CT-guided pretreatment biopsy diagnosis in patients with thymic epithelial tumours: diagnostic accuracy and risk of seeding.

AIM: To investigate the diagnostic performance of computed tomography (CT)-guided percutaneous transthoracic needle biopsy (PTNB) for thymic epithelial tumours (TETs) and the complication rate after PTNB including seeding after PTNB. MATERIALS AND METHODS: This retrospective study identified PTNBs for anterior mediastinal lesions between May 2007 and September 2021. The diagnostic performance for TETs and complications were investigated. The concordance of the histological grades of TETs between PTNB and surgery was evaluated. The factors associated with pleural seeding after PTNB were determined using Cox regression analysis. RESULTS: Of 387 PTNBs, 235 PTNBs from 225 patients diagnosed as TETs (124 thymomas and 101 thymic carcinomas) and 150 PTNBs from 133 patients diagnosed as other than TETs were included. The sensitivity, specificity, and accuracy for TETs were 89.4% (210/235), 100% (210/210), and 93.5% (360/385), respectively, with an immediate complication rate of 4.4% (17/385). The concordance rate of the histological grades between PTNB and surgery was 73.3% (77/105) after excluding uncategorised types of thymomas. During follow-up after PTNB (median duration, 38.8 months; range, 0.3-164.6 months), no tract seeding was observed. Pleural seeding was observed in 26 patients. Thymic carcinoma (hazard ratio [HR], 5.94; 95% confidence interval [CI], 2.07-17.08; p=0.001) and incomplete resection (HR, 3.29; 95% CI, 1.20-9.02; p=0.02) were associated with pleural seeding, while the biopsy approach type (transpleural versus parasternal) was not associated (p=0.12). CONCLUSIONS: Pretreatment biopsy for TETs was accurate and safe and may be considered for diagnosing TETs, particularly when the diagnosis is challenging and histological diagnosis is mandatory.

Using 3-Dimensional Motion Analysis to Optimize Treatment Planning for a Patient With Dropfoot: Case Report.

OBJECTIVE: This study demonstrated the use of computerized motion analysis to assist in evidence-based clinical decision-making. CASE DESCRIPTION: A 15-year-old girl who had right hemiparesis after a stroke was referred for 3-dimensional computerized motion analysis to determine the effect of 3 devices intended to control her dropfoot and to assist in developing a treatment plan. Four conditions were tested and compared: barefoot, lateral support ankle brace, functional electrical stimulation (FES) device, and dropfoot cuff. RESULTS: Kinematics showed the right ankle had significant dropfoot during swing phase (32.7 degrees of plantarflexion at terminal swing) in barefoot. The lateral support ankle brace, FES device, and dropfoot cuff reduced terminal swing plantarflexion to 27.2 degrees, 17.6 degrees, and 15.3 degrees, respectively, though ankle kinematics remained abnormal because of inadequate dorsiflexion. Improvements in gait variable score with FES (-8.2 degrees) or dropfoot cuff (-8.7 degrees) were significantly more than that with the lateral support brace (-2.2 degrees), and the difference in gait variable score between FES and dropfoot cuff was insignificant. Compared with the barefoot condition, the lateral support brace condition did not show a clinically significant difference in gait profile score; however, the gait profile scores of both FES and dropfoot cuff conditions showed clinically significant improvement (-1.7 degrees and -2.1 degrees, respectively). CONCLUSION: Objective data delineated subtle changes among 3 devices and led to the recommendation to discontinue the lateral support ankle brace, continue using her night ankle-foot orthosis and FES device, with the dropfoot cuff as a backup when she feels leg fatigue or skin irritation, and consider serial casting or surgical calf lengthening. IMPACT: Computerized motion analysis provides quantitative evaluation of subtle differences in the effect of braces with different designs, which are hard for the human eye to discern. The objective data inform and validate treatment decision-making. The recommendations were made as a result of evidence-based practice.

Calf lengthening may improve knee recurvatum in specific children with spastic diplegic cerebral palsy.

