Botulinum toxin blocks mast cells and prevents rosacea like inflammation

Background

Rosacea is a chronic inflammatory skin condition whose etiology has been linked to mast cells and the antimicrobial peptide cathelicidin LL-37. Individuals with refractory disease have demonstrated clinical benefit with periodic injections of onabotulinum toxin, but the mechanism of action is unknown.

Family Caregivers' Subjective Caregiving Burden,Quality of Life,and Depressive Symptoms Are Associated With Terminally Ill Cancer Patients' Distinct Patterns of Conjoint Symptom Distress and Functional Impairment in Their Last Six Months of Life

Context

Family caregivers constitute a critical component of the end-of-life care system with considerable cost to themselves. However, the joint association of terminally ill cancer patients' symptom distress and functional impairment with caregivers' subjective caregiving burden, quality of life (QOL), and depressive symptoms remains unknown.

INAUGURAL ARTICLE by a Recently Elected Academy Member:Functional redundancy of type I and type II receptors in the regulation of skeletal muscle growth by myostatin and activin A

Myostatin (MSTN) is a transforming growth factor-β (TGF-β) family member that normally acts to limit muscle growth. The function of MSTN is partially redundant with that of another TGF-β family member, activin A. MSTN and activin A are capable of signaling through a complex of type II and type I receptors. Here, we investigated the roles of two type II receptors (ACVR2 and ACVR2B) and two type I receptors (ALK4 and ALK5) in the regulation of muscle mass by these ligands by genetically targeting these receptors either alone or in combination specifically in myofibers in mice. We show that targeting signaling in myofibers is sufficient to cause significant increases in muscle mass, showing that myofibers are the direct target for signaling by these ligands in the regulation of muscle growth. Moreover, we show that there is functional redundancy between the two type II receptors as well as between the two type I receptors and that all four type II/type I receptor combinations are utilized in vivo. Targeting signaling specifically in myofibers also led to reductions in overall body fat content and improved glucose metabolism in mice fed either regular chow or a high-fat diet, demonstrating that these metabolic effects are the result of enhanced muscling. We observed no effect, however, on either bone density or muscle regeneration in mice in which signaling was targeted in myofibers. The latter finding implies that MSTN likely signals to other cells, such as satellite cells, in addition to myofibers to regulate muscle homeostasis.

Myostatin (MSTN) is a secreted signaling molecule that normally acts to limit skeletal muscle growth (for review, see ref. 1). Mice lacking MSTN exhibit dramatic increases in muscle mass throughout the body, with individual muscles growing to about twice the normal size (2). MSTN appears to play two distinct roles in regulating muscle size, one to regulate the number of muscle fibers that are formed during development and a second to regulate the growth of those fibers postnatally. The sequence of MSTN has been highly conserved through evolution, with the mature MSTN peptide being identical in species as divergent as humans and turkeys (3). The function of MSTN has also been conserved, and targeted or naturally occurring mutations in MSTN have been shown to cause increased muscling in numerous species, including cattle (3–5), sheep (6), dogs (7), rabbits (8), rats (9), swine (10), goats (11), and humans (12). Numerous pharmaceutical and biotechnology companies have developed biologic agents capable of blocking MSTN activity, and these have been tested in clinical trials for a wide range of indications, including Duchenne and facioscapulohumeral muscular dystrophy, inclusion body myositis, muscle atrophy following falls and hip fracture surgery, age-related sarcopenia, Charcot–Marie–Tooth disease, and cachexia due to chronic obstructive pulmonary disease, end-stage kidney disease, and cancer.The finding that certain inhibitors of MSTN signaling can increase muscle mass even in Mstn^−/− mice revealed that the function of MSTN as a negative regulator of muscle mass is partially redundant with at least one other TGF-β family member (13, 14), and subsequent studies have identified activin A as one of these cooperating ligands (15, 16). MSTN and activin A share many key regulatory and signaling components. For example, the activities of both MSTN and activin A can be modulated extracellularly by naturally occurring inhibitory binding proteins, including follistatin (17, 18) and the follistatin-related protein, FSTL-3 or FLRG (19, 20). Moreover, MSTN and activin A also appear to share receptor components. Based on in vitro studies, MSTN is capable of binding initially to the activin type II receptors, ACVR2 and ACVR2B (also called ActRIIA and ActRIIB) (18) followed by engagement of the type I receptors, ALK4 and ALK5 (21). In previous studies, we presented genetic evidence supporting a role for both ACVR2 and ACVR2B in mediating MSTN signaling and regulating muscle mass in vivo. Specifically, we showed that mice expressing a truncated, dominant-negative form of ACVR2B in skeletal muscle (18) or carrying deletion mutations in Acvr2 and/or Acvr2b (13) have significantly increased muscle mass. One limitation of the latter study, however, was that we could not examine the consequence of complete loss of both receptors using the deletion alleles, as double homozygous mutants die early during embryogenesis (22). Moreover, the roles that the two type I receptors, ALK4 and ALK5, play in regulating MSTN and activin A signaling in muscle in vivo have not yet been documented using genetic approaches. Here, we present the results of studies in which we used floxed alleles for each of the type II and type I receptor genes in order to target these receptors alone and in combination in muscle fibers. We show that these receptors are functionally redundant and that signaling through each of these receptors contributes to the overall control of muscle mass.     

