LRP1 regulates food intake and energy balance in GABAergic neurons independently of leptin action.

Low-density lipoprotein receptor-related protein 1 (LRP1) is a member of LDL receptor family that plays a key role in systemic glucose and lipid homeostasis. LRP1 also regulates energy balance in the hypothalamus by mediating leptin's anorexigenic action, although the underlying neurocircuitry involved is still unclear. Because GABAergic neurons are a major mediator of hypothalamic leptin action, we studied the role of GABAergic LRP1 in energy balance and leptin action using mice lacking LRP1 in Vgat- or AgRP-expressing neurons (Vgat-Cre; LRP1loxP/loxP or AgRP-Cre; LRP1loxP/loxP). Here, we show that LRP1 deficiency in GABAergic neurons results in severe obesity in male and female mice fed a normal-chow diet. This effect is most likely due to increased food intake and decreased energy expenditure and locomotor activity. Increased adiposity in GABAergic neuron-specific LRP1-deficient mice is accompanied by hyperleptinemia and hyperinsulinemia. Insulin resistance and glucose intolerance in these mice are occurred without change in body weight. Importantly, LRP1 in GABAergic neurons is not required for leptin action, as evidenced by normal leptin's anorexigenic action and leptin-induced hypothalamic Stat3 phosphorylation. In contrast, LRP1 deficiency in AgRP neurons has no effect on adiposity and caloric intake. In conclusion, our data identify GABAergic neurons as a key neurocircuitry that underpins LRP1-dependent regulation of systemic energy balance and body-weight homeostasis. We further find that the GABAergic LRP1 signaling pathway modulates food intake and energy expenditure independently of leptin signaling and AgRP neurons.

[18F]-THK5351 PET Imaging in Patients With Semantic Variant Primary Progressive Aphasia.

BACKGROUND: Semantic variant primary progressive aphasia (svPPA) has been associated with a variety of proteinopathies, mainly transactive response DNA-binding protein, but also with tau and ß-amyloid. Recently selective tau tracers for positron emission tomography (PET) have been developed to determine the presence of cerebral tau deposits in vivo. Here, we investigated the topographical distribution of THK5351 in svPPA patients. MATERIALS AND METHODS: Five svPPA patients, 14 Alzheimer's disease patients, and 15 age-matched normal controls underwent [F]-THK5351 PET scans, magnetic resonance imaging, and detailed neuropsychological tests. [F]-fluorodeoxyglucose PET was obtained in 3 svPPA patients, whereas the remaining 2 underwent amyloid PET using [F]-flutemetamol. Tau distribution among the 3 groups was compared using regions of interest-based and voxel-based statistical analyses. RESULTS: In svPPA patients, [F]-THK5351 retention was elevated in the anteroinferior and lateral temporal cortices compared with the normal controls group (left>right), and in the left inferior and temporal polar region compared with Alzheimer's disease patients. [F]-THK5351 retention inversely correlated with glucose metabolism, whereas regional THK retention correlated with clinical severity. [F]-flutemetamol scans were negative for ß-amyloid. CONCLUSIONS: These findings show that [F]-THK5351 retention may be detected in cortical regions correlating with svPPA pathology.

Risk factor analysis of parenteral nutrition-associated cholestasis in extremely low birth weight infants.

AIM: Parenteral nutrition (PN) provides an alternative nutrition source for preterm infants who are intolerant of enteral nutrition. However, prolonged PN increases the risk of PN-associated cholestasis (PNAC). We conducted this study to determine the incidence and risk factors of PNAC in extremely low birth weight (ELBW) infants. METHODS: We retrospectively reviewed the medical records of ELBW infants from March 2010 to April 2015. PNAC was diagnosed in infants with a history of PN for at least two weeks and direct bilirubin concentrations >2 mg/dL after other causes of neonatal cholestasis were excluded. RESULTS: Of the 114 eligible ELBW infants, 41 (36%) were diagnosed with PNAC. The multivariate analysis showed that birth weight, sepsis, necrotising enterocolitis, fluconazole prophylaxis and the duration of PN and hospitalisation were independent risk factors for the development of PNAC (p < 0.05). However, parenteral fish oil-based lipid preparation (FOLP) did not reduce the risk of PNAC. Although PNAC was not a direct cause of death, it was associated with an increased risk of mortality. CONCLUSION: PNAC was common in ELBW infants, was associated with various clinical factors and increased the risk of mortality. However, we did not observe the protective effect of FOLP against PNAC.

