ß-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain.

Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). Here, we identify ß-hydroxybutyrate (ßHB), a ketone body, as a regulator of protein solubility in the aging brain. ßHB is a small molecule metabolite which primarily provides an oxidative substrate for ATP during hypoglycemic conditions, and also regulates other cellular processes through covalent and noncovalent protein interactions. We demonstrate ßHB-induced protein insolubility across in vitro, ex vivo, and in vivo mouse systems. This activity is shared by select structurally similar metabolites, is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain in vivo after delivery of a ketone ester. Furthermore, this phenotype is selective for pathological proteins such as amyloid-ß, and exogenous ßHB ameliorates pathology in nematode models of amyloid-ß aggregation toxicity. We have generated a comprehensive atlas of the ßHB-induced protein insolublome ex vivo and in vivo using mass spectrometry proteomics, and have identified common protein domains within ßHB target sequences. Finally, we show enrichment of neurodegeneration-related proteins among ßHB targets and the clearance of these targets from mouse brain, likely via ßHB-induced autophagy. Overall, these data indicate a new metabolically regulated mechanism of proteostasis relevant to aging and AD.

'Post-Close' Femoral Arterial Haemostasis at Endovascular Aneurysm Repair using a Dedicated Large-Bore Vascular Closure Device: A Prospective Real-World Audit.

PURPOSE: Percutaneous access for endovascular aneurysm repair (EVAR) is commonplace, with its attendant benefits. The combination of continued reduction in device profile and evolution of vascular closure device (VCD) design drives successful and safe percutaneous EVAR. A new such VCD is the MANTA Large-Bore Closure Device designed in two iterations for closure of arterial defects from 10 to 25F. We present a prospective audit of 131 large-bore femoral closures using an 'all-comers' approach to device selection. MATERIALS AND METHODS: One hundred and thirty-one large-bore femoral arterial defects were analysed. Both 14F and 18F MANTA VCDs were deployed in this series as per instructions for use. Primary objectives were technical success, particularly successful deployment, and haemostasis achieved. Failures were denoted as failure to deploy; failure to achieve haemostasis was denoted as active bleeding, haematoma, or pseudoaneurysm formation requiring intervention. Later complications assessed were vessel occlusion/thrombosis or stenosis. RESULTS: Seventy-six patients (65 males and 11 females, age 75.2 ± 8.7 years) underwent a range of procedures including EVAR (n = 66), TEVAR (n = 2), and reinterventions (n = 8) requiring large-bore percutaneous femoral arterial access in 131 groins. Of these, the 14F MANTA VCD was used in 61 closures (defects ranging from 12 to 18F) and the 18F in 70 closures (defects ranging from 16 to 24F). Deployments achieved successful haemostasis in 120 (91.6%), and failures occurred in 11(8.4%) groins. CONCLUSIONS: This study indicates that a post-close approach using the novel MANTA Large-Bore Closure Device can be undertaken successfully to close a range of large-bore femoral arterial defects at EVAR/TEVAR with an acceptable rate of complications.

Guanylin and uroguanylin: a promising nexus in intestinal electrolyte and fluid homeostasis.

Intestinal guanyl peptides like guanylin and uroguanylin are the potent regulators of fluid-ion homeostasis. They are secreted from various cells of the intestinal mucosa, including enterochromaffin cells, epithelial cells, goblet cells, Paneth cells and others. These peptide hormones serve as ligands for receptor guanylyl cyclase-C (GC-C), which produces intracellular cyclic guanosine monophosphate (cGMP) and activates protein kinase G II (PKGII). cGMP/PKGII activates cystic fibrosis transmembrane conductance regulator for anion transport to the intestinal lumen, inhibits Na+/H+ exchanger that restricts H+ secretion and Na+ absorption, resulting in the retention of luminal fluid. These functions maintain intestinal pH, prevents hypernatremia and unwanted hypervolemic shock. Additionally, fluid balance in the intestine preserves the hydrated state of the colonic mucus that influences the growth of the commensal microorganisms and bowel clearance. Moreover, GC-C/cGMP signaling is involved in the regulation of intestinal barrier integrity, epithelial cell renewal, cell cycle, DNA damage repair, inflammatory responses, epithelial-mesenchymal transition and cancer progression. Impairment of GC-C activation causes functional gastrointestinal disorders, inflammatory bowel disease, visceral pain and colorectal cancer, suggesting that oral supplementation of guanyl peptide analogs (linaclotide, plecanatide) may prove useful for the treatment of these diseases.

