Apathy But Not Diminished Expression in Schizophrenia Is Associated With Discounting of Monetary Rewards by Physical Effort

Negative symptoms in schizophrenia have been grouped into the 2 factors of apathy and diminished expression, which might be caused by separable pathophysiological mechanisms. Recently, it has been proposed that apathy could be due to dysfunctional integration of reward and effort during decision making. We asked whether apathy in particular is associated with stronger devaluation (“discounting”) of monetary rewards that require physical effort. Thirty-one patients with schizophrenia and 20 healthy control participants performed a computerized effort discounting task in which they could choose to exert physical effort on a handgrip to obtain monetary rewards. This procedure yields an individual measure for the strength of effort discounting. The degree of effort discounting was strongly correlated with apathy, but not with diminished expression. Importantly, the association between apathy and effort discounting was not driven by cognitive ability, antipsychotic medication, or other clinical and demographic variables. This study provides the first evidence for a highly specific association of apathy with effort-based decision making in patients with schizophrenia. Within a translational framework, the present effort discounting task could provide a bridge between apathy as a psychopathological phenomenon and established behavioral tasks to address similar states in animals.Key words: negative symptoms, effort-based decision making, cost-benefit calculation     

Flexed-knee gait in children with cerebral palsy: a 10-year follow-up study

Background

While several studies have evaluated the short-term effectiveness of conservative and surgical treatment of flexed-knee gait in children with cerebral palsy (CP), few have explored the long-term outcomes using gait analysis. The purpose of this study was to examine, through gait analysis, the 10-year outcomes of flexed-knee gait in children with CP.

Methods

Ninety-seven children with spastic CP who walked with a flexed-knee gait underwent two gait evaluations [age 6.1 ± 2.1 and 16.2 ± 2.3 years, Gross Motor Function Classification System (GMFCS) I (12), II (45), III (37), IV (3)]. Limbs with knee flexion at initial contact >15° were considered walking with a flexed-knee gait and were included in the study (n = 185). Kinematic data were collected using an eight-camera motion analysis system (Motion Analysis, Santa Rosa, CA). Surgical and therapeutic interventions were not controlled.

Results

A comparison between the two gait studies showed an overall improvement in gait at 10 years follow-up. Significant improvements were seen in knee flexion at initial contact, Gait Deviation Index (GDI), Gross Motor Function Measure (GMFM), and gait speed (P < 0.01 for all). Outcome was also evaluated based on the severity of flexed-knee gait at the initial visit, with functional skills and overall gait (GDI) improving in all groups (P < 0.01 for all). The group with a severe flexed-knee gait exhibited the most improvement, while subjects with a mild flexed-knee improved the least.

Conclusions

Children at a specialty hospital whose orthopedic care included gait analysis and multi-level surgery showed improvement of flexed-knee gait and gross motor function over a 10-year course, regardless of the initial severity.     

Long-Acting FGF21 Has Enhanced Efficacy in Diet-Induced Obese Mice and in Obese Rhesus Monkeys

Fibroblast growth factor 21 (FGF21), a hormone with short half-life, has consistently shown strong pharmacological efficacy. We first assessed the efficacy of murine recombinant FGF21 in C57BL6 lean mice for 5 wk. We then generated a long-acting FGF21 molecule by fusing a Fc to a variant of human recombinant FGF21 (hrFGF21) that contained two engineered mutations [L98R, P171G; Fc-FGF21(RG)] and tested it in C57BL6 diet-induced obese mice and obese rhesus monkeys. We compared its metabolic properties with those of the hrFGF21. Groups of diet-induced obese mice were treated for 36 d with different doses of hrFGF21 (01, 0.3, and 1 mg/kg twice daily) and with Fc-FGF21(RG) (2.3 mg/kg, every 5 d). Body weight, glucose, insulin, cholesterol, and triglyceride levels were decreased after treatment with either compound. A glucose tolerance test (GTT) was also improved. Obese rhesus monkeys were treated with hrFGF21 (once a day) and Fc-FGF21(RG) (once a week) in a dose-escalation fashion. Doses started at 0.1 and 0.3 mg/kg and ended at 3 and 5 mg/kg for hrFGF21 and Fc-FGF21(RG), respectively. Doses were escalated every 2 wk, and animals were followed up for a washout period of 3 wk. Body weight, glucose, insulin, cholesterol, and triglyceride levels and the GTT profile were decreased to a greater extent with Fc-FGF21(RG) than with hrFGF21. The PK-PD relationship of Fc-FGF21(RG) exposure and triglyceride reduction was also conducted with a maximum response model. In conclusion, in more than one species, Fc-FGF21(RG) chronically administered once a week showed similar or greater efficacy than hrFGF21 administered daily.     