Low-frequency oscillations in cerebrovascular and cardiovascular hemodynamics: Their interrelationships and the effect of age.

The aim of this study was to investigate how the interrelationships between low-frequency oscillations (LFOs) in the cerebral and systemic cardiovascular hemodynamic systems change with aging and systemic hemodynamic perturbation. Seventeen young adult (28.4±3.5years) and seventeen elderly subjects (69.4±8.7years) underwent continuous measurements of arterial blood pressure (ABP), heart rate (HR), and cerebral oxygenation (oxy-hemoglobin, deoxy-hemoglobin, and total hemoglobin) using near-infrared spectroscopy. The LFOs were subdivided into three frequency intervals (FI-1: 0.01-0.02Hz, FI-2: 0.02-0.06Hz, and FI-3: 0.06-0.15Hz) via spectral analysis based on continuous wavelet transform. The amplitudes of the LFOs at these FIs were calculated to examine the effects of aging and head-up tilt (HUT) on cerebral and cardiovascular hemodynamics. Granger causality (GC) was used for analyzing the causal relationships between the LFOs observed in ABP, oxy-hemoglobin, and HR. The amplitudes of the LFOs were generally higher in young adults than in the elderly and increased significantly only in the younger subjects after HUT. GCs in FI-3 oscillations were significantly higher in young subjects compared to older participants in the HUT state. These results indicate that aging dampens systemic and cerebral hemodynamic regulatory mechanisms, and the interrelationships between systemic and cerebral hemodynamics become weaker with age.

Development-assistance Strategies for Stroke in Low- and Middle-income Countries.

While communicable diseases still pose a serious health threat in developing countries, previously neglected health issues caused by non-communicable diseases such as stroke are rapidly becoming a major burden to these countries. In this review we will discuss the features and current status of stroke in low- and middle-income countries (LMICs). Overall the global burden of hemorrhagic stroke is larger than ischemic stroke, with a disproportionately greater burden, measured in incidence and disability-adjusted life-years, regionally localized in LMICs. Patients in poorer countries suffer due to insufficient primary care needed to control risk factors such as hypertension, and inadequate emergency care systems through which sudden events should be managed. In light of these situations, we emphasize two strategic points for development assistance. First, assistance should be provided for bolstering, integrating, and coordinating both the primary health and emergency care systems, in order to prevent stroke and strengthen stroke management, respectively. Second, the assistance needs to focus on programs at the community level, to reduce life-style risks of stroke in a more sustainable manner, and to improve stroke outcomes more effectively.

Cystatin C, a novel indicator of renal function, reflects severity of cerebral microbleeds.

