Assessment of a novel, capsid-modified adenovirus with an improved vascular gene transfer profile

<p>Background: Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Gene therapy may provide a successful approach to improve the clinical outcome of these conditions, but would benefit from the development of more efficient vectors for vascular gene delivery. The aim of this study was to assess whether a novel genetically engineered Adenovirus could be utilised to produce enhanced levels of vascular gene expression.</p> <p>Methods: Vascular transduction capacity was assessed in primary human saphenous vein smooth muscle and endothelial cells using vectors expressing the LacZ reporter gene. The therapeutic capacity of the vectors was compared by measuring smooth muscle cell metabolic activity and migration following infection with vectors that over-express the candidate therapeutic gene tissue inhibitor of matrix metalloproteinase-3 (TIMP-3).</p> <p>Results: Compared to Adenovirus serotype 5 (Ad5), the novel vector Ad5T*F35++ demonstrated improved binding and transduction of human vascular cells. Ad5T*F35++ mediated expression of TIMP-3 reduced smooth muscle cell metabolic activity and migration in vitro. We also demonstrated that in human serum samples pre-existing neutralising antibodies to Ad5T*F35++ were less prevalent than Ad5 neutralising antibodies.</p> <p>Conclusions: We have developed a novel vector with improved vascular transduction and improved resistance to human serum neutralisation. This may provide a novel vector platform for human vascular gene transfer.</p&gt

Physical activity reduces the risk of incident type 2 diabetes in general and in abdominally lean and obese men and women: the EPIC-InterAct Study.

AIMS/HYPOTHESIS: We examined the independent and combined associations of physical activity and obesity with incident type 2 diabetes in men and women. METHODS: The InterAct case-cohort study consists of 12,403 incident type 2 diabetes cases and a randomly selected subcohort of 16,154 individuals, drawn from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. Physical activity was assessed by a four-category index. Obesity was measured by BMI and waist circumference (WC). Associations between physical activity, obesity and case-ascertained incident type 2 diabetes were analysed by Cox regression after adjusting for educational level, smoking status, alcohol consumption and energy intake. In combined analyses, individuals were stratified according to physical activity level, BMI and WC. RESULTS: A one-category difference in physical activity (equivalent to approximately 460 and 365 kJ/day in men and women, respectively) was independently associated with a 13% (HR 0.87, 95% CI 0.80, 0.94) and 7% (HR 0.93, 95% CI 0.89, 0.98) relative reduction in the risk of type 2 diabetes in men and women, respectively. Lower levels of physical activity were associated with an increased risk of diabetes across all strata of BMI. Comparing inactive with active individuals, the HRs were 1.44 (95% CI 1.11, 1.87) and 1.38 (95% CI 1.17, 1.62) in abdominally lean and obese inactive men, respectively, and 1.57 (95% CI 1.19, 2.07) and 1.19 (95% CI 1.01, 1.39) in abdominally lean and obese inactive women, respectively. CONCLUSIONS/INTERPRETATION: Physical activity is associated with a reduction in the risk of developing type 2 diabetes across BMI categories in men and women, as well as in abdominally lean and obese men and women

New insights into the Tyrolean Iceman's origin and phenotype as inferred by whole-genome sequencing

The Tyrolean Iceman, a 5,300-year-old Copper age individual, was discovered in 1991 on the Tisenjoch Pass in the Italian part of the Otztal Alps. Here we report the complete genome sequence of the Iceman and show 100% concordance between the previously reported mitochondrial genome sequence and the consensus sequence generated from our genomic data. We present indications for recent common ancestry between the Iceman and present-day inhabitants of the Tyrrhenian Sea, that the Iceman probably had brown eyes, belonged to blood group O and was lactose intolerant. His genetic predisposition shows an increased risk for coronary heart disease and may have contributed to the development of previously reported vascular calcifications. Sequences corresponding to similar to 60% of the genome of Borrelia burgdorferi are indicative of the earliest human case of infection with the pathogen for Lyme borreliosis

