Traditional Chinese medicine in thyroid-associated orbitopathy.

PURPOSE: Orbital fibroblasts (OF) are considered the central target cells in the pathogenesis of thyroid-associated orbitopathy (TAO), which comprises orbital inflammation, orbital tissue edema, adipogenesis, fibrosis, oxidative stress and autophagy. Certain active ingredients of traditional Chinese medicine (TCM) demonstrated inhibition of TAO-OF in pre-clinical studies and they could be translated into novel therapeutic strategies. METHODS: The pertinent and current literature of pre-clinical studies on TAO investigating the effects of active ingredients of TCM was reviewed using the NCBI PubMed database. RESULTS: Eleven TCM compounds demonstrated inhibition of TAO-OF in-vitro and three of them (polydatin, curcumin, and gypenosides) resulted in improvement in TAO mouse models. Tanshinone IIA reduced inflammation, oxidative stress and adipogenesis. Both resveratrol and its precursor polydatin displayed anti-oxidative and anti-adipogenic properties. Celastrol inhibited inflammation and triptolide prevented TAO-OF activation, while icariin inhibited autophagy and adipogenesis. Astragaloside IV reduced inflammation via suppressing autophagy and inhibited fat accumulation as well as collagen deposition. Curcumin displayed multiple actions, including anti-inflammatory, anti-oxidative, anti-adipogenic, anti-fibrotic and anti-angiogenic effects via multiple signaling pathways. Gypenosides reduced inflammation, oxidative stress, tissue fibrosis, as well as oxidative stress mediated autophagy and apoptosis. Dihydroartemisinin inhibited OF proliferation, inflammation, hyaluronan (HA) production, and fibrosis. Berberine attenuated inflammation, HA production, adipogenesis, and fibrosis. CONCLUSIONS: Clinical trials of different phases with adequate power and sound methodology will be warranted to evaluate the appropriate dosage, safety and efficacy of these compounds in the management of TAO.

Development of a prediction score (ThyroCOVID) for identifying abnormal thyroid function in COVID-19 patients.

PURPOSE: Thyroid dysfunction in COVID-19 carries clinical and prognostic implications. In this study, we developed a prediction score (ThyroCOVID) for abnormal thyroid function (TFT) on admission amongst COVID-19 patients. METHODS: Consecutive COVID-19 patients admitted to Queen Mary Hospital were prospectively recruited during July 2020-May 2021. Thyroid-stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) were measured on admission. Multivariable logistic regression analysis was performed to identify independent determinants of abnormal TFTs. ThyroCOVID was developed based on a clinical model with the lowest Akaike information criteria. RESULTS: Five hundred and forty six COVID-19 patients were recruited (median age 50 years, 45.4% men, 72.9% mild disease on admission). 84 patients (15.4%) had abnormal TFTs on admission. Patients with abnormal TFTs were more likely to be older, have more comorbidities, symptomatic, have worse COVID-19 severity, higher SARS-CoV-2 viral loads and more adverse profile of acute-phase reactants, haematological and biochemical parameters. ThyroCOVID consisted of five parameters: symptoms (malaise), comorbidities (ischaemic heart disease/congestive heart failure) and laboratory parameters (lymphocyte count, C-reactive protein, and SARS-CoV-2 cycle threshold values). It was able to identify abnormal TFT on admission with an AUROC of 0.73 (95% CI 0.67-0.79). The optimal cut-off of 0.15 had a sensitivity of 75.0%, specificity of 65.2%, negative predictive value of 93.5% and positive predictive value of 28.1% in identifying abnormal TFTs on admission amongst COVID-19 patients. CONCLUSION: ThyroCOVID, a prediction score to identify COVID-19 patients at risk of having abnormal TFT on admission, was developed based on a cohort of predominantly non-severe COVID-19 patients.

Attentional salience and the neural substrates of response inhibition in borderline personality disorder.

BACKGROUND: Impulsivity is a central symptom of borderline personality disorder (BPD) and its neural basis may be instantiated in a frontoparietal network involved in response inhibition. However, research has yet to determine whether neural activation differences in BPD associated with response inhibition are attributed to attentional saliency, which is subserved by a partially overlapping network of brain regions. METHODS: Patients with BPD (n = 45) and 29 healthy controls (HCs; n = 29) underwent functional magnetic resonance imaging while completing a novel go/no-go task with infrequent odd-ball trials to control for attentional saliency. Contrasts reflecting a combination of response inhibition and attentional saliency (no-go > go), saliency processing alone (oddball > go), and response inhibition controlling for attentional saliency (no-go > oddball) were compared between BPD and HC. RESULTS: Compared to HC, BPD showed less activation in the combined no-go > go contrast in the right posterior inferior and middle-frontal gyri, and less activation for oddball > go in left-hemispheric inferior frontal junction, frontal pole, superior parietal lobe, and supramarginal gyri. Crucially, BPD and HC showed no activation differences for the no-go > oddball contrast. In BPD, higher vlPFC activation for no-go > go was correlated with greater self-rated BPD symptoms, whereas lower vlPFC activation for oddball > go was associated with greater self-rated attentional impulsivity. CONCLUSIONS: Patients with BPD show frontoparietal disruptions related to the combination of response inhibition and attentional saliency or saliency alone, but no specific response inhibition neural activation difference when attentional saliency is controlled. The findings suggest a neural dysfunction in BPD underlying attention to salient or infrequent stimuli, which is supported by a negative correlation with self-rated impulsiveness.

