The Effect of Auditory Residual Inhibition on Tinnitus and the Electroencephalogram.

OBJECTIVES: Tinnitus is the perception of sound in the absence of an external physical sound source, for some people it can severely reduce the quality of life. Acoustic residual inhibition (ARI) is a suppression of tinnitus following the cessation of a sound. The present study investigated the effect of ARI on brain activity measured using EEG. DESIGN: Thirty adult participants (mean age of 58 years) experiencing chronic tinnitus (minimum 2 years) participated. Participants were presented broad band noise at 10 dB above minimum masking level (1 min followed by 4 min of silence, 4 times) counterbalanced with a control treatment of broad band noise at threshold (1 min followed by 4 min of silence, 4 times) while 64-channel EEG was simultaneously recorded. Tinnitus loudness was measured using a 9-point tinnitus loudness rating scale. RESULTS: The ARI stimulation resulted in a self-reported reduction in tinnitus loudness in 17 of the 30 participants. Tinnitus rating reduced following stimulation but gradually returned to near baseline during 4 min of silence post sound exposure; successive sound exposures resulted in lower loudness ratings. No significant reductions in loudness rating were found with the control stimulation. The EEG showed increases in power spectral density, particularly in the alpha and gamma bands, during ARI compared to the control periods. CONCLUSIONS: These results contribute to the understanding of ARI and tinnitus. We recommend that there be a closer examination of the relationship between onset and offset of sound in both tinnitus and nontinnitus control participants to ascertain if EEG changes seen with ARI relate to tinnitus suppression or general postsound activity.

The Effectiveness of a Functional Movement Assessment and 4-Week Exercise Training Program for Female High School Athletes.

ABSTRACT: Boucher, BK, Rich, AJ, Gobert, D, Gardner, B, Metzner, P, King, C, and Buse, M. The effectiveness of a functional movement assessment and 4-week exercise training program for female high school athletes. J Strength Cond Res 35(1): 102-110, 2021-The extent to which young females participate in school-sponsored athletics has grown significantly over the past 2 decades. The number of females in high school sports increased for the 25th consecutive year in 2012-2013, reaching an all-time record. Unfortunately, sports-related injury rates for female athletes have also continued to rise. A body of research exists to suggest that dysfunctional movement may be linked to increased risk of injury, and training programs designed to improve movement patterns are effective to both enhance performance and reduce the risk of injury. Effective training programs incorporate corrective exercises to retrain dysfunctional movement patterns. The Functional Movement ScreenTM (FMSTM) is a tool developed to assess 7 fundamental movement patterns. The FMSTM has been used extensively with a wide range of athletes at various levels of performance. The aim of this study was to investigate the effectiveness of a movement-training program with female high school athletes using the FMSTM. The overall purpose was to assess the effectiveness of a 4-week corrective exercise-training program at improving FMSTM scores. Data analysis using Wilcoxon signed-rank test revealed a statistically significant change in total group FMSTM scores (Z = -2.214, p = 0.027) after the corrective exercise-training program. Mean total group FMSTM scores increased from 14.43 ± 1.90 (pretest) to 17.29 ± 1.38 (posttest). Findings suggest that positive outcomes to a corrective exercise-training program, which targets specific movement impairments, can be achieved in a relatively short period of time.

Removing T-cell epitopes with computational protein design.

Immune responses can make protein therapeutics ineffective or even dangerous. We describe a general computational protein design method for reducing immunogenicity by eliminating known and predicted T-cell epitopes and maximizing the content of human peptide sequences without disrupting protein structure and function. We show that the method recapitulates previous experimental results on immunogenicity reduction, and we use it to disrupt T-cell epitopes in GFP and Pseudomonas exotoxin A without disrupting function.

Recombinant immunotoxin for cancer treatment with low immunogenicity by identification and silencing of human T-cell epitopes.