BACKGROUND: Chronic renal insufficiency, diagnosed using creatinine based estimated glomerular filtration rate (GFR) or microalbumiuria, has been associated with the presence of cerebral microbleeds (CMBs). Cystatin C has been shown to be a more sensitive renal indicator than conventional renal markers. Under the assumption that similar pathologic mechanisms of the small vessel exist in the brain and kidney, we hypothesized that the levels of cystatin C may delineate the relationship between CMBs and renal insufficiency by detecting subclinical kidney dysfunction, which may be underestimated by other indicators, and thus reflect the severity of CMBs more accurately. METHODS: Data was prospectively collected for 683 patients with ischemic stroke. The severity of CMBs was categorized by the number of lesions. Patients were divided into quartiles of cystatin C, estimated GFR and microalbumin/creatinine ratios. Ordinal logistic regression analysis was used to examine the association of each renal indicator with CMBs. RESULTS: In models including both quartiles of cystatin C and estimated GFR, only cystatin C quartiles were significant (the highest vs. the lowest, adjusted OR, 1.88; 95% CI 1.05-3.38; p = 0.03) in contrast to estimated GFR (the highest vs. the lowest, adjusted OR, 1.28; 95% CI 0.38-4.36; p = 0.70). A model including both quartiles of cystatin C and microalbumin/creatinine ratio also showed that only cystatin C quartiles was associated with CMBs (the highest vs. the lowest, adjusted OR, 2.06; 95% CI 1.07-3.94; p = 0.03). These associations were also observed in the logistic models using log transformed-cystatin C, albumin/creatinine ratio and estimated GFR as continuous variables. Cystatin C was a significant indicator of deep or infratenorial CMBs, but not strictly lobar CMBs. In addition, cystatin C showed the greatest significance in c-statistics for the presence of CMBs (AUC = 0.73 ± 0.03; 95% CI 0.66-0.76; p = 0.02). CONCLUSION: Cystatin C may be the most sensitive indicator of CMB severity among the renal disease markers.

LRP1 in GABAergic neurons is a key link between obesity and memory function.

OBJECTIVE: Low-density lipoprotein receptor-related protein-1 (LRP1) regulates energy homeostasis, blood-brain barrier integrity, and metabolic signaling in the brain. Deficiency of LRP1 in inhibitory gamma-aminobutyric acid (GABA)ergic neurons causes severe obesity in mice. However, the impact of LRP1 in inhibitory neurons on memory function and cognition in the context of obesity is poorly understood. METHODS: Mice lacking LRP1 in GABAergic neurons (Vgat-Cre; LRP1loxP/loxP) underwent behavioral tests for locomotor activity and motor coordination, short/long-term and spatial memory, and fear learning/memory. This study evaluated the relationships between behavior and metabolic risk factors and followed the mice at 16 and 32 weeks of age. RESULTS: Deletion of LRP1 in GABAergic neurons caused a significant impairment in memory function in 32-week-old mice. In the spatial Y-maze test, Vgat-Cre; LRP1loxP/loxP mice exhibited decreased travel distance and duration in the novel arm compared with controls (LRP1loxP/loxP mice). In addition, GABAergic neuron-specific LRP1-deficient mice showed a diminished capacity for performing learning and memory tasks during the water T-maze test. Moreover, reduced freezing time was observed in these mice during the contextual and cued fear conditioning tests. These effects were accompanied by increased neuronal necrosis and satellitosis in the hippocampus. Importantly, the distance and duration in the novel arm, as well as the performance of the reversal water T-maze test, negatively correlated with metabolic risk parameters, including body weight, serum leptin, insulin, and apolipoprotein J. However, in 16-week-old Vgat-Cre; LRP1loxP/loxP mice, there were no differences in the behavioral tests or correlations between metabolic parameters and cognition. CONCLUSIONS: Our findings demonstrate that LRP1 from GABAergic neurons is important in regulating normal learning and memory. Metabolically, obesity caused by GABAergic LRP1 deletion negatively regulates memory and cognitive function in an age-dependent manner. Thus, LRP1 in GABAergic neurons may play a crucial role in maintaining normal excitatory/inhibitory balance, impacting memory function, and reinforcing the potential importance of LRP1 in neural system integrity.

Building Better Bridges: Outcomes of a Community-Partnered New School Transition Intervention for Students on the Autism Spectrum.

New school transitions can be challenging for students on the autism spectrum. No published, evidence-based interventions exist to support families and teachers of students transitioning to elementary and secondary school during this critical period. Using Community Partnered Participatory Research, we developed Building Better Bridges (BBB), a caregiver coaching intervention that includes training on effective school communication, educational rights, advocacy, and child preparation strategies. We compared BBB (n = 83) to a module/resources-only comparison (n = 87) in a four-site randomized controlled trial in racially and ethnically diverse, under-resourced communities. In our intent-to-treat analysis, caregivers and teachers in BBB rated students' transitions to the new classroom as more positive, relative to the comparison group. Results suggest this low-cost intervention can improve the transition process for families and students at high risk of poor transitions.