PURPOSE: Knee hyperextension in stance is a difficult condition to treat in children with spastic diplegic cerebral palsy (CP). In children with passive knee hyperextension, the presence of contracture or spasticity of the calf leads to knee hyperextension in stance phase. We hypothesize surgical treatment of the contracture of the calf will lead to less knee hyperextension. METHODS: We performed a retrospective review of children who were evaluated in our movement laboratory over 23 years with a diagnosis of CP Gross Motor Function Classification System I, II or III. We selected children who had passive knee hyperextension on exam and who underwent calf lengthening surgery. Children were divided into two groups: early recurvatum (ER) (n = 20) and late recurvatum (LR) (n = 14). RESULTS: There was no difference in the preoperative passive knee extension among the groups or the surgeries performed. For children who had passive knee hyperextension, calf lengthening improved static dorsiflexion with knee flexion on clinical exam by 9.3° in the ER group, 9.6° in the LR group as well as dorsiflexion with knee extension on clinical exam by 9.5° in the ER group and 6.4° in the LR group. The kinematic data showed that the ER group improved their knee hyperextension by 11° (p < 0.001), whereas the LR group did not significantly change their stance phase knee position. CONCLUSION: Children with passive knee hyperextension who have a calf contracture and walk in knee hyperextension in the first half of stance phase may improve after calf lengthening.Level of Evidence: III.

Knee Recurvatum in Children With Spastic Diplegic Cerebral Palsy.

BACKGROUND: The purpose of this study is to determine which factors drive patients with diplegic cerebral palsy to walk without knee recurvatum despite hyperextension of the knee on physical examination. METHODS: A retrospective review was conducted of all data collected in the Gait Analysis Laboratory between 1999 and 2014. Patients with spastic diplegic cerebral palsy and at least 5 degrees of knee extension on clinical examination were identified for the study. After IRB approval, a total of 60 children ranging in age from 4 to 17 were included in the study. There were 27 female patients. Gross Motor Function Classification System level was distributed in the population as follows: 34 patients at Gross Motor Function Classification System level I, 18 at level II, and 8 at level III. Patients were excluded from this study if they had extrapyramidal involvement, history of selective dorsal rhizotomy or lower extremity surgery. Patient who received botulinum toxin A injections within 1 year of the study were excluded as well. Patients were divided into 2 groups: children that walked with knee hyperextension (KH) and children that walked without knee hyperextension (KF, "knee flexion"). There were 15 subjects in the KH group and 45 subjects in the KF group. Motion Laboratory evaluation included a comprehensive examination, kinematics, and kinetic analysis with a VICOM system. All data were analyzed with unpaired t test to detect differences between the 2 groups. All statistical analysis was done only for the right legs (unless the right leg did not meet the exclusion then the left leg was analyzed) to meet the statistical requirement for independence. The Pearson correlation was applied to correlate the maximum knee extension in stance with maximum ankle dorsiflexion in stance. RESULTS: The static measurement of dorsiflexion with knee flexed showed statistically significant difference (P=0.004) with KH group having 2.3±11.6 degrees and KF group having 13.1±12.2 degrees. There was also a statistically significant difference in the static measurement of dorsiflexion with knee extended (P=0.0014) with KH group having -3.3±9.0 degrees and KF group having 5.8±9.1 degrees. Maximum dorsiflexion in stance phase also showed significant difference (P=0.0022) with the KH group having 0.1±14.0 degrees and KF group having 11.5±11.2 degrees. Maximum dorsiflexion in stance phase also showed significant difference (P<0.001) with the DH group having 0.1 (SD) 14.0 degrees and KF group having 11.5 (SD) 11.2 degrees. There were no significant differences in popliteal angle measurements or any strength measurement. CONCLUSIONS: Our study shows that the plantar flexion knee extension couple is the major contributing factor to cause patients with passive knee hyperextension to walk in a recurvatum pattern. This would have implications of further treatment of the knee hyperextension in stance. LEVEL OF EVIDENCE: Level III-case-control study.

