Impaired Sensitivity Research Articles

Impaired Sensitivity to Thyroid Hormones is Associated with Mild Cognitive Impairment in Euthyroid Patients with Type 2 Diabetes.

The prevalence of mild cognitive impairment (MCI) in patients with type 2 diabetes (T2D)is rapidly increasing. Thyroid hormones are key regulators of cognitive function in adults. The purpose of this study was to investigate the relationship between thyroid hormone sensitivity and MCI in euthyroid T2D patients. A total of 400 euthyroid T2D patients were enrolled in this cross-sectional study, including 218 patients with normal cognition and 182 MCI patients. The Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive function. The free triiodothyronine to free thyroxine (FT3/FT4) ratio was calculated as a measure of peripheral sensitivity to thyroid hormones; the thyroid-stimulating hormone index (TSHI), thyrotrophic thyroxine resistance index (TT4RI) and thyroid feedback quantile-based index (TFQI) were calculated as measures of central sensitivity to thyroid hormones. Linear regression analysis and logistic regression analysis were performed to explore the relationships between these indices of thyroid hormone sensitivity and the MoCA score and MCI, respectively. Compared with the normal cognitive function group, patients in the MCI group had higher TSHI, TT4RI and TFQI but a lower FT3/FT4 ratio (P<0.05). The MoCA score was positively correlated with the FT3/FT4 ratio but negatively correlated with TSHI, TT4RI and TFQI (P< 0.05). Multivariate logistic regression analysis showed that a low FT3/FT4 ratio and high TSHI, TT4RI and TFQI were independentlyassociated with MCI (P<0.05). After adjustment for confounding factors, the odds ratio (OR) for the association between MCI and the highest tertile of the FT3/FT4 was 0.455 (95% CI: 0.264-0.785), for the highest tertile of TSHI, the OR was 2.380 (95% CI: 1.376-4.119), for the highest tertile of TT4RI, the OR was 2.342 (95% CI:1.353-4.054), and for the highest tertile of TFQI, the OR was 2.536 (95% CI: 1.466-4.387) (P< 0.05). Impaired sensitivity to thyroid hormones is associated with MCI in euthyroid T2D patients.

The association between the thyroid feedback quantile-based index and serum uric acid in U.S. adults

ObjectivesPrevious studies have shown that there may be a positive correlation between serum uric acid levels and hyperthyroidism. However, the relationship between thyroid function and serum uric acid in healthy people is unclear. This study analyzed the relationship between impaired thyroid hormone sensitivity and serum uric acid levels, and presented them in quantitative form.Research design and methodsThis is a cross-sectional study of 4460 adults (male: 2300; female: 2160) who participated in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2010. Parameters representing central sensitivity to thyroid hormones were calculated as: thyroid feedback quantile-based index (TFQIFT4), thyroid stimulating hormone index (TSHI), and total thyroxine (T4) resistance index (TT4RI); Peripheral sensitivity to thyroid hormone was evaluated by FT3/FT4 ratio. In addition, we have innovated total triiodothyronine (T3) resistance index (TT3RI) and TFQIFT3 indexes based on FT3 and TSH. Multiple linear regression models were used to evaluate the correlation between thyroid resistance index and serum uric acid, and the results were presented graphically as smooth curve fittings.ResultsHigher levels of serum uric acid were associated with decreased sensitivity to thyroid hormones in euthyroid individuals. In conjunction with an increase in the thyroid hormone sensitivity index value, uric acid levels gradually increased as well. Furthermore, we found a segmented relationship between TT3RI and serum uric acid changes. The saturation and threshold analyses indicated that 18.85 was the turning point (logarithmic likelihood ratio test = 0.036). When TT3RI < 18.85, the relationship between serum uric acid and TT3RI was not significant [β(95% CI) 0.47 (− 0.05, 1.00), P = 0.077], but when TT3RI > 18.85, there was a significant rise in serum uric acid with an increase in TT3RI [β(95% CI) 3.94 (0.94, 6.95), P = 0.010]. A further finding of the interaction test was that impaired thyroid hormone sensitivity and uric acid changes vary among different age groups and BMI levels.ConclusionsDecreased sensitivity to thyroid hormones was associated with high levels of serum uric acid in people with normal thyroid function. The interaction test shows that different age groups and BMI groups impact the association between impaired thyroid hormone sensitivity and serum uric acid. Furthermore, smooth curve fitting revealed a segmental relationship between TT3RI and serum uric acid levels.

