INTRODUCTION:Consolation is a complex empathic behavior that varies considerably across individuals, yet the neural basis of this heterogeneity remains poorly understood. The medial preoptic area is a key hub for instinctive social behaviors, but it remains unclear which of its subregions - the medial preoptic nucleus (MPN) versus the surrounding area (MPA) - or which neuronal subtypes (GABAergic, glutamatergic, or galanin-expressing) contribute to individual differences in consolation. METHODS:We used a social defeat-induced consolation paradigm in male mice and categorized them into low- and high-consolation groups based on allogrooming duration toward distressed partners. We performed c-Fos immunofluorescence to compare neuronal activation in the MPN versus MPA, and to identify the specific neuronal subtypes activated in each group. We then used chemogenetic approaches to manipulate MPN GABAergic neurons, as well as their projection to the periaqueductal gray (PAG), and examined the effects on consolation behavior, sociability, and anxiety. RESULTS:High-consolation mice showed selective c-Fos activation in the MPN, but not in the MPA, and this activation was specific to GABAergic neurons. Chemogenetic inhibition of MPN GABAergic neurons or the MPNGABA-PAG pathway selectively reduced allogrooming in high-consolation mice without affecting sociability or anxiety. CONCLUSION:The MPNGABA-PAG pathway is a critical modulator of individual variation in consolation-like behavior in mice, revealing a subregion- and cell-type-specific circuit mechanism underlying empathic heterogeneity.
INTRODUCTION:Congenital hypothyroidism (CH) is among the most common preventable causes of intellectual disability worldwide. In India, the absence of universal neonatal screening leads to delayed diagnosis and consequent neurocognitive morbidity. This study aimed to assess intelligence quotient (IQ) and behavioral profiles in children with CH in relation to the timing of levothyroxine (LT4) initiation and serum T4 levels at diagnosis. METHODS:A cross-sectional study of 30 children with CH aged ≥3 years attending the endocrinology outpatient clinic at Osmania General Hospital, Hyderabad, was conducted between January 2017 and December 2018. IQ was assessed using the Binet Kamat Scale of Intelligence. Behavioral profiling was performed using the Achenbach Child Behavior Checklist (CBCL). Patients were stratified by age of LT4 initiation (<1 month, 1-6 months, >6 months). Analysis included ANOVA, box plot analysis, and one-sample t tests using SPSS version 20. Statistical significance was set at p < 0.05. RESULTS:Of 30 patients (17 girls, 13 boys), 46.6% were initiated on LT4 after 6 months of age. Mean IQ was 79, 59.5, and 61.12 in those initiated on treatment within 1 month, 1-6 months, and after 6 months, respectively. Males had significantly lower serum T4 at diagnosis (0.45 ± 0.25 vs. 2.25 ± 1.48 μg/dL; p = 0.0002) and lower IQ (46.08 ± 22.59 vs. 76.6 ± 26.89; p = 0.003). Behavioral scores were within normal limits; however, withdrawn/anxiety/social/thought (WAST) composite score showed a trend toward elevation. Height SDS did not differ significantly between treatment initiation groups (p = 0.172). CONCLUSION:Children with CH in this Indian cohort demonstrated substantially lower IQ compared to internationally reported values, attributable to delayed diagnosis and suboptimal therapy adherence. Males exhibited more severe biochemical disease at diagnosis and greater neurocognitive impairment. Routine behavioral assessment and cognitive behavioral therapy should be incorporated into standard CH follow-up in resource-limited settings.
INTRODUCTION:Neurodevelopmental disorders (NDDs), such as attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and tic disorders (TD), have been frequently investigated due to their profound impacts on social and emotional functions. In this regard, there is a new focus on the possible association between these disorders and thyroid dysfunction. The purpose of this study was to explore the relationship between NDDs and hyperthyroidism and hypothyroidism. METHODS:In this study, we used MR analysis to explore the associations of ADHD, ASD, and TD with hyperthyroidism and hypothyroidism. MR analysis explores the associations between exposure and outcome using the Mendelian randomization framework and is based on extensive genomic datasets. RESULTS:Our results suggested that hypothyroidism was associated with TD, while no individual genetic variant was associated with hypothyroidism, ADHD, or ASD. Additionally, we found no reliable evidence that ADHD, ASD, or TD were causally linked to hyperthyroidism. There was also no credible evidence that any individual genetic variant was associated with an increased risk of hyperthyroidism. Our findings remained robust in sensitivity analyses. CONCLUSION:Our study provides new insights into the relationship between NDDs and thyroid dysfunction. It suggests that there were potential risk factors and causal pathways and calls for early diagnosis, intervention, and integrated health care.
