Barriers to seeking treatment for major depression

The purpose of this study was to examine the reasons people with an episode of Major Depression do or do not seek treatment for the episode. We interviewed 101 persons who met criteria for an RDC Major Depressive episode that lasted at least 4 weeks within 3 years of the interview date, exploring in detail the reasons they gave for seeking or not seeking treatment. GAS ratings indicated that all subjects were moderately impaired at the time of the episode. We found that 55% of the subjects did not seek treatment for this episode, while 45% did. Significant predictors of treatment seeking included a history of prior treatment, higher education, and greater episode length. Non-seekers felt they could handle the episode themselves, did not consider it serious or did not recognize it as an illness. Seekers on the other hand felt the episode was too painful and lasted too long and caused significant disruption in their interpersonal relationships and role functioning. We discuss the implications of these findings in terms of the importance of continued educational efforts to encourage treatment seeking as well as the need for further research to explore the manner in which people decide that affective signs and symptoms have reached a threshold that leads to treatment seeking. Depression and Anxiety 4:273–278, 1996/1997. © 1997 Wiley-Liss, Inc.     

CD81 costimulation skews CAR transduction toward naive T cells

Adoptive cellular therapy using chimeric antigen receptors (CARs) has revolutionized our treatment of relapsed B cell malignancies and is currently being integrated into standard therapy. The impact of selecting specific T cell subsets for CAR transduction remains under investigation. Previous studies demonstrated that effector T cells derived from naive, rather than central memory T cells mediate more potent antitumor effects. Here, we investigate a method to skew CAR transduction toward naive T cells without physical cell sorting. Viral-mediated CAR transduction requires ex vivo T cell activation, traditionally achieved using antibody-mediated strategies. CD81 is a T cell costimulatory molecule that when combined with CD3 and CD28 enhances naive T cell activation. We interrogate the effect of CD81 costimulation on resultant CAR transduction. We identify that upon CD81-mediated activation, naive T cells lose their identifying surface phenotype and switch to a memory phenotype. By prelabeling naive T cells and tracking them through T cell activation and CAR transduction, we document that CD81 costimulation enhanced naive T cell activation and resultantly generated a CAR T cell product enriched with naive-derived CAR T cells.

Genetic manipulation of T cells has enabled adoptive T cell therapy to be translated to the clinic (1–10). Chimeric antigen receptor (CAR) therapy has evoked recent enthusiasm upon mediating curative outcomes in aggressive, refractory B cell malignancies (1–7, 11–15), leading to Food and Drug Administration approval (16–18). The process of ex vivo transduction and expansion of T cells to express CARs influences the phenotype, function, and ultimate fate of the final CAR T cell product (19–23). Preclinical data in animal models indicate that selecting specific T cell subsets for CAR transduction improves efficacy (21, 22, 24–26). Naive-derived T cells have been shown to exhibit greater replicative capacity, persistence, and antitumor function, compared with both effector- and memory-derived T cells (19, 20, 27). Naive CD4⁺ T cells, specifically, have a critical role in enhancing the cytotoxic effect of the CD8⁺ cooperating central memory cell subset (21). Furthermore, the translational CAR experience demonstrates that the presence of cells consistent with the naive and early memory phenotype in premanufactured T cell products correlates with successful clinical responses in both pediatric and adult B cell leukemia (28–30). Here, we explore if selective activation of naive T cells can result in skewing of transduction toward this specific T cell subset without the need for physical subset sorting.CAR constructs rely on intrinsic costimulatory signals, such as the intracellular domains of CD28 or 41BB, for efficacy (1–9). Here we focus on exogenous costimulatory signals necessary to induce proliferation and permit viral-mediated gene transfer. Prior to CAR transduction and antigen encounter, the majority of T cells are in a state of rest. Resting T cells mandate primary and costimulatory signals for activation (31, 32). CD28 is best known for its ability to costimulate T cells (33–38) and along with CD3 activation renders T cells susceptible to viral transduction (1, 39). CD81 is a member of the tetraspanin family that physically associates with CD4 and CD8 on the surface of T cells. CD81 was shown to have independent costimulatory properties and, when used with anti-CD3 and -CD28 antibodies, preferentially activates naive T cells as compared with effector and memory T cells, despite conserved surface CD81 expression across T cell subsets (40). Tetraspanins have no known cell-surface ligands, and therefore antibodies are used to engage and stimulate them. CD81 is the only tetraspanin whose complete three-dimensional structure has been solved (41). Moreover, the crystal structure of 5A6, the anti-CD81 antibody used in our study, in complex with CD81 has also been most recently solved (42). These authors demonstrate that engagement by this antibody changes the conformation of the large extracellular loop of the CD81 molecule. This conformational change may affect the interaction of CD81 with its associated CD4 and CD8 molecules.Here, we costimulate purified T cells with CD81 as a proof of principle to illustrate that the in vitro activation window prior to CAR transduction can be leveraged to favor transduction of a specific T cell subset.     

