A study of the VaSera arterial stiffness device in US patients

The cardio‐ankle vascular index (CAVI) represents a promising index of arterial stiffness. However, neither the CAVI measure nor its measurement device, the VaSera, have undergone general testing in a North American clinical setting. To begin the process of collecting normal values in the United States, we studied 20 male and 28 female volunteers without reported cardiovascular or renal disease and no history of smoking. Their CAVIs, ankle‐brachial indices (ABIs), and four‐limb blood pressures were measured in three positions: supine, 7° Trendelenburg, and 7° reverse Trendelenburg. In addition, the ABI function was validated against an established ABI measurement technique. Position was found to affect CAVI and other hemodynamic parameters, indicating that CAVI is not robust to slight positional variations. No differences were found in the blood pressure between arms or legs (interbrachial or interankle), supporting recent findings from meta‐analyses and studies but contradicting other work. This study represents an early step in bringing the VaSera device and its CAVI measurement into clinical practice.     

Twelve-month Results of the EverFlex Stent in the Superficial Femoral Artery

PurposeTo evaluate the clinical efficacy of EverFlex stents (length, 6–20 cm) for the treatment of peripheral artery disease (PAD) in the superficial femoral artery (SFA).Material and MethodsOver a period of 18 months, 56 SFA lesions in 53 patients were treated with an EverFlex stent. The following parameters were documented before the intervention, immediately afterward, and 12 months later: clinical stage, ankle-brachial index, and peak systolic velocity ratio (PSVR). The primary study endpoint was the primary patency rate after 12 months (defined as a PSVR < 2.5).ResultsIn 18% of the 56 lesions, complete occlusions were present. Mean lesion length was 9.4 cm ± 5.3, and mean stent length was 12.6 cm ± 5.6. Of the 53 patients enrolled in the study, a 12-month follow-up was performed in 46. The primary patency rate after 12 months was 71.7%. In-stent restenosis or occlusion occurred in 13 patients. Compared with the total study group, the mean stent length in these 13 patients was greater (14.0 cm ± 7.3) and the incidence of de novo lesions was lower. In the patient group with stents less than 10 cm in length (n = 24), six patients (25%) required a repeat intervention, compared with seven patients (32%) in the group with stents longer than 12 cm.ConclusionsAlthough the primary patency rate associated with the EverFlex stent is comparable to those in published data, the present results demonstrate a higher percentage of in-stent stenoses in patients in whom longer SFA stents were implanted.     

Transient osteoporosis of pregnancy

Transient osteoporosis of pregnancy (TOP) is a rare yet perhaps under-reported condition that has affected otherwise healthy pregnancies throughout the world. The condition presents suddenly in the third trimester of a usually uneventful pregnancy and progressively immobilizes the mother. Radiographic studies detect drastic loss of bone mass, elevated rates of turnover in the bone, and oedema in the affected portion. Weakness of the bone can lead to fractures during delivery and other complications for the mother. Then, within weeks of labour, symptoms and radiological findings resolve. Aetiology is currently unknown, although neural, vascular, haematological, endocrine, nutrient-deficiency, and other etiologies have been proposed. Several treatments have also been explored, including simple bed rest, steroids, bisphosphonates, calcitonin, induced termination of pregnancy, and surgical intervention. The orthopedist plays an essential role in monitoring the condition (and potential complications) as well as ensuring satisfactory outcomes for both the mother and newborn.     

Cereblon Regulates the Proteotoxicity of Tau by Tuning the Chaperone Activity of DNAJA1

Protein aggregation can induce explicit neurotoxic events that trigger a number of presently untreatable neurodegenerative disorders. Chaperones, on the other hand, play a neuroprotective role because of their ability to unfold and refold abnormal proteins. The progressive nature of neurotoxic events makes it important to discover endogenous factors that affect pathologic and molecular phenotypes of neurodegeneration in animal models. Here, we identified microtubule-associated protein tau, and chaperones Hsp70 (heat shock protein 70) and DNAJA1 (DJ2) as endogenous substrates of cereblon (CRBN), a substrate-recruiting subunit of cullin4-RING-E3-ligase. This recruitment results in ubiquitin-mediated degradation of tau, Hsp70, and DJ2. Knocking out CRBN enhances the chaperone activity of DJ2, resulting in decreased phosphorylation and aggregation of tau, improved association of tau with microtubules, and reduced accumulation of pathologic tau across brain. Functionally abundant DJ2 could prevent tau aggregation induced by various factors like okadaic acid and heparin. Depletion of CRBN also decreases the activity of tau-kinases including GSK3α/β, ERK, and p38. Intriguingly, we found a high expression of CRBN and low levels of DJ2 in neuronal tissues of 5XFAD and APP knock-in male mouse models of Alzheimer’s disease. This implies that CRBN-mediated DJ2/Hsp70 pathway may be compromised in neurodegeneration. Being one of the primary pathogenic events, elevated CRBN can be a contributing factor for tauopathies. Our data provide a functional link between CRBN and DJ2/Hsp70 chaperone machinery in abolishing the cytotoxicity of aggregation-prone tau and suggest that Crbn^−/− mice serve as an animal model of resistance against tauopathies for further exploration of the molecular mechanisms of neurodegeneration.     