INTRODUCTION:Accurate identification of the primary tumor origin and differentiation grade of neuroendocrine liver metastases (NELMs) is critical for guiding treatment. This study aimed to evaluate contrast-enhanced CT (CECT) features of NELMs to differentiate pancreatic from non-pancreatic origins and neuroendocrine carcinoma (NEC) from neuroendocrine tumor (NET). METHODS:This single-center retrospective study (July 2019 - December 2022) included consecutive patients with pathologically proven NELM who underwent CECT prior to surgery or biopsy. CT features, including tumor burden, basic characteristics, enhancement patterns, and malignancy-related features, were analyzed. The enhancement pattern was categorized as follows: (A) hypoenhancement (hypodensity in both the arterial phase and portal venous phase); (B) arterial phase hyperenhancement (APHE) and washout; (C) APHE and fade. Univariate and multivariate analyses were performed to identify CT features that differentiated pancreatic from non-pancreatic origins and NEC from NET. RESULTS:Among 83 patients (median age, 52 years; 34 females), 49 patients had pancreatic NELM and 25 patients had NEC. In univariate analyses, hypoenhancement was significantly more frequent in non-pancreatic NELM compared to pancreatic NELM (32.4% vs. 8.2%; p = 0.01). This association was independent of age, sex, tumor size, and differentiation grade (p = 0.03). In addition, NEC was associated with ill-defined margins and targetoid appearances compared to NET, independent of age, sex, tumor size, and tumor origin (p = 0.045 and 0.003, respectively). CONCLUSION:The hypoenhancement of NELM facilitates identification of non-pancreatic primaries, and the presence of an ill-defined margin and a targetoid appearance are indicative of NEC. These features can aid in optimizing management strategies in patients with NELM.
BACKGROUND:Chronic stress profoundly disrupts homeostasis, with the hypothalamic-pituitary-gonadal (HPG) axis emerging as an active integrator rather than a passive target in stress pathophysiology. SUMMARY:This review synthesizes evidence that chronic stress acts on the HPG axis at multiple levels: hypothalamic-pituitary-adrenal (HPA)-derived corticotropin-releasing hormone and glucocorticoids suppress the gonadotropin-releasing hormone (GnRH) pulse generator through kisspeptin/KNDy and gonadotropin-inhibitory hormone pathways; sympathetic overdrive impairs gonadal steroidogenesis while parasympathetic tone declines; and metabolic-inflammatory crosstalk amplifies suppression. The resulting decline in sex steroids - estradiol, progesterone, and testosterone - creates sex-specific vicious cycles that further dysregulate stress and immune circuits, contributing to affective, reproductive, and neurodegenerative disorders. KEY MESSAGES:The HPG axis serves as a critical hub integrating stress signals, and its suppression is an active, regulated process with distinct sex differences. Hormone-based interventions, including estrogen, neurosteroid analogs, and testosterone, show therapeutic promise for stress-related conditions, and future research should focus on the neural circuits and molecular switches that govern HPA-HPG crosstalk to enable personalized, neuroendocrine-informed therapies.