Comparisons of intellectual performance among children with psychiatric disorders

The intellectual performances of children with a variety of psychiatric disorders were examined and compared with the findings from a similar study by Hodges and Plow (1990). Mean IQ scores were in the average range for both study samples, and no significant differences were found in WISC-R summary scores. Nevertheless, the Hodges and Plow findings were only partially corroborated. They observed, for instance, a relative deficit in verbal abilities for conduct-disordered children and lower IQ scores for children with anxiety disorders vs. children with all other disorders. Our replication study found no significant differences among the disorder groups for any of the scores examined. Possible explanations for the divergence in findings are discussed.     

The new “intermediate risk” group: A comparative analysis of the new 2013 ACC/AHA risk assessment guidelines versus prior guidelines in men

Background

The 2013 ACC/AHA Report on the Assessment of Cardiovascular (CVD) Risk redefined “intermediate risk”. We sought to critically compare the intermediate risk groups identified by prior guidelines and the new ACC/AHA guidelines.

Methods

We analyzed data from 30,005 adult men free of known CVD from a large, multi-ethnic study of middle-aged adults. The Framingham Risk Score was calculated using published equations, and CVD risk was calculated using the new ACC/AHA Pooled Cohort Equations Risk Estimator. We first compared the size and characteristics of the intermediate risk group identified by the old (ATP III, 10–20% 10-year CHD risk) and new guidelines (5–7.4% 10-year CVD risk). We then defined time-to-high-risk as the length of time an individual patient resides in the intermediate risk group before progressing to high risk status based on advancing age alone.

Results

The mean age of the study population was 53 ± 13 years, and 24% were African-American. Patients identified as intermediate risk by the new ACC/AHA Guidelines were younger and more likely to be African-American and have lower risk factor burden (all p < 0.05). The new intermediate risk group was just 37% the size of the traditional ATP III intermediate risk group, while the new high risk group was 103% larger. Under the new guidelines, men remain intermediate risk for an average of just 3 years, compared to 8 years under the prior guidelines (63% shorter time-to-high-risk, p < 0.05), before progressing to high risk based on advancing age alone.

Conclusion

The new 2013 ACC/AHA risk assessment guidelines produce a markedly smaller, lower absolute risk, and more temporary “intermediate risk” group. These findings reshape the modern understanding of “intermediate risk”, and have distinct implications for risk assessment, clinical decision making, and pharmacotherapy in primary prevention.     

Predicting Long-Term Absence of Coronary Artery Calcium in Metabolic Syndrome and Diabetes: The MESA Study

ObjectivesThe purpose of this study was to identify predictors of healthy arterial aging (long-term coronary artery calcification [CAC] of 0) among individuals with metabolic syndrome (MetS) or type 2 diabetes (T2D), which may improve primary prevention strategies.BackgroundIndividuals with MetS or T2D have a heterogeneously increased risk of atherosclerotic cardiovascular disease and not all have a high-intermediate risk.MethodsWe included 574 participants from the MESA (Multi-Ethnic Study of Atherosclerosis) with MetS or T2D who had CAC=0 at baseline and a repeat CAC scan 10 years later. Multivariable logistic regression assessed the association of traditional and novel atherosclerotic cardiovascular disease risk factors and the MetS severity score (based on the 5 MetS criteria) with healthy arterial aging.ResultsThe mean age of participants was 58.9 years, 67% were women, 422 participants had MetS, and 152 had T2D. The proportion with long-term CAC=0 was similar for MetS (42%) and T2D (44%). A younger age was the only individual low/normal traditional risk factor associated with an increased likelihood of long-term CAC=0 (odds ratio [OR]: 1.50; 95% confidence interval [CI]: 1.22 to 1.85 per 10-years younger). The strongest associations of nontraditional risk factors were observed for an absence of thoracic calcification (OR: 2.42; 95% CI: 1.24 to 4.72), absence of carotid plaque (OR: 1.81; 95% CI: 1.25 to 2.61), and among persons with a high sensitivity troponin <3 ng/ml (OR: 1.55; 95% CI: 1.01 to 2.38). In addition, persons with the lowest quartile MetS severity score had a substantially higher odds of healthy long-term CAC=0 (OR: 2.71; 95% CI: 1.27 to 5.76).ConclusionSMore than 40% of adults with MetS or T2D and baseline CAC=0 had long-term absence of CAC, which was most strongly associated with an absence of extracoronary atherosclerosis and a low MetS score. An optimal overall cardiovascular profile appears to be more important than an ideal value of any individual risk factor to maintain healthy arterial aging.     

