusive disease and two experienced reversible hepatotoxicity. These adverse events halted further dose escalation. A total of 46 participants were enrolled in phase II; results are on the 51 participants who received therapy at dose level 1, the maximum tolerated dose. Diagnoses included neuroblastoma (26), sarcoma (9), lymphoma (8), brain tumors (5), Wilms (2) and retinoblastoma (1). Twenty participants (39.3%) were in î¶CR1 at enrollment; median age was 5.1 years. Most common non-hematological grade III-IV toxicity was gastrointestinal (n=37). Neutrophil and platelet engraftment occurred at a median of 15 and 24 days, respectively. Twenty-six (51%) participants remain alive at a median of 6.4 years after AHCT. CY 3.75 g/m(2), and targeted topotecan followed by AHCT are feasible and produce acceptable toxicity in children with high-risk malignancies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Neoplasias/tratamento farmacológico , Neoplasias/cirurgia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Humanos , Fatores de Risco , Taxa de Sobrevida , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/efeitos adversos , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Transplante AutólogoRESUMO
CONTEXT: Increasing numbers of very low birth weight (VLBW) infants are surviving into adulthood because of improvements in neonatal intensive care. Adverse events in early life can have long-term effects through reprogramming of metabolic systems. OBJECTIVE: To determine whether young adult VLBW survivors have abnormalities of skeletal development or endocrine function. DESIGN: Cross-sectional, observational, case-control study. PARTICIPANTS: Thirty-seven VLBW subjects and 27 healthy controls at peak bone mass (mean age 23). MEASUREMENTS: Differences between cases and controls in body size, body composition, bone mass and bone geometry [assessed by dual-energy X-ray absorptiometry (DXA), hip structure analysis and peripheral quantitative computed tomography (pQCT)], bone turnover [urine N-terminal telopeptide of type I collagen (NTX), serum C-terminal telopeptide of type I collagen (CTX)], aminoterminal propeptide of type I procollagen (PINP) and bone alkaline phosphatase), hormones (sex steroids, IGF-1, PTH and 25-OH vitamin D) and insulin sensitivity (HOMA-IR and oral glucose tolerance testing). RESULTS: VLBW subjects had lower bone density at the lumbar spine (5.7%) and femoral neck (8.6%), which persisted after correction for bone size by the estimation of volumetric density (bone mineral apparent density). Urine NTX was higher in VLBW subjects than in controls, but there were no significant differences in other bone turnover markers. VLBW survivors had lower insulin sensitivity (mean INS-30 controls = 57.0, VLBW subjects = 94.3, P < 0.01), but there were no differences in whole body fat mass or truncal fat mass between VLBW subjects and controls. CONCLUSIONS: Young adult VLBW survivors have reduced bone density for their bone size and reduced insulin sensitivity, which may have significant implications for their risk of fracture and diabetes in later life.
Assuntos
Densidade Óssea/fisiologia , Recém-Nascido de muito Baixo Peso/sangue , Recém-Nascido de muito Baixo Peso/metabolismo , Resistência à Insulina/fisiologia , Absorciometria de Fóton , Adulto , Estudos de Casos e Controles , Colágeno Tipo I/sangue , Estudos Transversais , Feminino , Teste de Tolerância a Glucose , Articulação do Quadril/diagnóstico por imagem , Articulação do Quadril/metabolismo , Humanos , Recém-Nascido , Masculino , Peptídeos/sangue , Adulto JovemRESUMO
BACKGROUND: Lifestyle assessment and intervention tools are useful in promoting pediatric weight management. The present study aimed to establish convergent validity and reliability for a quick simple measure of food intake and physical activity/sedentary behaviour. The HABITS questionnaire can be used to identify and monitor behavioural intervention targets. METHODS: Thirty-five youths (ages 7-16 years) were recruited from the waiting area of the Jacobi Medical Center Child and Teen Health Services. To establish convergent validity for the HABITS questionnaire, study participants completed the HABITS questionnaire, a 24-h recall and a modified version of the Modifiable Activity Questionnaire for Adolescents (MAQ). Participants completed a second HABITS questionnaire within 1 month to assess test-retest reliability. Internal consistency for dietary and physical activity/sedentary behaviour subscales was assessed using Cronbach's alpha, and test-retest reliability was assessed using Cohen's Kappa coefficient. Spearman's rank correlation coefficients were calculated for individual items using the 24-h recall and the MAQ as reference standards. RESULTS: The HABITS questionnaire subscales showed moderate internal consistency (Cronbach's alpha of 0.61 and 0.59 for the dietary and physical activity/sedentary behaviour subscale, respectively). The test-retest reliability was 0.94 for the dietary subscale and 0.87 for the physical activity/sedentary behaviour subscale. Several items on the HABITS questionnaire were moderately correlated with information reported in the MAQ and the 24-h recall (r = 0.38-0.59, P < 0.05). CONCLUSIONS: The HABITS questionnaire can reliably be used in a paediatric setting to quickly assess key dietary and physical activity/sedentary behaviours and to promote behaviour change for weight management.