INTRODUCTION:Existing literature has primarily focused on the associations between active smoking and thyroid diseases, whereas the potential causal relationship between passive smoking and thyroid diseases remains insufficiently investigated. Therefore, we conducted a Mendelian randomization (MR) study to evaluate the potential associations of passive smoke exposure with seven prevalent thyroid diseases. METHODS:A two-sample MR design was employed using data from the IEU OpenGWAS Project. Five MR methods were applied to assess potential causal associations. Cochran's Q test assessed heterogeneity, MR-Egger regression evaluated horizontal pleiotropy, MR-PRESSO was used to detect global pleiotropy, and leave-one-out analyses tested result robustness. RESULTS:Genetically predicted passive smoking was associated with increased risks of Graves' disease (odds ratio [OR] = 1.873; 95% confidence interval [CI]: 1.011-3.470; p = 0.046) and thyroid cancer (OR = 1.515; 95% CI: 1.080-2.125; p = 0.016) in the primary inverse variance weighting analysis, while showing an inverse association with nontoxic single thyroid nodules (OR = 0.670; 95% CI: 0.480-0.935; p = 0.019). No causal associations were observed with hyperthyroidism/thyrotoxicosis, hypothyroidism, autoimmune thyroiditis, or subacute thyroiditis. CONCLUSION:This study provides suggestive evidence that genetically predicted passive smoking may be associated with increased risks of Graves' disease and thyroid cancer, as well as an inverse association with nontoxic single thyroid nodules. These findings support efforts to minimize exposure to tobacco smoke among passive smokers. The inverse association with nontoxic single thyroid nodules should be interpreted cautiously and warrants further investigation. Further studies using larger and more granular datasets are required to clarify the potential causal relationships between passive smoking and thyroid diseases.
BACKGROUND:Reproductive dysfunction is a major health concern affecting men and women globally, mediated by the activation of the hypothalamic-pituitary-adrenal axis as well as strongly influenced by exposure to stress. Consequently, this results in suppression of the hypothalamic-pituitary-gonadal (HPG) axis, facilitated by glucocorticoid signalling. Although we have a clear understanding of glucocorticoids as the main mediators of stress-induced reproductive suppression, evidence indicates that monoaminergic pathways, particularly serotonin (5-HT) and its receptors, play pivotal roles in linking stress to reproductive regulation. Kisspeptin neurons have emerged as crucial integrators of both glucocorticoid and serotonergic signals. SUMMARY:Current evidence from animal studies demonstrates that stress dysregulates reproductive function at multiple levels of the HPG axis. Glucocorticoids interact through combined genomic and non-genomic pathways to suppress the secretion of kisspeptin, gonadotropin-releasing hormone (GnRH), gonadotropins, as well as gonadal steroidogenesis. In addition to the well-established glucocorticoid mechanisms, monoamines such as 5-HT play a crucial role in mediating the link between stress and reproduction. Recent molecular, electrophysiological, and transcriptomic studies have highlighted the importance of the 5-HT7 receptor, which is highly expressed in kisspeptin neurons of the arcuate nucleus (ARC), where it acts as a critical excitatory driver of GnRH/luteinising hormone (LH) pulse generation. Stress, however, suppresses serotonergic signalling by lowering 5-HT levels and suppressing serotonin receptor expression, including 5-HT7 receptor, thereby reducing kisspeptin and GnRH neuronal excitation. Glucocorticoid-mediated suppression of kisspeptin signalling might be a key underexplored pathway contributing to stress-mediated reproductive dysfunction, particularly when combined with stress-induced reductions in 5-HT and 5-HT receptor expression, suggesting a dual suppressive mechanism. KEY MESSAGES:Stress suppresses reproductive function through the coordinated actions of glucocorticoids and monoaminergic, particularly serotonergic, signalling. Kisspeptin neurons situated in the ARC of the hypothalamus act as crucial integrators of glucocorticoid and serotonergic inputs and are particularly susceptible to stress-induced alterations. Normally, serotonin-mediated excitation via the 5-HT7 receptors plays an important role in promoting both kisspeptin and GnRH secretion, which are indispensable for reproductive function. However, stress downregulates 5-HT7 receptor expression in the kisspeptin-producing neurons in the arcuate, leading to the subsequent suppression of GnRH and LH pulsatility. This disruption ultimately results in reproductive dysfunction.