The mitochondrially targeted peptide elamipretide (SS-31) improves ADP sensitivity in aged mitochondria by increasing uptake through the adenine nucleotide translocator (ANT)

Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment, in vivo heart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function.Graphical abstractELAM binds directly to ANT and ATP synthase and ELAM treatment improves ADP sensitivity, increases ATP production, and improves physiological function in old muscles. ADP (adenosine diphosphate), ATP (adenosine triphosphate), VDAC (voltage-dependent anion channel), ANT (adenine nucleotide translocator), H+ (proton), ROS (reactive oxygen species), NADH (nicotinamide adenine dinucleotide), FADH2 (flavin adenine dinucleotide), O2 (oxygen), ELAM (elamipretide), –SH (free thiol), –SSG (glutathionylated protein)

Cardiovascular morbidity and mortality in patients in Wales, UK with resistance to thyroid hormone β (RTHβ): a linked-record cohort study

Individuals with resistance to thyroid hormone owing to mutations in the thyroid hormone receptor β gene (RTHβ) exhibit impaired tissue sensitivity to thyroid hormones, but retain sensitivity in cardiac tissue. Long-term health and survival outcomes in this rare disorder have not been evaluated. We investigated all-cause mortality and cardiovascular event risk in a cohort of patients with RTHβ, followed-up in UK endocrine clinics. In a retrospective cohort design, we linked genetically confirmed patients with RTHβ and age-matched and sex-matched population controls to outcomes in datasets within the Welsh Secure Anonymised Information Linkage (SAIL) Databank. Kaplan-Meier and Cox regression models analysed associations of RTHβ with all-cause mortality and cardiovascular events. We identified 61 patients with a genetic diagnosis of RTHβ between Jan 1, 1997, and Dec 31, 2019, and matched them with 2750 controls. Compared with controls, patients exhibited increased risks for all-cause mortality (hazard ratio [HR] 2·84, 95% CI 1·59-5·08), atrial fibrillation (10·56, 4·72-23·63), heart failure (HR 6·35, 95% CI 2·26-17·86), and major adverse cardiovascular events (MACE), comprising cardiovascular death, acute myocardial infarction, heart failure, or strokes (HR 3·49, 95% CI 2·04-5·99). The median age of first occurrence of any adverse event was 11 years earlier in patients (56 years, 95% CI 44-65) compared with controls (67 years, 65-70). Cubic spline analyses showed positive associations between FT4 concentrations at diagnosis and mortality or MACE, with FT4 concentration of 30 pmol/L or greater conferring increased risk. Compared with no intervention, treatment with antithyroid drugs, surgery or radioiodine gland ablation, or thyroxine did not control thyroid hormone excess. We have documented reduced survival and increased cardiovascular morbidity in a cohort of patients with RTHβ for the first time. These outcomes might be driven by lifelong cardiac exposure to thyroid hormone excess; and effective therapies, targeting hormone resistant pathways, could potentially curtail this risk. Royal College of Physicians, Wellcome Trust Investigator Award, and NIHR Cambridge Biomedical Research Centre.

Characterization of vision in pediatric retinoblastoma survivors beyond visual acuity

Retinoblastoma (RB) and its associated treatments can significantly impact visual acuity. However, little is known regarding other measures of vision, such as contrast sensitivity or saccades. The aim of this study was to describe contrast sensitivity and saccades in children treated for retinoblastoma. This cross-sectional study included children aged 5-17 years who had completed treatment for RB. Visual acuity, saccades via fixation analysis, and contrast sensitivity by Cardiff contrast sensitivity were assessed, and multivariable linear regression was performed. Eleven children were enrolled (mean age, 10.7 ± 3.9 years). Treatment included enucleation (8 children [73%]) and chemotherapy (10 [91%]). Of the 11, one participant was unable to complete testing of saccades, and another was unable to complete contrast sensitivity testing. Decreased saccade parameters (velocity, latency, or accuracy) and impaired contrast sensitivity were observed in all 10 participants who underwent visual testing. Multivariable analysis revealed that worse logMAR visual acuity (B, -4.54 [-6.8, -2.2]; P = 0.004) and bilateral disease (B, -3.9 [-6.4, -1.4]; P = 0.009) were associated with worse contrast sensitivity. Germline disease was associated with decreased vertical saccade accuracy (P = 0.02). Decreased contrast sensitivity and impaired saccades were universally observed in this cohort of RB survivors. Comprehensive visual evaluation should be considered for all RB survivors to provide optimal rehabilitative services for these patients.

Sensitivity to thyroid hormone and risk of components of metabolic syndrome in a Chinese euthyroid population.