Nonhuman proteins have valuable therapeutic properties, but their efficacy is limited by neutralizing antibodies. Recombinant immunotoxins (RITs) are potent anticancer agents that have produced many complete remissions in leukemia, but immunogenicity limits the number of doses that can be given to patients with normal immune systems. Using human cells, we identified eight helper T-cell epitopes in PE38, a portion of the bacterial protein Pseudomonas exotoxin A which consists of the toxin moiety of the RIT, and used this information to make LMB-T18 in which three epitopes were deleted and five others diminished by point mutations in key residues. LMB-T18 has high cytotoxic and antitumor activity and is very resistant to thermal denaturation. The new immunotoxin has a 93% decrease in T-cell epitopes and should have improved efficacy in patients because more treatment cycles can be given. Furthermore, the deimmunized toxin can be used to make RITs targeting other antigens, and the approach we describe can be used to deimmunize other therapeutically useful nonhuman proteins.

Utilizing time-driven activity-based costing to understand the short- and long-term costs of treating localized, low-risk prostate cancer.

BACKGROUND: Given the costs of delivering care for men with prostate cancer remain poorly described, this article reports the results of time-driven activity-based costing (TDABC) for competing treatments of low-risk prostate cancer. METHODS: Process maps were developed for each phase of care from the initial urologic visit through 12 years of follow-up for robotic-assisted laparoscopic prostatectomy (RALP), cryotherapy, high-dose rate (HDR) and low-dose rate (LDR) brachytherapy, intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and active surveillance (AS). The last modality incorporated both traditional transrectal ultrasound (TRUS) biopsy and multiparametric-MRI/TRUS fusion biopsy. The costs of materials, equipment, personnel, and space were calculated per unit of time and based on the relative proportion of capacity used. TDABC for each treatment was defined as the sum of its resources. RESULTS: Substantial cost variation was observed at 5 years, with costs ranging from $7,298 for AS to $23,565 for IMRT, and they remained consistent through 12 years of follow-up. LDR brachytherapy ($8,978) was notably cheaper than HDR brachytherapy ($11,448), and SBRT ($11,665) was notably cheaper than IMRT, with the cost savings attributable to shorter procedure times and fewer visits required for treatment. Both equipment costs and an inpatient stay ($2,306) contributed to the high cost of RALP ($16,946). Cryotherapy ($11,215) was more costly than LDR brachytherapy, largely because of increased single-use equipment costs ($6,292 vs $1,921). AS reached cost equivalence with LDR brachytherapy after 7 years of follow-up. CONCLUSIONS: The use of TDABC is feasible for analyzing cancer services and provides insights into cost-reduction tactics in an era focused on emphasizing value. By detailing all steps from diagnosis and treatment through 12 years of follow-up for low-risk prostate cancer, this study has demonstrated significant cost variation between competing treatments.

Automating human intuition for protein design.

In the design of new enzymes and binding proteins, human intuition is often used to modify computationally designed amino acid sequences prior to experimental characterization. The manual sequence changes involve both reversions of amino acid mutations back to the identity present in the parent scaffold and the introduction of residues making additional interactions with the binding partner or backing up first shell interactions. Automation of this manual sequence refinement process would allow more systematic evaluation and considerably reduce the amount of human designer effort involved. Here we introduce a benchmark for evaluating the ability of automated methods to recapitulate the sequence changes made to computer-generated models by human designers, and use it to assess alternative computational methods. We find the best performance for a greedy one-position-at-a-time optimization protocol that utilizes metrics (such as shape complementarity) and local refinement methods too computationally expensive for global Monte Carlo (MC) sequence optimization. This protocol should be broadly useful for improving the stability and function of designed binding proteins.

EEG Complexity Analysis of Brain States, Tasks and ASD Risk.

Autism spectrum disorder is an increasingly prevalent and debilitating neurodevelopmental condition and an electroencephalogram (EEG) diagnostic challenge. Despite large amounts of electrophysiological research over many decades, an EEG biomarker for autism spectrum disorder (ASD) has not been found. We hypothesized that reductions in complex dynamical system behaviour in the human central nervous system as part of the macroscale neuronal function during cognitive processes might be detectable in whole EEG for higher-risk ASD adults. In three studies, we compared the medians of correlation dimension, largest Lyapunov exponent, Higuchi's fractal dimension, multiscale entropy, multifractal detrended fluctuation analysis and Kolmogorov complexity during resting, cognitive and social skill tasks in 20 EEG channels of 39 adults over a range of ASD risk. We found heterogeneous complexity distribution with clusters of hierarchical sequences pointing to potential cognitive processing differences, but no clear distinction based on ASD risk. We suggest that there is indication of statistically significant differences between complexity measures of brain states and tasks. Though replication of our studies is needed with a larger sample, we believe that our electrophysiological and analytic approach has potential as a biomarker for earlier ASD diagnosis.

