Hypothyroidism and the risk of lower extremity arterial disease

Background: Although an independent association between hypothyroidism and coronary artery disease has been demonstrated, few studies have examined the association between hypo-thyroidism and peripheral arterial disease. In the current study, we test the hypothesis that there is an independent association between hypothyroidism and lower extremity arterial disease. Methods: We retrospectively compared the prevalence of hypothyroidism in patients who had infra-inguinal arterial bypass surgery over a 6-year period with that of a control group of surgical patients who had pure cardiac valve surgery during the same time period. Both unadjusted and adjusted odds ratios were calculated to estimate the association between hypothyroidism and lower extremity arterial disease. Results: A total of 614 cases and 529 control subjects had surgery during the study period. When comparing all subjects, there was no association between hypothyroidism and lower extremity arterial disease (unadjusted odds ratio 0.88; 95% confidence intervals [CI]: 0.61-1.28). However, gender was found to be a significant effect modifier (P \u3c 0.001), and gender-stratified analyses were subsequently performed. In men, there was a positive independent association between hypothyroidism and lower extremity arterial disease (adjusted odds ratio 2.65; 95% CI: 1.19-5.89), whereas in women there was a negative independent association (adjusted odds ratio 0.22; 95% CI: 0.11-0.46). Conclusions: Gender is a significant effect modifier for the association between hypothyroidism and lower extremity arterial disease. The association is positive in men and negative in women. Future prospective studies that evaluate hypothyroidism as a risk factor for peripheral arterial disease should consider gender stratification in order to corroborate this finding. © 2010 Mazzeffi et al, publisher and licensee Dove Medical Press Ltd

Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients.

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (mitochondrial HMG-CoA synthase deficiency or mHS deficiency, OMIM #605911) is an inborn error of metabolism that affects ketone body synthesis. Acute episodes include vomiting, lethargy, hepatomegaly, hypoglycemia and dicarboxylic aciduria. The diagnosis is difficult due to the relatively unspecific clinical and biochemical presentation, and fewer than 30 patients have been described. This work describes three new patients with mHS deficiency and two missense mutations c.334C>T (p.R112W) and c.430G>T (p.V144L) previously not reported. We developed a new method to express and measure the activity of the enzyme and in this work the study is extended to ten new missense variants including those of our patients. Enzymatic assays showed that three of the mutant proteins retained some but seven completely lacked activity. The identification of a patient homozygous for a mutation that retains 70% of enzyme activity opens the door to a new interpretation of the disease by demonstrating that a modest impairment of enzyme function can actually produce symptoms. This is also the first study employing molecular dynamics modelling of the enzyme mutations. We show that the correct maintenance of the dimerization surface is crucial for retaining the structure of the active center and therefore the activity of the enzyme.post-print1746 K

Critical analysis of vendor lock-in and its impact on cloud computing migration: a business perspective

Vendor lock-in is a major barrier to the adoption of cloud computing, due to the lack of standardization. Current solutions and efforts tackling the vendor lock-in problem are predominantly technology-oriented. Limited studies exist to analyse and highlight the complexity of vendor lock-in problem in the cloud environment. Consequently, most customers are unaware of proprietary standards which inhibit interoperability and portability of applications when taking services from vendors. This paper provides a critical analysis of the vendor lock-in problem, from a business perspective. A survey based on qualitative and quantitative approaches conducted in this study has identified the main risk factors that give rise to lock-in situations. The analysis of our survey of 114 participants shows that, as computing resources migrate from on-premise to the cloud, the vendor lock-in problem is exacerbated. Furthermore, the findings exemplify the importance of interoperability, portability and standards in cloud computing. A number of strategies are proposed on how to avoid and mitigate lock-in risks when migrating to cloud computing. The strategies relate to contracts, selection of vendors that support standardised formats and protocols regarding standard data structures and APIs, developing awareness of commonalities and dependencies among cloud-based solutions. We strongly believe that the implementation of these strategies has a great potential to reduce the risks of vendor lock-in

Personal non-commercial use only

ABSTRACT. Objective. To assess the overall safety, including rare events, of intravenous (IV) abatacept treatment in rheumatoid arthritis (RA). Methods. Data from 8 clinical trials of IV abatacept in RA were pooled. Safety events were assessed during the short-term (duration ≤ 12 months) and cumulative (short-term plus longterm extensions) abatacept treatment periods. Incidence rates per 100 patient-years were calculated. Standardized incidence ratios (SIR) for hospitalized infections and malignancies were compared with external RA cohorts and, for malignancies, with the US general population. Results. There were 3173 IV abatacept-treated patients with 2331 patient-years of exposure in the short-term periods, and 4149 IV abatacept-treated patients with 12,132 patient-years of exposure in the cumulative period. Incidence rates for serious infections were low and consistent over time (3.68 for abatacept vs 2.60 for placebo during the short-term, and 2.87 for abatacept during the cumulative period). Hospitalized infections were generally similar to external RA patient cohorts and were consistent over time. Incidence rates of malignancies were similar for abatacept-and placebo-treated patients during the short-term period (0.73 vs 0.59) and remained low during the abatacept cumulative period (0.73). SIR of some tissue-specific malignancies (e.g., colorectal and breast) in the cumulative period tended to be lower, while others (lymphoma and lung) tended to be higher, compared with the general population; however, incidence rates were comparable with RA cohorts. Autoimmune events were rare and infusion reactions uncommon. Conclusion. Longterm safety of IV abatacept was consistent with the short-term, with no unexpected events and low incidence rates of serious infections, malignancies, and autoimmune events. Leuven, Leuven, Belgium; Fox Chase Cancer Center, Philadelphia, Pennsylvania; Bristol-Myers Squibb, Princeton, New Jersey