INTRODUCTION:Acromegaly/gigantism is a rare disease primarily caused by growth hormone (GH)-secreting pituitary neuroendocrine tumors (PitNETs). With the update in the WHO 5th edition classification of pituitary tumors, particularly the introduction of the novel PIT1/SF1 co-expressing tumor subtype, our understanding of these neoplasms has significantly advanced. However, systematic pathological classification and clinical characterization studies of GH-secreting PitNETs remain relatively scarce. METHODS:A retrospective study was conducted on 143 patients with acromegaly/gigantism who underwent surgical treatment at Peking Union Medical College Hospital between June 2022 and December 2024. Tumor specimens were re-evaluated for pathological subtyping. Demographic data, radiological characteristics, hormone profiles, immunohistochemical findings, and clinical outcomes were collected and compared among subtypes. RESULTS:Forty-five cases (32%) were classified as pure GH-secreting tumors, while the remainder showed co-expression of other hormones and transcription factors. Among PIT1-lineage tumors, sparsely granulated somatotroph tumors (SGSTs) demonstrated greater cavernous sinus invasion, larger maximal tumor diameter, lower GH secretion index, and immunostaining intensity, and reduced SSTR2 expression, suggesting a more aggressive biological behavior. Co-expression of prolactin increased the risk of hyperprolactinemia (OR = 2.843), though only 23.7% of mammosomatotroph tumors and 32.6% of mixed somatotroph-lactotroph tumors presented with hyperprolactinemia. Additionally, 19 PIT1/SF1 co-expressing tumors were identified, showing diverse hormonal profiles and significantly higher cavernous sinus invasion compared to PIT1-lineage tumors. CONCLUSION:GH-secreting PitNETs exhibit marked heterogeneity in pathological subtypes. Current classification systems require clearer cutoff criteria to improve diagnostic consistency. SGSTs are associated with a more invasive phenotype, warranting close clinical monitoring and long-term follow-up. PIT1/SF1 co-expressing tumors represent a distinct and heterogeneous entity that should be considered in future classification frameworks.
BACKGROUND:Colorectal neuroendocrine neoplasms (CR-NENs) are traditionally classified into midgut and hindgut derivatives, a binary classification that potentially oversimplifies the underlying developmental continuum. We investigated whether CR-NEN phenotype and prognosis follow a continuous proximal-to-distal gradient to identify the optimal stratification strategy. METHODS:We analyzed 1,158 patients from the RGETNE registry. Anatomical location was modeled as a continuous variable using restricted cubic splines to dissect spatial trends in proliferation (Ki67), differentiation, and survival. Prognostic performance of the continuous spatial model was formally compared with categorical approaches (right/left/rectum and midgut/hindgut) using the Akaike Information Criterion (AIC). RESULTS:A distinct proximal-to-distal gradient was observed. The continuous spline-based model provided the superior fit for Ki-67 (R2 = 0.494), outperforming categorical approaches. Anatomical position was an independent prognostic factor, with risk increasing distally in localized disease (HR 1.79; 95% CI 1.31-2.45 for rectum vs. cecum) and significant mortality differences in metastatic disease (p < 0.001). Adjuvant benefit was also heterogeneously distributed, being concentrated in distal segments. Despite the biological continuum, the embryological midgut-hindgut dichotomy yielded the most efficient statistical fit (lowest AIC) for predicting clinical recurrence. CONCLUSIONS:CR-NENs exhibit a topographical biological continuum. Continuous modeling is optimal for molecular research and characterizing tumor aggressiveness. However, for clinical risk stratification and trial design, the traditional discrete classifications (midgut-hindgut or anatomical segments) remain the most robust, parsimonious, and practically applicable surrogates.