Effects of bone morphogenetic protein 2 on human umbilical vein endothelial cells

Bone morphogenetic proteins (BMPs) and their receptors play important roles in cellular processes such as proliferation, differentiation, migration and cell survival. It was also demonstrated that BMPs are involved in vasculogenesis and angiogenesis. In this study, we investigated the expression profile of BMP receptors in human umbilical vein endothelial cells (HUVECs) and determined the effect of BMP-2 on proliferation, migration, invasion, cell survival and tube formation. HUVECs express the type I BMP receptors ALK2, ALK3 and ALK6 and the type II receptor BMPR-II. Treatment of HUVECs with recombinant human BMP-2 induced migration, invasion and tube formation of HUVECs without affecting proliferation and apoptosis. Our data suggest that BMP-2 represents a chemoattractant and proangiogenic factor for HUVECs.     

FFPE tissue as a feasible source for gene expression analysis – A comparison of three reference genes and one tumor marker

Background

Formalin-fixation, paraffin-embedding is the standard processing technique for tumor tissue in modern pathology. New techniques such as cryo-conservation allow rapid fixation and long-time storage but come along with increased costs and enlarged storage complexity. However, formalin-fixed, paraffin-embedded (FFPE) tissue is available in a large quantity, making it the ideal material for retrospective studies.The following study was designed to investigate the influence of formalin-fixation on the quality of mRNA and applicability of FFPE-derived mRNA for gene expression analysis. Three potential reference genes for pulmonary tumors with neuroendocrine differentiation were included and tested for their robust expression.

Materials and methods

Eighty specimens collected from 2005 to 2012 at the Institute of Pathology and Neuropathology at the University Hospital Essen were analyzed for their gene expression by using TaqMan^® gene expression assays on demand (AoD). Three distinct potential reference genes (ACTB, GAPDH, HPRT1) were evaluated for their expression, and a proteasome subunit (PSMA1) was included in the analysis as tumor marker and functioned as an internal technical control.

Conclusion

For GAPDH and ACTB, a highly significant correlation and consistent expression between the investigated entities was found, making them reliable reference genes for further research. Additionally, the feasibility for a FFPE tissue-based gene expression analysis was verified by showing that the mRNA quality is sufficient. When standardized FFPE preparation is performed carefully, sufficient mRNA can be isolated for reliable and successful gene expression analysis. That provides the basis the door for large, retrospective studies that correlate molecular and clinical follow-up data.     

Impact of chromatin structure on PR signaling: transition from local to global analysis

The progesterone receptor (PR) interacts with chromatin in a highly dynamic manner that requires ongoing chromatin remodeling, interaction with chaparones and activity of the proteasome. Here we discuss dynamic interaction of steroid receptor with chromatin, with special attention not only to PR but also to the glucocorticoid receptor (GR), as these receptors share many similarities regarding interaction with, and remodeling of, chromatin. Both receptors can bind nucleosomal DNA and have accordingly been described as pioneering factors. However recent genomic approaches (ChIP-seq and DHS-seq) show that a large fraction of receptor binding events occur at pre-accessible chromatin. Thus factors which generate and maintain accessible chromatin during development, and in fully differentiated tissue, contribute a major fraction of receptor tissue specificity. In addition, chromosome conformation capture techniques suggest that steroid receptors preferentially sequester within distinct nuclear hubs. We will integrate dynamic studies from single cells and genomic studies from cell populations, and discuss how genomic approaches have reshaped our current understanding of mechanisms that control steroid receptor interaction with chromatin.     

IORT with electrons as boost strategy during breast conserving therapy in limited stage breast cancer: Long term results of an ISIORT pooled analysis

Purpose

Linac-based intraoperative radiotherapy with electrons (IOERT) was implemented to prevent local recurrences after breast conserving therapy (BCT) and was delivered as an intraoperative boost to the tumor bed prior to whole breast radiotherapy (WBI). A collaborative analysis has been performed by European ISIORT member institutions for long term evaluation of this strategy.

Material and methods

Until 10/2005, 1109 unselected patients of any risk group have been identified among seven centers using identical methods, sequencing and dosage for intra- and postoperative radiotherapy. A median IOERT dose of 10 Gy was applied (90% reference isodose), preceding WBI with 50–54 Gy (single doses 1.7–2 Gy).

Results

At a median follow up of 72.4 months (0.8–239), only 16 in-breast recurrences were observed, yielding a local tumor control rate of 99.2%. Relapses occurred 12.5–151 months after primary treatment. In multivariate analysis only grade 3 reached significance (p = 0.031) to be predictive for local recurrence development. Taking into account patient age, annual in-breast recurrence rates amounted 0.64%, 0.34%, 0.21% and 0.16% in patients <40 years; 40–49 years; 50–59 years and ?60 years, respectively.

Conclusion

In all risk subgroups, a 10 Gy IOERT boost prior to WBI provided outstanding local control rates, comparing favourably to all trials with similar length of follow up.