Effect of MDMA-assisted therapy on mood and anxiety symptoms in advanced-stage cancer (EMMAC): study protocol for a double-blind, randomised controlled trial.

BACKGROUND: Symptoms of anxiety and depression are common in patients with terminal illness and multiple challenges exist with timely and effective care in this population. Several centres have reported that one dose of the serotonergic psychedelic psilocybin, combined with therapeutic support, improves these symptoms for up to 6 months in this patient group. Drawing upon related therapeutic mechanisms, 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy may have the potential to achieve similar, positive mental health outcomes in this group. Preliminary evidence also supports the tolerability of MDMA-assisted therapy for anxiety and depression in advanced-stage cancer. METHODS: Up to 32 participants with advanced-stage cancer and associated depression and anxiety will be randomised in a 1:1 ratio into one of two blinded parallel treatment arms. The intervention group will receive 120 mg (+ 60 mg optional supplemental dose) MDMA-assisted therapy. The psychoactive control group will receive 20 mg oral (+ 10 mg optional supplemental dose) methylphenidate-assisted therapy. For each medication-assisted therapy session, participants will undergo two 90-min therapeutic support sessions in the week preceding, and one 90-min support session the day after the experimental session. A battery of measures (mood, anxiety, quality of life, mystical experience, spiritual wellbeing, attitudes towards death, personality traits, holistic health and wellbeing, connectedness, demoralisation, expectations, qualitative data and safety measures) will be assessed at baseline and through to the end of the protocol. Participants will be followed up until either 12 months post-randomisation or death, whichever occurs first. DISCUSSION: This study will examine the effect of MDMA-assisted therapy on symptoms of anxiety and depression in advanced-stage cancer. Potential therapeutic implications include establishing the safety and effectiveness of a novel treatment that may relieve mental suffering in patients with life-threatening illness. TRIAL REGISTRATION: Trial registered on Australian New Zealand Clinical Trials Registry. REGISTRATION NUMBER: ACTRN12619001334190p. Date registered: 30/09/2019. URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378153&showOriginal=true&isReview=true.

Chronic pain, perceived stress, and cellular aging: an exploratory study.

BACKGROUND: Chronic pain conditions are characterized by significant individual variability complicating the identification of pathophysiological markers. Leukocyte telomere length (TL), a measure of cellular aging, is associated with age-related disease onset, psychosocial stress, and health-related functional decline. Psychosocial stress has been associated with the onset of chronic pain and chronic pain is experienced as a physical and psychosocial stressor. However, the utility of TL as a biological marker reflecting the burden of chronic pain and psychosocial stress has not yet been explored. FINDINGS: The relationship between chronic pain, stress, and TL was analyzed in 36 ethnically diverse, older adults, half of whom reported no chronic pain and the other half had chronic knee osteoarthritis (OA) pain. Subjects completed a physical exam, radiographs, health history, and psychosocial questionnaires. Blood samples were collected and TL was measured by quantitative polymerase chain reaction (qPCR). Four groups were identified characterized by pain status and the Perceived Stress Scale scores: 1) no pain/low stress, 2) no pain/high stress, chronic pain/low stress, and 4) chronic pain/high stress. TL differed between the pain/stress groups (p = 0.01), controlling for relevant covariates. Specifically, the chronic pain/high stress group had significantly shorter TL compared to the no pain/low stress group. Age was negatively correlated with TL, particularly in the chronic pain/high stress group (p = 0.03). CONCLUSIONS: Although preliminary in nature and based on a modest sample size, these findings indicate that cellular aging may be more pronounced in older adults experiencing high levels of perceived stress and chronic pain.

Patients treated for acute headache with intranasal droperidol spend less time in the emergency department: A retrospective observational study.