BACKGROUND:Peptide receptor radionuclide therapy (PRRT) is an established treatment for somatostatin receptor (SSTR)-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), with eligibility determined by the Krenning score. While SSTR PET provides greater sensitivity than octreotide scintigraphy, its impact on PRRT eligibility remains unclear. We compared Krenning scores between [111In]octreotide scintigraphy and [68Ga]DOTATOC PET and assessed eligibility under NETTER-1 and NETTER-2 criteria. METHODS:We retrospectively assessed tumor Krenning scores in 115 patients with well-differentiated GEP-NETs who underwent both [111In]octreotide scintigraphy and [68Ga]DOTATOC PET. PRRT eligibility was defined according to NETTER-1 (Krenning ≥2) and NETTER-2 (Krenning ≥3) criteria. Logistic regression identified predictors of Krenning ≥3 on SSTR PET. Quantitative PET analysis was performed for patients with positive baseline [68Ga]DOTATOC PET scans. RESULTS:Median Krenning scores were higher with SSTR PET than planar imaging (3 [IQR 3-4] vs. 2 [IQR 0-3], p < 10-8). NETTER-1 eligibility increased from 59.1% with planar imaging to 81.7% with PET (p < 10-3), and NETTER-2 from 48.7% to 76.5% (p < 10-4). Among patients eligible on planar imaging, 95.6% (NETTER-1) and 98.2% (NETTER-2) had concordant PET findings. Conversely, 61.7% (NETTER-1) and 55.9% (NETTER-2) of patients ineligible on planar imaging were reclassified as eligible with PET. Metastatic disease was associated with higher SSTR PET uptake (odds ratio 9.5 [95% confidence interval: 2.7-32.8], p < 10-3). SUVmax discriminated patients with Krenning ≥3 using an optimal threshold of 9.2 (AUC 0.93). CONCLUSIONS:[68Ga]DOTATOC PET yields higher Krenning scores and increases PRRT eligibility compared with [111In]octreotide scintigraphy. PET may be unnecessary for clearly positive planar studies but identifies additional candidates with borderline or negative planar results.
INTRODUCTION:Postpartum depression (PPD) is a common and debilitating mood disorder that affects many mothers worldwide, presenting significant challenges to maternal and infant health. This study investigated the clinical relevance and functional mechanisms of miR-335-5p in PPD, to identify novel therapeutic strategies. METHODS:miR-335-5p expression was measured by RT-qPCR. Diagnostic value and clinical correlations of miR-335-5p were evaluated using ROC curve analysis, Spearman correlation, and logistic regression. A PPD mouse model was established to investigate the effects of miR-335-5p on depressive-like behaviors. Oxidative stress markers and inflammatory factors were assessed using commercial detection kits and ELISA, respectively. Potential target genes of miR-335-5p were predicted via online databases and further subjected to GO and KEGG enrichment analyses. RESULTS:Serum miR-335-5p was upregulated in patients with PPD and showed high diagnostic accuracy (AUC=0.862). Its expression correlated with sleep disorders, and both were identified as PPD risk factors. Similarly, miR-335-5p was elevated in a PPD mouse model. Knockdown of miR-335-5p alleviated depressive-like behaviors, including reduced rearing episodes, decreased total distance, increased feeding latency, and prolonged immobility time. Furthermore, miR-335-5p inhibition increased catalase activity, glutathione levels, and total antioxidant capacity, while reducing TNF-α, IL-6, and IL-1β levels. The targets of miR-335-5p were enriched in the circadian rhythm and MAPK signaling pathways. CONCLUSIONS:Elevated miR-335-5p expression represents a potential biomarker for PPD and is associated with sleep disorders. In mouse models, miR-335-5p knockdown alleviates depressive-like behaviors, decreases oxidative stress, and inhibits inflammatory responses, thereby offering mechanistic insights into PPD.
