Targeting NF-kappaB in Waldenstrom macroglobulinemia

The nuclear factor-B (NF-B) path-way has been implicated in tumor B-cell survival, growth, and resistance to therapy. Because tumor cells overcome single-agent antitumor activity, we hypothesized that combination of agents that target differentially NF-B pathway will induce significant cytotoxicity. Therapeutic agents that target proteasome and Akt pathways should induce significant activity in B-cell malignancies as both pathways impact NF-B activity. We demonstrated that perifosine and bortezomib both targeted NF-B through its recruitment to the promoter of its target gene IB using chromatin immunoprecipitation assay. This combination led to synergistic cytotoxicity in Waldenstrom macroglobulinemia (WM) cells that was mediated through a combined reduction of the PI3K/Akt and ERK signaling pathways, found to be critical for survival of WM cells. Moreover, a combination of these drugs with the CD20 monoclonal antibody rituximab further increased their cytotoxic activity. Thus, effective WM therapy may require combination regimens targeting the NF-B pathway.      

Affective temperaments: Unique constructs or dimensions of normal personality by another name?

Background

Current models theorize that affective temperaments underlie the development and expression of mood psychopathology. Recent studies support the construct validity of affective temperaments in clinical and non-clinical samples. However, one concern is that affective temperaments may be describing characteristics that are better captured by models of normal personality. We conducted two studies examining: (a) the association of affective temperaments with domains and facets of normal personality, and (b) whether affective temperaments accounted for variance in mood symptoms and disorders, impairment, and daily-life experiences over-and-above variance accounted for by normal personality.

Methods

Study 1 included 522 young adults who completed the TEMPS-A and the NEO-PI-3. Study 2 included 145 participants who were administered the TEMPS-A, NEO-FFI, interviews assessing psychopathology and impairment, and an assessment of daily life experiences.

Results

Study 1 revealed that personality domains and facets accounted for one-third to one-half of the variance in affective temperaments. However, study 2 demonstrated that affective temperaments accounted for unique variance in measures of psychopathology, impairment, and daily-life experiences after partialling variance associated with personality domains. Specifically, cyclothymic/irritable temperament predicted bipolar disorders, impairment, borderline personality traits, urgency, and anger in daily life. Hyperthymic temperament predicted hypomanic episodes, grandiosity, sensation seeking, and increased activity in daily life.

Limitations

The study was limited by the fact that only domain, not facet-level, measures of FFM were available in study 2.

Conclusions

The findings support the validity of hyperthymic and cyclothymic/irritable temperaments as indicators of clinical psychopathology and indicate that they provide information beyond normal personality.     

Examining Relations Between Obsessive-Compulsive Features,Substance-Use Disorders,and Antisocial Personality Disorder in the Vietnam Era Twin Cohort

Classes of obsessive-compulsive features differing both quantitatively and qualitatively have been linked to gambling disorder. This secondary data analysis sought to extend this line of investigation to examine the extent to which previously reported latent obsessive-compulsive classes may relate to externalizing conditions in a sample of 1675 twin male veterans recruited and surveyed for studies of gambling behaviors/disorder. Using latent class analysis and multivariate regression, we found that participants who reported the highest levels of obsessive-compulsive features were more likely to meet criteria for cannabis abuse and dependence and antisocial personality disorder. When adjusting for co-occurring disorders, the relationship with antisocial personality disorder remained significant whereas those for cannabis use disorders did not. These results highlight the potential utility of considering obsessive-compulsive features within a transdiagnostic framework and suggest that specific externalizing disorders have important links to obsessive-compulsive features. Future research is needed to extend these findings to other samples.

     

Selective breeding in domestic dogs: How selecting for a short face impacted canine neuroanatomy