学龄期儿童前房深度发育状况分析

目的了解7~14岁学龄期儿童前房深度发育情况。探索其与屈光度数间的关系。方法收集2012年6月至2014年6月眼科门诊7~14岁儿童为研究对象，共计521例（1042只眼）。采用IOLMaster人工晶状体生物测量仪测量各屈光参数，同时测量身高、体重。散瞳后验光测得静态屈光度。分析前房深度发育情况及不同屈光状态的学龄期儿童前房深度发育情况。结果（1）随着年龄的增长，7~14岁学龄期的儿童前房深度随之增长，差异具有统计学意义（P＜0.01）。同一年龄段儿童的左右眼之间的均值相近，且生长发育趋势相近（均P＞0.05）。（2）随着年龄的增长，男女的前房深度均逐渐增大，同一年龄段男性前房深度大于女性前房深度（均P＜0.01）。（3）儿童前房深度与身高正相关（P＜0.01）。（4）前房深度随近视度数增高而增大，低度近视组与中度近视组及高度近视组差异有统计学意义（P＜0.05）。结论学龄期儿童的前房深度的发育受到身高、性别及屈光度数的影响，与身高呈正相关，同一年龄段，男性前房深度大于女性。双眼前房深度发育同步。低中度近视的儿童前房深度增大。     

Comparison of the Emergency Severity Index (ESI) and the Taiwan Triage System in predicting resource utilization.

BACKGROUND/PURPOSE: The importance of accurate triage in Taiwan is becoming more apparent with the increasing number of emergency department (ED) patients, and resources for the National Health Insurance becoming constrained. This study compared the ability of the Taiwan triage system (TTS) and the standardized 5-level Emergency Severity Index (ESI) triage system to predict ED resource utilization. METHODS: Patients arriving at the ED were triaged by both TTS and by using a two-page checklist of ESI criteria during the 3-month study period. The ESI triage level was calculated independently to avoid bias. Disease category (trauma vs. nontrauma), length of stay (LOS) and hospitalization data were evaluated. RESULTS: A total of 3172 patients with both ESI and TWN evaluation were included. The distributions of ESI ratings within TTS level 1 were: ESI 1, 21.1%; ESI 2, 68.1%; ESI 3, 7.4%; ESI 4, 3.4%; ESI 5, 0%. For TTS level 3, they were: ESI 1, 0.1%; ESI 2, 26.2%; ESI 3, 39.5%; ESI 4, 27.5%; ESI 5, 6.8%. Hospitalization rates were 74.5%, 40.9% and 22.2% in TTS levels 1, 2 and 3, respectively; and were 96.2%, 47.0%, 30.9%, 6.7%and 6.6% in ESI levels 1, 2, 3, 4 and 5, respectively. TTS triaged more trauma patients as life-threatening/emergent condition than nontrauma patients (68.8% vs. 48.4%, p < 0.001). Triage by ESI, however, showed no significant difference in the percentage of trauma and nontrauma patients with highly acute conditions (44.2% vs. 46.6%, p = 0.230). Patients with ESI level 4 or 5 have significantly shorter ED LOS than those with ESI level 3. CONCLUSION: ESI produces more accurate discriminating patient acuity, ED LOS and hospitalization rate than TTS. Adopting a standardized 5-level triage tool might improve resource utilization planning of ED practice.