INTRODUCTION:Neuroendocrine neoplasms (NENs) are rare and biologically heterogeneous tumors with limited evidence-based systemic treatment options, particularly in advanced disease stages. Molecular Tumor Boards (MTBs) offer an interdisciplinary framework for interpreting genomic alterations and identifying personalized treatment strategies. METHODS:We conducted a retrospective two-center analysis of patients with NENs discussed at the MTBs of the University Medical Center Freiburg and the Technical University of Munich between 2019 and 2024. Clinical characteristics, molecular profiling results, MTB-based therapy recommendations, treatment implementation, and outcomes were evaluated. Overall survival (OS) was analyzed using a predefined 6-month landmark approach to account for immortal time bias. Treatment efficacy was further assessed using progression-free survival (PFS) and PFS2/PFS1 ratio. RESULTS:A total of 87 patients were discussed at both MTBs, 74 of whom underwent molecular profiling. Actionable therapy recommendations were issued for 58 patients, and 20 patients ultimately received MTB-guided therapy. Molecular alterations frequently involved DNA damage repair pathways, immune-related biomarkers, and signaling cascades relevant to targeted therapy. 6-month landmark OS analysis demonstrated significantly improved OS for patients receiving MTB-guided therapy. At the individual level, 8 of 20 treated patients achieved a PFS2/PFS1 ratio >1.3. CONCLUSION:Molecular-guided precision oncology can provide clinically meaningful benefit for selected patients with NENs, despite limited overall implementation rates. Earlier integration of molecular profiling may increase the feasibility and impact of personalized treatment approaches in these rare tumor entities.
BACKGROUND:Oxytocin (OXT), a neuropeptide synthesized in the hypothalamic paraventricular and supraoptic nuclei, is traditionally known for its roles in parturition and lactation. However, accumulating evidence indicates that OXT also functions as an endogenous analgesic modulator acting through central and peripheral pathways. SUMMARY:In this review, we summarize recent advances in the understanding of the role of OXT for pain modulation, focusing on descending hypothalamo-spinal projections, peripheral neuroendocrine mechanisms, and novel experimental approaches using transgenic and chemogenetic rat models. We also discuss new findings on the OXT-mediated analgesic effects of the traditional Kampo medicine Kamikihi-to and chemogenetic activation of OXT neurons in fibromyalgia models. KEY MESSAGES:Together, these studies establish OXT as a multi-level modulator of nociception, bridging neuroendocrinology and pain research.
BACKGROUND:Neuroendocrine neoplasms (NENs) are rare, heterogeneous malignancies with increasing incidence and poor survival in China. Beyond physical symptoms, patients frequently experience psychological distress and impaired quality of life (QOL), yet comprehensive evidence remains limited. METHODS:Patients with NENs were recruited from the oncology outpatient clinic at Fudan University Shanghai Cancer Center. Psychological status and QOL were assessed using the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder Questionnaire-7 (GAD-7), and the Quality-of-Life Questionnaire-Gastrointestinal Neuroendocrine Tumors-21 (QLQ-GI.NET21). Multivariable regression and network analysis were performed. RESULTS:Among 327 patients, 34.3% exhibited significant depressive symptoms and 34.9% anxiety. Nonmetastatic NEN patients showed higher anxiety, although this finding should be interpreted with caution. Survival time, gender, tumor site, and disease phase significantly influenced anxiety and depression scores. In the gastrointestinal subgroup, G3-grade patients experienced greater distress and poorer QOL. Network analysis revealed a complex interrelationship among anxiety, depression, and QOL dimensions. High-centrality nodes included GAD2 ("uncontrollable worry"), the QLQ-GI.NET21 social function domain, GAD5 ("restlessness"), PHQ9 ("suicide"), and PHQ4 ("fatigue"). Key bridge symptoms were identified as PHQ2 ("sad mood"), GAD5 ("restlessness"), the QLQ-GI.NET21 sexual function domain, PHQ1 ("anhedonia"), and GAD7 ("feeling afraid"). Gender and metastatic status did not significantly affect network structure. CONCLUSION:These findings underscore the need for integrated psychological assessments and tailored interventions throughout treatment, particularly for high-risk subgroups. The core symptoms and bridge nodes identified may serve as potential targets for reducing psychological distress in NEN patients.
BACKGROUND:Asthma is a common chronic inflammatory airway disease, characterized clinically by recurrent wheezing, shortness of breath, chest tightness, and cough. The roles of inflammatory cells such as T cells, eosinophils, and basophils in asthma are now well established. Recent studies have further revealed that the nervous system is not merely a "bystander" to the inflammatory response. Consequently, the peripheral nerves and the neural nuclei involved in asthma have attracted increasing research interest. SUMMARY:This review summarizes the currently identified peripheral and central nerves implicated in transmitting airway inflammatory signals in asthma. It describes the principal mechanisms through which various brain nuclei - including nucleus tractus solitarius, paraventricular nucleus, and amygdala - participate in asthma regulation. We also discuss whether these nuclei interact to form specific neural circuits that modulate the disease. First-line anti-inflammatory medications remain ineffective for a subset of patients, and current pharmacological interventions targeting neural pathways show limited clinical efficacy. KEY MESSAGES:A clear elucidation of the neural circuits regulating asthma would advance our understanding of its pathogenesis, offer new directions and targets for drug development, and raise the possibility of treating asthma through direct central nervous system interventions.
