HDAC inhibitor protects chronic cerebral hypoperfusion and oxygen-glucose deprivation injuries via H3K14 and H4K5 acetylation-mediated BDNF expression.

Vascular dementia (VaD) is the second most common cause of dementia, but the treatment is still lacking. Although many studies have reported that histone deacetylase inhibitors (HDACis) confer protective effects against ischemic and hypoxic injuries, their role in VaD is still uncertain. Previous studies shown, one HDACi protected against cognitive decline in animals with chronic cerebral hypoperfusion (CCH). However, the underlying mechanisms remain elusive. In this study, we tested several 10,11-dihydro-5H-dibenzo[b,f]azepine hydroxamates, which act as HDACis in the CCH model (in vivo), and SH-SY5Y (neuroblastoma cells) with oxygen-glucose deprivation (OGD, in vitro). We identified a compound 13, which exhibited the best cell viability under OGD. The compound 13 could increase, in part, the protein levels of brain-derived neurotrophic factor (BDNF). It increased acetylation status on lysine 14 residue of histone 3 (H3K14) and lysine 5 of histone 4 (H4K5). We further clarified which promoters (I, II, III, IV or IX) could be affected by histone acetylation altered by compound 13. The results of chromatin immunoprecipitation and Q-PCR analysis indicate that an increase in H3K14 acetylation leads to an increase in the expression of BDNF promoter II, while an increase in H4K5 acetylation results in an increase in the activity of BDNF promoter II and III. Afterwards, these cause an increase in the expression of BDNF exon II, III and coding exon IX. In summary, the HDACi compound 13 may increase BDNF specific isoforms expression to rescue the ischemic and hypoxic injuries through changes of acetylation on histones.

Time-Varying Effects of Psychological Distress on the Functional Recovery of Stroke Patients.

OBJECTIVE: To explore the temporal effects of psychological distress on the functional recovery of stroke survivors. DESIGN: A longitudinal follow-up study. All participants were interviewed at 5 days after stroke onset, and at 1, 2, 3, and 6 months after discharge from acute care hospitals. SETTING: Neurology inpatient and outpatient departments and rehabilitation clinics. PARTICIPANTS: First-time stroke participants (N=62) without cognitive impairment, psychiatric disorders, or cancer were recruited. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Measurements consisted of demographic characteristics, disease severity, social support, the Chinese version of the Emotional and Social Dysfunction Questionnaire (ESDQ_C), and the Barthel Index. RESULTS: Our findings showed that psychological distress had a dynamic effect on functional recovery over time, and as the total ESDQ_C score increased by 1 point, the concurrent functional recovery decreased by .23 points (P<.001). Additionally, 5 subscales of the ESDQ_C including anger, emotional dyscontrol, helplessness, indifference, and euphoria also had dynamic effects on functional recovery over time (P<.05). Regardless of when a single form or various forms of psychological distress occurred over time from stroke onset, the functional recovery over time was simultaneously affected. CONCLUSIONS: The time-varying effect of psychological distress on functional recovery was significant. Adopting comprehensive instruments and regular assessments for the early detection of various psychological distresses while under clinical care is needed. Effective interventions targeting both physical and mental functions would further improve the functional recovery and overall health of stroke patients.

Predicting Mortality in Patients With "Malignant" Middle Cerebral Artery Infarction Using Susceptibility-Weighted Magnetic Resonance Imaging: Preliminary Findings.

