Lipoprotein(a), Cardiovascular Disease,and Contemporary Management

Elevated lipoprotein(a) (Lp[a]) is a causal genetic risk factor for cardiovascular disease. To determine if current evidence supports both screening and treatment for elevated Lp(a) in high-risk patients, an English-language search of PubMed and MEDLINE was conducted. In population studies, there is a continuous association between Lp(a) concentrations and cardiovascular risk, with synergistic effects when low-density lipoprotein (LDL) is also elevated. Candidates for Lp(a) screening include patients with a personal or family history of premature cardiovascular disease, familial hypercholesterolemia, recurrent cardiovascular events, or inadequate LDL cholesterol (LDL-C) responses to statins. Given the comparative strength of clinical evidence, reducing LDL-C to the lowest attainable value with a high-potency statin should be the primary focus of lipid-modifying therapies. If the Lp(a) level is 30 mg/dL or higher in a patient who has the aforementioned characteristics plus residual LDL-C elevations (≥70-100 mg/dL) despite maximum-potency statins or combination statin therapy, the clinician may consider adding niacin (up to 2 g/d). If, after these interventions, the patient has progressive coronary heart disease (CHD) or LDL-C levels of 160-200 mg/dL or higher, LDL apheresis should be contemplated. Although Lp(a) is a major causal risk factor for CHD, no currently available controlled studies have suggested that lowering it through either pharmacotherapy or LDL apheresis specifically and significantly reduces coronary risk. Further research is needed to (1) optimize management in order to reduce CHD risk associated with elevated Lp(a) and (2) determine what other intermediate- or high-risk groups might benefit from Lp(a) screening.     

Sub-concussive brain injury in the Long-Evans rat induces acute neuroinflammation in the absence of behavioral impairments

Sub-concussive brain injuries may result in neurophysiological changes, cumulative effects, and neurodegeneration. The current study investigated the effects of a mild lateral fluid percussion injury (0.50-0.99 atm) on rat behavior and neuropathology to address the need to better understand sub-concussive brain injury. Male Long-Evans rats received either a single mild lateral fluid percussion injury or a sham-injury, followed by either a short (24 h) or long (4 weeks) recovery period. After recovery, rats underwent extensive behavioral testing consisting of tasks for rodent cognition, anxiety- and depression-like behaviors, social behavior, and sensorimotor function. At the completion of behavioral testing rats were sacrificed and brains were examined immunohistochemically with markers for neuroinflammation and axonal injury. No significant group differences were found on behavioral and axonal injury measures. However, rats given one mild fluid percussion injury displayed an acute neuroinflammatory response, consisting of increased microglia/macrophages and reactive astrogliosis, at 4 days post-injury. Neuroinflammation is a mechanism with the potential to contribute to the cumulative and neurodegenerative effects of repeated sub-concussive injuries. The current findings are consistent with findings in humans experiencing a sub-concussive blow, and provide support for the use of mild lateral fluid percussion injury in the rat as a model of sub-concussive brain injury.     

Shortcomings on genetic testing of Familial hypercholesterolemia (FH) in India: Can we collaborate to establish Indian FH registry?

Familial hypercholesterolemia (FH) is a common autosomal dominant disorder that affects ～1 in 250–500 individuals globally. The only prevalence study in India shows FH in 15% of patients with premature CAD in North Indians. There are only 6 genetic studies in India of the total mutations, 32% are LDLR mutations, 4% are ApoB, 2% are PCSK9 mutations and the mutational spectrum for 37% is unknown. This calls for widespread genetic screening which could help identify definite FH patients.European Atherosclerosis Society-Familial Hypercholesterolemia Studies Collaboration (EAS- FHSC) has taken an initiative to develop a worldwide registry of FH. India is also a part of the collaboration and 3 groups from Mumbai, Delhi and Chennai are actively contributing to this registry. We believe this review might help to understand the Indian scenario of FH and investigators across India can contribute in managing FH in India and further help in the detection, diagnosis and treatment.     