To evaluate the association of sensitivity to thyroid hormone with metabolic syndrome (MetS) and its components in a Chinese euthyroid population. A total of 3573 participants from Pinggu Metabolic Disease Study were analyzed. Serum-free triiodothyronine (FT3), free thyroxine (FT4), thyrotropin (TSH), total adipose tissue (TAT), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) area of abdominal, and lumbar skeletal muscle area (SMA) were measured. Central thyroid hormone resistance was calculated by the Thyroid Feedback Quantile-based Index (TFQI) and Chinese-referenced Parametric TFQI (PTFQI), Thyrotroph T4 Resistance Index (TT4RI) and TSH Index (TSHI). Peripheral thyroid hormone resistance was assessed by FT3/FT4 ratio. Higher values of TSHI (odds ratio [OR] = 1.167, 95% confidence interval [CI]: 1.079-1.262, p < .001), TT4RI (OR = 1.115, 95% CI: 1.031-1.206, p = .006), TFQI (OR = 1.196, 95% CI: 1.106-1.294, p < .001), PTFQI (OR = 1.194, 95% CI: 1.104-1.292, p < .001), and lower values of FT3/FT4 ratio (OR = 0.914, 95% CI: 0.845-0.990, p = .026) were associated with MetS. Increased levels of TFQI and PTFQI were associated with abdominal obesity, hypertriglyceridemia, and hypertension. Increased levels of TSHI and TT4RI were associated with hypertriglyceridemia, abdominal obesity, low high-density lipoprotein cholesterol. Reduced levels of FT3/FT4 ratio were associated with hyperglycemia, hypertension, and hypertriglyceridemia. The levels of TSHI, TFQI, and PTFQI were negatively related to SMA and positively related to VAT, SAT, and TAT (all p < .05). Reduced thyroid hormone sensitivity was associated with MetS and its components. Impaired thyroid hormone sensitivity might affect the distribution of adipose tissue and muscle.

Association of impaired sensitivity to thyroid hormones with hyperuricemia through obesity in the euthyroid population

BackgroundImpaired sensitivity to thyroid hormones is a newly proposed clinical entity associated with hyperuricemia in the subclinical hypothyroid population. However, it is unknown whether the association exists in the euthyroid population. This study aimed to explore the association of impaired sensitivity to thyroid hormones (assessed by the thyroid feedback quantile-based index [TFQI], parametric thyroid feedback quantile-based index [PTFQI], thyrotrophic thyroxine resistance index [TT4RI] and thyroid-stimulating hormone index [TSHI]) with hyperuricemia and quantify the mediating effect of body mass index BMI in the euthyroid population.MethodsThis cross-sectional study enrolled Chinese adults aged ≥ 20 years who participated in the Beijing Health Management Cohort (2008–2019). Adjusted logistic regression models were used to explore the association between indices of sensitivity to thyroid hormones and hyperuricemia. Odds ratios [OR] and absolute risk differences [ARD] were calculated. Mediation analyses were performed to estimate direct and indirect effects through BMI.ResultsOf 30,857 participants, 19,031 (61.7%) were male; the mean (SD) age was 47.3 (13.3) years; and 6,515 (21.1%) had hyperuricemia. After adjusting for confounders, individuals in the highest group of thyroid hormone sensitivity indices were associated with an increased prevalence of hyperuricemia compared with the lowest group (TFQI: OR = 1.18, 95% CI 1.04–1.35; PTFQI: OR = 1.20, 95% CI 1.05–1.36; TT4RI: OR = 1.17, 95% CI 1.08–1.27; TSHI: OR = 1.12, 95% CI 1.04–1.21). BMI significantly mediated 32.35%, 32.29%, 39.63%, and 37.68% of the associations of TFQI, PTFQI, TT4RI and TSHI with hyperuricemia, respectively.ConclusionsOur research revealed that BMI mediated the association between impaired sensitivity to thyroid hormones and hyperuricemia in the euthyroid population. These findings could provide useful evidence for understanding the interaction between impaired sensitivity to thyroid hormone and hyperuricemia in euthyroid individuals and suggest the clinical implications of weight control in terms of impaired thyroid hormones sensitivity.