Prosthetics, Medicine, and Disability in Modern America: The Case of the A. A. Marks Artificial Limb Company.

Through the case of the A. A. Marks Artificial Limb Company, this article explores how the technology and business of prosthetics grew in America up to the First World War. In 1853, Amasa A. Marks established the artificial limb company A. A. Marks in New York. By the time of the First World War, the company had become the largest supplier of artificial limbs in the United States and had gained international recognition, exporting its products all over the world. Focusing on the company's growth before the war, this paper analyzes how American artificial limb makers positioned themselves between art and medicine and between surgeons and disabled customers at a time when their occupation had yet to be established as a specialized profession. From the mid-nineteenth century when the artificial limb business burgeoned to the First World War, American society went through various social and cultural changes that influenced the prosthetics industry and the perception of disability. During the Civil War, numerous soldiers were injured but survived because advancements in amputation techniques enabled surgeons to save more lives despite limb loss. The growing number of maimed veterans required more mechanical and public support for their rehabilitation. As a reconstruction project of the nation and a way to address the sense of damaged masculinity felt by injured war veterans, both Union and Confederate states approved support for providing them with artificial limbs at public expense. In postbellum America, as well as deformity and amputation, industrialization created a need for artificial limbs as the brutality of advanced weapons and unfortunate accidents involving machines and railroads increased the number of amputees. Thus during the late nineteenth century and early twentieth century, recognition of maimed bodies in public places went through a legislative and cultural transformation. The growth of artificial limb manufacturer A. A. Marks was in tune with such technological, medical, and sociocultural changes. Along with technological innovations and patents to protect these innovations, Amasa Marks devised various marketing methods and strategies through which the company secured customers and finally expanded the prosthetics market. As its customers increased, the company accumulated quantitative and qualitative data from patients' responses and interviews, and its own observations. In the late nineteenth century, George E. Marks, Amasa Marks's son and a representative of the company, analyzed customers' experiences of disability, gathering information on patterns of disability and mortality rates. Based on the company's rich experience with a large number of patient cases, George Marks advanced criticisms of surgical methods and provided second opinions on amputation surgeries. In doing so, he attempted to promote the limb maker's position from mere artisan to specialist, redefining the relationship between medicine and prosthetics and between surgeon and prosthetist. He also conveyed patients' complaints and needs to the medical men in the process, and distributed the company's findings and knowledge to surgeons and the general public by publishing treatises, articles, and manuals. Consequently, the company influenced an important epistemological turn in which the prosthetic perspective was considered prior to amputation surgery, not just as an inevitable follow-up.

"It's Taboo to Talk About It": Korean American Clergy Members' Views of Mental Health.

Korean Americans are more likely to seek guidance from church leaders than to use traditional mental health services. Through semistructured key informant interviews with 16 Christian clergy members serving later-generation Korean Americans, the authors explored clergy members' perceptions of the mental health needs of their congregants. Insights from the study suggested that communication and collaboration between mental health professionals and church leaders may be helpful in addressing the Korean American community's emotional and mental health needs.

Sex Differences in Periprocedural and Long-Term Outcomes Following Transcatheter Left Atrial Appendage Occlusion: A Systematic Review and Meta-Analysis.