Leptin and obesity.

An imbalance between calorie intake and energy expenditure produces obesity. It has been a major problem in societies of the developing and developed world. In obesity an excessive amount of fat accumulates in adipose tissue cells as well as in other vital organs like liver, muscles, and pancreas. The adipocytes contain ob genes and express leptin, a 16 kDa protein. In the present communication, we reviewed the molecular basis of the etiopathophysiology of leptin in obesity. Special emphasis has been given to the use of leptin as a drug target for obesity treatment, the role of diet in the modulation of leptin secretion, and reduction of obesity at diminished level of blood leptin induced by physical exercise.

Improved Midterm Outcomes Using Standard Devices and EndoAnchors for Endovascular Repair of Abdominal Aortic Aneurysms with Hyperangulated Necks.

PURPOSE: Loss of fixation and seal represent a key problem when undertaking endovascular repair of abdominal aortic aneurysms (AAA) with hyperangulated necks (HAN). This study assesses the outcomes following the use of adjunct endostapling to supplement proximal aorto-prosthetic fixation in patients who have AAAs with HAN. METHODS: A retrospective review of a prospective database of 42 patients with HAN (> 60°) who underwent endovascular aneurysm repair (EVAR) with supplementary endostapling was undertaken. Primary outcomes assessed were: change in post-EVAR neck angulation at first post-procedure scan, freedom from type 1 endoleaks, migration and reintervention for proximal seal complications. Secondary parameters included assessment for neck dilatation, sac size changes and EndoAnchor distribution patterns. RESULTS: In total, 42 patients underwent EVAR between 2013 and 2019. There was one 30-day mortality resulting in 41 patients (34 male, 7 females aged 76.8 ± 8.9 years)) being analysed; 251 EndoAnchors were deployed in total, averaging 6 ± 2 per patient; 38 such cases were primary deployments. Neck angulation was 76.9 ± 14 degrees pre-EVAR and 50.2 ± 14.5 degrees post-procedure (p < .001, paired T test). Mean follow-up time was 18.5 (95% CI 13.3-23.9) months. One patient had persistent type Ia endoleak, successfully banded. There was 6.8 ± 10.2 mm sac size reduction (p < .001, paired T test). There were no other neck-related reinterventions, despite continued neck dilatation (3.2 ± 3.7 mm, p < .001, paired T test). CONCLUSION: This study suggests successful EVAR with adjunct endostapling for AAA with hyperangulated necks, with significant sac shrinkage and low rates of endoleaks, migration and reinterventions. More data are needed to consider influencing current instructions for use.

Ultrasound Assisted On-Table Management of Type III Endoleak at Endovascular Repair of Isolated Giant Common Iliac Aneurysm.

OBJECTIVES: This report presents the endovascular treatment of a large isolated common iliac artery aneurysm, focusing on the use of on table ultrasonography to characterise and treat an early endoleak that could not be defined by angiography alone. REPORT: A 58 year old man presented with an asymptomatic, large (13cm) left common iliac artery aneurysm (LCIAA) whilst being investigated for change in bowel habit. This was treated successfully via a percutaneous approach using left internal iliac embolisation followed by endovascular aneurysm repair (EVAR) with deployment of an aorto-uni-iliac converter system from the LCIA origin to the external iliac artery. A non-characterised endoleak at the end of the procedure was shown to be a type IIIb endoleak by application of immediate on table ultrasonography, allowing immediate supplementary targeted stent graft deployment to cover the leaking segment. DISCUSSION: The patient was discharged uneventfully and will remain on follow up. On table ultrasonography allowed both localisation and characterisation of an immediate intra-procedural endoleak and confirmed cessation of the endoleak with supplementary stent grafting and thrombosis within the sac. CONCLUSIONS: Isolated CIAA is rare, and endovascular therapy is appropriate for them, given that open surgery, whilst feasible, carries a high morbidity and mortality risk. Application of on-table ultrasound allows definition and targeted treatment of endoleaks, reducing the need for further intervention at a later stage, and thus also reducing the risk of continued pressurisation of the large sac post-EVAR till the next surveillance episode.

