GPR40 deficiency is associated with hepatic FAT/CD36 upregulation, steatosis, inflammation, and cell injury in C57BL/6 mice.

G-protein-coupled receptor 40 (GPR40) is highly expressed in pancreatic islets, and its activation increases glucose-stimulated insulin secretion from pancreas. Therefore, GPR40 is considered as a target for type 2 diabetes mellitus (T2DM). Since nonalcoholic fatty liver disease (NAFLD) is associated with T2DM and GPR40 is also expressed by hepatocytes and macrophages, it is important to understand the role of GPR40 in NAFLD. However, the role of GPR40 in NAFLD in animal models has not been well defined. In this study, we fed wild-type or GPR40 knockout C57BL/6 mice a high-fat diet (HFD) for 20 wk and then assessed the effect of GPR40 deficiency on HFD-induced NAFLD. Assays on metabolic parameters showed that an HFD increased body weight, glucose, insulin, insulin resistance, cholesterol, and alanine aminotransferase (ALT), and GPR40 deficiency did not mitigate the HFD-induced metabolic abnormalities. In contrast, we found that GPR40 deficiency was associated with increased body weight, insulin, insulin resistance, cholesterol, and ALT in control mice fed a low-fat diet (LFD). Surprisingly, histology and Oil Red O staining showed that GPR40 deficiency in LFD-fed mice was associated with steatosis. Immunohistochemical analysis showed that GPR40 deficiency also increased F4/80, a macrophage biomarker, in LFD-fed mice. Furthermore, results showed that GPR40 deficiency led to a robust upregulation of hepatic fatty acid translocase (FAT)/CD36 expression. Finally, our in vitro studies showed that GPR40 knockdown by siRNA or a GPR40 antagonist increased palmitic acid-induced FAT/CD36 mRNA in hepatocytes. Taken together, this study indicates that GPR40 plays an important role in homeostasis of hepatic metabolism and inflammation and inhibits nonalcoholic steatohepatitis by possible modulation of FAT/CD36 expression.

Fenestrated Endovascular Aortic Aneurysm Repair as a First Line Treatment Option to Treat Short Necked, Juxtarenal, and Suprarenal Aneurysms.

OBJECTIVES: The outcomes of fenestrated endovascular aneurysm repair (FEVAR) as a first line strategy is reported. METHODS: All consecutive patients treated with FEVAR for short neck, juxtarenal, or suprarenal aortic aneurysms under the guidance of the senior author within the period January 2010 to December 2014 were included. Data were collected from a prospectively maintained database. Analyzed outcomes included technical success, defined by successful stent graft implantation with patent stented target vessels and no Type I/III endoleak, operative mortality and morbidity, target vessel patency, endoleak, re-intervention, and death. Survival, target vessel stent patency, and re-intervention during follow up were calculated by Kaplan-Meier analysis. RESULTS: A total of 281 patients (245 male, mean age 72.1 ± 7.7 years) were treated. The mean aneurysm diameter was 60.2 ± 9.3 mm and median proximal neck length 2 mm (range 0-10 mm). Technical success was 96.8% (272/281). Technical failure included one intra-operative death due to embolization and cardiac arrest, one open conversion due to iliac rupture, and seven target vessel complications. The thirty day mortality was 0.7% (2/281). Mean follow up was 21 ± 15.9 months. Estimated survival at 1 and 3 years was 94.7% ± 1.6% and 84.6% ± 3.0%, respectively. Estimated freedom from re-intervention at 1 and 3 years was 96.1% ± 1.4%, and 90% ± 2.7%. Estimated target vessel stent patency at 1 and 3 years was 98.6% ± 0.5%, and 98.1% ± 0.6%, respectively. Mean aneurysm sac diameter decreased from 60.2 ± 9.3 mm pre-operatively to 53.2 ± 12.8 mm (p < .001). CONCLUSIONS: FEVAR as a first line strategy was associated with high technical success and a low operative mortality rate. Efficacy and durability in the mid-term appear very good, with significant regression of aneurysm sac diameter, high target vessel patency, and acceptable rate of re-intervention.