BACKGROUND: Atrial fibrillation (AF) is among the most common arrhythmias associated with an increased risk of cardioembolic phenomena, including stroke. Percutaneous left atrial appendage occlusion (LAAO) has proven beneficial in reducing stroke and mortality in patients with atrial fibrillation who have contraindications to anticoagulation. However, the sex differences in outcomes following LAAO have not been studied systematically. METHODS: Electronic databases PUBMED, Embase, and Web of Science were systematically searched until March 2022 for studies evaluating patient outcomes following LAAO for AF. The primary outcomes of interest were the risks of periprocedural stroke, major bleeding, pericardial complications, and all-cause mortality. Secondary outcomes included stroke risks, major bleeding, device-related thrombus, cardiovascular and all-cause mortality on long-term follow-up. A random-effects model meta-analysis was conducted, and heterogeneity was assessed using the I-squared test. RESULTS: Sixteen studies were included in the final analysis encompassing 111,775 patients, out of which 45,441 (40.7 %) were women. Women had a significantly higher risk of peri-procedural complications including all-cause mortality [relative risk (RR), 95 % confidence intervals (CI); RR 1.94, 95 % CI 1.40-2.69], stroke [RR 1.85, 95 % CI 1.29-2.67], major bleeding [RR 1.63, 95 % CI 1.08-2.44], and pericardial events [RR 1.80, 95 % CI 1.58-2.05]. However, there were no statistically significant differences between sexes in terms of risk of stroke, major bleeding, device-related thrombus, cardiovascular and all-cause mortality on long-term follow-up. CONCLUSION: Among patients undergoing LAAO implantation, women were at higher risk of periprocedural complications than men. This risk was not significant on long-term follow-up.

Change in prostaglandin expression levels and synthesizing activities in dry eye disease.

OBJECTIVE: To investigate the expression level of prostaglandins (PGs) and their de novo synthesis in dry eye (DE) disease. DESIGN: Cross-sectional case-control study and in vivo mouse experimental study. PARTICIPANTS: Forty-six eyes from 23 DE patients and 33 eyes from 17 age- and sex-matched controls were studied. Also, DE-induced murine eyes were compared with control eyes. METHODS: Patients completed a symptom questionnaire using a 100-mm visual analog scale (VAS). Nano-liquid chromatography tandem mass spectrometry was used for the quantification of PGE2 and PGD2. A DE disease environmental chamber was used to induce DE in mice. One week after induction, enzyme expressions of cyclooxygenase-1, cyclooxygenase-2 (COX-2), PG E synthase (PGES), and PG D synthase (PGDS) in the lacrimal glands, meibomian glands, and corneas were examined using immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). MAIN OUTCOME MEASURES: The mean PGE2 and PGD2 levels in the tears of DE patients were measured and compared with symptom severity scores. Immunohistochemistry staining patterns and qRT-PCR data of DE mice were quantified. RESULTS: The mean PGE2 level in the tears of DE patients (2.72 ±3 .42 ng/ml) was significantly higher than that in the control group (0.88 ± 0.83 ng/ml; P = 0.003). However, the mean PGD2 level in the tears of DE patients (0.11 ± 0.22 ng/ml) was significantly lower (0.91 ± 3.28 ng/ml; P = 0.028). The mean PGE2-to-PGD2 ratio correlated strongly with VAS scoring (P = 0.008). In DE mice, COX-2 mRNA was significantly higher in ocular surface tissue and lacrimal glands. Furthermore, PGES mRNA was significantly higher in ocular surface tissue, whereas PGDS mRNA was decreased. Immunohistochemistry staining showed elevated COX-2 expression in the lacrimal glands, meibomian glands, corneas, and conjunctivas. Furthermore, PGES expression was found in periductal infiltrated cells of the lacrimal glands and conjunctival epithelium. Also, PGDS expression was decreased in meibomian glands and increased focally in the conjunctival epithelium. CONCLUSIONS: A reciprocal change in PGE2 and PGD2 levels was found in the tears of DE patients, which correlated with patients' symptom scores. These clinical results were supported by increased COX-2 and PGES expression levels found in tear-producing tissues of DE mice.

Dr. James Smith's Dream of Eradicating Smallpox and the National Vaccine Institution.