OBJECTIVE: Headache is a common presenting complaint to the ED. Using time from the first provider to discharge as a surrogate for effectiveness, we aimed to determine if intranasal (IN) droperidol is as beneficial as usual treatment for acute headache in the ED. METHODS: There were 1213 consecutive presentations of adults with acute headache over a 42-month period. Electronic records for each event were interrogated, 406 events met pre-determined exclusion criteria. Of the remaining 805 eligible patient events, 139 received IN droperidol, whereas 666 were given usual therapy. RESULTS: There was a 20 min reduction of mean and median ED length of stay (LOS) for the group that got treated with IN droperidol. CONCLUSIONS: IN droperidol reduced LOS in the ED. There are potential cost savings of this effective treatment via this novel route. A prospective multi-centre study of the use of IN droperidol for the treatment of acute headache in the ED is recommended.

THE PREVALENCE OF INSOMNIA AND SLEEP APNEA IN DISCHARGE ABSTRACT DATA: A CALL TO IMPROVE DATA QUALITY.

Insomnia and sleep apnea are associated with a variety of comorbid conditions and carry a symptom burden to patients. As the prevalence of insomnia and sleep apnea continue to rise, it is imperative that appropriate tools are implemented to accurately capture their prevalence in acute care settings. A retrospective chart review was conducted on 3,074 inpatient charts in Calgary, Alberta. The estimated prevalence of insomnia was 10.36 percent, and sleep apnea was 6.56 percent in inpatient visits between January 1, 2015, and June 30, 2015. The sensitivity of insomnia and sleep apnea were low, and the specificity was high when comparing the chart review to the ICD-10. As both insomnia and sleep apnea were associated with various comorbid conditions, it would be imperative that alternate methods are identified to capture and code them. This would enable clinicians to better identify and treat them, and ultimately improve patient care.

Internal herniation of the caecum into the lesser sac: an unusual cause of an acute abdomen (2009: 10b).

Internal hernias are rare, occurring in 0.2-0.9% of autopsy cases. Hernias through the foramen of Winslow are even rarer, occurring in up to 8% of internal hernias. The clinical presentation is variable, making diagnosis difficult, and a delay in diagnosis can result in significant morbidity. As such, early radiological diagnosis is paramount. We report a rare case of caecal herniation through the foramen of Winslow in a 49-year-old female patient in whom the diagnosis was made radiologically and allowed appropriate and prompt management.

Experience of transfer from child to adult mental health services of young people with autism spectrum disorder.

BACKGROUND: Transition from child-centred to adult mental health services has been reported as challenging for young people. It can be especially difficult for young people with autism spectrum disorder (ASD) as they manage the challenges of adolescence and navigate leaving child and adolescent mental health services (CAMHS). AIMS: This study examines the predictors of transfer to adult mental health services, and using a qualitative analysis, explores the young people's experiences of transition. METHOD: A UK sample of 118 young people aged 14-21 years, with ASD and additional mental health problems, recruited from four National Health Service trusts were followed up every 12 months over 3 years, as they were discharged from CAMHS. Measures of mental health and rich additional contextual information (clinical, family, social, educational) were used to capture their experiences. Regression and framework analyses were used. RESULTS: Regression analysis showed having an attention-deficit hyperactivity disorder diagnosis and taking medication were predictors of transfer from child to adult mental health services. Several features of young people's transition experience were found to be associated with positive outcomes and ongoing problems, including family factors, education transitions and levels of engagement with services. CONCLUSIONS: The findings show the importance of monitoring and identifying those young people that might be particularly at risk of negative outcomes and crisis presentations. Although some young people were able to successfully manage their mental health following discharge from CAMHS, others reported levels of unmet need and negative experiences of transition.

Does an abnormally elevated maternal alkaline phosphatase pose problems for the fetus?

We report a potential association between an abnormally raised pregnancy level of alkaline phosphatase (ALP) and intrauterine growth restriction (IUGR). There are few reports of women with abnormally high ALP during pregnancy. However, there is work to suggest an association with placental insufficiency, low birth weight and preterm delivery. In conjunction with a rising ALP, fetal IUGR and intermittent absence of umbilical artery end diastolic flow had evolved. A greatly elevated ALP may be a marker for placental insufficiency and IUGR.

Potential Impact of 68Ga-PSMA-11 PET/CT on the Planning of Definitive Radiation Therapy for Prostate Cancer.