Central Visual Attention in Primary Open-angle Glaucoma

SIGNIFICANCE To better understand the implication of a potential cognitive change in glaucoma, patients were stimulated in central visual areas considered functionally normal to discard an effect due to the loss of vision during an attentional task. The outcome might improve the follow-up on the impact of the pathology. PURPOSE This study aimed to evaluate the effect of primary open-angle glaucoma on the visual attention system by recording responses of behavioral and oculomotor strategies. METHODS We included 20 individuals with primary open-angle glaucoma (62.1 ± 7.2 years old), 18 age-matched control subjects (58.4 ± 7.2 years old), and 20 young control subjects (25.7 ± 3.5 years old). The procedure consisted of visual (eye-tracking recordings) and manual detection of a target. All participants had to detect a square with a vertical bar within distractors (squares, triangles, and circles with a horizontal or vertical bar) of identical size of 1.6 × 1.6° visual angle. The shapes were displayed concentrically on a radius of 5° of visual angle. All participants were tested to ensure that their visual field sensitivity was normal within ±5° central vision. RESULTS In responding manually, glaucoma participants were slower than age-matched control subjects (1723 ± 488 vs. 1263 ± 385 milliseconds; P &lt; .01). Eye-tracking recordings showed that glaucoma participants found the target within the same time frame as age-matched control subjects. Compared with the young group, the scanpath length and average fixation duration on distractors were significantly longer for the glaucoma patients (+235 pixels, +104 milliseconds) and the age-matched control participants (+120 pixels, +39 milliseconds). Impaired contrast sensitivity was correlated with longer response time, longer scanpath, and longer fixation on distractors. CONCLUSIONS Glaucoma affects the manual response times in a visual attention task, but patients can visually detect the target as quickly as age-matched control subjects. Different clinical factors predicted the performances. The age of the patients was associated with longer scanpath. The visual field loss (mean deviation) was linked with longer visual response time. The loss of contrast sensitivity predicted the behavioral change on fixation duration to the distractors, global response time, visual response time, and scanpath length.

Impaired foot vibration sensitivity is related to altered plantar pressures during walking in people with multiple sclerosis

Balance and mobility impairment are two of the most common and debilitating symptoms among people with multiple sclerosis (MS). Somatosensory symptoms, including reduced plantar cutaneous sensation, have been identified in this cohort. Given the importance of the somatosensory system in gait, it is likely that impaired plantar sensation may play a role in the walking adaptations commonly observed in people with MS, including decreased stride length and increased stride width and dual support time, often described as a cautious gait strategy. Understanding the contributions of plantar sensation to these alterations may provide targets for interventions that seek to improve sensory feedback and normalize gait patterns. This cross-sectional study determined whether individuals with MS who demonstrate reduced sensitivity of the plantar surfaces also demonstrate altered plantar pressure distributions during walking compared to a control cohort.Twenty individuals with MS and twenty age- and sex-matched control participants walked barefoot at preferred and three matched speeds. Participants walked across a walkway with an embedded pressure plate used to quantify pressures within ten plantar zones. In addition, vibration perception thresholds were assessed at four sites on the plantar surface.Individuals with MS demonstrated increased peak total plantar pressures compared to control participants, that increased with walking speed. For the MS group, plantar pressures were higher on the less sensitive foot, although pressures on both feet exceeded those of the control cohort. Positive correlations between vibration perception threshold and peak total pressure were evident, although generally stronger in the MS cohort.A relationship between plantar vibration sensitivity and pressure could indicate that individuals with MS seek to increase plantar sensory feedback during walking. However, because proprioception may also be impaired, increased plantar pressure could result from inaccurate foot placement. Interventions targeting improved somatosensation may have the potential to normalize gait patterns and should be investigated.

Autonomic modulation, spontaneous baroreflex sensitivity and fatigue in young men after COVID-19.

Impaired autonomic modulation and baroreflex sensitivity (BRS) have been reported during and after COVID-19. Both impairments are associated with negative cardiovascular outcomes. If these impairments were to exist undetected in young men after COVID-19, they could lead to negative cardiovascular outcomes. Fatigue is associated with autonomic dysfunction during and after COVID-19. It is unclear if fatigue can be used as an indicator of impaired autonomic modulation and BRS after COVID-19. This study aims to compare parasympathetic modulation, sympathetic modulation, and BRS between young men who had COVID-19 versus controls and to determine if fatigue is associated with impaired autonomic modulation and BRS. Parasympathetic modulation as the high-frequency power of R-R intervals (lnHFR-R), sympathetic modulation as the low-frequency power of systolic blood pressure variability (LFSBP), and BRS as the -index were measured by power spectral density analysis. These variables were compared between 20 young men who had COVID-19 and 24 controls. Independent t-tests and Mann-Whitney U tests indicated no significant difference between the COVID-19 and the control group in: lnHFR-R, P=0.20; LFSBP, P=0.11, and -index, P=0.20. Fatigue was not associated with impaired autonomic modulation or BRS. There is no difference in autonomic modulations or BRS between young men who had COVID-19 compared to controls. Fatigue did not seem to be associated with impaired autonomic modulation or impaired BRS in young men after COVID-19. Findings suggest that young men might not be at increased cardiovascular risk from COVID-19-related dysautonomia and impaired BRS.

