AI-Powered Microfluidics: Shaping the Future of Phenotypic Drug Discovery.

Phenotypic drug discovery (PDD), which involves harnessing biological systems directly to uncover effective drugs, has undergone a resurgence in recent years. The rapid advancement of artificial intelligence (AI) over the past few years presents numerous opportunities for augmenting phenotypic drug screening on microfluidic platforms, leveraging its predictive capabilities, data analysis, efficient data processing, etc. Microfluidics coupled with AI is poised to revolutionize the landscape of phenotypic drug discovery. By integrating advanced microfluidic platforms with AI algorithms, researchers can rapidly screen large libraries of compounds, identify novel drug candidates, and elucidate complex biological pathways with unprecedented speed and efficiency. This review provides an overview of recent advances and challenges in AI-based microfluidics and their applications in drug discovery. We discuss the synergistic combination of microfluidic systems for high-throughput screening and AI-driven analysis for phenotype characterization, drug-target interactions, and predictive modeling. In addition, we highlight the potential of AI-powered microfluidics to achieve an automated drug screening system. Overall, AI-powered microfluidics represents a promising approach to shaping the future of phenotypic drug discovery by enabling rapid, cost-effective, and accurate identification of therapeutically relevant compounds.

Brachytherapy in craniopharyngiomas: a systematic review and meta-analysis of long-term follow-up.

OBJECTIVE: Brachytherapy has been indicated as an alternative option for treating cystic craniopharyngiomas (CPs). The potential benefits of brachytherapy for CPs have not yet been clarified. The purpose of this work was to conduct a meta-analysis to analyze the long-term efficacy and adverse reactions profile of brachytherapy for CPs. MATERIALS AND METHODS: The relevant databases were searched to collect the clinical trials on brachytherapy in patients with CPs. Included studies were limited to publications in full manuscript form with at least 5-year median follow-up, and adequate reporting of treatment outcomes and adverse reactions data. Stata 12.0 was used for data analysis. RESULTS: According to the inclusion and exclusion criteria, a total of 6 clinical trials involving 266 patients with CPs were included in this meta-analysis. The minimum average follow-up was 5 years. The results of the meta-analysis showed that 1-year, 2-3 years and 5 years progression free survival rates (PFS) are 75% (95%CI: 66-84%), 62% (95%CI: 52-72%) and 57% (95%CI: 22-92%), respectively. At the last follow-up, less than 16% of patients with visual outcomes worser than baseline in all included studies. While, for endocrine outcomes, less than 32% of patients worser than baseline level. CONCLUSION: In general, based on the above results, brachytherapy should be considered as a good choice for the treatment of CP.

Artificial intelligence facial recognition system for diagnosis of endocrine and metabolic syndromes based on a facial image database.

AIM: To build a facial image database and to explore the diagnostic efficacy and influencing factors of the artificial intelligence-based facial recognition (AI-FR) system for multiple endocrine and metabolic syndromes. METHODS: Individuals with multiple endocrine and metabolic syndromes and healthy controls were included from public literature and databases. In this facial image database, facial images and clinical data were collected for each participant and dFRI (disease facial recognition intensity) was calculated to quantify facial complexity of each syndrome. AI-FR diagnosis models were trained for each disease using three algorithms: support vector machine (SVM), principal component analysis k-nearest neighbor (PCA-KNN), and adaptive boosting (AdaBoost). Diagnostic performance was evaluated. Optimal efficacy was achieved as the best index among the three models. Effect factors of AI-FR diagnosis were explored with regression analysis. RESULTS: 462 cases of 10 endocrine and metabolic syndromes and 2310 controls were included into the facial image database. The AI-FR diagnostic models showed diagnostic accuracies of 0.827-0.920 with SVM, 0.766-0.890 with PCA-KNN, and 0.818-0.935 with AdaBoost. Higher dFRI was associated with higher optimal area under the curve (AUC) (P = 0.035). No significant correlation was observed between the sample size of the training set and diagnostic performance. CONCLUSIONS: A multi-ethnic, multi-regional, and multi-disease facial database for 10 endocrine and metabolic syndromes was built. AI-FR models displayed ideal diagnostic performance. dFRI proved associated with the diagnostic performance, suggesting inherent facial features might contribute to the performance of AI-FR models.

CARDS, a Novel Prognostic Index for Risk Stratification and In-Hospital Monitoring.