Ilioprofunda Endobypass Can Successfully Treat a Post-Operative Femoral Pseudo-Aneurysm.

INTRODUCTION: A 75-year-old male patient with significant cardiopulmonary comorbidity presented with a 70-mm left femoral pseudoaneurysm 6 years after aortobifemoral bypass (and prior femoral endarterectomy). REPORT: As the left superficial femoral artery was occluded, an ilioprofunda endobypass was undertaken following extraperitoneal exposure of the left limb of the bypass graft with subsequent deployment of four Viabahn endoprostheses via the left limb into the proximal left deep femoral artery with successful exclusion of the pseudoaneurysm. The endografts remain patent at 6 months with regression noted in the pseudoaneurysm itself. DISCUSSION: Post-operative femoral pseudoaneurysm following anastomotic dehiscence has traditionally been treated by open surgical repair. Re-re-do open femoral vascular surgery has a high complication rate. Scarring and potential graft infection may necessitate ligation of involved arteries and extra-anatomic bypasses with an attendant risk of limb loss. Although the common femoral artery is conventionally contraindicated for endograft deployment because of the perceived high risk of stent fracture in a highly mobile zone, an endobypass can avoid the potential complications of open revision groin surgery in an unfit, high-risk patient.

Femoral Arterial Haemostasis Using an Anchored Collagen Plug after Percutaneous EVAR with an Ultra-Low Profile Device: Prospective Audit of an Evolving "Post-Close" Technique.

OBJECTIVE: To present an audit of a successful "post-close" haemostatic technique using the Angio-Seal VIP vascular closure device (VCD) after percutaneous endovascular aneurysm repair (p-EVAR) using an ultra-low profile (ULP) device. METHODS: Thirty patients underwent EVAR using the Ovation device, of which 26 procedures were totally percutaneous. Data including patient habitus, procedural details, number of VCDs deployed including use of the double wire approach, and technical success/complications were prospectively recorded. Numerical/statistical analyses were undertaken using Microsoft Excel 2007 and Minitab for Windows. RESULTS: Thirty consecutive patients (27 male, 3 female; age range 70-85 years [mean 76.1, SD 6.5]) underwent EVAR for an infrarenal AAA (mean size 61 mm, SD 9.7) between March 2014 and August 2016 using the Ovation endograft system. In a few patients open ipsilateral femoral access was used (n=4); the remainder underwent p-EVAR (n=26), and these results are presented hereafter. Ipsilateral sheath sizes used varied between 14F (n=22), 15F (n=3), and 16F (n=1), and were closed using a single 8F Angio-Seal (n=7), a combination of 8F/6F Angio-Seal VCDs (n=18), or two 8F Angio-Seal VCDs (n=1) with prior double wire set up. Contralateral punctures were closed mostly with a single 8F Angio-Seal (n=24) or combination of 8F/6F Angio-Seal VCDs (n=2) to seal defects downsized to 12F. The overall immediate haemostasis success rate was 100%. Mean length of stay in the p-EVAR cohort was 2 days (SD 1.5). All patients had a post-EVAR computed tomography angiogram (n=24) or duplex ultrasound (n=2) which did not reveal any stenoses or seromas; two patients developed an ipsilateral femoral pseudoaneurysm successfully treated by thrombin injection. CONCLUSION: A "post-close" technique can be employed successfully for haemostasis after p-EVAR using an ULP device. An 8F Angio-Seal is usually effective in closing a 12F femoral arterial defect. This represents a viable option for femoral arterial closure in this scenario.