Perspektif Masyarakat terhadap Terjadinya Diabetes Melitus dan Hipertensi Di Desa Sembahe Kecamatan Sibolangit Kabupaten Deli Serdang

Diabetes Mellitus is a condition when blood glucose in the body is not controlled due to impaired sensitivity of pancreatic cells to produce the hormone insulin. Hypertension is a common public health problem in developing countries. Hypertension that is not treated immediately has an impact on the emergence of degenerative diseases, such as heart disease (Hypertension Heart Disease), end-stage renal failure (End Stage Renal Disease), and peripheral vascular disease. Risk factors such as heart disease, hypertension, dyslipidemia, diabetes mellitus (DM) should be monitored regularly so as not to cause more serious complications. This paper describes the implementation and evaluation of the achievement of Minimum Service Standards and to find out how the characteristics of patients with diabetes are and to find out how the relationship between blood sugar levels and blood pressure of patients with diabetes type Mellitus in Health Sector cases of hypertension and Diabetes Mellitus (DM) in Sembahe Village, Sibolangit District, Deli Serdang Regency. The method used is a qualitative study with a phenomenological method approach, with the focus of the research on clean and healthy living behavior towards the occurrence of hypertension and diabetes mellitus. The results of this study indicate that it is important to know and prevent hypertension and diabetes mellitus from an early age. With seminars and counseling or education regarding hypertension and diabetes mellitus, this has been carried out for 1 month with the assistance of the Field Supervisor, the village midwife of worship and colleagues - his partner. Door to door counseling, Healthy Gymnastics and health checks have also been carried out once a month to find out how the health condition of the worshipers is.

284-LB: From Metabolically Healthy Obesity (MHO) to Metabolically Unhealthy Obesity (MUHO)—Decreased Thyroid Hormone Sensitivity

Background: To explore the difference of thyroid hormone sensitivity between metabolically healthy and metabolically unhealthy obesity patients and its influence on obesity phenotype. Methods: 10927 euthyroid adults were enrolled, 4 groups based on the presence/absence of metabolic disorders (MD) and BMI were divided: 1) NC (n=1441): no MD and 22≤BMI &amp;lt; 25Kg/m2. 2) NMu (n=3765): MD and 22≤BMI &amp;lt; 25Kg/m2. 3) MHO (n=148): obese with no MD (BMI≥28Kg/m2). 4) MuHO (n=1981): obese with MD (BMI≥28Kg/m2). MD was defined as meeting none of the following criteria: fasted blood glucose ≤6.1 mmol/L; triglycerides ≥1.7 mmol/L; high density lipoprotein (HDL) &amp;lt;1.0 mmol/L (male) and &amp;lt;1.3 mmol/L (female); elevated SBP (≥130 mmHg) or/and DBP (≥85 mmHg). Thyroid hormone central sensitivity indices were calculated by thyroid feedback quantile-based index (TFQI), TSH index (TSHI), Chinese-referenced parametric TFQI (PTFQI) and thyrotropin thyroxine resistance index (TT4RI). Peripheral thyroid hormone sensitivity was evaluated by FT3/FT4 ratio. Results: Compared with MHO group, TFQI, PTFQI and TT4RI elevated in MuHO group, and the trend still existed after adjusting for confounding factors. High FT3/FT4 ratio was an independent risk factor for MuHO (OR = 1.22, 95%CI: 1.13, 1.37, P&amp;lt;0.001). In euthyroid obese patients, decreased TFQI was a protective factor for MHO (OR=0.71, 95%CI 0.51, 0.83, P=0.036), while TSHI (OR= 1.27, 95%CI: 1.11, 1.38, P =0.027) and TT4RI (OR= 1.08, 95%CI: 1.03, 1.16, P =0.022) were significantly correlated with the occurrence of MuHO. Conclusions: Thyroid hormone sensitivity is impaired with elevated BMI. Impaired thyroid hormone sensitivity associated with the development of metabolically unhealthy obesity in patients with similar BMI. Keywords Metabolically Healthy Obesity, Thyroid Hormone Sensitivity Disclosure N. Zhang: None. G. Wang: None. Funding National Natural Science Foundation of China (81770792)

Molecular Mechanisms for the Vicious Cycle between Insulin Resistance and the Inflammatory Response in Obesity.