Background: Sodium fluctuation is independently associated with clinical deterioration. We developed and validated a prognostic index based on sodium fluctuation for risk stratification and in-hospital monitoring. Methods: This study included 33,323 adult patients hospitalized at a tertiary care hospital in 2014. The first 28,279 hospitalizations were analyzed to develop the model and then the validity of the model was tested using data from 5044 subsequent hospitalizations. We predict in-hospital mortality using age, comorbidity, range of sodium fluctuation, and duration of sodium fluctuation, abbreviated as CARDS. Results: In-hospital mortality was similar in the derivation (0.6%) and validation (0.4%) cohorts. In the derivation cohort, four independent risk factors for mortality were identified using logistic regression: age (66-75, 2 points; >75, 3 points); Charlson comorbidity index (>2, 5 points); range of sodium fluctuation (7-10, 4 points; >10, 10 points); and duration of fluctuation (≤3, 3 points). The AUC was 0.907 (95% CI: 0.885-0.928) in the derivation cohort and 0.932 (95% CI: 0.895-0.970) in the validation cohort. In the derivation cohort, in-hospital mortality was 0.106% in the low-risk group (0-7 points), 1.076% in the intermediate-risk group (8-14 points), and 8.463% in the high-risk group (15-21 points). In the validation cohort, in-hospital mortality was 0.049% in the low-risk group, 1.064% in the intermediate-risk group, and 8.403% in the high-risk group. Conclusions: These results suggest that patients at low, intermediate, and high risk for in-hospital mortality may be identified by CARDS mainly based on sodium fluctuation.

Blood Lipid Disorders in Post-Operative Craniopharyngioma Children and Adolescents and the Improvement with Recombinant Human Growth Hormone Replacement.

Context: The high prevalence of hypothalamic obesity (HO) and dyslipidemia in individuals with craniopharyngioma (CP) following surgery is a cause for increasing concern. However, few studies have explored the lipid profile in pediatric CP patients, with inconsistent findings. In addition, the role of recombinant human growth hormone (rhGH) replacement remains unclear in these patients. Objective: To compare the blood lipid profile among post-operative craniopharyngioma children and adolescents with that among healthy controls and to reveal the effects of rhGH replacement. Methods: Data of 79 post-operative craniopharyngioma children and adolescents in our center were retrospectively collected. Sixty patients underwent rhGH replacement during the follow-ups. We selected 36 patients who received rhGH replacement therapy, while 20 patients received rhGH replacement for at least 1 year and had complete lipid data before and after treatment and compared them with 19 patients who did not receive rhGH replacement therapy. Results: Craniopharyngioma patients had higher total cholesterol (TC) (5.17 vs 3.77 mmol/L), triglyceride (TG) (1.51 vs 0.73 mmol/L), and low-density lipoprotein cholesterol (LDL-C) (3.14 vs 2.10 mmol/L), and lower high-density lipoprotein cholesterol (HDL-C) (1.06 vs 1.39 mmol/L) than controls (all p < 0.001). The lipid profile of obese and non-obese patients was not significantly different. After rhGH replacement, TC was 0.90 mmol/L lower (p = 0.002) and LDL-C was 0.73 mmol/L lower (p = 0.010) than baseline. Although the baseline LDL-C was higher, patients with rhGH replacement had lower LDL-C (-0.73 mmol/L adjusted for age and sex, p = 0.045) after the initiation of replacement compared with patients without rhGH replacement. Conclusion: The lipid profile of obese and non-obese children and adolescents with craniopharyngioma was unfavorable, and rhGH replacement could improve their lipid profile.

Interaction of PM2.5 and pre-pregnancy body mass index on birth weight: A nationwide prospective cohort study.