Rheumatoid arthritis - treatment: 180. Utility of Body Weight Classified Low-Dose Leflunomide in Japanese Rheumatoid Arthritis

Background: In Japan, more than 20 rheumatoid arthritis (RA) patients died of interstitial pneumonia (IP) caused by leflunomide (LEF) were reported, but many of them were considered as the victims of opportunistic infection currently. In this paper, efficacy and safety of low-dose LEF classified by body weight (BW) were studied. Methods: Fifty-nine RA patients were started to administrate LEF from July 2007 to July 2009. Among them, 25 patients were excluded because of the combination with tacrolimus, and medication modification within 3 months before LEF. Remaining 34 RA patients administered 20 to 50 mg/week of LEF were followed up for 1 year and enrolled in this study. Dose of LEF was classified by BW (50 mg/week for over 50 kg, 40 mg/week for 40 to 50 kg and 20 to 30 mg/week for under 40 kg). The average age and RA duration of enrolled patients were 55.5 years old and 10.2 years. Prednisolone (PSL), methotrexate (MTX) and etanercept were used in 23, 28 and 2 patients, respectively. In case of insufficient response or adverse effect, dosage change or discontinuance of LEF were considered. Failure was defined as dosages up of PSL and MTX, or dosages down or discontinuance of LEF. Last observation carried forward method was used for the evaluation of failed patients at 1 year. Results: At 1 year after LEF start, good/ moderate/ no response assessed by the European League Against Rheumatism (EULAR) response criteria using Disease Activity Score, including a 28-joint count (DAS28)-C reactive protein (CRP) were showed in 14/ 10/ 10 patients, respectively. The dosage changes of LEF at 1 year were dosage up: 10, same dosage: 5, dosage down: 8 and discontinuance: 11 patients. The survival rate of patients in this study was 23.5% (24 patients failed) but actual LEF continuous rate was 67.6% (11 patients discontinued) at 1 year. The major reason of failure was liver dysfunction, and pneumocystis pneumonia was occurred in 1 patient resulted in full recovery. One patient died of sepsis caused by decubitus ulcer infection. DAS28-CRP score was decreased from 3.9 to 2.7 significantly. Although CRP was decreased from 1.50 to 0.93 mg/dl, it wasn't significant. Matrix metalloproteinase (MMP)-3 was decreased from 220.0 to 174.2 ng/ml significantly. Glutamate pyruvate transaminase (GPT) was increased from 19 to 35 U/l and number of leukocyte was decreased from 7832 to 6271 significantly. DAS28-CRP, CRP, and MMP-3 were improved significantly with MTX, although they weren't without MTX. Increase of GPT and leukopenia were seen significantly with MTX, although they weren't without MTX. Conclusions: It was reported that the risks of IP caused by LEF in Japanese RA patients were past IP history, loading dose administration and low BW. Addition of low-dose LEF is a potent safe alternative for the patients showing unsatisfactory response to current medicines, but need to pay attention for liver function and infection caused by leukopenia, especially with MTX. Disclosure statement: The authors have declared no conflicts of interes

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Intralaminar shear loading effects on the damage process of multiply composites at impact rates

Les matériaux composites, comme matériaux constitutifs d'éléments de structures dédiés à l'absorption d'énergie lors d'un crash, sont a priori les mieux adaptés pour répondre à cette spécification de besoins. Cependant, l'absorption peut être stoppée par l'apparition de mécanismes, comme le cisaillement intralaminaire, conduisant à la ruine prématurée de la structure. Ce travail a alors pour but l'étude de l'effet de ces contraintes de cission aux interfaces fibre-matrice pour tels matériaux soumis à un impact. Deux dispositifs d'impacts ont été modifiés afin d'étudier, sous différentes vitesses de sollicitation, le comportement macroscopique des processus d'endommagement initiés au sein de stratifiés verre E - époxyde. Une analyse microscopique du dommage permet de déterminer la nature de l'endommagement, son mode de propagation et sa localisation.Composite materials, when they are used as structural elements to ensure absorption energy during impacts, can give better results than those of steel. However, their energy absorption capacities can be reduced due to some damage mechanisms, like intralaminar shear, which induce a premature failure. The aim of this study is to investigate the intralaminar shear effects at fibre-matrix interfaces when composite materials are subjected to impacts. A servo-hydraulic testing machine and a Hopkinson bars tensile apparatus were improved to investigate, by using Damage Mechanics, the shear behaviour under high strain rates of E-glass reinforced epoxy crossply laminates. A microscopical analysis of the damage phenomena allows us to know the damage initiation and propagation processes