608 research outputs found
Peroxisomal proliferator activated receptor-γ deficiency in a Canadian kindred with familial partial lipodystrophy type 3 (FPLD3)
BACKGROUND: Familial partial lipodystrophy (Dunnigan) type 3 (FPLD3, Mendelian Inheritance in Man [MIM] 604367) results from heterozygous mutations in PPARG encoding peroxisomal proliferator-activated receptor-γ. Both dominant-negative and haploinsufficiency mechanisms have been suggested for this condition. METHODS: We present a Canadian FPLD3 kindred with an affected mother who had loss of fat on arms and legs, but no increase in facial, neck, suprascapular or abdominal fat. She had profound insulin resistance, diabetes, severe hypertriglyceridemia and relapsing pancreatitis, while her pre-pubescent daughter had normal fat distribution but elevated plasma triglycerides and C-peptide and depressed high-density lipoprotein cholesterol. RESULTS: The mother and daughter were each heterozygous for PPARG nonsense mutation Y355X, whose protein product in vitro was transcriptionally inactive with no dominant-negative activity against the wild-type receptor. In addition the mutant protein appeared to be markedly unstable. CONCLUSION: Taken together with previous studies of human PPARG mutations, these findings suggest that PPAR-γ deficiency due either to haploinsufficiency or to substantial activity loss due to dominant negative interference of the normal allele product's function can each contribute to the FPLD3 phenotype
Quantitative and qualitative differences in subcutaneous adipose tissue stores across lipodystrophy types shown by magnetic resonance imaging
BACKGROUND: Lipodystrophies are characterized by redistributed subcutaneous fat stores. We previously quantified subcutaneous fat by magnetic resonance imaging (MRI) in the legs of two patients with familial partial lipodystrophy subtypes 2 and 3 (FPLD2 and FPLD3, respectively). We now extend the MRI analysis across the whole body of patients with different forms of lipodystrophy. METHODS: We studied five subcutaneous fat stores (supraclavicular, abdominal, gluteal, thigh and calf) and the abdominal visceral fat stores in 10, 2, 1, 1 and 2 female subjects with, respectively, FPLD2, FPLD3, HIV-related partial lipodystrophy (HIVPL), acquired partial lipodystrophy (APL), congenital generalized lipodystrophy (CGL) and in six normal control subjects. RESULTS: Compared with normal controls, FPLD2 subjects had significantly increased supraclavicular fat, with decreased abdominal, gluteal, thigh and calf subcutaneous fat. FPLD3 subjects had increased supraclavicular and abdominal subcutaneous fat, with less severe reductions in gluteal, thigh and calf fat compared to FPLD2 subjects. The repartitioning of fat in the HIVPL subject closely resembled that of FPLD3 subjects. APL and CGL subjects had reduced upper body, gluteal and thigh subcutaneous fat; the APL subject had increased, while CGL subjects had decreased subcutaneous calf fat. Visceral fat was markedly increased in FPLD2 and APL subjects. CONCLUSION: Semi-automated MRI-based adipose tissue quantification indicates differences between various lipodystrophy types in these studied clinical cases and is a potentially useful tool for extended quantitative phenomic analysis of genetic metabolic disorders. Further studies with a larger sample size are essential for confirming these preliminary findings
Influence of laser polishing on the material properties of aluminium L-PBF components
In this study, the influence of laser polishing on the microstructural and mechanical properties of additively manufactured aluminium AlSi10Mg Laser Powder Bed Fusion (L-PBF) parts is analysed. The investigation is carried out on a 5-axis laser cell equipped with 1D Scanner optics driven by a solid-state disc laser at a wavelength of 1030 nm. Laser polishing is performed with pulsed or continuous laser radiation on samples in the initial L-PBF state or after stress relief treatment in a furnace. The metallurgical investigation of the remelting zone with a depth of 101–237 µm revealed an unchanged and homogeneous chemical composition, with a coarsened α-phase and a changed grain structure. The hardness within the remelting zone is reduced to 102–104 HV 0.1 compared to 146 HV 0.1 at the L-PBF initial state. Below the remelting zone, within the heat affected zone, a reduced microhardness, which can reach a thickness up to 1.5 mm, occurs. Laser polishing results in a reduction in residual stresses and resulting distortions compared to the L-PBF initial state. Nevertheless, the re-solidification shrinkage of the polished surface layer introduces additional tensions, resulting in sample distortions well above ones remaining after a stress relieve heat treatment of the initial state. The mechanical properties, analysed on laser polished flat tensile specimens, revealed an increase in the ultimate elongation from 4.5% to 5.4–10.7% and a reduction in the tensile strength from 346 N/mm2 to 247–271 N/mm2 through laser polishing. Hence, the strength resulting from this is comparable to the initial L-PBF specimens after stress relieve heat treatment
Vinflunine in the treatment of relapsed metastatic urothelial cancer: A systematic review and meta-analysis of real-world series
Background. Vinflunine (VFL) is approved in Europe as second-line treatment of metastatic urothelial cancer after failure of platinum-containing therapy. We performed a systematic review and meta-analysis of real-world data (RWD) to assess utilization, efficacy and safety of VFL.
Methods. We performed a MEDLINE search for the period of 1/1/2000-31/8/2017. Full-length articles providing post-marketing RWD on VFL in patients failing previous chemotherapy were eligible. Interventional clinical trials were excluded.
Results: Ten studies with 797 patients were identified. According to pooled REs analysis, overall response rate was 19%, most frequent, all-grade toxicities were fatigue (41%), constipation (39%), nausea/vomiting (25%), and most prevalent Grade 3–4 toxicities were neutropenia (13%), anaemia (9%), fatigue (8%). Median OS was comparable to results reported in recent randomized studies.