Background: Fine particulate matter (PM2.5), one of the most common air pollutants worldwide, has been associated with many adverse birth outcomes in some studies. Pre-pregnancy body mass index (BMI) is an important indicator of maternal obesity that may also contribute to a wide range of birthweight outcomes. Both PM2.5 and maternal obesity have been found associated with issues on neonatal birthweight respectively, and more attentions and interests are focusing on their combined effect on pregnancy outcomes. Purpose: To explore the modifying effect of pre-pregnancy BMI on the association between gestational PM2.5 and birthweight; to investigate the interactive effect between gestational PM2.5 and pre-pregnancy BMI on birthweight among pregnant women during three trimesters and the whole pregnancy. Methods: This nationwide cohort study used the National Free Preconception Health Examination Project (NFPHEP) data collected from January 1, 2010, to December 31, 2012. A total population of 248,501 Chinese women from 220 counties registered this project. Pre-pregnancy BMI as a common anthropometric examination was collected during preconception investigation, and gestational PM2.5 was derived from a hindcast model for historical PM2.5 estimation from satellite-retrieved aerosol optic depth. Subgroup analysis was conducted to explore a potential modifying effect on the association between PM2.5 and birthweight during pregnancy by four pre-pregnancy BMI subgroups. Interaction analysis by introducing product terms to multivariable linear regression was also used to examine whether there was an interactive relationship between PM2.5 and pre-pregnancy BMI. Results: Totally, 193,461 participants were included in our study. The average concentration of PM2.5 was 75.33 µg/m3. Higher exposure of PM2.5 during the entire pregnancy was associated with higher birthweight (17.15 g per 10 µg/m3; 95% CI:16.15, 18.17). Each 10 µg/m3 increase in PM2.5 during the first, second, and third trimesters was associated with increases in birthweight by 14.93 g (95%CI: 13.96, 15.89), 13.75 g (95% CI: 12.81, 14.69), and 8.79 g (95% CI: 8.09, 9.49), respectively. Higher pre-pregnancy BMI per kg/m2 was associated with an increase of birthweight by 7.012 g (95% CI: 6.121, 7.902). Product terms between PM2.5 and pre-pregnancy BMI were significant for the first, second trimesters, and the entire duration of pregnancy. Conclusions: Our results found both gestational PM2.5 exposure and pre-pregnancy BMI respectively correlated with the increase of birthweight. A negative interaction between pre-pregnancy BMI and gestational PM2.5 was discovered in term of birthweight gain. Avoidance of high-dose exposure to PM2.5 during the early and middle stages of pregnancy and pre-pregnancy overweight/obesity may help prevent high birthweight.

Review on Facial-Recognition-Based Applications in Disease Diagnosis.

Diseases not only manifest as internal structural and functional abnormalities, but also have facial characteristics and appearance deformities. Specific facial phenotypes are potential diagnostic markers, especially for endocrine and metabolic syndromes, genetic disorders, facial neuromuscular diseases, etc. The technology of facial recognition (FR) has been developed for more than a half century, but research in automated identification applied in clinical medicine has exploded only in the last decade. Artificial-intelligence-based FR has been found to have superior performance in diagnosis of diseases. This interdisciplinary field is promising for the optimization of the screening and diagnosis process and assisting in clinical evaluation and decision-making. However, only a few instances have been translated to practical use, and there is need of an overview for integration and future perspectives. This review mainly focuses on the leading edge of technology and applications in varieties of disease, and discusses implications for further exploration.

Preconception TSH and Adverse Pregnancy Outcomes in China: A Nationwide Prospective Cohort Study.

BACKGROUND: The relationship between maternal thyroid function and pregnancy outcomes remains controversial and the safe range of TSH is still unclear in women planning pregnancy. METHODS: This population-based cohort study enrolled Chinese women who became pregnant in 30 provinces from 2010 to 2012 from the National Free Preconception Checkups Project. The maternal TSH level within 6 months before pregnancy and different pregnancy outcomes were collected and analyzed using restricted cubic spline regression model for dose-response relationship and potential optimal cutoff values. Logistic regression was used to reveal the relationship between different TSH groups and the risk of adverse outcomes. RESULTS: Among 175 112 women, a J-shaped association was revealed between TSH and large for gestational age (LGA; P < 0.001). When TSH was lower than 1.27 or 0.91 mIU/L, lower TSH was associated with higher odds ratio of low birth weight (LBW; P = 0.003) or preterm delivery (P < 0.001). There was no significant association of preconception TSH with SGA, macrosomia, fetal anomalies, stillbirth, natural or induced abortion, and cesarean delivery. The range of TSH for odds ratio lower than 1.0 was within 0.91 to 1.82 mIU/L in dose-response association. Compared with TSH 0.91 to 1.82 mIU/L, TSH low (< 0.40 mIU/L and 0.40-0.90 mIU/L) and high (1.83-2.49 mIU/L, 2.50-3.99 mIU/L, and >4.00 mIU/L) were associated with higher risk of preterm delivery and LGA. There was no significant association between TSH groups and the risk of LBW except for TSH < 0.40 mIU/L. CONCLUSION: Preconception TSH was associated with preterm delivery, LGA, and LBW. Preconception TSH had a bidirectional effect on LGA, indicating a potential mechanism regarding influence of TSH on birth weight. TSH within 0.91 to 1.82 mIU/L was the potential safe range for preconception women.

