The study was focused on leukoencephalopathies of unknown cause in order to define a novel, homogeneous phenotype suggestive of a common genetic defect, based on clinical and MRI findings, and to ...identify the causal genetic defect shared by patients with this phenotype.
Independent next-generation exome-sequencing studies were performed in 2 unrelated patients with a leukoencephalopathy. MRI findings in these patients were compared with available MRIs in a database of unclassified leukoencephalopathies; 11 patients with similar MRI abnormalities were selected. Clinical and MRI findings were investigated.
Next-generation sequencing revealed compound heterozygous mutations in AARS2 encoding mitochondrial alanyl-tRNA synthetase in both patients. Functional studies in yeast confirmed the pathogenicity of the mutations in one patient. Sanger sequencing revealed AARS2 mutations in 4 of the 11 selected patients. The 6 patients with AARS2 mutations had childhood- to adulthood-onset signs of neurologic deterioration consisting of ataxia, spasticity, and cognitive decline with features of frontal lobe dysfunction. MRIs showed a leukoencephalopathy with striking involvement of left-right connections, descending tracts, and cerebellar atrophy. All female patients had ovarian failure. None of the patients had signs of a cardiomyopathy.
Mutations in AARS2 have been found in a severe form of infantile cardiomyopathy in 2 families. We present 6 patients with a new phenotype caused by AARS2 mutations, characterized by leukoencephalopathy and, in female patients, ovarian failure, indicating that the phenotypic spectrum associated with AARS2 variants is much wider than previously reported.
Innovative research relating oceans and human health is advancing our understanding of disease-causing organisms in coastal ecosystems. Novel techniques are elucidating the loading, transport and ...fate of pathogens in coastal ecosystems, and identifying sources of contamination. This research is facilitating improved risk assessments for seafood consumers and those who use the oceans for recreation. A number of challenges still remain and define future directions of research and public policy. Sample processing and molecular detection techniques need to be advanced to allow rapid and specific identification of microbes of public health concern from complex environmental samples. Water quality standards need to be updated to more accurately reflect health risks and to provide managers with improved tools for decision-making. Greater discrimination of virulent versus harmless microbes is needed to identify environmental reservoirs of pathogens and factors leading to human infections. Investigations must include examination of microbial community dynamics that may be important from a human health perspective. Further research is needed to evaluate the ecology of non-enteric water-transmitted diseases. Sentinels should also be established and monitored, providing early warning of dangers to ecosystem health. Taken together, this effort will provide more reliable information about public health risks associated with beaches and seafood consumption, and how human activities can affect their exposure to disease-causing organisms from the oceans.
Highlights • There was an inverse association between diabetes and head and neck cancer. • The inverse association may be explained by metformin, since in separated analysis by use of metformin in ...diabetic patients there was protection for head and neck cancer only among metformin users.
Summary The study estimated the cost-effectiveness of risedronate compared to no treatment in UK women using the FRAX algorithm for fracture risk assessment. A Markov cohort model was used to ...estimate the cost-effectiveness. Risedronate was found cost-effective from the age of 65 years, assuming a willingness to pay for a QALY of £30,000. Introduction The aim of this study was to assess the cost-effectiveness of risedronate for the prevention and treatment in a UK setting using the FRAX® algorithm for fracture risk assessment. A further aim was to establish intervention thresholds with risedronate treatment. Methods The cost-effectiveness of risedronate was compared to no treatment in post-menopausal women with clinical risk factors for fracture using a Markov cohort model populated with data relevant for the UK. The model incorporated the features of FRAX® (the WHO risk assessment tool). The analysis had a health care perspective and quality adjusted life years was used as the main outcome measure. Results Treatment was cost-effective from the age of 65 years, assuming a willingness to pay for a QALY of £30,000. Treatment was also cost-effective at all ages in women who had previously sustained a fragility fracture or in women with a parental history of hip fracture with a bone mineral density set at the threshold of osteoporosis. At the £30,000 threshold value for a QALY, risedronate was on average found to cost-effective below the 10-year probability of a major osteoporotic fractures of 13.0%. Conclusions Risedronate is a cost-effective agent for the treatment of established osteoporosis (osteoporosis and a prior fragility fracture) in women from the age of 50 years and older and above 65 years in women with osteoporosis alone. The results support the treatment recommendations in recent UK guidelines for osteoporosis.