Potential role of fibroblast growth factor 21 in the deterioration of bone quality in impaired glucose tolerance.

PURPOSE: Findings on trabecular bone score (TBS), an index of bone quality, have been reported in prediabetes defined by impaired fasting glucose or HbA1c. Here, we assessed the bone mineral density (BMD) and TBS in prediabetes individuals with impaired glucose tolerance (IGT), and investigated the association of these bone parameters with serum levels of fibroblast growth factor 21 (FGF21), a hormone implicated in bone metabolism and with higher levels in IGT. METHODS: Chinese postmenopausal women aged 55-80 years, without diabetes, were recruited from the Hong Kong Cardiovascular Risk Factor Prevalence Study in 2016-2018. Normal glucose tolerance (NGT) was defined by fasting glucose < 5.6 mmol/L and 2-h plasma glucose (2hG) < 7.8 mmol/L, and IGT by 2hG 7.8-11 mmol/L. Serum levels of FGF21 and other bone metabolism regulators were measured. Insulin sensitivity was assessed by the Matsuda index. Independent determinants of TBS were evaluated using multivariable stepwise linear regression. RESULTS: 173 individuals with NGT and 73 with IGT were included. TBS was lower in those with IGT compared to those with NGT, while BMD was comparable. Individuals with IGT had significantly higher serum FGF21 levels, which in turn showed an independent inverse relationship with TBS, attenuated after inclusion of the Matsuda index. Serum FGF21 levels, however, did not correlate with BMD. CONCLUSION: Among Chinese postmenopausal women, bone quality was worse in IGT, despite comparable bone density. FGF21 levels showed a significant independent inverse relationship with TBS, partly attributed to insulin resistance. Whether FGF21 contributes to the impaired bone quality in IGT remains speculative.

Systemic safety analysis of mycophenolate in Graves' orbitopathy.

PURPOSE: The dual antiproliferative mechanism of mycophenolate appears to be beneficial in Graves' orbitopathy (GO). METHODS: Safety data from the two published mycophenolate trials and the original database of the European Group on Graves' Orbitopathy (EUGOGO) trial were systematically analyzed. Treatment efficacy stratified by individual visual parameters of activity and severity were compared. RESULTS: A total of 129 adverse events (AE) involving 50 patients (29.4%) were noted among all mycophenolate-treated patients. Mycophenolate sodium plus intravenous glucocorticoid (MPS + GC) group of the EUGOGO trial recorded significantly more AE (55.4% versus 4.6% of patients affected) and serious adverse events (SAE) (12.5% versus 0%) than mycophenolate mofetil (MMF) group of the Chinese trial. None of those SAE was side effect (SE). Most SE in MPS + GC group were mild. Gastrointestinal disorders, infection and liver dysfunction affected 8.8%, 7.1% and 1.2% of all mycophenolate-treated patients (versus 5.4%, 5.4% and 1.2% of all patients on GC monotherapy, respectively). MPS + GC did not significantly increase the risk of infection or liver dysfunction when compared to GC monotherapy. No cytopenia, serious infection or treatment-related mortality was reported. The much higher AE rates of mycophenolate trials in other autoimmune diseases or transplantations suggested that major mycophenolate toxicities were mostly dose- and duration dependent. Mycophenolate, either as monotherapy or as combination, achieved better overall response than GC monotherapy. CONCLUSION: The risk-benefit ratio of low-dose mycophenolate treatment in active moderate-to-severe GO is highly favorable given its reassuring safety profile with low rate of mild-to-moderate SE and promising efficacy.

Immunohistochemical analysis of human orbital tissue in Graves' orbitopathy.

PURPOSE: Immunohistochemistry of orbital tissues offers a correlation between the microscopic changes and macroscopic clinical manifestation of Graves' orbitopathy (GO). Summarizing the participation of different molecules will help us to understand the pathogenesis of GO. METHODS: The pertinent and current literature on immunohistochemistry of human orbital tissue in GO was reviewed using the NCBI PubMed database. RESULTS: 33 articles comprising over 700 orbital tissue samples were included in this review. The earliest findings included the demonstration of HLA-DR and T cell (to a lesser extent B cell) markers in GO orbital tissues. Subsequent investigators further contributed by characterizing cellular infiltration, confirming the presence of HLA-DR and TSHR, as well as revealing the participation of cytokines, growth factors, adhesion molecules and miscellaneous substances. HLA-DR and TSHR are over-expressed in orbital tissues of GO patients. The inflammatory infiltration mainly comprises CD4 + T cells and macrophages. Cytokine profile suggests the importance of Th1 (especially in early active phase) and Th17 immunity in the pathogenesis of GO. Upregulation of proinflammatory/profibrotic cytokines, adhesion molecules and growth factors finally culminate in activation of orbital fibroblasts and perpetuation of orbital inflammation. The molecular status of selected parameters correlates with the clinical presentation of GO. CONCLUSION: Further investigation is warranted to define precisely the role of different molecules and ongoing search for new players yet to be discovered is also important. Unfolding the molecular mechanisms behind GO will hopefully provide insights into the development of novel therapeutic strategies and optimize our clinical management of the disease.