Evaluation of efficacy and safety of long-acting PEGylated recombinant human growth hormone (Jintrolong) for patients with growth hormone deficiency.

OBJECTIVES: This study aimed to compare the efficacy, safety and metabolic effects of once-weekly pegylated human growth hormone (PEG-rhGH) with daily rhGH in patients with growth hormone deficiency (GHD). DESIGN: 48 patients enrolled in this 12-month single-center, open-label, prospective, randomized controlled trial is allocated to PEG-rhGH 0.12 mg/kg/w and 0.20 mg/kg/w treatment. Besides, the control group allocated 23 patients treated with daily rhGH 0.28 mg/kg/w matched with sex, age, and baseline IGF-1 levels. The primary endpoint included height velocity (HV) and IGF-1 increase at the end of treatment. Other parameters associated with growth, metabolism and safety were also monitored. RESULTS: In terms of HV increase, the efficacy of PEG-rhGH dosed at 0.12 mg/kg/w and 0.20 mg/kg/w was comparable to that of daily rhGH dosed at 0.28 mg/kg/w after 3, 6 and 12 treatment (p>0.05). IGF-1 concentration and IGF-1 SDS were both elevated significantly at 3, 6 and 12 months (p=0.000) into normal range following PEG-rhGH treatment. BMI SDS elevated after PEG-rhGH treatment for 3, 6 and 12 months (p=0.000). HbA1c elevated after 3 and 12 months (p=0.009) and METS-IR elevated after 6 months (p=0.019) compared with baseline. The differences of other metabolic indexes (such as blood glucose, blood lipid, etc.) have no statistical significance (p>0.05). No severe adverse event was observed among the three groups. CONCLUSIONS: The efficacy and safety were promising and comparable between once-weekly PEG-rhGH and daily rhGH injection within 12 months. The negative influence on glucose homeostasis needed attention and monitoring.

Facial Recognition Intensity in Disease Diagnosis Using Automatic Facial Recognition.

Artificial intelligence (AI) technology is widely applied in different medical fields, including the diagnosis of various diseases on the basis of facial phenotypes, but there is no evaluation or quantitative synthesis regarding the performance of artificial intelligence. Here, for the first time, we summarized and quantitatively analyzed studies on the diagnosis of heterogeneous diseases on the basis on facial features. In pooled data from 20 systematically identified studies involving 7 single diseases and 12,557 subjects, quantitative random-effects models revealed a pooled sensitivity of 89% (95% CI 82% to 93%) and a pooled specificity of 92% (95% CI 87% to 95%). A new index, the facial recognition intensity (FRI), was established to describe the complexity of the association of diseases with facial phenotypes. Meta-regression revealed the important contribution of FRI to heterogeneous diagnostic accuracy (p = 0.021), and a similar result was found in subgroup analyses (p = 0.003). An appropriate increase in the training size and the use of deep learning models helped to improve the diagnostic accuracy for diseases with low FRI, although no statistically significant association was found between accuracy and photographic resolution, training size, AI architecture, and number of diseases. In addition, a novel hypothesis is proposed for universal rules in AI performance, providing a new idea that could be explored in other AI applications.

The Negative Impacts of Acromegaly on Bone Microstructure Not Fully Reversible.