Summary Assessment and intervention thresholds are developed and proposed in men aged over 50 years and postmenopausal women for the UK based on fracture probability from the WHO fracture risk ...assessment tool (FRAX®). Introduction The FRAX® tool has recently become available to compute the 10-year probability of fractures in men and women from clinical risk factors (CRFs) with or without the measurement of femoral neck bone mineral density (BMD). The aim of this study was to develop a case-finding strategy for men and women from the UK at high risk of osteoporotic fracture by delineating the fracture probabilities at which BMD testing or intervention should be recommended. Methods Fracture probabilities were computed using the FRAX® tool calibrated to the epidemiology of fracture and death in the UK. The relationship between cost effectiveness and fracture probability used the source data from a prior publication that examined the cost effectiveness of generic alendronate in the UK. An intervention threshold was set by age in men and women, based on the fracture probability equivalent to that of women with a history of a prior osteoporosis related fracture. In addition, assessment thresholds for the use of BMD testing were explored. Assessment thresholds for the measurement of BMD followed current practice guidelines where individuals were considered to be eligible for assessment in the presence of one or more CRF. An upper assessment threshold (i.e. a fracture probability above which patients could be treated without recourse to BMD) was based on optimisation of the positive predictive value of the assessment tool. The consequences of assessment and intervention thresholds on the requirement for BMD test and interventions were assessed using the distribution of clinical risk factors and femoral neck BMD for women in the source cohorts used for the development of the FRAX® models Results Treatment was cost effective at all ages when the 10-year probability of a major fracture exceeded 7%. The intervention threshold at the age of 50 years corresponded to a 10-year probability of a major osteoporotic fracture of 7.5%. This rose progressively with age to 30% at the age of 80 years, so that intervention was cost effective at all ages. Assessment thresholds for testing with BMD (6-9% at the age of 50 years) also rose with age (18-36% at the age of 80 years). The use of these thresholds in a case-finding strategy would identify 6-20% of women as eligible for BMD testing and 23-46% as eligible for treatment, depending on age. The same threshold can be used in men. Conclusion The study provides a method of developing management algorithms for osteoporosis from the estimation of fracture probabilities, rather than those based on BMD alone or BMD with single or multiple CRFs.
Freeze-drying of protein formulations is frequently used to maintain protein activity during storage. The freeze-drying process usually requires long primary drying times because the highest ...acceptable drying temperature to obtain acceptable products is dependent on the glass transition temperature of the maximally freeze-concentrated solution (T
g
′). On the other hand, retaining protein activity during storage is related to the glass transition temperature (T
g
) of the final freeze-dried product. In this study, dextrans with different molecular weight (1 and 40 kDa) and mixtures thereof at the ratio 3:1, 1:1, and 1:3 (w/w) were used as cryo-/lyoprotectant and their impact on the stability of the model protein lactate dehydrogenase (LDH) was investigated at elevated temperatures (40 °C and 60 °C). The dextran formulations were then compared to formulations containing sucrose as cryo-/lyoprotectant. Because of the higher T
g
′ values of the dextrans, the primary drying times could be reduced compared to freeze-drying with sucrose. Similarly, the higher T
g
and T
g
′ of dextrans relative to sucrose led to benefits during storage which was shown through improved protection of LDH activity.
Background: Chronic obstructive pulmonary disease (COPD) is a largely underdiagnosed disease including several phenotypes. In this report, the design of a study intending to evaluate the ...pathophysiological mechanism in COPD in relation to the specific phenotypes non-rapid and rapid decline in lung function is described together with the recruitment process of the study population derived from a population based study.
Method: The OLIN COPD study includes a population-based COPD cohort and referents without COPD identified in 2002-04 (n = 1986), and thereafter followed annually since 2005. Lung function decline was estimated from baseline in 2002-2004 to 2010 (first recruitment phase) or to 2012/2013 (second recruitment phase). Individuals who met the predefined criteria for the following four groups were identified; group A) COPD grade 2-3 with rapid decline in FEV
1
and group B) COPD grade 2-3 without rapid decline in FEV
1
(≥60 and ≤30 ml/year, respectively), group C) ever-smokers, and group D) non-smokers with normal lung function. Groups A-C included ever-smokers with >10 pack years. The intention was to recruit 15 subjects in each of the groups A-D.
Results: From the database groups A-D were identified; group A n = 37, group B n = 29, group C n = 41, and group D n = 55. Fifteen subjects were recruited from groups C and D, while this goal was not reached in the groups A (n = 12) and B (n = 10). The most common reasons for excluding individuals identified as A or B were comorbidities contraindicating bronchoscopy, or inflammatory diseases/immune suppressive medication expected to affect the outcome.