The comprehensive anabolic effects of insulin throughout the body, in addition to the control of glycemia, include ensuring lipid homeostasis and anti-inflammatory modulation, especially in adipose tissue (AT). The prevalence of obesity, defined as a body mass index (BMI) ≥ 30 kg/m2, has been increasing worldwide on a pandemic scale with accompanying syndemic health problems, including glucose intolerance, insulin resistance (IR), and diabetes. Impaired tissue sensitivity to insulin or IR paradoxically leads to diseases with an inflammatory component despite hyperinsulinemia. Therefore, an excess of visceral AT in obesity initiates chronic low-grade inflammatory conditions that interfere with insulin signaling via insulin receptors (INSRs). Moreover, in response to IR, hyperglycemia itself stimulates a primarily defensive inflammatory response associated with the subsequent release of numerous inflammatory cytokines and a real threat of organ function deterioration. In this review, all components of this vicious cycle are characterized with particular emphasis on the interplay between insulin signaling and both the innate and adaptive immune responses related to obesity. Increased visceral AT accumulation in obesity should be considered the main environmental factor responsible for the disruption in the epigenetic regulatory mechanisms in the immune system, resulting in autoimmunity and inflammation.

Role of BRCA1 promotor methylation (BRCA1meth) in homologous recombination deficiency (HRD) in high-grade epithelial ovarian cancer.

e17592 Background: In TCGA data BRCA1meth was found to be inferior to BRCAmut regarding prognosis in high-grade ovarian cancer. This was explained by a probably lower sensitivity to platinum-based chemotherapy. Methods: In 151 high-grade epithelial ovarian cancers (HGOC) tested for BRCA status, BRCA DNA methylation was determined using MethyLight PCR. Additionally, genome-wide loss of heterozygosity (LOH) and Aneuploidy Normalized Telemetric imbalance (ANTI) by means of SNP-Array analysis (GSA-24 v 3.0/Ilumina) as surrogates for “genomic scaring” in BRCA-independent HRD. For both parameters a “clinical-threshold” was calculated on the basis of platinum-response determined at the first recurrence according to the platinum-free interval. Both variables were integrated in a common HRD-Score with a cut-off value of ≥ 10.3 for HRD positivity. Results: In the present cohort PFS of BRCA1meth HGOC (n = 15; 10%) was not revealed to be inferior to BRCAmut HGOC. Worst PFS was observed in the subgroup of BRCAwt-unmethylated HGOC (p = 0.013) as compared to HGOC with genetic and epigenetic BRCA alterations. In line, neither LOH nor ANTI and consecutively also HRD-Score did prove to be statistically different in BRCAmut - and BRCA1meth-HGOC. However, BRCAwt-unmethylated HGOC exhibited significantly lower HRD-, LOH- and ANTI-Scores when compared with BRCAmut (p &lt; 0.001) and BRCA1meth-HGOC (p &lt; 0.005). All but one of the HGOC classified as platinum-refractory or -resistant at first relapse (92%) were BRCAwt-unmethylated. None of the BRCA1meth cancers were rated platinum-refractory or -resistant at progression and only one of the BRCAmut cancers was associated with platinum-resistant first relapse. 99% of the recurrences from HGOC with genetically or epigenetically altered BRCA genes were platinum sensitive, from which 78% were classified as “high-sensitive”. In multivariate analysis, HRD-Score was found to be of independent prognostic significance regarding PFS (p = 0.022); this was mainly due to the prognostic power of ANTI-Score (multivariate: p = 0.014) but not to that of genome wide LOH (univariate: p = 0.771). Conclusions: HGOC without genetic or epigenetic BRCA alterations exhibit the most unfavorable PFS. This is related to impaired platinum sensitivity. From a clinical point of view BRCA1 promotor methylation seems to confer an equivalent detrimental effect on the homologous recombination DNA repair mechanism than do pathogenic mutations of the BRCA genes. This is corroborated by a nearly identical extent of genome-wide scaring in both cancer subgroups.

Validation and psychometric properties of the Word Choice Test-10 as an abbreviated performance validity test

Objective: The objective of the current investigation was to validate and establish the psychometric properties of an abbreviated, 10-item version of the Word Choice Test (WCT). Method: Data from one hundred ten clinically-referred participants (M age = 55.92, SD = 14.07; M education = 13.74, SD = 2.43; 84.5% Male) in a Veterans Affairs neuropsychology outpatient clinic was analyzed. All participants completed the WCT, the TOMM T1, the WMT, and the Digit Span subtest of the WAIS-IV as part of a larger battery of neuropsychological tests. Results: Correlation analyses revealed significant relationships between the 10-item WCT-10, the TOMM T1, the RDS forward/backward, as well as the IR, DR, and CNS subtests of the WMT. ROC analysis for the WCT-10 indicated optimal cutoff of 2 or more errors, with 52% sensitivity and 97% specificity (AUC=.786, p<.001), compared with the standard administration of the WCT with a cutoff of 8 or more errors, which had 67% sensitivity and 91% specificity. Specificity/sensitivity values remained adequate at a cutoff of two or more errors when participants with cognitive impairment (Sensitivity=.52, Specificity=.92) and without cognitive impairment (Sensitivity=.52, Specificity = 1.0) were examined separately. Conclusions: The present investigation revealed that the WCT-10, an abbreviated free-standing PVT comprised of the initial 10 items of the WCT, demonstrated clinical utility in a mixed clinical sample of Veterans and was robust to cognitive impairment. This abbreviated PVT may benefit researchers and clinicians through adequate identification of invalid performance while minimizing completion time.