Purpose: This study aimed to evaluate the bone turnover markers and bone microarchitecture parameters derived from high-resolution peripheral quantitative computed tomography (HR-pQCT) in active and controlled acromegaly patients. Methods: This cross-sectional study involved 55 acromegaly patients from a tertiary hospital (23 males and 32 females, aged 45.0 ± 11.6 years). Firstly, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and markers for bone turnover were assessed. Next, we derived peripheral bone microstructure parameters and volumetric bone mineral density (vBMD) through HR-pQCT. These parameters were compared between acromegaly patients and 110 healthy controls, as well as between 27 active and 28 controlled acromegaly patients. Moreover, the relationship between GH/IGF-1 and bone microstructure parameters was analyzed through multiple linear regression. Results: As compared with healthy controls, acromegaly patients exhibited elevated cortical vBMD, reduced trabecular vBMD, and increased trabecular inhomogeneity in the distal radius and tibia. While controlled acromegaly patients had slower bone turnover, they did not necessarily have better bone microstructure relative to active patients in intergroup comparison. Nevertheless, multiple regression indicated that higher IGF-1 was associated with lower tibial stiffness and failure load. Additionally, males with higher IGF-1 typically had larger trabecular separation, lower trabecular number, and larger cortical pores in the radius. Moreover, patients with elevated GH typically had more porous cortical bone in the radius and fewer trabeculae in the tibia. However, the compromised bone strength in active patients was partially compensated by increased bone thickness. Furthermore, no significant linkage was observed between elevated GH/IGF-1 and the most important HR-pQCT parameters such as trabecular volumetric bone density. Conclusion: Acromegaly adversely affected bone quality, even in controlled patients. As the deterioration in bone microstructure due to prolonged GH/IGF-1 exposure was not fully reversible, clinicians should be aware of the bone fragility of acromegaly patients even after they had achieved biochemical remission.

Experience of Ectopic Adrenocorticotropin Syndrome: 88 Cases With Identified Causes.

OBJECTIVE: Ectopic adrenocorticotropic hormone syndrome (EAS) is a rare cause of Cushing's syndrome and diagnosis and management remain challenging. The aim of this study was to present the clinical spectrum of a group of EAS cases in a single center to explore better management strategies. METHODS: A retrospective study was conducted to identify 88 confirmed EAS cases at our hospital from 1984 to 2019. The clinical, biochemical, imaging, and pathological features were analyzed. RESULTS: Of the 88 eligible patients with EAS, 38 (43.2%) cases of pulmonary neuroendocrine tumors (NETs) and a larger number of thymic/mediastinal NETs (29 cases, 33%) were identified. The clinical and biological features of EAS and Cushing's disease overlapped but were more severe in EAS. Inferior petrosal sinus sampling (97.4%) and computed tomography (85.4%) provided the highest positive diagnostic accuracy. Computed tomography is also a useful tool to identify tumors in chest cavity compared with nonchest lesions (91.2% vs 57.1%). Although a greater tumor size (4.54 cm vs 1.44 cm) and higher rate of insuppressible high-dose dexamethasone suppression test (83.3% vs 51.5%) were found in thymic/mediastinum NETs than in pulmonary NETs, the level of hormone production had no difference. CONCLUSION: EAS had more common and severe clinical presentations than Cushing's disease, and multiple imaging approaches are required for reliable diagnosis. A higher proportion of thymic/mediastinal NETs was found in our study. For patients without a certain tumor source, long-term follow-up and further evaluations are needed.

Efficacy and safety of long-acting growth hormone in children with short stature: a systematic review and meta-analysis.

PURPOSE: Long-acting growth hormone (GH) has been developed to address the noncompliance and decreased efficacy associated with daily GH injections. We aimed to evaluate the efficacy and safety of long-acting GH replacement therapy in children with short stature. METHODS: Randomized controlled trials (RCTs) that investigated the efficacy and safety of long-acting GH therapy in children with short stature in comparison with daily GH injections were searched in Medline, Embase, and the Cochrane Central Register of Controlled Trials. A random-effect model was used to pool data using mean difference and odds ratios (OR). (PROSPERO registration number: CRD42018111105). RESULTS: Seven relevant studies were finally included. Meta-analysis found there was no significant difference between high-dose long-acting GH and daily GH in terms of height velocity (HV) (mean difference (MD) = -0.10, 95% CI, -0.79 to 0.60, P = 0.79). Moreover, no significant difference was observed in height standard deviation scores (Ht SDS) between high-dose long-acting GH and daily GH (MD = -0.07, 95% CI, -0.18 to 0.03, P = 0.17). Treatment with high-dose long-acting GH significantly increased IGF-1 SDS when compared with daily GH (MD = 0.31, 95% CI, 0.06-0.56, P = 0.02). In safety assessment, no significant difference was observed in the incidence of adverse events between high-dose long-acting GH and daily GH (OR 1.42, 95% CI, 0.65-3.11, P = 0.38). CONCLUSIONS: There is no evidence to support differences in the effects of long-acting GH compared with those of daily GH. More RCTs that focus on the safety of high-dose long-acting GH treatment, especially the detection of adverse events caused by elevated levels of serum IGF-1, are needed in the future.