Editor's Choice - Ten-year Experience with Endovascular Repair of Thoracoabdominal Aortic Aneurysms: Results from 166 Consecutive Patients.

OBJECTIVE: To present a 10 year experience with endovascular thoracoabdominal aortic aneurysm (TAAA) repair using fenestrated and branched stent grafts. MATERIALS AND METHODS: Consecutive patients with TAAA treated with fenestrated and branched stent grafts within the period January 2004-December 2013. Data were collected prospectively. RESULTS: 166 patients (125 male, 41 female, mean age 68.8 ± 7.6 years) were treated. The mean TAAA diameter was 71 ± 9.3 mm. Types of TAAA were: type I, n = 12 (7.2%), type II, n = 50 (30.1%), type III, n = 53 (31.9%), type IV, n = 41 (24.8%), and type V, n = 10 (6%). Fifteen (9%) patients had an acute TAAA (11 contained rupture, 4 symptomatic). One hundred and eight (65%) patients were refused for open surgery earlier. Seventy eight (47%) patients had previously undergone one or more open/endovascular aortic procedures. Technical success was 95% (157/166). Thirty day operative mortality was 7.8% (13/166), with an in hospital mortality of 9% (15/166). Peri-operative spinal cord ischemia (SCI) was observed in 15 patients (9%), including permanent paraplegia in two (1.2%). Mean follow up was 29.2 ± 21 months. During follow up 40 patients died, two of them probably from aneurysm related cause. Re-intervention, mostly by endovascular means, was needed in 40 (24%) patients. Estimated survival at 1, 2, and 5 years was 83% ± 3%, 78% ± 3.5%, and 66.6% ± 6.1%, respectively. Estimated target vessel stent patency at 1, 2, and 5 years was 98% ± 0.6%, 97% ± 0.8%, and 94.2% ± 1.5%, respectively. Estimated freedom from re-intervention at 1 and 3 years was 88.3% ± 2.7%, and 78.4% ± 4.5%, respectively. CONCLUSIONS: Endovascular repair of TAAA with fenestrated and branched stent grafts in high volume centers appears safe and effective in the mid-term in a high risk patient cohort. A considerable reintervention rate should be acknowledged, however.

The new C3 Gore Excluder stent-graft: single-center experience with 100 patients.

OBJECTIVES: To present results from the first 100 patients treated with the new C3 Gore Excluder stent-graft in a single institution. METHODS: All patients treated with the C3 Excluder stent-graft between August 2010 and July 2013 in our institution were included. Patient demographics, treatment indication, need for intraoperative stent-graft repositioning, immediate technical success, survival, endoleak and migration rate, and need for reintervention during follow-up were analyzed. RESULTS: A total of 100 patients (86% male, mean age 71.1 ± 9.3 years) were enrolled. Elective abdominal aortic aneurysm (AAA) was the most common indication for treatment (n = 90), followed by common iliac artery aneurysm (n = 5), ruptured AAA (n = 2), type Ia endoleak (n = 1), and type IV endoleak (n = 1) after prior EVAR, and penetrating aortic ulcer (n = 1). Technical success was achieved in 98 patients. In two patients a small type I endoleak persisted at completion angiography, but had disappeared at the first control computed tomography angiogram. Stent-graft repositioning after initial deployment was required in 49 patients, almost equally distributed for level and contralateral gate reorientation. Exact positioning of the proximal trunk was achieved in 98 patients, with the remaining two cases within 5 mm of the intended location. Adverse events related to repositioning maneuvers were noticed in two cases. Mean follow-up duration was 12.2 ± 9.4 months (range 0-36 months). Eight patients died, none from aneurysm related causes. Cumulative patient survival was 96.2 ± 2.1% at 1 year, and 84 ± 6.1% at 2 years, respectively. No migration, or type I or III endoleak was detected during follow-up. Estimated freedom from reintervention was 96 ± 2.4% at 1 year, and 91 ± 5.2% at 2 years, respectively. CONCLUSIONS: The new C3 Excluder stent-graft provides excellent short-term outcomes and offers important advantages in terms of stent-graft repositioning to achieve high proximal deployment accuracy. Longer follow-up is required to confirm improved long-term outcome compared with the previous generation Excluder stent-graft.