Temporal lobe contribution to perceptual function: A tale of three patient groups.

There has been growing recognition of the contribution of medial and anterior temporal lobe structures to non-mnemonic functions, such as perception. To evaluate the nature of this contribution, we contrast the perceptual performance of three patient groups, all of whom have a perturbation of these temporal lobe structures. Specifically, we compare the profile of patients with focal hippocampal (HC) lesions, those with more extensive lesions to the medial temporal lobe (MTL) that include HC and perirhinal cortex (PrC), and those with congenital prosopagnosia (CP), whose deficit has been attributed to the disconnection of the anterior temporal lobe from more posterior structures. All participants completed a range of'oddity' tasks in which, on each trial, they determined which of four visual stimuli in a display was the'odd-one-out'. There were five stimulus categories including faces, scenes, objects (high and low ambiguity) and squares of different sizes. Comparisons were conducted separately for the HC, MTL and CP groups against their matched control groups and then the group data were compared to each other directly. The group profiles were easily differentiable. Whereas the HC group stood out for its difficulty in discriminating scenes and the CP group stood out for its disproportionate difficulty in discriminating faces with milder effects for scenes and high ambiguity objects, the MTL group evinced a more general discrimination deficit for faces, scenes and high ambiguity objects. The group differences highlight distinct profiles for each of the three groups and distinguish the signature perceptual impairments following more extended temporal lobe alterations. In the recent reconsideration of the role of the hippocampus and neocortex, Moscovitch and colleagues (Moscovitch et al., 2016) note that the medial temporal lobe structures play a role in non-mnemonic functions, such as perception, problem solving, decision-making and language. Here, we address this exact issue, specifically with respect to perception, and we dedicate this paper to Morris Moscovitch in recognition of his profound contribution to science, to his students and to his colleagues.

Tailgut cyst in a neonate with anal stenosis.

Tailgut cysts, embryological remnants of the hindgut, are rare retrorectal tumours. They have been described in adults but are rare in children, especially neonates. We report a case of a neonate, who presented with anal stenosis and an incidental ultrasonographic finding of a presacral mass. Excision and histological examination of the mass confirmed the appearance of a tailgut cyst. There were no postoperative complications and no evidence of recurrence of the presacral mass over one year after excision. The clinical, pathological, and radiological findings of the tailgut cyst are described with a review of the literature.

"Pray or Prey?" dissociation of semantic memory retrieval from episodic memory processes using positron emission tomography and a novel homophone task.

One problem in studying the neural basis of semantic memory using functional neuroimaging is that it is often difficult to disentangle activation associated with semantic memory retrieval from that associated with episodic memory encoding and retrieval. To address this issue, a novel homophone task was used in which subjects were PET scanned whilst learning a series of real words (e.g., prey). In a subsequent scan, the subjects were presented with homophone pairs (e.g., prey vs pray) and were required to choose the one that had been shown previously. In two corresponding baseline tasks, the subjects were scanned whilst learning and recognizing pronounceable nonwords. Thus, while all of these tasks recruited either episodic memory encoding or retrieval processes, only the homophone tasks involved semantic memory retrieval. A conjunction analysis designed to isolate activation associated with semantic memory retrieval, revealed changes in several left lateral frontal regions (BA 9/10, 9/45), the left middle temporal cortex (BA 21), and in the left inferior temporoparietal cortex (BA 39). In contrast, a conjunction analysis designed to isolate activation associated with episodic memory encoding, revealed significant changes in the left hippocampus, as well as in the frontopolar cortex (BA 10) bilaterally, the left inferior parietal cortex (BA 40), and the left superior temporal gyrus (BA 22, 28). The present results clarify and extend recent attempts to understand the neural basis of semantic memory retrieval, by actively controlling for the confounding effects of episodic memory encoding and retrieval processes.

An enhanced autogene-based dual-promoter cytoplasmic expression system yields increased gene expression.

The relatively low levels of transfection that can be achieved by current gene-delivery systems have limited the therapeutic utility of gene transfer. This is especially true for nonviral gene-delivery systems, where the levels of gene expression achieved are usually below the levels achieved by viral gene transfer systems. One strategy for increasing gene expression is to design a cytoplasmic expression system that does not require nuclear delivery for gene expression to occur. This can be achieved through the use of an autocatalytic cytoplasmic expression system using phage RNA polymerases. Here we describe cytoplasmic expression systems that yield increased levels of gene expression following in vitro transfection. We demonstrate direct evidence for an exponential, autocatalytic increase in gene expression using autogenes, as well as levels of reporter gene expression that are 20-fold higher than standard CMV-based nuclear expression systems. The development of a high-efficiency plasmid-based expression system could significantly improve the gene expression properties of nonviral gene-delivery systems, thereby increasing their clinical utility.