Characteristics and reference values of fat mass index and fat free mass index by bioelectrical impedance analysis in an adult population.

BACKGROUND & AIMS: We aim to examine the influence of sex, age, region and ethnicity on fat mass index (FMI) and fat free mass index (FFMI), and to establish FMI and FFMI reference values in Chinese adults. METHODS: A stratified cluster sampling method was adopted to enroll Chinese participants in this cross-sectional study. Questionnaire surveys and medical examinations were performed to collect data, and body composition parameters were measured by bioelectrical impedance analysis. FMI and FFMI were calculated as the ratio of fat mass and fat free mass to the square of height. Differences in mean values for parameters were tested by Student's t-test or one-way analysis of variance. Reference values of FMI and FFMI were obtained using the percentiles method. RESULTS: A total of 8959 multiethnic healthy Chinese adults were included in the analysis. Males had higher mean FFMI (males, 18.6 ± 1.6 kg/m2; females, 15.7 ± 1.1 kg/m2, P < 0.001) but lower mean FMI (males, 5.1 ± 2.1 kg/m2; females, 7.8 ± 2.8 kg/m2, P < 0.001) than did female participants regardless of age and ethnicity. For both sexes, FMI (Male: Bouyei, 4.2 ± 1.8 kg/m2; Uygur, 5.8 ± 2.2 kg/m2, P < 0.001; Female: Bouyei, 6.7 ± 2.3 kg/m2; Uygur, 9.0 ± 3.2 kg/m2, P < 0.001) and FFMI (Male: Bouyei, 17.8 ± 1.4 kg/m2; Uygur, 19.4 ± 1.6 kg/m2, P < 0.001; Female: Bouyei, 15.1 ± 1.0 kg/m2; Uygur, 16.3 ± 1.1 kg/m2, P < 0.001) were lowest in Bouyeis and highest in Uygurs. FMI and FFMI values increased with age until they peaked in the 30-39 year age group in males and after the age of 40 years in females for all ethnic groups. Reference values (5th-95th percentile) of FMI and FFMI were presented according to gender, age, region and ethnicity. CONCLUSION: The body composition of Chinese population differs in different age, sex, ethnicity and region subgroups. Practitioners and future studies may need to consider different reference values for FMI and FFMI in Chinese adults among Han, Bouyei and Uygur populations; these values can serve as indices for evaluating nutrition status and identifying abnormalities in body composition.

11ß-Hydroxysteroid dehydrogenase type 1 shRNA ameliorates glucocorticoid-induced insulin resistance and lipolysis in mouse abdominal adipose tissue.

Long-term glucocorticoid exposure increases the risk for developing type 2 diabetes. Prereceptor activation of glucocorticoid availability in target tissue by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) coupled with hexose-6-phosphate dehydrogenase (H6PDH) is an important mediator of the metabolic syndrome. We explored whether the tissue-specific modulation of 11ß-HSD1 and H6PDH in adipose tissue mediates glucocorticoid-induced insulin resistance and lipolysis and analyzed the effects of 11ß-HSD1 inhibition on the key lipid metabolism genes and insulin-signaling cascade. We observed that corticosterone (CORT) treatment increased expression of 11ß-HSD1 and H6PDH and induced lipase HSL and ATGL with suppression of p-Thr(172) AMPK in adipose tissue of C57BL/6J mice. In contrast, CORT induced adipose insulin resistance, as reflected by a marked decrease in IR and IRS-1 gene expression with a reduction in p-Thr(308) Akt/PKB. Furthermore, 11ß-HSD1 shRNA attenuated CORT-induced 11ß-HSD1 and lipase expression and improved insulin sensitivity with a concomitant stimulation of pThr(308) Akt/PKB and p-Thr(172) AMPK within adipose tissue. Addition of CORT to 3T3-L1 adipocytes enhanced 11ß-HSD1 and H6PDH and impaired p-Thr(308) Akt/PKB, leading to lipolysis. Knockdown of 11ß-HSD1 by shRNA attenuated CORT-induced lipolysis and reversed CORT-mediated inhibition of pThr(172) AMPK, which was accompanied by a parallel improvement of insulin signaling response in these cells. These findings suggest that elevated adipose 11ß-HSD1 expression may contribute to glucocorticoid-induced insulin resistance and adipolysis.