[Results of endovascular repair of TAAA in the first 50  patients]. / Bericht über die ersten 50 endovaskulären thorako-abdominellen Behandlungen mit Seitenarmprothesen.

BACKGROUND: Developments with fenestrated and branched stent grafts have opened the way to treat complex aortic aneurysms involving the visceral arteries. First reports on endovascular treatment of thoracoabdominal aneurysms have demonstrated the feasibility of the technique. METHODS: A literature review and results of first 50  patients treated with a custom-made Zenith device with fixed branches are presented. Most of the patients were refused open surgery mainly for the extent of the disease combined with co-morbidity, which included in most patients a combination of several risk factors. Mean aneurysm size was 71 mm and extent of the aneurysm was type  I (n = 9), type  II (n = 13), type  III (n = 19), and type  IV (n = 9), respectively. RESULTS: Primary and primary assisted technical successes in our series were 88 % (44 / 50) and 92 % (46 / 50), respectively. One patient died on day  1 from an intraoperative aneurysm rupture. In two patients a renal artery was lost, one due to rupture and one due to malpositioning of the bridging stent graft. In a fourth patient, a celiac artery could not be catheterised and was lost. Finally, in two more patients, catheterisation of in total three renal arteries proved impossible. This was solved by a retrograde approach for two renal arteries via laparotomy in one patient, and a spleno-renal bypass in the other patient. Thirty-day mortality was 8 %. Estimated survival at 6  months, 1  year, and 2  years was 91.2 %, 79.8 %, and 69.7 %, respectively. Freedom of reintervention of all kinds at 1 and 2  years was 81.9 % and 73.7 %, respectively. CONCLUSION: Results of fully endovascular repair of thoracoabdominal aneurysms in a high-risk cohort are promising. A learning curve should be expected. Although longer term results need to be awaited, it is likely that endovascular repair of thoracoabdominal aneurysms will become a preferential treatment option for many patients in the future.

Averaged evoked responses in vigilance and discrimination: a reassessment.

With the use of monopolar recordings for averaged evoked responses, detected signals in a vigilance task are associated with a late positive component which is absent for undetected signals as well as nonsignals. Bipolar recordings obscure the late positive component associated with detected signals. The data suggest that the late positive component represents cerebral processes associated with evaluation of unpredictable changes in stimulation.

A brain event related to the making of a sensory discrimination.

Event-related potentials associated with detected targets in a vigilance task were analyzed in two ways: (i) by sorting the potentials in terms of sequential reaction time bins of 50 milliseconds and (ii) by examining the single trial waveforms. A negative component (N2) covaried in latency with reaction time. These results support the hypothesis that N2 reflects a decision process which controls behavioral responses in sensory discrimination tasks.

Manipulation of event-related potential manifestations of information processing stages.

The timing of two event-related potential components was differentially affected by two experimental variables. The earlier component (NA) was affected by degradation of the stimuli and the later component (N2) by the nature of a classification task. The results support the hypothesis that NA and N2 reflect sequential stages of information processing, namely, pattern recognition and stimulus classification.

Impaired mismatch negativity generation reflects widespread dysfunction of working memory in schizophrenia.