To evaluate malignant middle cerebral artery (MCA) infarction (defined as space-occupying edema in more than 50% to 75% of the MCA territory) on magnetic resonance imaging (MRI) with susceptibility-weighted imaging (SWI) sequence and assess the usefulness of SWI findings, diffusion-weighted imaging (DWI) findings, and apparent diffusion coefficient (ADC) as predictors of clinical outcome.Data from 16 patients with large MCA infarction previously admitted to our institution between December 2009 and October 2012 were retrospectively collected and analyzed. Within 7 days after stroke onset, 1 neurologist and 1 neuroradiologist estimated the area of infarction on DWI/ADC and extent of prominent vessel sign (PVS) on SWI images using the Stroke Program Early MR Score (SPEMRS). The PVS on SWI was defined as a local prominence of hypointense vessels with either increased vessel number or diameter in the target area, when compared with the number or diameter of the contralateral MCA territory vessels.Six patients died and 10 survived. Although the DWI/ADC-SPEMRS and clinical profiles were similar between the nonsurvivor and survivor groups, SWI-SPEMRS was significantly lower in the nonsurvivor group (P < 0.001).The area of deoxygenation on SWI in patients with malignant MCA infarction can predict mortality. Lower SWI-SPEMRS is a potentially better predictor of poor outcome than lower DWI-SPEMRS. A larger prospective study is needed to clarify the role of SWI as a therapeutic guide in malignant MCA.

Adiponectin and leptin in overweight/obese and lean women with polycystic ovary syndrome.

AIM: The objective of this study was to evaluate the adiponectin and leptin levels in overweight/obese and lean women with polycystic ovary syndrome (PCOS). DESIGN: This was a retrospective study. PATIENTS: Of the 422 studied patients, 224 women with PCOS and 198 women without PCOS were evaluated. MAIN OUTCOME MEASURE(S): Insulin resistance and the metabolic components were assessed. The adiponectin and leptin levels were also evaluated. RESULTS: Adiponectin was negatively correlated with insulin resistance, body mass index (BMI), and total testosterone, triglyceride, and low-density lipoprotein (LDL) levels; conversely, leptin reversed the aforementioned reaction and was negatively correlated with adiponectin levels. The adiponectin to leptin ratios were significantly lower in PCOS women than in those without PCOS. Compared to women with non-PCOS, overweight/obese women with PCOS had lower serum adiponectin levels than women without PCOS, which was not the case for lean women. Conversely, lean women with PCOS had higher serum leptin levels than those without PCOS, which was not the case for overweight/obese women. CONCLUSIONS: Adipose tissue might play an important role in the metabolic complications in women with PCOS. To study the impact of obesity biomarkers in women with PCOS, overweight/obese and lean women should be considered separately.

The relationship between carotid intima-media thickness and endogenous androgens in young women with polycystic ovary syndrome in Taiwan.

Polycystic ovary syndrome (PCOS) is a common and complex female endocrinopathy that is associated with multiple vascular risk factors. Our objective was to investigate the relationship between carotid intima-media thickness (CIMT) and endogenous androgens in young Taiwanese-Chinese women with PCOS. We measured CIMT with B-mode ultrasound in 42 young PCOS patients and 43 controls. Atherosclerosis-associated profiles and endocrinological parameters were also measured. The results showed that although Taiwanese-Chinese PCOS patients tend to possess more risk factors for atherosclerosis than controls, there was no evidence to support that they have a greater CIMT at this age. Furthermore, androstenedione appears to be inversely associated with CIMT.

Epistasis analysis for estrogen metabolic and signaling pathway genes on young ischemic stroke patients.

BACKGROUND: Endogenous estrogens play an important role in the overall cardiocirculatory system. However, there are no studies exploring the hormone metabolism and signaling pathway genes together on ischemic stroke, including sulfotransferase family 1E (SULT1E1), catechol-O-methyl-transferase (COMT), and estrogen receptor α (ESR1). METHODS: A case-control study was conducted on 305 young ischemic stroke subjects aged

An old lady with anterior chest pain and unilateral facial flushing.