Familial Hypercholesterolemia Among Young Adults With Myocardial Infarction

BackgroundThere are limited data on the prevalence and treatment of familial hypercholesterolemia (FH) among U.S. adults who experience a myocardial infarction (MI) at a young age.ObjectivesThis study aimed to evaluate the prevalence of clinically defined FH and examine the rates of statin utilization and low-density lipoprotein cholesterol (LDL-C) achieved 1-year post MI.MethodsThe YOUNG-MI registry is a retrospective cohort study that includes patients who experience an MI at or below age 50 years between 2000 and 2016 at 2 academic centers. Probable or definite FH was defined by the Dutch Lipid Clinic criteria. Outcomes included the proportion of patients classified as probable or definite FH, use of lipid-lowering therapy, and LDL-C achieved 1-year post MI.ResultsThe cohort consisted of 1,996 adults with a median age of 45 years; 19% were women, and 54% had ST-segment elevation MI. Probable/definite FH was present in 180 (9%) of whom 42.8% were not on statins prior to their MI. Of the 1,966 patients surviving until hospital discharge, 89.4% of FH patients and 89.9% of non-FH patients were discharged on statin therapy (p = 0.82). Among FH patients, 63.3% were discharged on high-intensity statin compared with 48.4% for non-FH patients (p < 0.001). At 1-year follow-up, the percent reduction in LDL-C among FH patients was ?44.4% compared with ?34.5% (p = 0.006) in non-FH patients. The proportion of patients with LDL-C ≥70 mg/dl was higher among FH patients (82.2%) compared with non-FH patients (64.5%; p < 0.001).ConclusionsClinically defined FH was present in nearly 1 of 10 patients with MI at a young age. Only two-thirds of FH patients were discharged on high-intensity statin therapy, and the vast majority had elevated LDL-C at 1 year. These findings reinforce the need for more aggressive lipid-lowering therapy in young FH and non-FH patients post-MI.     

FH联合TCT、高危型HPV检测筛查宫颈癌及癌前期病变价值

目的:探讨子宫上皮细胞游离亚铁原卟啉(FH)检测联合液基细胞学(TCT)或高危型人乳头瘤病毒(HPV)检测对宫颈癌及癌前期病变的筛查效能。方法:选取2016年1月-2018年1月本院妇产科行宫颈癌筛查128例,均行妇科检查、FH、TCT及HPV检测,最终经宫颈组织病理学检查。病理诊断为宫颈癌前病变13例(HSIL 5例、LSIL患者8例),宫颈癌3例,余112例未发现宫颈癌及癌前病变。采用ROC曲线分析3种检测方法单独检测及联合检测对宫颈癌及癌前病变的筛查效能。结果:FH、TCT、HPV检测诊断宫颈癌及癌前病变的ROC曲线下面积(AUC)分别为0.814、0.895、0.937,FH检测与TCT检测无差异(P>0.05),HPV检测最优。FH+TCT、FH+HPV、TCT+HPV检测诊断的AUC分别为0.793、0.903、0.950,敏感度、特异度分别为FH+TCT(87.19%、71.68%)和FH+HPV(95.01%、85.48%)。结论:子宫上皮细胞稳定性FH检测对宫颈癌的筛查具有操作简单、快速、价格低廉等优点,筛查效果与TCT检查类似,但略差于高危型HPV检测,联合检测可提高其诊断准确率。     

Low-density lipoprotein receptor gene mutations in a Southeast Asian population with familial hypercholesterolemia

The aim of this study was to detect mutations in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in patients of Southeast Asian origin with clinically diagnosed familial hypercholesterolemia (FH) and to relate these findings with the observed lower incidence of coronary heart disease in this part of the world. A total of 86 unrelated patients with FH were selected on clinical grounds, and complete DNA analysis of the low-density lipoprotein (LDL)-receptor and apolipoprotein B (apoB) genes by DGGE and DNA-sequencing was performed. In the majority (73%) of the cohort studied, no mutations could be detected, even after extensive analysis of the LDL-receptor and apoB genes. However, the 22 patients with a mutation had significantly more xanthomas and a higher incidence of coronary heart disease and levels of low-density lipoproteins were also significantly different. There was no correlation between the type of the mutation and lipoprotein levels or clinical signs of atherosclerosis. The fact that the majority of the FH patients studied had no detectable mutation and that this group had a significant milder phenotype, suggests the presence of a third gene in the Southeast Asian population, predominantly leading to a disorder resembling a milder form of FH. A similar, but less frequent, trait has recently been described in a number of European families.     

Epstein-Barr virus: transformation of lymphocytes separated by size or exposed to bromodeoxyuridine and light.