BACKGROUND: Impaired P300 (P3) generation is one of the most robust indices of brain dysfunction in schizophrenia. This study investigates the integrity of cognitive event-related potentials that precede P3 in an "oddball" paradigm to determine the earliest stages at which auditory information processing is impaired in schizophrenia. METHODS: Cognitive event-related potential components including mismatch negativity (MMN), N2, and P3 were recorded from subjects with chronic schizophrenia who were receiving medication (n = 20), from those who were withdrawn from drug treatment (n = 11), and from healthy volunteers (n = 11) during an auditory oddball paradigm. Recordings were made in both passive and active response conditions. The MMN, N2, and P3 amplitudes were compared across groups and the degree of MMN deficit was correlated with the degree of P3 reduction as a function of diagnostic group. RESULTS: Schizophrenic subjects showed severe impairments in the generation of MMN and N2 as well as P3. Across groups, the decrement in MMN amplitude correlated significantly with the decrement in P3 amplitude. There were no significant between-group differences in MMN topography. CONCLUSIONS: The present study demonstrates that the neurophysiological deficits associated with schizophrenia, as reflected in cognitive event-related potential generation, are pervasive, extending even to the level of the sensory cortex. Mismatch negativity indexes the functioning of an automatic alerting mechanism designed to stimulate individuals to explore unexpected environmental events. Dysfunction of this mechanism may contribute to the deficit state associated with schizophrenia.

Reduction in exertional myoglobinemia after physical conditioning.

The development of a sensitive radioimmunoassay for the measurement of myoglobin now permits the accurate determination and detection of even small concentrations of serum myoglobin. To determine the effect of exercise and physical conditioning on serum myoglobin levels, 16 male Army recruits (ages 18 to 28 years) underwent treadmill exercise and strenuous physical evaluation tests (PETs) that consisted of sit-ups, push-ups, horizontal ladder, obstacle course, and 3.2-km run. These tests and exercise were performed before and after 12 weeks of physical conditioning performed in conjunction with basic military training. Serum myoglobin levels did not rise after treadmill exercise, but they were increased greatly six hours after PET. After physical conditioning, serum myoglobin concentrations measured after the treadmill exercise remained normal and values after PET showed a significant decrease (P less than 0.001) as compared with those measured before physical conditioning (mean +/- SD, 160 +/- 81 ng/mL after initial PET vs 76 +/- 60 ng/mL after physical conditioning). These results demonstrate that physical training reduces the degree of myoglobinemia occurring after strenuous exercise, possibly by modifying skeletal muscle alterations that allow myoglobin release in this setting.

Percutaneous endovascular thrombosuction for acute lower limb ischemia: a 5-year single center experience.

AIM: The aim of this paper was to report a 5-year single center experience with the use of percutaneous endovascular thrombosuction (PET) for acute lower limb ischemia (ALLI). METHODS: All patients that underwent PET for ALLI within the period January 2009-December 2013 in our institution were included. Data were collected retrospectively. RESULTS: A total of 262 patients (132 female, mean age 74.5±11 years) were treated. Level of severity of ALLI preoperatively was stratified as class I (viable) in 76% (199/262) of patients, class IIa (threatened marginally) in 19.4% (51/262), and class IIb (threatened immediately) in 4.6% (12/262). Initial technical success was 91% (237/262). Additional PTA was performed in 29.8% (78/262) of patients, and PTA with stenting in 27.5% (72/262). Open surgery due to technical failure of PET was required in 4.2% (11/262) of patients. Thirty-day mortality was 4.6% (12/262). Perioperative complications occurred in 9.2% (24/262). Thirty-day amputation rate was 3.8% (10/262). The mean duration of follow-up was 26.2±16 months. Estimated cumulative survival was 84.2±2.5% at 1 year, and 73.7±3.6% at 3 years. Estimated freedom from amputation during follow-up was 92.4±1.8% at 1 year, and 91.2±2% at 3 years. Estimated freedom from reintervention was 90.4±2% at 1 year, and 80±3.7% at 3 years. CONCLUSION: PET in selected patients with ALLI provides high initial technical success, low mortality and morbidity rates, and favorable early and mid-term limb salvage rates.

Mismatch negativity during attend and ignore conditions in Alzheimer's disease.