A 26-year-old female with metastatic primary gastrointestinal malignancy presenting as menorrhagia

Krukenberg tumor is a metastatic malignant tumor of the ovary arising from a wide variety of primary sources, with the stomach being the most common. The presenting symptoms are non-specific and the primary source is often un-identified. Here, we describe a case of a 26-year-old Hispanic gravida 4, para 3 female who presented to our hospital with dysuria, pelvic pain and irregular, heavy menstrual cycles for three months duration. An endometrial biopsy was suggestive of carcinosarcoma. The patient underwent debulking surgery with partial cystectomy and bladder repair. A week later, she presented with hematemesis and an endoscopic biopsy revealed a diagnosis of poorly differentiated gastric adenocarcinoma. The tissue specimen obtained during the initial surgery was identified as Krukenberg tumor. The patient underwent adjuvant chemotherapy with FOLFOX along with gastrectomy with intraperitoneal chemotherapy.     

Endoscopic advances in the management of non-variceal upper gastrointestinal bleeding:A review

Upper gastrointestinal bleeding is defined as the bleeding originating from the esophagus to the ligament of Treitz and further classified into variceal and nonvariceal gastrointestinal bleeding.Non-variceal upper gastrointestinal bleeding remains a common clinical problem globally.It is associated with high mortality,morbidity,and cost of the health care system.Despite the continuous improvement of therapeutic endoscopy,the 30-d readmission rate secondary to rebleeding and associated mortality is an ongoing issue.Available Food and Drug Administration approved traditional or conventional therapeutic endoscopic modalities includes epinephrine injection,argon plasma coagulation,heater probe,and placement of through the scope clip,which can be used alone or in combination to decrease the risk of rebleeding.Recently,more attention has been paid to the novel advanced endoscopic devices for primary treatment of the bleeding lesion and as a secondary measure when conventional therapies fail to achieve hemostasis.This review highlights emerging endoscopic modalities used in the management of non-variceal upper gastrointestinal related bleeding such as over-the-scope clip,Coagrasper,hemostatic sprays,radiofrequency ablation,cryotherapy,endoscopic suturing devices,and endoscopic ultrasound-guided angiotherapy.In this review article,we will also discuss the technical aspects of the common procedures,outcomes in terms of safety and efficacy,and their advantages and limitations in the setting of non-variceal upper gastrointestinal bleeding.     

Thrombophilia-hypofibrinolysis and atherothrombotic cardiovascular disease < or = age 45 years

Thrombophilia-hypofibrinolysis may play an important role in rare premature (< or = age 45 years) arterial occlusive events in atherothrombotic cardiovascular (ATCVD) disease, particularly in normolipidemic patients. Whether thrombophilia-hypofibrinolysis contributed to ATCVD < or = age 45 years was assessed in 78 men and 40 women with 230 ATCVD events (myocardial infarction (MI) [n = 60], coronary artery bypass graft [CABG, n = 33], angioplasty [n = 52], chronic angina [n = 41], ischemic stroke [n = 11], transient ischemic attack [TIA, n = 24], claudication [n = 9]). Cases were compared with healthy normal adult controls (44 men and 76 women). In men, the Factor V Leiden mutation was present in 6/63 (10%) cases versus 0/44 (0%) controls (P = 0.042), Factor VIII was high (>150%) in 16/60 (27%) cases versus 1/42 (2%) controls (P = 0.001), Factor XI was high (>150%) in 9/57 (16%) cases versus 0/42 (0%) controls (P = 0.009), and plasminogen activator inhibitor activity (PAI-Fx) was high (>21.1 U/mL) in 15/63 (24%) cases versus 3/43 (7%) controls (P = 0.023). In women, protein C was low (<73%) in 4/26 (15%) cases versus 0/74 (0%) controls (P = 0.004), and free protein S was low (<66%) in 5/27 (19%) cases versus 2/74 (3%) controls (P = 0.014). In women, Factor XI was high (>150%) in 3/27 (11%) cases versus 1/74 (1%) controls (P = 0.057), and the lupus anticoagulant was present in 9/32 (28%) cases versus 2/51 (4%) controls (P = 0.002). In patients with ATCVD < or = age 45 years, thrombophilias (Factor V Leiden, Factor VIII, Factor XI, protein C and S deficiency, lupus anticoagulant) and hypofibrinolysis (PAI-Fx, Lp[a]) may promote arterial thrombosis, which is synergistic with atherosclerotic endothelial injury.     