The Iceman's Last Meal Consisted of Fat, Wild Meat, and Cereals

The history of humankind is marked by the constant adoption of new dietary habits affecting human physiology, metabolism, and even the development of nutrition-related disorders. Despite clear archaeological evidence for the shift from hunter-gatherer lifestyle to agriculture in Neolithic Europe [1], very little information exists on the daily dietary habits of our ancestors. By undertaking a complementary -omics approach combined with microscopy, we analyzed the stomach content of the Iceman, a 5,300-yearold European glacier mummy [2, 3]. He seems to have had a remarkably high proportion of fat in his diet, supplemented with fresh or dried wild meat, cereals, and traces of toxic bracken. Our multipronged approach provides unprecedented analytical depth, deciphering the nutritional habit, meal composition, and food-processing methods of this Copper Age individual

Lymphangiogenesis Is Required for Pancreatic Islet Inflammation and Diabetes

Lymphangiogenesis is a common phenomenon observed during inflammation and engraftment of transplants, but its precise role in the immune response and underlying mechanisms of regulation remain poorly defined. Here we showed that in response to injury and autoimmunity, lymphangiogenesis occurred around islets and played a key role in the islet inflammation in mice. Vascular endothelial growth factors receptor 3 (VEGFR3) is specifically involved in lymphangiogenesis, and blockade of VEGFR3 potently inhibited lymphangiogenesis in both islets and the draining LN during multiple low-dose streptozotocin (MLDS) induced autoimmune insulitis, which resulted in less T cell infiltration, preservation of islets and prevention of the onset of diabetes. In addition to their well-known conduit function, lymphatic endothelial cells (LEC) also produced chemokines in response to inflammation. These LEC attracted two distinct CX3CR1hi and LYVE-1+ macrophage subsets to the inflamed islets and CX3CR1hi cells were influenced by LEC to differentiate into LYVE-1+ cells closely associated with lymphatic vessels. These observations indicate a linkage among lymphangiogenesis and myeloid cell inflammation during insulitis. Thus, inhibition of lymphangiogenesis holds potential for treating insulitis and autoimmune diabetes

The middle interscalene block: cadaver study and clinical assessment

BACKGROUND AND OBJECTIVES: A variety of brachial plexus block techniques via the interscalene approach have been proposed. We describe here a new middle interscalene perivascular approach to the brachial plexus. To verify its effectiveness, we studied 719 patients scheduled for shoulder arthroscopy. Furthermore, to verify the accuracy of the proposed bony landmarks to use in the case of inability to palpate the subclavian artery pulse, we simulated the block on 10 cadavers. METHODS: The aim of our technique is to cannulate the neurovascular bundle by inserting a 35-mm needle lateral to the subclavian arterial pulse near the midpoint of the upper edge of the clavicle in a horizontal or slightly cephalad direction while pointing toward the seventh cervical vertebra. If the pulse of the subclavian artery is not palpable, we localize the direction of the needle with reference to 3 bony landmarks (the middle point of the clavicle, the spinous process of C7, and the sternoclavicular joint). By connecting these 3 landmarks, we obtain an angle whose apex lies at the midpoint of the clavicle and its bisecting line points to the plexus. The needle is introduced in the transverse plane of C7. RESULTS: The block was performed successfully in 692 of 719 cases (96.2\%). Horner's syndrome occurred in 93.5\% of the cases, arterial puncture with hematoma occurred in <1\%, phrenic nerve block without respiratory impairment in 60\%, with transient respiratory failure in <1\%, and laryngeal nerve block in <1\%. The incidence of severe complications or permanent injuries was zero (upper limit 95\% confidence interval = 0.4\% or 1:250 patients). The technique performed on cadavers showed that the previously mentioned bony landmarks were reliable reference points in reaching the brachial plexus. CONCLUSIONS: Our technique via a middle interscalene approach is easy to perform and provides a high success rate. Even in the absence of a subclavian artery pulse, the easily recognizable bony landmarks reliably guide us in the insertion of the needle. Furthermore, this technique appears to avoid complications that are theoretically possible in other supraclavicular perivascular approaches (pneumothorax) and paravertebral approaches (injection into the vertebral artery and subarachnoidal injection). However, further comparative studies will be required to assess the clinical relevance of the block