This article re-examines from a new perspective the efforts of James Smith (1771-1841), a Maryland doctor, to eradicate smallpox in the United States. As one of the few successful cowpox inoculators at the turn of the nineteenth century, Smith recognized the necessity for a public vaccine institution that could ensure the safe production and continuous preservation and circulation of vaccine matter. Thus, he devoted himself to creating statewide and national vaccine institutions funded by the state and federal governments. He established the National Vaccine Institution (NVI), but despite his efforts, the NVI existed only a short time from 1813 to 1822. Previous studies on Smith have focused on the 1813 Vaccination Act (An Act to Encourage Vaccination) and the NVI, and have evaluated them as failed projects or historically missed opportunities. However, this kind of approach does not justly place the act and institutions within Smith's larger plan and do not fully discuss the role of the NVI in his system of promoting vaccination in the United States. This article analyzes how he responded to the problems hindering cowpox vaccination, including spurious vaccine, failed vaccination, and low public acceptance of cowpox vaccine. In doing so, this study shows that Smith attempted to establish a universal and systematic vaccination system connecting citizens, government, and medical personnel through the NVI, as well as ensuring a safe and regular supply of vaccine.

Translocator Protein (18 kDa) Polymorphism (rs6971) in the Korean Population.

Background and Purpose: The expression of the 18-kDA mitochondrial translocator protein (TSPO) in the brain is an attractive target to study neuroinflammation. However, the binding properties of TSPO ligands are reportedly dependent on genetic polymorphism of the TSPO gene (rs6971). The objective of this study is to investigate the rs6971 gene polymorphism in the Korean population. Methods: We performed genetic testing on 109 subjects including patients with mild cognitive impairment, Alzheimer's disease (AD) dementia, non-AD dementia, and cognitively unimpaired participants. Magnetic resonance imaging scans and detailed neuropsychological tests were also performed, and 29 participants underwent 18F-DPA714 PET scans. Exon 4 of the TSPO gene containing the polymorphism rs6971 (Ala or Thr at position 147) was polymerase chain reaction amplified and sequenced using the Sanger method. The identified rs6971 genotype codes (C/C, C/T, or T/T) of the TSPO protein generated high-, mixed-, or low-affinity binding phenotypes (HABs, MABs, and LABs), respectively. Results: We found that 96.3% of the study subjects were HAB (105 out of 109 subjects), and 3.7% of the subjects were MAB (4 out of 109 subjects). 18F-DPA-714 PET scans showed nonspecific binding to the thalamus and brainstem, and increased tracer uptake throughout the cortex in cognitively impaired patients. The participant with the MAB polymorphism had a higher DPA714 signal throughout the cortex. Conclusions: The majority of Koreans are HAB (aprox. 96%). Therefore, the polymorphism of the rs6971 gene would have a smaller impact on the availability of second-generation TSPO PET tracers.

Executive Summary of the 2021 International Conference of Korean Dementia Association: A Report From the Academic Committee of the Korean Dementia Association.

Recently, aducanumab, a beta amyloid targeted immunotherapy, has been approved by the US Food and Drug Administration for the treatment of Alzheimer's dementia (AD). Although many questions need to be answered, this approval provides a promising hope for the development of AD drugs that could be supported by new biomarkers such as blood-based ones and composite neuropsychological tests that can confirm pathologic changes in early stages of AD. It is important to elucidate the complexity of AD which is known to be associated with other factors such as vascular etiologies and neuro-inflammation. Through the second international conference of the Korean Dementia Association (KDA), researchers from all over the world have participated in the exchange of opinions with KDA members on the most up-to-date topics. The Academic Committee of the KDA summarizes lectures to provide the depth of the conference as well as discussions. This will be an important milestone to widen the latest knowledge in the research of AD's diagnosis, therapeutics, pathogenesis that can lead to the establishment of future directions.

Recent progress in development and applications of second near-infrared (NIR-II) nanoprobes.