Conclusion. Our findings confirm the efficacy and safety of VFL in an unselected population and support the use of VFL in the changing treatment paradigm of relapsed mUC
A comparison of ultrasound measurements to assess carotid atherosclerosis development in subjects with and without type 2 diabetes
BACKGROUND: Subjects with type 2 diabetes are at an increased risk of vascular complications. The use of carotid ultrasound remains an attractive, non-invasive method to monitor atherosclerotic disease progression and/or response to treatment in patients with type 2 diabetes, with intima-media thickness routinely used as the gold standard to detect pathology. However, alternative measurements, such as plaque area or volume, may represent a potentially more powerful approach. Thus, the objective of this study was to compare the traditional intima-media thickness measurement against the novel total plaque volume measurement in analyzing carotid atherosclerosis development in individuals with type 2 diabetes. METHODS: The case-control study included 49 Oji-Cree adults with diabetes or impaired glucose tolerance, aged 21–69, and 49 sex- and age-matched normoglycemic subjects. At baseline, metabolic variables were measured, including body mass index, waist circumference, total cholesterol:high density lipoprotein ratio, plasma triglycerides, plasma glucose, and serum insulin. Carotid ultrasound measurements, 7 years later, assessed carotid arterial intima-media thickness and total plaque volume. RESULTS: At baseline, the two groups were well matched for smoking habits, hypertension, body mass index, and waist circumference. Differences were noted in baseline measurements of total cholesterol:high density lipoprotein (P = 0.0006), plasma triglycerides (P < 0.0001) and fasting glucose (P < 0.0001). After seven years, carotid ultrasound scans revealed that total plaque volume measurements (P = 0.037), but not intima-media thickness measurements, were higher in subjects with diabetes/impaired glucose tolerance compared to the normoglycemic controls. Correlation between intima-media thickness and total plaque volume was moderate. Based on our study findings, to achieve power levels >0.70 when comparing intima-media thickness measurements for diabetics versus non-diabetics, thousands of study subjects are required. For comparing total plaque volume measurements, only hundreds of study subjects are required. CONCLUSION: The development of atherosclerotic plaque is greater in subjects with diabetes/impaired glucose tolerance. Total plaque volume appears to capture the atherosclerotic disease burden more effectively in subjects with type 2 diabetes, and would be an appropriate outcome measure for studies aimed at changing the diabetic milieu
Clinical and pharmacogenetic predictors of circulating atorvastatin and rosuvastatin concentrations in routine clinical care
Background-A barrier to statin therapy is myopathy associated with elevated systemic drug exposure. Our objective was to examine the association between clinical and pharmacogenetic variables and statin concentrations in patients. Methods and Results-In total, 299 patients taking atorvastatin or rosuvastatin were prospectively recruited at an outpatient referral center. The contribution of clinical variables and transporter gene polymorphisms to statin concentration was assessed using multiple linear regression. We observed 45-fold variation in statin concentration among patients taking the same dose. After adjustment for sex, age, body mass index, ethnicity, dose, and time from last dose, SLCO1B1 c.521T\u3eC (P\u3c0.001) and ABCG2 c.421C\u3eA (P\u3c0.01) were important to rosuvastatin concentration (adjusted R2=0.56 for the final model). Atorvastatin concentration was associated with SLCO1B1 c.388A\u3eG (P\u3c0.01) and c.521T\u3eC (P\u3c0.05) and 4β-hydroxycholesterol, a CYP3A activity marker (adjusted R2=0.47). A second cohort of 579 patients from primary and specialty care databases were retrospectively genotyped. In this cohort, genotypes associated with statin concentration were not differently distributed among dosing groups, implying providers had not yet optimized each patient\u27s risk-benefit ratio. Nearly 50% of patients in routine practice taking the highest doses were predicted to have statin concentrations greater than the 90th percentile. Conclusions-Interindividual variability in statin exposure in patients is associated with uptake and efflux transporter polymorphisms. An algorithm incorporating genomic and clinical variables to avoid high atorvastatin and rosuvastatin levels is described; further study will determine whether this approach reduces incidence of statin myopathy. © 2013 American Heart Association, Inc
Relationship of the metabolic syndrome to carotid ultrasound traits
BACKGROUND: The metabolic syndrome is associated with increased vascular disease risk. We evaluated two carotid ultrasound measurements, namely intima media thickness and total plaque volume, in a Canadian Oji-Cree population with a high metabolic syndrome prevalence rate. METHODS: As part of the Sandy Lake Complications Prevalence and Risk Factor Study, 166 Oji-Cree subjects (baseline metabolic syndrome prevalence, 44.0%, according to the National Cholesterol Education Program Adult Treatment Panel III guidelines) were examined using a high-resolution duplex ultrasound scanner. RESULTS: Image analysis showed that mean intima media thickness was elevated in subjects with the metabolic syndrome (818 ± 18 vs 746 ± 20 μm), as was total plaque volume (125 ± 26 vs 77.3 ± 17.0 mm(3)). However, after adjustment for age and sex, the differences were significant only for intima media thickness (P = 0.039). Furthermore, a significant trend towards increased intima media thickness was observed with increasing numbers of metabolic syndrome components: mean intima media thickness was highest among individuals with all five metabolic syndrome components compared to those with none (866 ± 55 vs 619 ± 23 μm, P = 0.0014). A similar, but non-significant trend was observed for total plaque volume. CONCLUSION: This is the first study of the relationship between the metabolic syndrome and two distinct carotid ultrasound traits measured in the same individuals. The results suggest that standard intima media thickness measurement shows a more consistent and stronger association with the metabolic syndrome than does total plaque volume
Mannose-Binding Lectin Genotype and Phenotype in Patients With Type 2 Diabetes and Myocardial Infarction: A report from the DIGAMI 2 trial
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