INTRODUCTION:Neuroendocrine tumors (NETs) are uncommon malignancies with increasing incidence in Canada. Long-acting somatostatin analogs (SSA) such as Lanreotide Autogel® (LAN-ATG) and Octreotide Long-Acting Release (OCT-LAR) are first-line treatments for well-differentiated gastroenteropancreatic neuroendocrine tumors either with or without carcinoid syndrome. Despite their efficacy, many patients require short-acting SSA for breakthrough symptoms. We investigated the impact of switching between long-acting SSAs on the usage of breakthrough medications and the incidence of above maximum recommended dose (AMRD) prescriptions. METHODS:This population-based study used claims data from the IQVIA Canadian Private Drug Plan (PDP) that includes data from all Canadian provinces and public drug programs from Ontario and Québec. We identified NET patients who switched SSAs between September 2015 and December 2021. We analyzed breakthrough medication usage and AMRD prescriptions before and after the switch. RESULTS:Among 170 patients who switched SSAs, there was a 59.1% overall reduction in breakthrough medication claims post-switch. Patients switching from OCT-LAR to LAN-ATG experienced a 66.5% reduction, while those switching from LAN-ATG to OCT-LAR saw a 21.9% decrease. Pre-switch, significantly more patients on OCT-LAR exceeded the AMRD threshold compared to those on LAN-ATG (43.8% vs. 18.2%, p value = 0.008). CONCLUSION:Switching between long-acting SSAs can reduce the need for breakthrough medications and lower the incidence of AMRD prescriptions, with a more pronounced effect observed when switching from OCT-LAR to LAN-ATG. These findings have potential implications for improving quality of life and reducing treatment costs for NET patients, which should be evaluated in a formal health economic analysis.
BACKGROUND:Aggressive pituitary tumors (APTs) are commonly defined as invasive neoplasms refractory to treatment with early recurrences, while pituitary carcinomas (PCs) represent a subset of APTs that have developed metastases. However, the diagnostic criteria for APTs remain poorly standardized, and many different classifications of these tumors currently exist. Early and accurate identification of APTs is essential, as these tumors frequently recur and are associated with significant therapeutic challenges. SUMMARY:In this review we provide an overview of different classifications of APTs and summarize the key characteristics and treatment methods for these tumors. Proposed criteria of APTs include histopathological features (such as high Ki-67 index, increased mitotic activity, aggressive histopathological subtypes), genetic alterations (most commonly involving TP53 and ATRX), radiological findings (like invasive behavior, multilobulated morphology, microcystic changes, low signal intensity on T2-weighted magnetic resonance imaging), and clinical characteristics (including rapid growth, early recurrences, resistance to standard therapies). Treatment of APTs typically requires a multimodal approach. Most patients undergo at least one surgical resection, followed by radiotherapy, and in selected cases, pharmacological treatment with temozolomide. Other drugs like immunotherapeutics or cytotoxic agents are also used. In this review we provide an overview of different classifications of APTs and summarize the key characteristics and treatment methods for these tumors. KEY MESSAGES:Early identification of APTs and PCs may be achieved by integrating histopathological, genetic, radiological, and clinical features.