Experiments designed to assess the physiological state of cells susceptible to transformation by Epstein-Barr virus (EBV) indicated that transformation does not require cellular DNA synthesis at the time of virus exposure and that a resting lymphocyte can be the target cell. The following results support this conclusion: Lymphocyte preparations from different human umbilical cords vary in extent of spontaneous DNA synthesis, but EBV-induced transformation is independent of this variation. Increases in spontaneous DNA synthesis which occur after several days in culture are not accompanied by increased cell sensitivity to transformation. Transformation occurs in highest frequency in partially purified cell subpopulations with low levels of DNA synthesis. Conversely, lymphocyte subpopulations with high rates of spontaneous DNA synthesis are relatively refractory to transformation. The fraction of cells transformed by EBV (which we estimate to be about 10% after correction for plating efficiency) exceeds the fraction in DNA synthesis at the time of virus exposure (less than 1%). Treatment of cells with bromodeoxyuridine (BrdU) followed by light before virus exposure does not impair the ability of EBV to stimulate DNA synthesis in human leukocytes or to transform marmoset leukocytes. However BrdU-light treatment is inhibitory to transformation if treatment is delivered about 24 hr after virus exposure or thereafter.     

Long-term effects of LDL apheresis on carotid arterial atherosclerosis in familial hypercholesterolaemic patients

OBJECTIVES: To assess the long-term effect of LDL apheresis on carotid arterial atherosclerosis in severe familial hypercholesterolaemic (FH) patients. DESIGN: Changes in existing plaque, new plaque formation and annual progression rate of carotid early plaque were evaluated by B-mode ultrasonography. SUBJECTS: LDL apheresis group: two homozygous FH and nine heterozygous FH patients received a combination of LDL apheresis and cholesterol-lowering drug therapy for a mean of 7.8 years. Control group: 10 heterozygous FH patients were maintained by medication only for a mean of 5.5 years. RESULTS: As a result of LDL apheresis treatment, LDL cholesterol levels reduced from 16.0+/-3.60 to 6.43+/-0.07 mmol L(-1) in homozygous FH patients and from 11.5+/-2.46 to 4.32+/-1.2 mmol L(-1) in heterozygous FH patients. During the long-term treatment period, the existing plaque tended to progress and new plaque formation in carotid arteries was also observed in both groups. The annual progression rate of mean maximum intima-media thickness in the common carotid artery was a mean of -0.0023+/-0.0246 mm year(-1) in heterozygous FH patients in the LDL apheresis group, suggesting regression. This was significantly lower when compared with the control group, which had a mean of 0.0251+/-0.0265 mm year(-1) CONCLUSION: The results suggest that the long-term treatment with combined LDL apheresis and drugs may delay the progression of the atherosclerotic process and prompt the stabilization of atheromatous plaque in severe FH patients.     

Electrophysiological correlates of performance monitoring in binge drinking: Impaired error-related but preserved feedback processing

Objective

Performance monitoring, which allows efficient behavioral regulation using either internal (error processing) or external (feedback processing) cues, has not yet been explored in binge drinking despite its adaptive importance in everyday life, particularly in the regulation of alcohol consumption. Capitalizing on a theoretical model of risky behaviors, the present study aimed at determining the behavioral and electrophysiological correlates of the cognitive (inhibition) and motivational (reward sensitivity) systems during performance monitoring.

A single mild fluid percussion injury induces short-term behavioral and neuropathological changes in the Long-Evans rat: support for an animal model of concussion

Brain concussion is a serious public health concern and is associated with short-term cognitive impairments and behavioral disturbances that typically occur in the absence of significant brain damage. The current study addresses the need to better understand the effects of a mild lateral fluid percussion injury on rat behavior and neuropathology in an animal model of concussion. Male Long-Evans rats received either a single mild fluid percussion injury or a sham-injury, and either a short (24 h) or long (4 weeks) post-injury recovery period. After recovery, rats underwent a detailed behavioral analysis consisting of tests for rodent anxiety, cognition, social behavior, sensorimotor function, and depression-like behavior. After testing all rats were sacrificed and brains were examined immunohistochemically with markers for microglia/macrophage activation, reactive astrocytosis, and axonal injury. Injured rats (mean injury force: 1.20 ± .03 atm) displayed significant short-term cognitive impairments in the water maze and significantly more anxiolytic-like behavior in the elevated-plus maze compared to sham controls. Neuropathological analysis of the brains of injured rats showed an acute increase in reactive astrogliosis and activated microglia in cortex and evidence of axonal injury in the corpus callosum. There were no significant long-term effects on any behavioral or neuropathological measure 4 weeks after injury. These short-term behavioral and neuropathological changes are consistent with findings in human patients suffering a brain concussion, and provide further evidence for the use of a single mild lateral fluid percussion injury to study concussion in the rat.