Mismatch negativities (MMNs) of the event-related potential to deviant tones and environmental sounds were recorded during active and ignore oddball sequences in young and elderly controls and patients with probable Alzheimer's disease (PAD). MMNs were smaller in the PAD waveforms compared to those of the controls, suggesting a degraded sensory memory trace in these subjects; however, under ignore conditions, environmental sounds elicited robust MMNs in the PAD group along with N2b and novelty P3 components in similar fashion to controls. As N2b and P3 are usually elicited by attended stimuli, these data suggest that in the PAD subjects, the highly deviant events involuntarily captured attention, perhaps reflecting the activation of an attentional switching mechanism. Because this passive switching is thought to reflect activation of a mechanism located in the frontal lobes, the data suggest that this putative frontal lobe mechanism is relatively intact in the early stages of the disease.

Impairment of early cortical processing in schizophrenia: an event-related potential confirmation study.

Abnormalities of auditory information processing represent a core feature of schizophrenic psychopathology. Event-related potentials (ERP) provide an objective index of the information processing deficits associated with schizophrenia and a tool for investigation of the underlying pathophysiology. The best established abnormality is a decrease in the amplitude of auditory P300. In an "oddball" paradigm, P300 is preceded by a series of earlier, negative-polarity ERP components that index discrete, prior information-processing events. The earliest such component, mismatch negativity (MMN), is elicited whenever a deviant, "oddball" stimulus interrupts a sequence of repetitive standard stimuli. MMN is generated principally within primary auditory cortex or adjacent structures on the superior temporal plane, suggesting that it indexes the earliest cortical event in the cognitive processing of auditory information. In the present study, MMN was studied in a group of 14 chronic schizophrenic subjects relative to 12 age- and IQ-matched normal controls in a passive auditory oddball paradigm in order to test the hypothesis that auditory information processing is impaired in schizophrenia, even at the level of primary sensory cortex. Schizophrenic subjects showed a significant reduction in MMN amplitude relative to controls, with a trend toward a greater deficit on the left than the right side. The finding of impaired MMN generation in schizophrenia suggests that information processing is impaired even at the level of auditory cortex and that the pathophysiological processes underlying information processing dysfunction in schizophrenia are widespread throughout the cortex, rather than limited to high-order association cortex such as prefrontal or mesial temporal cortex.

Early and late cognitive event-related potentials mark stages of HIV-1 infection in the drug-user risk group.

HIV-1 (Human immunodeficiency virus) infection of the brain causes delays in auditory event-related potential (ERP) components. We recorded auditory ERPs from 38 former parenteral drug users (PDUs) at three stages of HIV-1 infection: seronegative; seropositive; stage II; and seropositive, stage IV. There were five response conditions: Go Nogo, Count, Simple Response, Simple Count, and Ignore. P3 peak latencies were significantly delayed and P3 amplitudes were significantly reduced for all seropositives, including asymptomatics, when compared to PDU seronegative controls. In contrast, the P1 and N1 peak latency measures were delayed only for seropositives with acquired immunodeficiency syndrome (AIDS) qualifying illnesses. There was a significant negative correlation between the CD4 count and the latency of P1, N1, and the MMN. Also, increased P1 and N1 amplitudes correlated with indices of disease progression (Choice RT and CD4 counts, respectively). The results extend previous findings by clarifying the pattern of auditory ERP markers of disease progression. Early, as well as late, brain involvement caused by HIV-1 is marked by delays and decreased amplitudes in cognitive components. In addition, late brain involvement is marked by delays and increased amplitudes in specific, automatic, and/or obligatory components.

An event-related potential study of age-related changes in sensitivity to stimulus deviance.

The mismatch negativity (MMN) of the event-related (brain) potential (ERP) has been shown to reflect the storage of information in sensory memory and is thought to reflect the operation of a mechanism that compares frequently occurring standard with infrequently occurring deviant acoustic events. The MMN was recorded from young (mean = 23 years) and elderly (mean = 72 years) adults to small (50 Hz) and large (300 Hz) frequency deviants and to a variety of novel, environmental sounds. At each level of deviance, MMN amplitude was smaller in the ERPs of older relative to younger adults. Young, but not older adults showed robust MMNs at the smallest level of deviance. Moreover, a P3 component was observed in the ERPs of the young to both large tonal and novel deviants, whereas a robust P3 component was evident only to the novel deviants in the ERPs of the old. The data suggest that older adults demonstrate less sensitivity to stimulus deviance and that only highly deviant events are likely to involuntarily capture their attention.