Vitamin A deficiency compromises the barrier function of the retinal pigment epithelium.

A major cause for childhood blindness worldwide is attributed to nutritional vitamin A deficiency. Surprisingly, the molecular basis of the ensuing retinal degeneration has not been well defined. Abundant expression of the retinoid transporter STRA6 in the retinal pigment epithelium (RPE) and homeostatic blood levels of retinol-binding protein delay vitamin A deprivation of the mouse eyes. Hence, genetic dissection of STRA6 makes mice susceptible to nutritional manipulation of ocular retinoid status. We performed RNA-seq analyses and complemented the data with tests of visual physiology, ocular morphology, and retinoid biochemistry to compare eyes with different vitamin A status. Mild ocular vitamin A deficiency decreased transcripts of photoreceptor transduction pathway-related genes and increased transcripts of oxidative stress pathways. The response was associated with impaired visual sensitivity and an accumulation of fluorescent debris in the retina. Severe vitamin A deficiency did not only impair visual perception but also decreased transcripts of genes encoding cell adhesion and cellular junction proteins. This response altered cell morphology, resulted in significant changes in transport pathways of small molecules, and compromised the barrier function of the RPE. Together, our analyses characterize the molecular events underlying nutritional blindness in a novel mouse model and indicate that breakdown of the outer blood-retinal barrier contributes to retinal degeneration and photoreceptor cell death in severe vitamin A deficiency.

Inhibition of GSK3B phosphorylation improves glucose and lipid metabolism disorder

Hepatic glycolipid metabolism disorder is considered as one of the key pathogenic factors for many chronic diseases. Revealing the molecular mechanism of metabolic disorder and exploring drug targets are crucial for the treatment of glucose and lipid metabolic diseases. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been reported to be associated with the pathogenesis of various metabolic diseases. Herein, GAPDH-knockdown ZFL cells and GAPDH-downregulation zebrafish exhibited significant lipid deposition increase and glycogen reduction, thus inducing glucose and lipid metabolism disorders. Using high-sensitivity mass spectrometry-based proteomic and phosphoproteomic analysis, we identified 6838 proteins and 3738 phosphorylated proteins in GAPDH-knockdown ZFL cells. The protein-protein interaction network and DEPPs analyses showed that gsk3baY216 were involved in lipid and glucose metabolism, which was verified by In vitro study. The enzyme activity analysis and cell staining results showed that HepG2 and NCTC-1469 cells transfected with GSK3BY216F plasmid had significantly lower glucose and insulin levels, the decreased lipid deposition, and the increased glycogen synthesis than those transfected with GSK3BY216E plasmid, suggesting that inhibition of GSK3B phosphorylation could significantly improve GSK3B hyperphosphorylation-induced glucose tolerance impairment and insulin sensitivity reduction. To our knowledge, this is the first multi-omic study of GAPDH-knockdown ZFL cells. This study provides insights into the molecular mechanism of glucose and lipid metabolic disorder, and provides potential targets (kinases) for the treatments of human glucose and lipid metabolic diseases.

Gold nanoparticles-decorated peptide hydrogel for antifouling electrochemical dopamine determination.

A reliable and brief ultralow fouling electrochemical sensing system capable of monitoring targets in complex biological media was constructed and validated based on gold nanoparticles-peptide hydrogel-modified screen-printed electrode. The self-assembled zwitterionic peptide hydrogel was prepared by a newly designed peptide sequence of Phe-Phe-Cys-Cys-(Glu-Lys)3 with the N-terminal modified with a fluorene methoxycarbonyl group. The thiol groups on cysteine of the designed peptide are able to self-assemble with AuNPs to form a three-dimensional nanonetwork structure, which showed satisfactory antifouling capability in complex biological media (human serum). The developed gold nanoparticles-peptide hydrogel-based electrochemical sensing platform displayed notably sensing properties for dopamine determination, with a wide linear range (from 0.2 nM to 1.9 μM), a low limit of detection (0.12 nM), and an excellent selectivity. This highly sensitive and ultralow fouling electrochemical sensor was fabricated via simple preparation with concise components that avoid the accumulation of layers with single functional material and complex activation processes. This ultralow fouling and highly sensitive strategy based on the gold nanoparticles-peptide hydrogel with a three-dimensional nanonetwork offers a solution to the current situation of various low-fouling sensing systems facing impaired sensitivity and provides a potential path for the practical application of electrochemical sensors.

