Sorsby fundus dystrophy: Insights from the past and looking to the future

Sorsby fundus dystrophy (SFD), an autosomal dominant, fully penetrant, degenerative disease of the macula, is manifested by symptoms of night blindness or sudden loss of visual acuity, usually in the third to fourth decades of life due to choroidal neovascularization (CNV). SFD is caused by specific mutations in the Tissue Inhibitor of Metalloproteinase-3, (TIMP3) gene. The predominant histo-pathological feature in the eyes of patients with SFD are confluent 20–30 m thick, amorphous deposits found between the basement membrane of the retinal pigment epithelium (RPE) and the inner collagenous layer of Bruch's membrane. SFD is a rare disease but it has generated significant interest because it closely resembles the exudative or “wet” form of the more common age-related macular degeneration (AMD). In addition, in both SFD and AMD donor eyes, sub-retinal deposits have been shown to accumulate TIMP3 protein. Understanding the molecular functions of wild-type and mutant TIMP3 will provide significant insights into the patho-physiology of SFD and perhaps AMD. This review summarizes the current knowledge on TIMP3 and how mutations in TIMP3 cause SFD to provide insights into how we can study this disease going forward. Findings from these studies could have potential therapeutic implications for both SFD and AMD.     

Left Ventricular Systolic Dysfunction and Cardiovascular Outcomes in Tetralogy of Fallot: Systematic Review and Meta-analysis

BackgroundAlthough there are robust data about the pathophysiology and prognostic implications of left ventricular (LV) systolic dysfunction in patients with acquired heart disease, similar prognostic data about LV systolic dysfunction are sparse in the tetralogy of Fallot (TOF) population. The purpose of this study was to perform a meta-analysis of all studies that assessed the relationship between LV ejection fraction (LVEF) and cardiovascular adverse events (CAEs) defined as death, aborted sudden death, or sustained ventricular tachycardia.MethodsWe used random-effects models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsOf the 1,809 citations, 7 studies with 2,854 patients (age 28 ± 4 years) were included. During 5.6 ± 3.4 years' follow-up, there were 82 deaths, 17 aborted sudden cardiac deaths, and 56 sustained ventricular tachycardia events. Overall, CAEs occurred in 5.1% (144 patients). As a continuous variable, LVEF was a predictor of CAE (HR 1.29, 95% CI, 1.09-1.53, P = 0.001) per 5% decrease in LVEF. Similarly, LVEF < 40% was also a predictor of CAE (HR 3.22, 95% CI, 2.16-4.80, P < 0.001).ConclusionsLV systolic dysfunction was an independent predictor of CAE, and we observed a 30% increase in the risk of CAE for every 5% decrease in LVEF, and a 3-fold increase in the risk of CAE in patients with LVEF <40% compared with other patients. These findings underscore the importance of incorporating LV systolic function in clinical risk stratification of patients with TOF and the need to explore new treatment options to address this problem.     

Trabecular Bone Score Reference Values for Children and Adolescents According to Age,Sex, and Ancestry

Trabecular bone score (TBS) is used for fracture prediction in adults, but its utility in children is limited by absence of appropriate reference values. We aimed to develop reference ranges for TBS by age, sex, and population ancestry for youth ages 5 to 20 years. We also investigated the association between height, body mass index (BMI), and TBS, agreement between TBS and lumbar spine areal bone mineral density (aBMD) and bone mineral apparent density (BMAD) Z-scores, tracking of TBS Z-scores over time, and precision of TBS measurements. We performed secondary analysis of spine dual-energy X-ray absorptiometry (DXA) scans from the Bone Mineral Density in Childhood Study (BMDCS), a mixed longitudinal cohort of healthy children (n = 2014) evaluated at five US centers. TBS was derived using a dedicated TBS algorithm accounting for tissue thickness rather than BMI. TBS increased only during ages corresponding to pubertal development with an earlier increase in females than males. There were no differences in TBS between African Americans and non-African Americans. We provide sex-specific TBS reference ranges and LMS values for calculation of TBS Z-scores by age and means and SD for calculation of Z-scores by pubertal stage. TBS Z-scores were positively associated with height Z-scores at some ages. TBS Z-scores explained only 27% and 17% of the variance of spine aBMD and BMAD Z-scores. Tracking of TBS Z-scores over 6 years was lower (r = 0.47) than for aBMD or BMAD Z-scores (r = 0.74 to 0.79), and precision error of TBS (2.87%) was greater than for aBMD (0.85%) and BMAD (1.22%). In sum, TBS Z-scores provide information distinct from spine aBMD and BMAD Z-scores. Our robust reference ranges for TBS in a well-characterized pediatric cohort and precision error estimates provide essential tools for clinical assessment using TBS and determination of its value in predicting bone fragility in childhood and adolescence. © 2022 American Society for Bone and Mineral Research (ASBMR).     

对乙酰氨基酚引起的急性肝衰竭：一项美国多中心前瞻性研究结果

严重的对乙酰氨基酚肝毒性常常会引起急性肝衰竭（ALF），作者在美国的22所三级护理中心调查了由对乙酰氨基酚引起的肝衰竭的发生率、危险因素和预后，用超过6年的时间收集到662例完全符合ALF（包括肝源性凝血症和肝性脑病）标准的患者资料，详细分析后发现：其中有275例（45％）是由对乙酰氨基酚引起的。调查发现，对乙酰氨基酚相关性ALF的年度百分比由1998年的28％上升至2003年的51％。对乙酰氨基酚的中位摄入量为24g（相当于48个高含量的片剂）。在上述275例中，误服过量者有131例（48％），有意服用者（即有自杀倾向者）有122例（44％），还有22例（8％）为不明意图。在误服组中38％同时服用了两种或多种对乙酰氨基酚制剂，63％患者服用了含有镇静剂的复合制剂。据报道，81％患者因为急性或慢性疼痛误服了对乙酰氨基酚和（或）其他镇痛剂。总体上，有178例研究对象（65％）存活，74例（27％）未经肝移植而死亡，23例（8％）进行了肝移植，其中71％的患者仅存活了3周。未接受移植的存活率和肝移植存活率在误服组和有意服用组差别不明显。     

Cytokines as therapeutic drugs.

Cytokines are a growing group of proteins that are responsible for the communication of cells of the immune system, hematopoietic cells, and other cell types. They play a dominant role in various diseases, particularly in promoting and perpetuating inflammation. Cytokine production is a reaction of the body to a pathologic state to restore homeostasis. In such cases, the therapeutic intervention should support the reaction of the body by giving the cytokine itself (agonistic therapeutics). In other cases, manifestation of a disease results from an overproduction of cytokines, making cytokine antagonists desirable therapeutic drugs. Furthermore, cytokines may be good candidates as cancer therapeutics, especially to support the restoration of blood cell populations after chemotherapy or radiation.