Auditory sensory ("echoic") memory dysfunction in schizophrenia.

OBJECTIVE: Studies of working memory dysfunction in schizophrenia have focused largely on prefrontal components. This study investigated the integrity of auditory sensory ("echoic") memory, a component that shows little dependence on prefrontal functioning. METHOD: Echoic memory was investigated in 20 schizophrenic subjects and 20 age- and IQ-matched normal comparison subjects with the use of nondelayed and delayed tone matching. RESULTS: Schizophrenic subjects were markedly impaired in their ability to match two tones after an extremely brief delay between them (300 msec) but were unimpaired when there was no delay between tones. CONCLUSIONS: Working memory dysfunction in schizophrenia affects brain regions outside the prefrontal cortex as well as within.

Multiple visuospatial working memory buffers: evidence from spatiotemporal patterns of brain activity.

Numerous studies have shown that the visual system involves different cortical pathways in the perception of object (ventral visual pathway) and spatial (dorsal visual pathway) information. The present study was concerned with whether human visuospatial working memory divides along similar lines. We used event-related brain potentials (ERPs) recorded from scalp of normal humans to show the existence of different buffering systems for the retention of object and spatial visual information. Subjects were presented with object or spatial stimuli to be retained for a 3.6-sec interval. The ERPs isolated brain activity associated with retention from earlier storage and later retrieval processes. The ERP scalp topographies indicated that the underlying patterns of brain activation were different during retention of object and spatial information.

The development of auditory attention in children.

In this paper we review the development of four components of auditory attention: arousal, orienting, selective attention and sustained attention. We focus especially on the processes responsible for the selection of specific stimuli for further processing because these are essential for learning and development. Although much work still needs to be done, there is evidence of developmental change in some of the components of attention, especially early in infancy. Later developmental improvements seem to be primarily attributable to higher cognitive processes, such as motivation, strategy development and implementation, and voluntary direction and regulation of attention.

The molecular structure of indium-DTPA.

The x-ray structural characterization of Na2In(DTPA).7 H2O is described. The structure is notable for two reasons. It is the first In3+-complex with relevance to antibody attachment to be structurally characterized. Surprisingly, the complex has coordination number eight and is the first monomeric In3+-complex with such a high coordination number. The potentially octadentate ligand binds through three amino groups and five deprotonated carboxylate groups to the metal ion. The ligand atoms surround the central indium atom in a slightly distorted Archimedian antiprismatic configuration. High resolution nuclear magnetic resonance studies in solution show that this high coordination number also pertains in aqueous medium. Consequently, one may conclude that octadentate ligands are optimal for the thermodynamic and kinetic stabilization of In3+ in living systems. It is also indicated that bifunctional diethylenetriaminepentaacetic acid (DTPA) is superior to amide bound (= sevendentate) DTPA in antibody labeling.

Permanent pacing in patients with transient trifascicular block during acute myocardial infarction.

Patients with acute myocardial infarction and transient complete atrioventricular (A-V) block in association with right bundle branch block and left anterior hemiblock have a high incidence rate of late sudden death presumably due to recurrent A-V block. Over a 5 year period, 18 patients demonstrated right bundle branch block and left anterior hemiblock and had transient complete block during an acute myocardial infarction and survived to hospital discharge. Of six patients who did not have permanent pacing, five died suddenly (one was lost to follow-up) with a mean survival time of 2.4 months after hospital discharge. Twelve subsequent patients received permanent demand pacemakers and had a significantly improved prognosis with a mean survival time of 18 months (P less than 0.001). Six patients were still alive at an average follow-up time of 20 months. Prophylactic permanent pacing significantly improves the prognosis after acute myocardial infarction in this select subgroup of patients.