Abstract #1406483: Thyroid Hormone Resistance Diagnostic and Therapeutic Challenges

Resistance to thyroid hormone (RTH) is a clinical syndrome defined by impaired sensitivity to thyroid hormone (TH). We present the challenges in diagnosing and treating a 24-year-old male who presented with a mixed picture of hypothyroidism and hyperthyroidism with elevated TSH, upper normal free T4, and elevated free T3 and was found to have a mutation in the THRβ gene. A 24-year-old male was referred for a second opinion of post-ablative hypothyroidism with elevated TSH, elevated free T3, and suspicion of pituitary microadenoma. He complained of fatigue, weight gain, tremors heat cold intolerance. Family history is Graves’ disease in his mother's status post partial thyroidectomy due to a salivary tumor. Initially, in 2020, he was diagnosed with negative antibody Grave’s disease. Labs were TSH 0.86 mIU/L, free T4 1.99 ng/dl (0.89-1.76), and free T3 4.66 pg/ml (2.3-4.2). A thyroid ultrasound showed mild thyromegaly. A thyroid uptake scan showed 24-hour thyroid uptake of 36.7%. Thyroid antibodies including thyroglobulin, TPO, thyroid receptor, and thyroid stimulating immunoglobulin were negative. He was treated with radioactive iodine ablation (I-131). Afterward, His TSH increased gradually along with free T3. Free T4 was normal. The patient remained symptomatic, and he was not on any thyroid replacement therapy. A repeat thyroid uptake scan showed an increase uptake of 36% at 24 hrs. During our evaluation, a repeat TSH 54.05 mIU/l, free T4 1.3 ng/dl, free T3 4.3 pg/ml, and T3 by equilibrium dialysis 4.0. A repeat magnetic resonance imaging of the head showed no definitive focal enhancing lesion. Pituitary axis hormones were normal, and the alpha subunit was 0.73 (high); however, the alpha-glycoprotein subunit /TSH molar ratio 0.135 sex hormone binding globulin 5.8 nmol/l (low), macro TSH was not detected. These findings raised suspicion for THRB mutation; hence genetic studies were obtained. PCR amplification of THRB gene exons 10, 9, and 8, followed by gene sequencing, showed a heterozygous missense mutation C >G located at exon 10. The mutation caused a change in thyroid hormone receptor beta protein amino acid 453 proline to an alanine, P453A Initially, he was started on levothyroxine 25 mg PO daily but soon after, it was stopped due to palpitations; a beta blocker was started along with liothyronine 5 mg every other day and levothyroxine 50 mg every other day. The patient tolerated the regimen with significant improvement in his symptoms. RTH is rather uncommon; it is important to be able to recognize the syndrome to avoid unnecessary invasive treatment. There is no specific therapy currently available to fully correct the TRβ defect. The goal of treatment is based on the patient's symptoms and clinical picture instead of aiming to normalize thyroid hormone levels. Thyroidectomy and radioactive iodine ablation result in lifelong levothyroxine replacement therapy and RTHβ persistently high serum TSH. Levothyroxine therapy is challenging, and supraphysiologic doses are often needed to maintain serum TSH in the lowest tolerable level.

Degeneration of muscle spindles in a murine model of Pompe disease

Pompe disease is a debilitating medical condition caused by a functional deficiency of lysosomal acid alpha-glucosidase (GAA). In addition to muscle weakness, people living with Pompe disease experience motor coordination deficits including an instable gait and posture. We reasoned that an impaired muscle spindle function might contribute to these deficiencies and therefore analyzed proprioception as well as muscle spindle structure and function in 4- and 8-month-old Gaa−/− mice. Gait analyses showed a reduced inter-limb and inter-paw coordination in Gaa−/− mice. Electrophysiological analyses of single-unit muscle spindle proprioceptive afferents revealed an impaired sensitivity of the dynamic and static component of the stretch response. Finally, a progressive degeneration of the sensory neuron and of the intrafusal fibers was detectable in Gaa−/− mice. We observed an increased abundance and size of lysosomes, a fragmentation of the inner and outer connective tissue capsule and a buildup of autophagic vacuoles in muscle spindles from 8-month-old Gaa−/− mice, indicating lysosomal defects and an impaired autophagocytosis. These results demonstrate a structural and functional degeneration of muscle spindles and an altered motor coordination in Gaa−/− mice. Similar changes could contribute to the impaired motor coordination in patients living with Pompe disease.