Electrochemical and spectroscopic investigations of isoniazide and its analogs with ds.DNA at physiological pH: evaluation of biological activities

Interaction and binding of isonicotinic acid hydrazide (INH) and its two analogs; pyrazine carboxylic acid hydrazide (PCH) and 2,4-dihydroxy benzoic acid hydrazide (2,4-DHBAH) with DNA has been investigated by UV-spectroscopy and cyclic voltammetry (CV) at physiological conditions of pH and temperature. Experimental results from both techniques were in good agreement and indicated stronger binding and formation of hydrazides-DNA complexes via intercalation. Among three hydrazides, 2,4-DHBAH showed greater interaction toward DNA at stomach pH (4.7) as evident from its comparatively greater binding constant, {K(b); 2.02?×?10(4)?M(-1) (UV), 3.13?×?10(4)?M(-1) (CV)}. The greater binding site size (n?=?3) for 2,4-DHBAH at stomach pH inferred 3:1 binding stoichiometry and possibility of electrostatic interactions or hydrogen bonding along with intercalative mode of interaction between 2,4-DHBAH and DNA. The free energies of hydrazides-DNA complexes indicated the spontaneity of their binding. 2,4-DHBAH has shown promising anti-bacterial activities while anti-oxidant and cytotoxic potentials were exhibited by all three hydrazides.     

Role of intestinal circadian genes in alcohol-induced gut leakiness

Background: Several studies have indicated that endotoxemia is the required co‐factor for alcoholic steatohepatitis (ASH) that is seen in only about 30% of alcoholics. Recent studies have shown that gut leakiness that occurs in a subset of alcoholics is the primary cause of endotoxemia in ASH. The reasons for this differential susceptibility are not known. Since disruption of circadian rhythms occurs in some alcoholics and circadian genes control the expression of several genes that are involved in regulation of intestinal permeability, we hypothesized that alcohol induces intestinal hyperpermeability by stimulating expression of circadian clock gene proteins in the intestinal epithelial cells. Methods: We used Caco‐2 monolayers grown on culture inserts as an in vitro model of intestinal permeability and performed Western blotting, permeability, and siRNA inhibition studies to examine the role of Clock and Per2 circadian genes in alcohol‐induced hyperpermeability. We also measured PER2 protein levels in intestinal mucosa of alcohol‐fed rats with intestinal hyperpermeability. Results: Alcohol, as low as 0.2%, induced time dependent increases in both Caco‐2 cell monolayer permeability and in CLOCK and PER2 proteins. SiRNA specific inhibition of either Clock or Per2 significantly inhibited alcohol‐induced monolayer hyperpermeability. Alcohol‐fed rats with increased total gut permeability, assessed by urinary sucralose, also had significantly higher levels of PER2 protein in their duodenum and proximal colon than control rats. Conclusions: Our studies: (i) demonstrate a novel mechanism for alcohol‐induced intestinal hyperpermeability through stimulation of intestinal circadian clock gene expression, and (ii) provide direct evidence for a central role of circadian genes in regulation of intestinal permeability.     

Lesions of basolateral and central amygdala differentiate conditioned cue preference learning with and without unreinforced preexposure

In the separated arms conditioned cue preference (CCP) task rats are trained by confining them in one arm of an eight-arm radial maze with food and in another arm on the opposite side of the maze with no food on alternate days. After two such trials, rats prefer the food-paired arm when allowed to move freely between the two arms, neither of which contains food. However, if the rats are preexposed to the maze by exploring it without food before training, no preference is observed and at least 4 training trials are required to produce a CCP, suggesting that unreinforced preexposure to the maze latently inhibits acquisition. If this interpretation is correct, preexposure should reduce the size of the preference acquired with both 2 and 4 training trials. In Experiment 1, this prediction was replicated for 2 training trials; however, with 4 training trials, eliminating preexposure also eliminated the CCP. A previous finding that basolateral amygdala lesions impair the CCP with preexposure and 4 training trials was replicated in Experiment 2, but similar lesions had no effect on the CCP in non-preexposed rats given 2 training trials. In contrast, lesions of the central nucleus impaired the 2 training trial CCP but had no effect on the 4 training trial CCP. This double dissociation suggests that the BLA-mediated 4 training trial CCP may be due to learning about the reward features of the maze space, while the central-nucleus-mediated 2 training trial CCP may be due to a conditioned approach response.