BACKGROUND:Postoperative cognitive dysfunction (POCD) is a common disorder following surgery. The mechanisms underlying this are still under exploration. We hypothesize that hormonal changes in patients who have undergone pituitary surgery contribute to the pathogenesis of POCD. METHODS:In a 12-month follow-up study, a total of 103 patients with pituitary adenoma who received pituitary surgery were included. Patients were categorized into three groups based on their postoperative hormonal supplement: stable, sufficient, and insufficient to eliminate the effects of surgery and hormone dosage. Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were employed as evaluation tools to assess the degree of cognitive impairment. RESULTS:The MoCA score in the stable group showed no significant decrease, while in the sufficient and insufficient groups, the score began to decrease from the 6th month compared to the 0 month of each group. Compared to the stable group at the same time point, the MoCA scores in both groups decreased at the 6th month and 12th month. A similar trend was observed in the MMSE score. Cognitive impairment (mild cognitive impairment and dementia) in both the sufficient group and the insufficient group increased significantly by the 3rd month after surgery, but the rate of increase was much slower subsequently in the sufficient group than in the insufficient group. CONCLUSION:Our study confirms that POCD is highly prevalent in patients after pituitary tumor surgery. Postoperative hormone deficiency plays a crucial role in the progression of POCD, especially adrenocorticotropic hormone and the glucocorticoids it affects. It is worth mentioning that a novel aspect of our study is the identification of hormonal rhythm disturbance as a potential contributor to POCD, which provides valuable insights into the mechanisms of POCD in pituitary surgery. We call for more personalized and chronobiological hormone replacement therapy approaches.
INTRODUCTION:Diabetic gastroparesis (DGP) is a severe diabetic complication with limited therapeutic options. This study investigates the effects of Foxiangsan on DGP and elucidates its molecular mechanisms. METHODS:A rat model of DGP was established and divided into 5 groups: model (MG), western medicine (WMG, domperidone), and 3 Foxiangsan dose groups (LDG, MDG, HDG). Serum dopamine (DA) and motilin levels, along with striatal DA receptor D2 (DRD2) expression, were measured. Network pharmacology identified bioactive compounds and targets, and pathway enrichment and molecular docking were used to evaluate mechanistic interactions. RESULTS:Foxiangsan significantly improved gastrointestinal motility, increased motilin levels, reduced DA levels, and enhanced DRD2 expression in the striatum. Network pharmacology identified DRD2, AKT1, and MAPK3 as key targets, while molecular docking confirmed strong binding affinities of bioactive compounds such as β-sitosterol and baicalein with DRD2. The therapeutic effects of Foxiangsan involve modulation of the cAMP, serotonin, and DA pathways. CONCLUSION:Foxiangsan exerts multicomponent, multi-target, and multi-pathway actions in DGP by modulating neuroendocrine function, suggesting its potential as a novel therapeutic approach. Further investigations are needed to confirm its clinical efficacy.
Introduction: The glymphatic system (GS) is a brain-wide clearance pathway whose dysfunction has been implicated in cognitive decline. This study was designed to assess GS alterations in prediabetes and type 2 diabetes mellitus (T2DM) using multiple MRI-derived metrics and to examine their associations with cognitive performance. Methods: This cross-sectional study was conducted from October 2023 to June 2024 at Nanfang Hospital, a tertiary care center. A total of 147 participants were recruited, including 52 patients with T2DM, 44 with prediabetes, and 51 healthy controls (HC). All participants underwent brain MRI, laboratory examinations, and cognitive function assessments. GS function was evaluated using MRI-derived metrics, including choroid plexus (CP) volume, perivascular space (PVS) volume, free water (FW) index, and the diffusion tensor imaging analysis along the PVS (DTI-ALPS) index. Group differences were tested with general linear models adjusted for sex, age, and education, and associations with clinical variables were evaluated using partial correlations. Results: Compared with HC, prediabetes showed increased CP volume and FW index, without significant changes in DTI-ALPS index or PVS volume. T2DM showed reduced DTI-ALPS index, increased CP volume, and higher FW index, with unchanged PVS volume. In both groups, lower DTI-ALPS index and higher CP volume or FW index correlated with poorer cognitive performance. Conclusion: Prediabetes and T2DM exhibit GS alterations, including reduced DTI-ALPS index and increased CP volume and FW index, which are associated with poorer cognition. GS metrics may serve as potential neuroimaging biomarkers for cognitive impairment in this population.