Optical probes for near-infrared (NIR) light have clear advantages over UV/VIS-based optical probes, such as their low levels of interfering auto-fluorescence and high tissue penetration. The second NIR (NIR-II) window (1000-1350 nm) offers better light penetration, lower background signal, higher safety limit, and higher maximum permitted exposure than the first NIR (NIR-I) window (650-950 nm). Therefore, NIR-II laser-based photoacoustic (PA) and fluorescence (FL) imaging can offer higher sensitivity and penetration depth than was previously available, and deeper lesions can be treated in vivo by photothermal therapy (PTT) and photodynamic therapy (PDT) with an NIR-II laser than with an NIR-I laser. Advances in creation of novel nanomaterials have increased options for improving light-induced bioimaging and treatment. Nanotechnology can provide advantages such as good disease targeting ability and relatively long circulation times to supplement the advantages of optical technologies. In this review, we present recent progress in development and applications of NIR-II light-based nanoplatforms for FL, PA, image-guided surgery, PDT, and PTT. We also discuss recent advances in smart NIR-II nanoprobes that can respond to stimuli in the tumor microenvironment and inflamed sites. Finally, we consider the challenges involved in using NIR-II nanomedicine for effective diagnosis and treatment.

Meta-Analysis of Gender Disparities in In-hospital Care and Outcomes in Patients with ST-Segment Elevation Myocardial Infarction.

Gender disparities in ST-segment elevation myocardial infarction (STEMI) outcomes continue to be reported worldwide; however, the magnitude of this gap remains unknown. To evaluate gender-based discrepancies in clinical outcomes and identify the primary driving factors a global meta-analysis was performed. Studies were selected if they included all comers with STEMI, reported gender specific patient characteristics, treatments, and outcomes, according to the registered PROSPERO protocol: CRD42020161469. A total of 56 studies (705,098 patients, 31% females) were included. Females were older, had more comorbidities and received less antiplatelet therapy and primary percutaneous coronary intervention (PCI). Females experienced significantly longer delays to first medical contact (mean difference 42.5 min) and door-to-balloon time (mean difference 4.9 min). In-hospital, females had increased rates of mortality (odds ratio [OR] 1.91, 95% confidence interval [CI] 1.84 to 1.99, p <0.00001), repeat myocardial infarction (MI) (OR 1.25, 95% CI 1.00 to 1.56, p=0.05), stroke (OR 1.67, 95% CI 1.27 to 2.20, p <0.001), and major bleeding (OR 1.82, 95% CI 1.56 to 2.12, p <0.00001) compared with males. Older age at presentation was the primary driver of excess mortality in females, although other factors including lower rates of primary PCI and aspirin usage, and longer door-to-balloon times contributed. In contrast, excess rates of repeat MI and stroke in females appeared to be driven, at least in part, by lower use of primary PCI and P2Y12 inhibitors, respectively. In conclusion, despite improvements in STEMI care, women continue to have in-hospital rates of mortality, repeat MI, stroke, and major bleeding up to 2-fold higher than men. Gender disparities in in-hospital outcomes can largely be explained by age differences at presentation but comorbidities, delays to care and suboptimal treatment experienced by women may contribute to the gender gap.

Functional MR angiography using phase contrast imaging technique at 3T MRI.

PURPOSE: Phase contrast magnetic resonance angiography (PC MRA) is an important, non-invasive method for obtaining quantitative information on blood flow. The purpose of the present study was to investigate the dynamic cerebral arterial response in humans to visual stimulation by quantitative velocity analysis using PC MRA. METHODS: Functional PC MRA (fPCA) images at 3 Tesla MRI were acquired with a total acquisition time of 10 m 18 s for 2 rest and 1 visual stimulation sessions using a flashing checker board. Twelve healthy subjects participated in this study. Circular regions of interest (ROIs) consisting of 21 pixels were analyzed to determine the velocity changes due to visual stimulation in selected vessel segments supplying the visual cortex. Time-of-flight (TOF) MRA and PC MRA reference volume images were then compared to measure the signal intensity and quantitative blood velocity changes in the cerebral vessels. RESULTS: The mean velocity changes measured by PC MRA between rest and stimulation were 0.64 and 0.42 cm/s within the peak ROI and distal ROIs of the selected blood vessels, which corresponds to a 42.9% and 30.1% increase, respectively. Both TOF MRA and PC MRA reference volume images also exhibited an increase in the signal intensity of the target vessels during stimulation. CONCLUSION: This study demonstrated that fPCA could play a role in the quantitative analysis of the functional cerebral vascular response by measuring dynamic vascular changes in intensity and velocity in small arteries.