Conclusion: The study is expected to generate important results regarding pathophysiological mechanisms associated with rate of decline in lung function among subjects with COPD and the in-detail described recruitment process, including reasons for non-participation, is a strength when interpreting the results in forthcoming studies.
OBJECTIVE To describe the radiographic outcome of root canal treatment (RCT) of canine teeth of cats. DESIGN Retrospective case series. ANIMALS 32 cats with 37 canine teeth with complicated crown ...fractures that underwent RCT. PROCEDURES Medical record databases of 5 referral veterinary hospitals were searched to identify cats that underwent RCT between 1998 and 2016. Only cats that had at least 1 follow-up examination during which radiographs were obtained of the treated canine tooth or teeth were included in the study. Dental radiographs obtained before and immediately after RCT and during all follow-up examinations were reviewed. Treatment was considered successful if the periodontal ligament space was within reference limits and preoperative external inflammatory root resorption (EIRR), if present, had stabilized. Treatment was considered to have no evidence of failure if preoperative EIRR had stabilized and preexisting periapical lucency was stable or decreased in size but had not resolved. Treatment was considered to have failed if periapical lucency or EIRR developed subsequent to RCT or preexisting periapical lucency increased in size or preoperative EIRR progressed following RCT. RESULTS Follow-up time after RCT ranged from 3 to 72 months. The RCT was successful for 18 (49%) of the 37 treated teeth, had no evidence of failure for 12 (32%), and failed for 7 (19%). Preexisting EIRR and patient age ≥ 5 years significantly increased the rate of RCT failure. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that RCT was a viable treatment option to salvage endodontically diseased canine teeth in cats.
Summary
The cost-effectiveness of strontium ranelate was compared to no treatment in UK women using the FRAX® algorithm for fracture risk assessment. At a willingness-to-pay of £30,000 per ...quality-adjusted life-year (QALY), strontium ranelate was generally cost-effective in women with prior fracture at the threshold of osteoporosis from an age of 65 years.
Introduction
The objectives of the study were to estimate the cost-effectiveness of strontium ranelate in the UK for the treatment of osteoporosis and to establish intervention thresholds for treatment using the FRAX® tool.
Methods
The cost-effectiveness of strontium ranelate was compared to no treatment in postmenopausal women with clinical risk factors for fracture using a lifetime simulation model based on Markov cohort methodology that incorporated the features of FRAX®.
Results
At a threshold of £30,000 per QALY, strontium ranelate was generally cost-effective in women from an age of 65 years with prior fracture at the threshold of osteoporosis (i.e., a T-score of −2.5 SD) and in women with a prior fracture (and no information on bone mineral density) from the age of 65 years. At a threshold of £20,000, strontium ranelate became cost-effective at a 10-year fracture probability of 25.7% and at 16.9% with a threshold of £30,000 for a QALY.
Conclusions
Strontium ranelate is a cost-effective agent for the treatment of established osteoporosis in women over the age of 65 years. Cost-effective scenarios were also found for the prevention and treatment of fractures associated with osteoporosis, in younger women with additional clinical risk factors.
It is well established that decreased brain blood flow, increased reactive oxygen species production (ROS), and pro-inflammatory mechanisms accelerate neurodegenerative disease progressions, ...including vascular cognitive impairment and dementia (VCID). Previous studies in our laboratory have shown that our novel glycosylated Angiotensin-(1-7) Mas receptor agonist PNA5 reverses cognitive deficits, decreases ROS production, and inhibits inflammatory cytokine production in our preclinical mouse model of VCID that is induced by chronic heart failure (VCID-HF). In the present study, the effects of VCID-HF and treatment with PNA5 on microglia activation, blood-brain-barrier (BBB) integrity, and neurovascular coupling were assessed in our mouse model of VCID-HF. Three-month-old male C57BL/6J mice were subjected to myocardial infarction (MI) to induce heart failure for four weeks and then treated with subcutaneous injections of extended-release PNA5. Microglia activation, BBB permeability, cerebral perfusion, and neurovascular coupling were assessed. Results show that in our VCID-HF model, there was an increase in microglial activation and recruitment within the CA1 and CA3 regions of the hippocampus, a disruption in BBB integrity, and a decrease in neurovascular coupling. Treatment with PNA5 reversed these neuropathological effects of VCID-HF, suggesting that PNA5 may be an effective disease-modifying therapy to treat and prevent VCID. This study identifies potential mechanisms by which heart failure may induce VCID and highlights the possible mechanisms by which treatment with our novel glycosylated Angiotensin-(1-7) Mas receptor agonist, PNA5, may protect cognitive function in our model of VCID.
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