Standard-of-care imaging for initial staging of prostate cancer (PCa) underestimates disease burden. Prostate-specific membrane antigen (PSMA) PET/CT detects PCa metastasis with superior accuracy, having a potential impact on the planning of definitive radiation therapy (RT) for nonmetastatic PCa. Our objectives were to determine how often definitive RT planning based on standard target volumes covers 68Ga-PSMA-11 PET/CT-defined disease and to assess the potential impact of 68Ga-PSMA-11 PET/CT on definitive RT planning. Methods: This was a post hoc analysis of an intention-to-treat population of 73 patients with localized PCa without prior local therapy who underwent 68Ga-PSMA PET/CT for initial staging as part of an investigational new drug trial. Eleven of the 73 were intermediate-risk (15%), 33 were high-risk (45%), 22 were very-high-risk (30%), and 7 were N1 (9.5%). Clinical target volumes (CTVs), which included the prostate, seminal vesicles, and (in accord with the Radiation Therapy Oncology Group consensus guidelines) pelvic lymph nodes (LNs), were contoured on the CT portion of the PET/CT images by a radiation oncologist masked to the PET findings. 68Ga-PSMA-11 PET/CT images were analyzed by a nuclear medicine physician. 68Ga-PSMA-11-positive lesions not covered by planning volumes based on the CTVs were considered to have a major potential impact on treatment planning. Results: All patients had one or more 68Ga-PSMA-11-positive primary prostate lesions. Twenty-five (34%) and 7 (9.5%) of the 73 patients had 68Ga-PSMA-11-positive pelvic LN and distant metastases, respectively. The sites of LN metastases in decreasing order of frequency were external iliac (20.5%), common iliac (13.5%), internal iliac (12.5%) obturator (12.5%), perirectal (4%), abdominal (4%), upper diaphragm (4%), and presacral (1.5%). The median size of the LN lesions was 6 mm (range, 4-24 mm). RT planning based on the CTVs covered 69 (94.5%) of the 73 primary lesions and 20 (80%) of the 25 pelvic LN lesions, on a per-patient analysis. Conclusion:68Ga-PSMA-11 PET/CT had a major impact on intended definitive RT planning for PCa in 12 (16.5%) of the 73 patients whose RT fields covered the prostate, seminal vesicles, and pelvic LNs and in 25 (37%) of the 66 patients whose RT fields covered the prostate and seminal vesicles but not the pelvic LNs.

68Ga-PSMA-11 PET/CT Mapping of Prostate Cancer Biochemical Recurrence After Radical Prostatectomy in 270 Patients with a PSA Level of Less Than 1.0 ng/mL: Impact on Salvage Radiotherapy Planning.

Target volume delineations for prostate cancer (PCa) salvage radiotherapy (SRT) after radical prostatectomy are usually drawn in the absence of visibly recurrent disease. 68Ga-labeled prostate-specific membrane antigen (PSMA-11) PET/CT detects recurrent PCa with sensitivity superior to standard-of-care imaging at serum prostate-specific antigen (PSA) values low enough to affect target volume delineations for routine SRT. Our objective was to map the recurrence pattern of PCa early biochemical recurrence (BCR) after radical prostatectomy with 68Ga-PSMA-11 PET/CT in patients with serum PSA levels of less than 1 ng/mL, determine how often consensus clinical target volumes (CTVs) based on the Radiation Therapy Oncology Group (RTOG) guidelines cover 68Ga-PSMA-11 PET/CT-defined disease, and assess the potential impact of 68Ga-PSMA-11 PET/CT on SRT. Methods: This was a post hoc analysis of an intention-to-treat population of 270 patients who underwent 68Ga-PSMA-11 PET/CT at 4 institutions for BCR after prostatectomy without prior radiotherapy at a PSA level of less than 1 ng/mL. RTOG consensus CTVs that included both the prostate bed and the pelvic lymph nodes were contoured on the CT dataset of the PET/CT image by a radiation oncologist masked to the PET component. 68Ga-PSMA-11 PET/CT images were analyzed by a nuclear medicine physician. 68Ga-PSMA-11-positive lesions not covered by planning volumes based on the consensus CTVs were considered to have a potential major impact on treatment planning. Results: The median PSA level at the time of 68Ga-PSMA-11 PET/CT was 0.48 ng/mL (range, 0.03-1 ng/mL). One hundred thirty-two of 270 patients (49%) had a positive 68Ga-PSMA-11 PET/CT result. Fifty-two of 270 (19%) had at least one PSMA-11-positive lesion not covered by the consensus CTVs. Thirty-three of 270 (12%) had extrapelvic PSMA-11-positive lesions, and 19 of 270 (7%) had PSMA-11-positive lesions within the pelvis but not covered by the consensus CTVs. The 2 most common 68Ga-PSMA-11-positive lesion locations outside the consensus CTVs were bone (23/52, 44%) and perirectal lymph nodes (16/52, 31%). Conclusion: Post hoc analysis of 68Ga-PSMA-11 PET/CT implied a major impact on SRT planning in 52 of 270 patients (19%) with PCa early BCR (PSA < 1.0 ng/mL). This finding justifies a randomized imaging trial of SRT with or without 68Ga-PSMA-11 PET/CT investigating its potential benefit on clinical outcome.