Use of Comprehensive Geriatric Assessment and Geriatric Screening for Older Adults in the Radiation Oncology Setting: A Systematic Review.

AIMS: Comprehensive geriatric assessment (CGA) is a multidisciplinary diagnostic process that evaluates medical, psychological, social and functional capacity. No systematic review of the use of CGA in radiation oncology has been conducted. This paper reviews the use of CGA in radiation oncology, examines whether such assessments are feasible and evaluates the effectiveness of these assessments in predicting and modifying outcomes. MATERIALS AND METHODS: We searched Medline, EMBASE, PsycINFO, CINAHL and the Cochrane Library for articles published between 1 January 1996 and 24 January 2017. RESULTS: Twelve non-randomised studies were identified; four studies used a geriatric screening tool only and the eight other studies combined a screening tool with a CGA. Most studies had small samples (mean 63 participants). Two studies identified a significant (95% confidence interval 1.5-4.8 and 1.5-6.9) association between an abnormal screening and increased risk of mortality. One study showed an ability of the CGA to influence treatment decision making, whereas six papers suggested a non-significant association between the screening tool/CGA and treatment tolerance. CONCLUSION: The studies suggest the feasibility of using a screening tool to select patients for CGA. 'Vulnerability' showed a non-statistically significant association with treatment tolerance, but a significant association with mortality.

Impulsivity in early psychosis: A complex link with violent behaviour and a target for intervention.

BACKGROUND: Violent behaviour (VB) occurs in first episode of schizophrenia and can have devastating impact both on victims and patients themselves. A better knowledge of the underlying mechanisms of VB may pave the way to preventive treatments. OBJECTIVES: 1) To explore the nature of the link between impulsivity and VB in early psychosis (EP) patients; 2) To explore the interactions between impulsivity and substance abuse, insight, and positive symptoms, the main dynamic risk factors of VB described to date. DESIGN AND METHODS: Post hoc analysis of data acquired in the frame of a 36-months EP cohort study. A total of 265 EP patients, aged 18 to 35, treated at TIPP (Treatment and early Intervention in Psychosis Program), at the Department of Psychiatry in Lausanne, Switzerland, were included in the study. Logistic regression analyzes were performed as well as mediation analysis and interaction analysis RESULTS: Our data suggest that impulsivity is a predictor of VB when analyzed independently and as part of a multi-factorial model. Impulsivity continues to differentiate violent patients from non-violent ones at the end of the program. In addition, the relationship between impulsivity and VB is not mediated by substance abuse. Finally, the effect of impulsivity on the probability of VB is potentiated by the interaction of different levels of insight and positive symptoms. CONCLUSIONS: Early intervention strategies in psychotic disorders should include evaluation of impulsivity considering it is linked to increased risk of VB and may respond to treatment.

Effect of an Arm Traction Device on Image Quality and Radiation Exposure during Neck CT: A Prospective Study.

BACKGROUND AND PURPOSE: The image quality of neck CT is frequently disturbed by streak artifact from the shoulder girdles. Our aim was to determine the effects of an arm traction device on image quality and radiation exposure in neck CT. MATERIALS AND METHODS: Patients with lymphoma with complete remission who were scheduled to undergo 2 consecutive follow-up neck CT scans for surveillance within a 1-year interval were enrolled in this prospective study. They underwent 2 consecutive neck CT scans (intervention protocol: patients with an arm traction device; standard protocol: no positioning optimization) on the same CT system. The primary outcome measures were image noise in the lower neck and dose-length product. Secondary outcomes were streak artifacts in the supraclavicular fossa, volume CT dose index, and the extent of the biacromial line shift. RESULTS: Seventy-three patients were enrolled and underwent 2 consecutive CT scans with a mean interval of 155 days. In the intervention protocol, a mean noise reduction in the lower neck of 25.2%-28.5% (P < .001) was achieved, and a significant decrease in dose-length product (413 versus 397, P < .001) was observed. The intervention protocol significantly decreased streak artifacts (P < .001) and volume CT dose index (13.9 versus 13.4, P < .001) and could lower the biacromial line an average of 2.1 cm. CONCLUSIONS: An arm traction device can improve image quality and reduce radiation exposure during neck CT. The device can be simply applied in cooperative patients with suspected lower neck lesions, and the approach offers distinct advantages over the conventional imaging protocol.