Activation of the stress protein response inhibits the STAT1 signalling pathway and iNOS function in alveolar macrophages: role of Hsp90 and Hsp70.

BACKGROUND AND AIM: Alveolar fluid clearance is impaired by inducible nitric oxide synthase (iNOS)/nitric oxide (NO)-dependent mechanisms in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). The activation of the stress protein response (SPR) in alveolar macrophages on iNOS-dependent NO production in response to interferon gamma (IFNgamma), a major cytokine present in the airspace of patients with ALI, was investigated. METHODS: The SPR was activated in murine and primary human alveolar macrophages prior to analysis of signal transducer and activator of transcription factor 1 (STAT1) activation, iNOS mRNA and protein synthesis, and NO production. RESULTS: SPR activation resulted in inhibition of IFNgamma-mediated NO production (p=0.001) with >95% detergent insolubilisation of the STAT1 protein. Its subsequent proteasomal degradation was partially reversed with pretreatment of cells with the chemical chaperone glycerol. This early effect of the SPR was caused by the complete disruption of heat shock protein 90 (Hsp90)-STAT1 binding, as shown by immunoprecipitation. Recovery of STAT1 activation and recovery of iNOS synthesis occurred within 12 h after SPR activation (p=0.02). NO production (as compared with non-SPR controls) did not occur until 48 h later (p=0.02). SPR-induced Hsp70 (Hsp70i) expression caused a late inhibition of NO production (p=0.02). Inhibiting >50% Hsp70i expression recovered NO production to control levels whereas overexpressing Hsp70i in the absence of the SPR inhibited NO production (p=0.02). CONCLUSION: Early inhibition of STAT1 following its dissociation from Hsp90, and later inhibition of iNOS activity by Hsp70i, represent novel mechanisms by which SPR activation modulates the IFNgamma signalling in alveolar macrophages. These results highlight a potential clinical application for Hsp90 inhibitors in modulating NO signalling during the early phase of acute lung injury.

Effect of stellate ganglion block on the cerebrovascular system: magnetic resonance angiography study.

BACKGROUND: Several studies have shown that stellate ganglion block (SGB) is an effective treatment for certain cerebrovascular related diseases; however, the direct effect of SGB on the cerebral vasculature is still unknown. The present study investigated the effect of SGB on the cerebral vascular system using magnetic resonance angiography. METHODS: Time-of-flight magnetic resonance angiography images of 19 healthy female volunteers (mean ages of 46.4 ± 8.9 yr) were obtained before and after SGB with 1.5-T magnetic resonance imaging. The authors determined successful interruption of sympathetic innervation to the head with the appearance of Horner syndrome and conjunctival injection. We measured changes in the average signal intensity and diameter of the major intracranial and extracranial arteries and their branches, which were presented with mean (±SE). RESULTS: The signal intensity changes were observed mainly in the ipsilateral extracranial vessels; the external carotid artery (11.2%, P < 0.001) and its downstream branches, such as the occipital artery (9.5%, P < 0.001) and superficial temporal artery (14.1%, P < 0.001). In contrast, the intensities of the intracranial arteries did not change with the exception of the ipsilateral ophthalmic artery, which increased significantly (10.0%, P = 0.008). After SGB, only the diameter of the ipsilateral external carotid artery was significantly increased (26.5%, P < 0.001). CONCLUSIONS: We were able to observe significant changes in the extracranial vessels, whereas the intracranial vessels were relatively unaffected (except for the ophthalmic artery), demonstrating that both perivascular nerve control and sympathetic nerve control mechanisms may contribute to the control of intracranial and extracranial blood vessels, respectively, after SGB.