Hyaluronan accumulation in thyroid tissue: evidence for contributions from epithelial cells and fibroblasts.

Graves' disease (GD) and Hashimoto's thyroiditis (HT) are autoimmune processes often associated with hyperthyroidism and hypothyroidism, respectively. Despite their diverging clinical presentations, immune activation drives both diseases and results in connective tissue accumulation of the nonsulfated glycosaminoglycan, hyaluronan. The hydrophilic property of hyaluronan contributes to the pathogenesis of thyroid-associated ophthalmopathy, dermopathy and hypothyroid myxedema. Whether hyaluronan accumulates in the thyroid and plays a role in goiter formation in GD and HT remains unknown. We report here that levels of hyaluronan are increased in thyroid tissue from individuals with both diseases compared with glands uninvolved with autoimmune disorders. The transcript encoding hyaluronan synthase (HAS)-3, one of three mammalian HAS isoforms, was detected in thyroid tissue. Isolated thyrocytes in primary culture express all three HAS isoforms when treated with IL-1beta. Thyrocytes and thyroid fibroblasts produce hyaluronan under basal culture conditions and IL-1beta enhances levels of this molecule in both cell types. On a per-cell basis, fibroblasts produce more hyaluronan than do thyrocytes under basal conditions and after cytokine treatment. Synthesis in thyrocytes can also be altered by increasing serum concentration in the medium and by modifying culture density. Our findings suggest that hyaluronan accumulation in thyroid tissue might derive from thyrocytes and fibroblasts. Moreover, this glycosaminoglycan becomes more abundant as a consequence of autoimmune disease. It may therefore contribute to increased thyroid volume in GD and HT. Coupled with the newly identified influence exerted by hyaluronan on immunocompetent cells, our findings represent potentially important insights into the pathogenesis of autoimmune thyroid diseases.

Racial Disparity in Prostate Cancer-Specific Mortality for High-Risk Prostate Cancer: A Population-Based Study.

INTRODUCTION: Race may be a significant factor that influences prostate cancer (PCa) survival, with the Asian (AsA) race being associated with better outcomes compared to African American (AA) and Non-Hispanic Whites (NHW). This study evaluates race-dependent variation in PCa-specific mortality (PCSM) associated with radiation dose-escalation exemplified by external beam radiotherapy (EBRT) with a brachytherapy (BT) boost in Gleason score 8-10 PCa. METHODS: 28,956 men diagnosed with clinically localized PCa and Gleason score 8-10 from 2004-2013 who received EBRT, EBRT with a BT boost, or radical prostatectomy (RP) were identified using the Surveillance, Epidemiology, and End Results (SEER) database. PCSM adjusted for age, diagnosis year, T-stage, Gleason scores, and treatment modalities was compared between races using a competing risk model that accounted for other-cause mortality (OCM). RESULTS: Compared to AsA, AA and NHW are associated with significantly increased PCSM with adjusted hazard ratios (AHR) of 2.295 and 1.989, respectively (p < 0.001 for both). In a subgroup analysis stratified by race, dose-escalation exemplified by EBRT with a BT boost in both AA and AsA failed to demonstrate a significant difference in PCSM compared to EBRT alone (p = 0.530 and 0.990, respectively), while a significant PCSM decrease was seen in NHW (p = 0.006). CONCLUSIONS: Dose-escalation exemplified by EBRT with a BT boost had no significant effect on PCSM of AsA and AA, while it did decrease PCSM amongst NHW. Further evaluation of race as a factor impacting PCSM in the era of dose-escalation is needed in the prospective setting.