Association between excessive Internet use and oral health behaviors of Korean adolescents: A 2015 national survey.

OBJECTIVE: This study aimed to investigate excessive Internet use's (EIU's) association with oral health behaviors among Korean adolescents. BASIC RESEARCH DESIGN: This cross-sectional study was based on the 11th Korea Youth Risk Behavior Web-based Survey (2015). PARTICIPANTS: 68,043 school students aged 13-18 years (35,204 boys and 32,839 girls). Data on, 45,271 (23,354 males and 21,917 females using the Internet on weekdays) and 49,324 (27,448 males and 21,876 females using the Internet on weekends) were analyzed after excluding questionnaires with missing values. MAIN OUTCOME MEASURES: The key variables were oral health behaviors (tooth-brushing frequency and tooth brushing after lunch at school, and preventive oral health behaviors), EIU (hours of Internet use on weekdays and weekends, excluding use for academic purposes). RESULTS: Compared to the general groups, the odds ratio (OR) for less tooth-brushing was 4.04 (95%CI=2.990-5.459) and 3.55-fold higher (95% CI=2.703-4.659) in the high-risk groups for weekday and weekend EIU, respectively. For post-lunch tooth-brushing, compared to the general groups, the OR for less tooth-brushing was 1.7-fold higher in the high-risk groups for EIU during weekdays and weekends. The OR for no preventive behavior was significantly higher in the high-risk groups than in the potential-risk and general groups. CONCLUSIONS: Policies moderating adolescents' EIU may enable appropriate oral health behaviors.

Implication of the glutamate-cystine antiporter xCT in schizophrenia cases linked to impaired GSH synthesis.

xCT is the specific chain of the cystine/glutamate antiporter, which is widely reported to support anti-oxidant defenses in vivo. xCT is therefore at the crossroads between two processes that are involved in schizophrenia: oxidative stress and glutamatergic neurotransmission. But data from human studies implicating xCT in the illness and clarifying the upstream mechanisms of xCT imbalance are still scarce. Low glutathione (GSH) levels and genetic risk in GCLC (Glutamate-Cysteine Ligase Catalytic subunit), the gene of limiting synthesizing enzyme for GSH, are both associated with schizophrenia. In the present study, we aimed at determining if xCT regulation by the redox system is involved in schizophrenia pathophysiology. We assessed whether modulating GCLC expression impact on xCT expression and activity (i) in fibroblasts from patients and controls with different GCLC genotypes which are known to affect GCLC regulation and GSH levels; (ii) in rat brain glial cells, i.e., astrocytes and oligodendrocytes, with a knock-down of GCLC. Our results highlight that decreased GCLC expression leads to an upregulation of xCT levels in patients' fibroblasts as well as in astrocytes. These results support the implication of xCT dysregulation in illness pathophysiology and further indicate that it can result from redox changes. Additionally, we showed that these anomalies may already take place at early stages of psychosis and be more prominent in a subgroup of patients with GCLC high-risk genotypes. These data add to the existing evidence identifying the inflammatory/redox systems as important targets to treat schizophrenia already at early stages. SCHIZOPHRENIA: ANTIOXIDANT DEFICIT INCREASES A KEY NEUROTRANSMITTER TRANSPORTER: Deficit of antioxidant synthesis in schizophrenia leads to oxidative stress and changes in neurotransmitter transporter. Led by Kim Do, a team of researchers from Lausanne University in Switzerland investigated the role of the cell-surface transport protein xCT in schizophrenia. They found that an enzyme responsible for antioxidant production is disturbed in patients. This leads to decreased antioxidant levels and consequently to oxidative stress-i.e. the accumulation of reactive oxygen molecules, damaging the cells component and impairing cell functioning-which in turn affects the functioning of the antioxidant pathway, including xCT. xCT, which exports the neurotransmitter glutamate, is thus overproduced in schizophrenia. The resulting increase of neurotransmitter activity, alongside the increase in oxidative stress, is thought to play a major role in the pathophysiology of schizophrenia, including at early stages of the disease.