Harlequin syndrome is rare and typically characterized by asymmetric flushing and sweating. Although it is usually considered idiopathic, literature review shows that it may be caused by lesion over lung apex or after central venous catheterization in the internal jugular vein. We present a 74-year-old woman who had been experiencing recurrent chest pain and right shoulder pain since 2 weeks ago. The tentative diagnosis was made by the emergency physician (EP) as acute coronary syndrome. The patient was given nitroglycerin treatment. Twelve hours later, the patient developed another episode of chest pain. The electrocardiogram and cardiac enzyme study results were, however, both normal. Further evaluation showed intermittent flushing over the left side of her face, as well as right-eye ptosis. A chest computed tomography (CT) was conducted, under the suspicion of Harlequin syndrome in combination with Horner syndrome, to derive the diagnosis of a right lung apex tumor. This case showed that history taking and physical examination are very important in the emergency department. It is particularly vital to observe the microchanges in the patient's symptoms and signs. It is also imperative to reassess the patient whose symptoms fail to improve under treatment, to look for other underlying lesions.

Neuropathologic correlates for diffusion tensor imaging in postinfectious encephalopathy.

Acute necrotizing encephalopathy and acute disseminated encephalomyelitis are 2 rare types of acute postinfectious encephalopathy in children. Acute necrotizing encephalopathy is characterized by multiple symmetric lesions in the thalami, putamena, cerebral and cerebellar white matter, and brainstem. Acute disseminated encephalomyelitis is an immune-mediated demyelinating central nervous system disorder that predominantly affects the white matter. Diffusion magnetic resonance imaging is sensitive to measuring water diffusion in the central nervous system in human and animal models. Recent studies have demonstrated that by using an analytical approach to directional diffusivity-derived parameters, the axial diffusivity and the radial diffusivity, one can assess the extent of axonal or myelin injury in the central nervous system white matter. We applied directional diffusivity to acute necrotizing encephalopathy, acute disseminated encephalomyelitis, and control subjects correlating with neuropathology findings. In acute necrotizing encephalopathy, axonal injury without demyelination, noted on biopsy samples of brain tissue, was suggested by a decreased apparent diffusion coefficient, unchanged fractional anisotropy, and decreased axial and radial diffusivity. In acute disseminated encephalomyelitis, an increased apparent diffusion coefficient, decreased fractional anisotropy, unchanged axial diffusivity, and markedly increased radial diffusivity compatible with active inflammatory demyelination were noted, consistent with tissue biopsy sample neuropathology. In conclusion, diffusion tensor parameters can potentially depict more microstructural changes than conventional magnetic resonance imaging in postinfectious encephalopathy in children.

Rostrocaudal analysis of corpus callosum demyelination and axon damage across disease stages refines diffusion tensor imaging correlations with pathological features.

Noninvasive assessment of the progression of axon damage is important for evaluating disease progression and developing neuroprotective interventions in multiple sclerosis patients. We examined the cellular responses correlated with diffusion tensor imaging-derived axial (lambda(parallel)) and radial (lambda(perpendicular)) diffusivity values throughout acute (4 weeks) and chronic (12 weeks) stages of demyelination and after 6 weeks of recovery using the cuprizone demyelination of the corpus callosum model in C57BL/6 and Thy1-YFP-16 mice. The rostrocaudal progression of pathological alterations in the corpus callosum enabled spatially and temporally defined correlations of pathological features with diffusion tensor imaging measurements. During acute demyelination, microglial/macrophage activation was most extensive and axons exhibited swellings, neurofilament dephosphorylation, and reduced diameters. Axial diffusivity values decreased in the acute phase but did not correlate with axonal atrophy during chronic demyelination. In contrast, radial diffusivity increased with the progression of demyelination but did not correlate with myelin loss or astrogliosis. Unlike other animal models with progressive neurodegeneration and axon loss, the acute axon damage did not progress to discontinuity or loss of axons even after a period of chronic demyelination. Correlations of reversible axon pathology, demyelination, microglia/macrophage activation, and astrogliosis with regional axial and radial diffusivity measurements will facilitate the clinical application of diffusion tensor imaging in multiple sclerosis patients.