Transgenic overexpression of hexose-6-phosphate dehydrogenase in adipose tissue causes local glucocorticoid amplification and lipolysis in male mice.

The prereceptor activation of glucocorticoid production in adipose tissue by NADPH-dependent 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) has emerged as a potential mechanism in the pathogenesis of visceral obesity and metabolic syndrome. Hexose-6-phosphate dehydrogenase (H6PDH) is an endoplasmic reticulum lumen-resident enzyme that generates cofactor NADPH and thus mediates 11ß-HSD1 activity. To determine the role of adipose H6PDH in the prereceptor modulation of 11ß-HSD1 and metabolic phenotypes, we generated a transgenic (Tg) mouse model overexpressing H6PDH under the control of the enhancer-promoter region of the adipocyte fatty acid-binding protein (aP2) gene (aP2/H6PDH Tg mice). Transgenic aP2/H6PDH mice exhibited relatively high expression of H6PDH and elevated corticosterone production with induction of 11ß-HSD1 activity in adipose tissue. This increase in corticosterone production in aP2-H6PDH Tg mice resulted in mild abdominal fat accumulation with induction of C/EBP mRNA expression and slight weight gain. Transgenic aP2/H6PDH mice also exhibited fasting hyperglycemia and glucose intolerance with insulin resistance. In addition, the aP2/H6PDH Tg mice have elevated circulating free fatty acid levels with a concomitant increased adipose lipolytic action associated with elevated HSL mRNA and Ser(660) HSL phosphorylation within abdominal fat. These results suggest that increased H6PDH expression specifically in adipose tissue is sufficient to cause intra-adipose glucocorticoid production and adverse metabolic phenotypes. These findings suggest that the aP2/H6PDH Tg mice may provide a favorable model for studying the potential impact of H6PDH in the pathogenesis of human metabolic syndrome.

Specific reduction of G6PT may contribute to downregulation of hepatic 11ß-HSD1 in diabetic mice.

Pre-receptor activation of glucocorticoids via 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1 (HSD11B1)) has been identified as an important mediator of the metabolic syndrome. Hexose-6-phosphate dehydrogenase (H6PDH) mediates 11ß-HSD1 amplifying tissue glucocorticoid production by driving intracellular NADPH exposure to 11ß-HSD1 and requires glucose-6-phosphate transporter (G6PT (SLC37A4)) to maintain its activity. However, the potential effects of G6PT on tissue glucocorticoid production in type 2 diabetes and obesity have not yet been defined. Here, we evaluated the possible role of G6PT antisense oligonucleotides (G6PT ASO) in the pre-receptor metabolism of glucocorticoids as related to glucose homeostasis and insulin tolerance by examining the production of 11ß-HSD1 and H6PDH in both male db/+ and db/db mouse liver tissue. We observed that G6PT ASO treatment of db/db mice markedly reduced hepatic G6PT mRNA and protein levels and substantially diminished the activation of hepatic 11ß-HSD1 and H6PDH. Reduction of G6pt expression was correlated with the suppression of both hepatic gluconeogenic enzymes G6Pase and PEPCK and corresponded to the improvement of hyperglycemia and insulin resistance in db/db mice. Addition of G6PT ASO to mouse hepa1-6 cells led to a dose-dependent decrease in 11B-Hsd1 production. Knockdown of G6PT with RNA interference also impaired 11B-Hsd1 expression and showed comparable effects to H6pdh siRNA on silencing of H6pdh and 11B-Hsd1 expression in these intact cells. These findings suggest that G6PT plays an important role in the modulation of pre-receptor activation of glucocorticoids and provides new insights into the role of G6PT in the development of type 2 diabetes.

Long-term follow-up and humanistic care for patients with hypophyseal tumor.

The number of new cases of hypophyseal tumor increases along with the advances in neuroimaging technology in recent years. The common treatment models include surgical treatment, radiotherapy, and medical therapies. This article discusses the application of long-term follow-up in non-operative hypophyseal tumor patients and its influence on the prognosis. Meanwhile, since the medical mode has switched from biomedical model to biopsychosocial medical model, management of hypophyseal tumor should not be limited in its biological aspect, but also from the perspective of psychology by providing more humanistic care to meet the patients'psychological needs.