Relationship between mental health risk factors and oral symptoms in adolescents: Korea Youth Risk Behavior Web-based Survey, 2013.

OBJECTIVE: To investigate the relationship between mental health risk factors and Korean adolescents' oral health. BASIC RESEARCH DESIGN: Cross-sectional study was based on the 9th Korea Youth Risk Behavior Web-based Survey (2013). PARTICIPANTS: Data were selected for 66,951 adolescents (33,777 males and 33,174 females; aged 13-18 years) out of 72,435 participants were analysed, after excluding cases with missing values. MAIN OUTCOME MEASURES: Oral health (experience of one or more of six oral symptoms), demographic characteristics (seven factors), and mental health risk (five factors). METHOD: Logistic regression analysis determined the effects of mental health risk factors on subjects' oral symptoms after adjustment for general characteristics. RESULTS: The adjusted odds ratio (AOR) was 1.52 (95%CI 1.50,1.54) for sleep satisfaction self-described as "not sufficient at all" and AOR 2.64 (95%CI 2.59,2.69) for those reporting very high stress levels. The AOR was 1.26 times (95%CI 1.24,1.27) higher for those using the internet on weekends for non-study purposes for ⟩6 hours than those using it for one hour. The AOR for experiencing oral symptoms was 1.44 times (95%CI 1.41,1.47) higher for those who had experienced school violence than for those who had not. CONCLUSIONS: Mental health risk factors were associated with oral symptoms. These results should inform the development of school health policies and comprehensive adolescent health promotion programs in Korea.

Potential mechanisms of development-dependent adverse effects of the herbicide paraquat in 3D rat brain cell cultures.

Exposure to environmental toxicants during vulnerable windows of brain development is suspected to raise the prevalence for neurological dysfunctions at later stages in life. Differentiation processes and changes in morphology, as well as a lack of physiological barriers, might be reasons that render a developing brain more susceptible to neurotoxicants than an adult. However, also the intrinsic capacity of cells to combat toxicant induced cellular stress might differ between the immature- and mature brain. In order to study whether this intrinsic protection capacity differs between immature and maturated brain cells we chose to study the maturation-dependent adverse effects of the known neurotoxicant Paraquat Dichloride (PQ) in 3D rat brain cell cultures. This in vitro system consists of the major brain cell types - neurons, astrocytes, oligodendrocytes and microglia - and over the time in vitro cultured cells undergo differentiation and maturation into a tissue-like organization. PQ was applied repeatedly over ten days in the sub-micromolar range, and effects were evaluated on neurons and glial cells. We observed that despite a higher PQ-uptake in mature cultures, PQ-induced adverse effects on glutamatergic-, GABAergic- and dopaminergic neurons, as assessed by gene expression and enzymatic activity, were more pronounced in immature cultures. This was associated with a stronger astrogliosis in immature- as compared to mature cultures, as well as perturbations of the glutathione-mediated defense against oxidative stress. Furthermore we observed evidence of microglial activation only in mature cultures, whereas immature cultures appeared to down-regulate markers for neuroprotective M2-microglial phenotype upon PQ-exposure. Taken together our results indicate that immature brain cell cultures have less intrinsic capacity to cope with cellular stress elicited by PQ as compared to mature cells. This may render immature brain cells more susceptible to the adverse effects of PQ.

Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia.

Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. On the basis of published and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. A series of animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders show PVI deficits to be all accompanied by oxidative stress in the anterior cingulate cortex. Specifically, oxidative stress is negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune and antioxidant signaling. As convergent end point, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models. This opens up new perspectives for the use of antioxidant treatments to be applied to at-risk individuals, in close temporal proximity to environmental impacts known to induce oxidative stress.

A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma.

Background: Activation of the phosphoinisitide-3 kinase (PI3K) pathway through mutation and constitutive upregulation has been described in renal cell carcinoma (RCC), making it an attractive target for therapeutic intervention. We performed a randomized phase II study in vascular endothelial growth factor (VEGF) therapy refractory patients to determine whether MK-2206, an allosteric inhibitor of AKT, was more efficacious than the mammalian target of rapamycin inhibitor everolimus. Patients and methods: A total of 43 patients were randomized in a 2:1 distribution, with 29 patients assigned to the MK-2206 arm and 14 to the everolimus arm. Progression-free survival (PFS) was the primary endpoint. Results: The trial was closed at the first futility analysis with an observed PFS of 3.68 months in the MK-2206 arm and 5.98 months in the everolimus arm. Dichotomous response rate profiles were seen in the MK-2206 arm with one complete response and three partial responses in the MK-2206 arm versus none in the everolimus arm. On the other hand, progressive disease was best response in 44.8% of MK2206 versus 14.3% of everolimus-treated patients. MK-2206 induced significantly more rash and pruritis than everolimus, and dose reduction occurred in 37.9% of MK-2206 versus 21.4% of everolimus-treated patients. Genomic analysis revealed that 57.1% of the patients in the PD group had either deleterious TP53 mutations or ATM mutations or deletions. In contrast, none of the patients in the non-PD group had TP53 or ATM defects. No predictive marker for response was observed in this small dataset. Conclusions: Dichotomous outcomes are observed when VEGF therapy refractory patients are treated with MK-2206, and MK-2206 does not demonstrate superiority to everolimus. Additionally, mutations in DNA repair genes are associated with early disease progression, indicating that dysregulation of DNA repair is associated with a more aggressive tumor phenotype in RCC.

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression.

Stressful life events produce a state of vulnerability to depression in some individuals. The mechanisms that contribute to vulnerability to depression remain poorly understood. A rat model of intense stress (social defeat (SD), first hit) produced vulnerability to depression in 40% of animals. Only vulnerable animals developed a depression-like phenotype after a second stressful hit (chronic mild stress). We found that this vulnerability to depression resulted from a persistent state of oxidative stress, which was reversed by treatment with antioxidants. This persistent state of oxidative stress was due to low brain-derived neurotrophic factor (BDNF) levels, which characterized the vulnerable animals. We found that BDNF constitutively controlled the nuclear translocation of the master redox-sensitive transcription factor Nrf2, which activates antioxidant defenses. Low BDNF levels in vulnerable animals prevented Nrf2 translocation and consequently prevented the activation of detoxifying/antioxidant enzymes, ultimately resulting in the generation of sustained oxidative stress. Activating Nrf2 translocation restored redox homeostasis and reversed vulnerability to depression. This mechanism was confirmed in Nrf2-null mice. The mice displayed high levels of oxidative stress and were inherently vulnerable to depression, but this phenotype was reversed by treatment with antioxidants. Our data reveal a novel role for BDNF in controlling redox homeostasis and provide a mechanistic explanation for post-stress vulnerability to depression while suggesting ways to reverse it. Because numerous enzymatic reactions produce reactive oxygen species that must then be cleared, the finding that BDNF controls endogenous redox homeostasis opens new avenues for investigation.

Comparison of Rectus Femoris Transfer Surgery Done Concomitant With Hamstring Lengthening or Delayed in Patients With Cerebral Palsy.