Reliability and relationship of various ages of onset criteria for major affective disorder

This paper presents data on six different clinical definitions (indices) of age of onset for major affective disorders. The inter-rater reliability for each index and the relationships among these indices are discussed. Age of onset for impairment with affective symptoms was found to be a reliable and useful index of early onset. It discriminated between unipolar depressed subjects and both bipolar I and bipolar II subjects.     

循环中胰岛素样生长因子-Ⅰ水平调节结肠癌的生长和转移研究

目的　探讨血清中肝特异性胰岛素样生长因子 Ⅰ (IGF Ⅰ )水平在刺激小鼠结肠癌生长和转移中的作用。方法　我们实验中所用的肝脏特异性IGF Ⅰ基因缺失 (LID)小鼠 ,其循环中IGF Ⅰ水平仅为正常小鼠 (对照组小鼠 )的 2 5 %。将Colon 3 8腺癌组织块 (碎片 )植入LID和对照组小鼠的盲肠表面。总共 15 6只 5周龄的雄鼠 (其中 82只LID小鼠 ,74只对照鼠 )接受了肿瘤移植。小鼠被随机分成两组 :一组接受腹腔注射重组人IGF 1(rhIGF 1) ,每天 2次 ,共 6周 ,另一组接受生理盐水注射。结果　接受rhIGF Ⅰ注射组的LID和对照小鼠 ,血清IGF 1和IGFBP 3水平均升高。在生理盐水注射组中 ,对照鼠的盲肠肿瘤的发生率和肝脏转移率显著高于LID小鼠。和盐水注射组相比 ,腹腔注射rhIGF 1组中 ,LID和对照组小鼠均有显著的盲肠癌发生率和肝脏转移率。对照小鼠的肝脏转移结节数明显高于LID鼠。结肠癌组织VEGF的表达和血管的密度依赖于血液中IGF Ⅰ水平。结论　血液循环中IGF I水平在结肠癌发展和转移中起了重要作用。     

Intervertebral cages for degenerative spinal diseases.

Interbody fusion techniques have been used for many years for the treatment of a variety of lumbar spine diagnoses. Part of the interest in increasing methods of interbody fusion has stemmed from concern that posterior fusion alone may allow micro-motion, which may generate pain in a ruptured or degenerated disc. Stabilization of the anterior segment led to the development of interbody fusion cages. These devices were designed to stabilize the spine while bony ingrowth from the vertebrae to the bone graft occurred. There are a variety of techniques for cage insertion, including open and laparoscopic techniques anteriorly, and open posterior approach. A lateral approach for cage placement has also been reported. The purpose of this paper is to present a review of the literature on lumbar intervertebral fusion performed using interbody cages. The reported results for these procedures vary, but in general the majority of patients have had favorable results. The complications are similar to those encountered with traditional interbody fusion procedures using bone grafts. There is a learning curve associated with the procedures, particularly with the laparoscopic techniques. Appropriate training for the spine surgeon as well as the access surgeon is important. There is a great deal of disparity in reports on using the cages as stand-alone devices as well as on laparoscopic approaches. Overall, the use of interbody cages for fusion appears to be a viable treatment, yielding good results. Fusion cages appear to have a role in spine care; however, as with any procedure, patient selection and proper training of the surgeon are critical.