Immunoglobulin G from patients with Graves' disease induces interleukin-16 and RANTES expression in cultured human thyrocytes: a putative mechanism for T-cell infiltration of the thyroid in autoimmune disease.

Mechanisms underlying lymphocyte infiltration of the thyroid gland and orbit in Graves' disease (GD) are poorly understood. The IGF-I receptor (IGF-IR) is a newly recognized self-antigen that, when activated in GD fibroblasts by IGF-I or GD-IgGs, provokes the expression of IL-16 and RANTES (regulated upon activation, normal T cell expressed and secreted)-dependent T lymphocyte chemoattraction and hyaluronan synthesis. IL-16 is a CD4(+)-specific ligand, and RANTES is a C-C chemokine. Here we report that IGF-I and GD-IgG could induce IL-16 and RANTES in cultured human thyrocytes in a time-dependent manner. Importantly, human TSH failed to induce either chemoattractant. This induction could be attenuated by dexamethasone. Rapamycin, a specific inhibitor of the FRAP/mammalian target of rapamycin/p70(s6k) pathway, prevented GD-IgG-provoked IL-16 synthesis. IH7, a monoclonal antibody directed at IGF-IR also blocked the induction of chemoattraction as well as RANTES mRNA synthesis. Our findings suggest that thyrocytes can be activated by GD-IgG and IGF-I to express powerful T-cell chemoattractants. These actions of GD-IgG appear to be mediated through pathways independent of the TSH receptor. Thus, in GD, thyrocytes may participate directly in lymphocyte recruitment through their expression of IL-16 and RANTES.

Association of perfluoroalkyl substances exposure with reproductive hormone levels in adolescents: By sex status.

Polyfluoroalkyl substances (PFASs) are a group of common chemicals that ubiquitously exist in wildlife and humans. However, few studies have researched the effect of PFASs on reproductive hormones in adolescents. To provide information in this regard, we recruited 225 Taiwanese adolescents aged 13-15years from 2009 to 2010 to investigate the relationship between serum PFASs (PFOS, PFOA, PFBS, PFDA, PFDoA, PFHxA, PFHxS, PFNA and PFTA) and reproductive hormone concentrations using a cross-sectional study design. Results showed PFOS and PFTA levels were highest among the PFASs, with a median concentrations of 29.9 (interquartile range: 13.0-43.8) ng/mL and 6.0 (0.6-25.9) ng/mL in males, and a median concentrations of 28.8 (14.8-42.6) ng/mL and 4.5 (0.3-18.4) ng/mL in females. After adjustment for confounding factors, nonsignificant associations between PFASs and reproductive hormone were found except for PFNA with ln(estradiol) (ß=0.2060, 95%CI: 0.0016, 0.4105). When stratified by sex, more significant associations were found in males than in females. Among males, PFASs were negatively associated with ln(testosterone) level for PFOS (ß=-0.0029, 95%CI: -0.0055, -0.0003), PFDA (ß=-0.2565, 95%CI: -0.4135, -0.0994), PFHxA (ß=-0.3095, 95%CI: -0.5942, -0.0248), and PFNA (ß=-0.4233, 95%CI: -0.6998, -0.1467). Furthermore, male participant ln(estradiol) levels were positively associated with PFOA (ß=0.0921, 95%CI: 0.0186, 0.1656), and PFHxS (ß=0.0462, 95%CI: 0.0020, 0.0905). Among females, a significant relationship was found only for PFDoA with ln(testosterone) (ß=-0.0119, 95%CI: -0.0227, -0.0010). In conclusion, this study showed higher levels of PFASs coincide with lower testosterone and higher estradiol levels, and more significant associations of PFASs with reproductive hormone were found in males than in females.