BACKGROUND: Children with spastic cerebral palsy frequently develop stiff knee gait. A common treatment of flexed knee gait is lengthening of the hamstring tendons. It has been shown that minimum knee extension improves after hamstring surgeries. However, it has been observed that a decreased peak knee flexion in swing may be a complication of hamstring lengthening (HSL). This has been noted to occur because of an overactive rectus femoris during the swing phase of gait. A common treatment of decreased knee flexion in swing is distal rectus femoris transfer (DRFT). The purpose of this study is to compare the differences between doing DRFT concomitantly with HSL and doing delayed DRFT after HSL. METHODS: A total of 111 children with cerebral palsy (74 males and 37 females) who underwent HSL were reviewed retrospectively. All patients who met the inclusion criteria were divided into 3 groups, 28 subjects in the HSL alone group (H), 57 subjects in the HSL with concomitant rectus femoris transfer group (C), and 26 subjects in the HSL with delayed rectus femoris transfer group (D). RESULTS: The groups had similar minimum knee flexion in stance preoperatively and postoperatively. Group D's minimum knee flexion in stance improved to 5.5±12.7 degrees after HSL, but increased to 8.8±11.6 degrees after DRFT. Groups D and H had statistically significant reduction in maximum knee flexion in swing after HSL (P<0.05). Maximum knee flexion in swing was statistically significantly reduced in the D group after DRFT (P<0.05), but the C group was not statistically different from preoperative after DRFT (P>0.05). The C and D groups had similar total knee excursion postoperatively. The H group had less knee excursion than the other 2 groups, but it was not significant. CONCLUSIONS: The group that had DRFT concomitantly with HSL maintained maximum knee flexion in swing phase postoperatively. Although the group that had delayed DRFT had a reduction in maximum knee flexion after isolated HSL, gains in swing phase motion were achieved after delayed DRFT (comparable to that of the simultaneous group). LEVEL OF EVIDENCE: Level II.

Utility of 18F-fluoroestradiol (18F-FES) PET/CT imaging as a pharmacodynamic marker in patients with refractory estrogen receptor-positive solid tumors receiving Z-endoxifen therapy.

BACKGROUND: Z-endoxifen is the most potent of the metabolites of tamoxifen, and has the potential to be more effective than tamoxifen because it bypasses potential drug resistance mechanisms attributable to patient variability in the expression of the hepatic microsomal enzyme CYP2D6. 18F-FES is a positron emission tomography (PET) imaging agent which selectively binds to estrogen receptor alpha (ER-α) and has been used for non-invasive in vivo assessment of ER activity in tumors. This study utilizes 18F-FES PET imaging as a pharmacodynamic biomarker in patients with ER+ tumors treated with Z-endoxifen. METHODS: Fifteen patients were recruited from a parent therapeutic trial of Z-endoxifen and underwent imaging with 18F-FES PET at baseline. Eight had positive lesions on the baseline scan and underwent follow-up imaging with 18F-FES 1-5 days post administration of Z-endoxifen. RESULTS: Statistically significant changes (p = 0.0078) in standard uptake value (SUV)-Max were observed between the baseline and follow-up scans as early as 1 day post drug administration. CONCLUSION: F-FES PET imaging could serve as a pharmacodynamic biomarker for patients treated with ER-directed therapy.

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression.

This corrects the article DOI: 10.1038/mp.2016.144.

Tollip, an early regulator of the acute inflammatory response in the substantia nigra.