Assuntos
Terapia Comportamental/normas , Comportamento Infantil/fisiologia , Estilo de Vida , Avaliação Nutricional , Inquéritos e Questionários/normas , Adolescente , Comportamento do Adolescente/fisiologia , Terapia Comportamental/métodos , Peso Corporal/fisiologia , Criança , Feminino , Promoção da Saúde , Humanos , Masculino , Atividade Motora/fisiologia , Obesidade/prevenção & controle , Obesidade/terapia , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Molecular mechanisms predisposing people to insulin resistance are starting to emerge. Altered insulin signaling for hepatic gluconeogenesis and muscle glucose uptake is thought to play a central role. Development under suboptimal conditions is also known to increase the risk of insulin resistance in adulthood. However, the partial contributions of reduced oxygen vs. nutrient delivery to the fetus, two common adverse conditions in utero, to developmental programming of insulin resistance remain unknown. The aim of this study was to determine the effects of developmental hypoxia or undernutrition on the expression of insulin-signaling proteins in liver and skeletal muscle in adult rat offspring. We show that the expression of hepatic phospho-Akt and muscle Akt2 were significantly reduced in offspring of hypoxic, relative to offspring from normoxic or undernourished, pregnancies. Hepatic Akt-1, Akt-2, and PKCζ protein expression was reduced in offspring from both hypoxic and undernourished pregnancies. Muscle GLUT4 expression was decreased in undernourished, and further decreased in hypoxic, offspring. These findings link prenatal hypoxia to down-regulation of components of hepatic and muscle Akt expression in adult offspring. Akt may represent a pharmaceutical target for clinical intervention against the developmental programming of metabolic disease resulting from prenatal hypoxia.
Assuntos
Biomarcadores/metabolismo , Hipóxia/fisiopatologia , Resistência à Insulina/fisiologia , Efeitos Tardios da Exposição Pré-Natal , Animais , Western Blotting , Peso Corporal , Feminino , Transportador de Glucose Tipo 4/metabolismo , Insulina/sangue , Lipídeos/sangue , Tamanho da Ninhada de Vivíparos , Fígado/metabolismo , Masculino , Desnutrição/fisiopatologia , Músculo Esquelético/metabolismo , Gravidez , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Fatores de TempoRESUMO
There is growing evidence that lesions of the anterior thalamic nuclei cause long-lasting intrinsic changes to retrosplenial cortex, with the potential to alter its functional properties. The present study had two goals. The first was to identify the pattern of changes in eight markers, as measured by in-situ hydridisation, in the granular retrosplenial cortex (area Rgb) following anterior thalamic lesions. The second was to use retrograde trans-neuronal tracing methods to identify the potential repercussions of intrinsic changes within granular retrosplenial cortex. In Experiment 1, adult rats received unilateral lesions of the anterior thalamic nuclei and were perfused 4 weeks later. Of the eight markers, four (c-fos, zif268, 5ht2rc, kcnab2) showed a very similar pattern of change, with decreased levels in superficial retrosplenial cortex (lamina II) in the ipsilateral hemisphere but little or no change in deeper layers (lamina V). A fifth marker (cox6b) showed a shift in activity levels in the opposite direction to the previous four markers. Three other markers (cox6a1, CD74, ncs-1) did not appear to change activity levels after surgery. The predominant pattern of change, a decrease in superficial cortical activity, points to potential alterations in plasticity and metabolism. In Experiment 2, wheat germ agglutin (WGA) was injected into the anterior thalamic nuclei in rats given different survival times, sometimes in combination with the retrograde, fluorescent tracer, Fast Blue. Dense aggregations of retrogradely labeled cells were always found in lamina VI of granular retrosplenial cortex, but additional labeled cells in lamina II were only found: (1) in WGA cases, that is never after Fast Blue injections, and (2) after longer WGA survival times (3 days). These layer II Rgb cells are likely to have been trans-neuronally labeled, revealing a pathway from lamina II of Rgb to those deeper retrosplenial cells that project directly to the anterior thalamic nuclei.