The range of cranial morphology seen in domestic dogs (Canis lupus familiaris) is a direct result of thousands of years of selective breeding. This article is the first to investigate how selection for reduced faces in brachycephalic dogs impacted the neuroanatomy of the canine brain through the analysis of endocasts. Previous research has demonstrated global effects on the shape of the bony cranium as the result of these breeding practices; however, these studies have largely focused on the bony structures of the skull and failed to consider the influence of facial reduction on the soft tissues of the brain. We generated endocasts from an existing set of clinically-obtained CT scans representing a variety of dogs with various cranial morphologies. These dogs represented four breeds as well as a comparative sample of dogs of unknown breed. We recorded three-dimensional coordinate data for 31 landmarks representing various gyri, sulci, and other neuroanatomical landmarks that allowed us to analyze differences in shape of the endocasts. Through geometric morphometric analyses, we determined that the endocast shape variance in this sample is correlated with cephalic index, and thus the selection for facial reduction has caused a perceivable effect on canine neuroanatomy. Additionally, we found the majority of the shape variance in the sample to be associated with olfactory anatomy; however, the rest of the morphology also correlates with cephalic index. The results of this article indicate that modern breeding practices and the selection for dogs with short faces have significantly influenced canine neuroanatomy.     

Efficacy of a Work Disability Prevention Program for People with Rheumatic and Musculoskeletal Conditions: A Single‐Blind Parallel‐Arm Randomized Controlled Trial

Objective

Work disability rates are high among people with rheumatic and musculoskeletal conditions. Effective disability preventive programs are needed. We examined the efficacy of a modified vocational rehabilitation approach delivered by trained occupational therapists and physical therapists on work limitation and work loss over 2 years among people with rheumatic and musculoskeletal conditions.

Methods

Eligibility criteria for this single‐blind, parallel‐arm randomized trial included ages 21–65 years, 15 or more hours/week employment, a self‐reported doctor‐diagnosed rheumatic or musculoskeletal condition, and concern about staying employed. The intervention consisted of a 1.5‐hour meeting, an action plan, written materials on employment supports, and telephone calls at 3 weeks and 3 months. Control group participants received the written materials. The primary outcome was the Work Limitations Questionnaire (WLQ) output job demand subscale. The secondary outcome was work loss. Intent‐to‐treat analyses were performed.

Results

Between October 2011 and January 2014, 652 individuals were assessed for eligibility. A total of 287 participants were randomized: 143 intervention and 144 control participants. In total, 264 participants (92%) completed 2‐year data collection. There was no difference in the mean ± SD WLQ change scores from baseline to 2‐year followup (?8.6 ± 1.9 intervention versus ?8.3 ± 2.2 control; P = 0.93). Of the 36 participants who experienced permanent work loss at 2 years, 11 (8%) were intervention participants and 25 (18%) control participants (P = 0.03).

Conclusion

The intervention did not have an effect on work limitations but reduced work loss. The intervention can be delivered by trained rehabilitation therapists.

     

ULTRASOUND IMAGING MEASUREMENT OF THE TRANSVERSUS ABDOMINIS IN SUPINE,STANDING, AND UNDER LOADING: A RELIABILITY STUDY OF NOVICE EXAMINERS

Background

Military personnel and first responders (police and firefighters) often carry large amounts of gear. This increased load can negatively affect posture and lead to back pain. The ability to quantitatively measure muscle thickness under loading would be valuable to clinicians to assess the effectiveness of core stabilization treatment programs and could aid in return to work decisions. Ultrasound imaging (USI) has the potential to provide such a measure, but to be useful it must be reliable.

Purpose

To assess the intrarater and interrater reliability of measurements of transversus abdominis (TrA) and internal oblique (IO) muscle thickness conducted by novice examiners using USI in supine, standing, and with an axial load.

Study Design

Prospective, test‐retest study

Methods

Healthy, active duty military (N=33) personnel were examined by two physical therapy doctoral students (primary and secondary ultrasound technicians) without prior experience in USI. Thickness measurements of the TrA and IO muscles were performed at rest and during a contraction to preferentially activate the TrA in three positions (hook‐lying, standing, and standing with body armor). Percent thickness changes and intraclass correlation coefficients (ICC) were calculated.

Results

Using the mean of three measurements for each of the three positions in resting and contracted muscle states, the intrarater ICC (3,3) values ranged from 0.90 to 0.98. The interrater ICC (2,1) values ranged from 0.39 to 0.79. The ICC values of percent thickness changes were lower than the individual ICC values for all positions and muscle states.

Conclusion

There is excellent intrarater reliability of novice ultrasound technicians measuring abdominal muscle thickness using USI in three positions during the resting and contracted muscle states. However, interrater reliability of two novice technicians was poor to fair, so additional training and experience may be necessary to improve reliability.

Level of Evidence

2b