BACKGROUND: Tollip is a ubiquitously expressed protein, originally described as a modulator of the IL-1R/TLR-NF-κB signaling pathways. Although this property has been well characterized in peripheral cells, and despite some evidence of its expression in the central nervous system, the role of Tollip in neuroinflammation remains poorly understood. The present study sought to explore the implication of Tollip in inflammation in the substantia nigra pars compacta, the structure affected in Parkinson's disease. METHODS: We first investigated Tollip distribution in the midbrain by immunohistochemistry. Then, we addressed TLR4-mediated response by intra-nigral injections of lipopolysaccharide (LPS), a TLR4 agonist, on inflammatory markers in Tollip knockout (KO) and wild-type (WT) mice. RESULTS: We report an unexpectedly high Tollip immunostaining in dopaminergic neurons of the mice brain. Second, intra-nigral injection of LPS led to increased susceptibility to neuroinflammation in Tollip KO compared to Tollip WT mice. This was demonstrated by a significant increase of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), and interferon gamma (IFN-γ) messenger RNA (mRNA) in the midbrain of Tollip KO mice upon LPS injection. Consistently, brain rAAV viral vector transduction with a nuclear factor kappa B (NF-κB)-inducible reporter gene confirmed increased NF-κB activation in Tollip KO mice. Lastly, Tollip KO mice displayed higher inducible NO synthase (iNOS) production, both at the messenger and protein level when compared to LPS-injected WT mice. Tollip deletion also aggravated LPS-induced oxidative and nitrosative damages, as indicated by an increase of 8-oxo-2'-deoxyguanosine and nitrotyrosine immunostaining, respectively. CONCLUSIONS: Altogether, these findings highlight a critical role of Tollip in the early phase of TLR4-mediated neuroinflammation. As brain inflammation is known to contribute to Parkinson's disease, Tollip may be a potential target for neuroprotection.

ATM function and its relationship with ATM gene mutations in chronic lymphocytic leukemia with the recurrent deletion (11q22.3-23.2).

Approximately 10-20% of chronic lymphocytic leukemia (CLL) patients exhibit del(11q22-23) before treatment, this cohort increases to over 40% upon progression following chemoimmunotherapy. The coding sequence of the DNA damage response gene, ataxia-telangiectasia-mutated (ATM), is contained in this deletion. The residual ATM allele is frequently mutated, suggesting a relationship between gene function and clinical response. To investigate this possibility, we sought to develop and validate an assay for the function of ATM protein in these patients. SMC1 (structural maintenance of chromosomes 1) and KAP1 (KRAB-associated protein 1) were found to be unique substrates of ATM kinase by immunoblot detection following ionizing radiation. Using a pool of eight fluorescence in situ hybridization-negative CLL samples as a standard, the phosphorylation of SMC1 and KAP1 from 46 del (11q22-23) samples was analyzed using normal mixture model-based clustering. This identified 13 samples (28%) that were deficient in ATM function. Targeted sequencing of the ATM gene of these samples, with reference to genomic DNA, revealed 12 somatic mutations and 15 germline mutations in these samples. No strong correlation was observed between ATM mutation and function. Therefore, mutation status may not be taken as an indicator of ATM function. Rather, a direct assay of the kinase activity should be used in the development of therapies.

Impaired fornix-hippocampus integrity is linked to peripheral glutathione peroxidase in early psychosis.

Several lines of evidence implicate the fornix-hippocampus circuit in schizophrenia. In early-phase psychosis, this circuit has not been extensively investigated and the underlying mechanisms affecting the circuit are unknown. The hippocampus and fornix are vulnerable to oxidative stress at peripuberty in a glutathione (GSH)-deficient animal model. The purposes of the current study were to assess the integrity of the fornix-hippocampus circuit in early-psychosis patients (EP), and to study its relationship with peripheral redox markers. Diffusion spectrum imaging and T1-weighted magnetic resonance imaging (MRI) were used to assess the fornix and hippocampus in 42 EP patients compared with 42 gender- and age-matched healthy controls. Generalized fractional anisotropy (gFA) and volumetric properties were used to measure fornix and hippocampal integrity, respectively. Correlation analysis was used to quantify the relationship of gFA in the fornix and hippocampal volume, with blood GSH levels and glutathione peroxidase (GPx) activity. Patients compared with controls exhibited lower gFA in the fornix as well as smaller volume in the hippocampus. In EP, but not in controls, smaller hippocampal volume was associated with high GPx activity. Disruption of the fornix-hippocampus circuit is already present in the early stages of psychosis. Higher blood GPx activity is associated with smaller hippocampal volume, which may support a role of oxidative stress in disease mechanisms.