Decreased complexity of glucose time series index associated with adverse pregnancy outcomes in gestational diabetes mellitus.

AIM: We investigated the relationship between the complexity of the glucose time series index (CGI) during pregnancy and adverse pregnancy outcomes in women with gestational diabetes mellitus (GDM). MATERIALS AND METHODS: In this retrospective cohort study, 388 singleton pregnant women with GDM underwent continuous glucose monitoring (CGM) at a median of 26.86 gestational weeks. CGI was calculated using refined composite multiscale entropy based on CGM data. The participants were categorized into tertiles according to their baseline CGI (CGI <2.32, 2.32-3.10, ≥3.10). Logistic regression was used to assess the association between CGI and composite adverse outcomes or large for gestational age (LGA). The discrimination performance of CGI was estimated using receiver operating characteristic analysis. RESULTS: Of the 388 participants, 71 (18.3%) had LGA infants and 63 (16.2%) had composite adverse outcomes. After adjustments were made for confounders, compared with those with a high CGI (CGI ≥3.10), participants with a low CGI (CGI <2.32) had a higher risk of composite adverse outcomes (odds ratio: 12.10, 95% confidence interval: 4.41-33.18) and LGA (odds ratio: 12.68, 95% confidence interval: 4.04-39.75). According to the receiver operating characteristic analysis, CGI was significantly better than glycated haemoglobin and conventional CGM indicators for the prediction of adverse pregnancy outcomes (all p < .05). CONCLUSION: A lower CGI during pregnancy was associated with composite adverse outcomes and LGA. CGI, a novel glucose homeostasis predictor, seems to be superior to conventional glucose indicators for the prediction of adverse pregnancy outcomes in women with GDM.

Implications of gut microbiota dysbiosis and metabolic changes in prion disease.

Evidence of the gut microbiota influencing neurodegenerative diseases has been reported for several neural diseases. However, there is little insight regarding the relationship between the gut microbiota and prion disease. Here, using fecal samples of 12 prion-infected mice and 25 healthy controls, we analyzed the structure of the gut microbiota and metabolic changes by 16S rRNA sequencing and LC-MS-based metabolomics respectively as multi-omic analyses. Additionally, SCFAs and common amino acids were detected by GC-MS and UPLC respectively. Enteric changes induced by prion disease affected both structure and abundances of the gut microbiota. The gut microbiota of infected mice displayed greater numbers of Proteobacteria and less Saccharibacteria at the phylum level and more Lactobacillaceae and Helicobacteraceae and less Prevotellaceae and Ruminococcaceae at the family level. A total of 145 fecal metabolites were found to be significantly different in prion infection, and most (114) of these were lipid metabolites. Using KEGG pathway enrichment analysis, we found that 3 phosphatidylcholine (PC) compounds significantly decreased and 4 hydrophobic bile acids significantly increased. Decreases of 8 types of short-chain acids (SCFAs) and increases of Cys and Tyr and decreases of His, Trp, and Arg were observed in prion infection. Correlation analysis indicated that the gut microbiota changes observed in our study may have been the shared outcome of prion disease. These findings suggest that prion disease can cause significant shifts in the gut microbiota. Certain bacterial taxa can then respond to the resulting change to the enteric environment by causing dramatic shifts in metabolite levels. Our data highlight the health impact of the gut microbiota and related metabolites in prion disease.

Combinatory FK506 and Minocycline Treatment Alleviates Prion-Induced Neurodegenerative Events via Caspase-Mediated MAPK-NRF2 Pathway.

Transcription factors play a significant role during the symptomatic onset and progression of prion diseases. We previously showed the immunomodulatory and nuclear factor of activated T cells' (NFAT) suppressive effects of an immunosuppressant, FK506, in the symptomatic stage and an antibiotic, minocycline, in the pre-symptomatic stage of prion infection in hamsters. Here we used for the first time, a combinatory FK506+minocycline treatment to test its transcriptional modulating effects in the symptomatic stage of prion infection. Our results indicate that prolonged treatment with FK506+minocycline was effective in alleviating astrogliosis and neuronal death triggered by misfolded prions. Specifically, the combinatory therapy with FK506+minocycline lowered the expression of the astrocytes activation marker GFAP and of the microglial activation marker IBA-1, subsequently reducing the level of pro-inflammatory cytokines interleukin 1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α), and increasing the levels of anti-inflammatory cytokines IL-10 and IL-27. We further found that FK506+minocycline treatment inhibited mitogen-activated protein kinase (MAPK) p38 phosphorylation, NF-kB nuclear translocation, caspase expression, and enhanced phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated Bcl2-associated death promoter (pBAD) levels to reduce cognitive impairment and apoptosis. Interestingly, FK506+minocycline reduced mitochondrial fragmentation and promoted nuclear factor⁻erythroid2-related factor-2 (NRF2)-heme oxygenase 1 (HO-1) pathway to enhance survival. Taken together, our results show that a therapeutic cocktail of FK506+minocycline is an attractive candidate for prolonged use in prion diseases and we encourage its further clinical development as a possible treatment for this disease.

Comparison of serum concentrations of humanin in women with and without gestational diabetes mellitus.

Humanin (MT-RNR2) is an endogenous polypeptide that is involved in many diseases, including T2DM. Gestational diabetes mellitus (GDM) is defined as hyperglycemia during pregnancy. The aim of this study was to evaluate serum humanin levels in women with or without GDM and to elucidate possible correlations with anthropometric parameters, metabolic parameters and the incidence of GDM. Eighty-four women with GDM and 73 control women were enrolled in this study. The clinical and biochemical parameters of all subjects were determined. Serum humanin levels were measured by an ELISA. Serum humanin levels were significantly lower in women with GDM than in control women. Moreover, humanin levels were significantly negatively correlated with the presence of GDM, body weight, BMI at 24 weeks of gestation, TG, FPG, 1 hPG, 2 hPG, FINS, and HOMA-IR. In contrast, humanin levels were significantly positively correlated with FT3 and FT4. A binary logistic analysis showed that humanin levels were associated with the incidence of GDM. Additional follow-up studies are needed to highlight whether and how decreased humanin levels play an important role in GDM.

A common glycan structure on immunoglobulin G for enhancement of effector functions.

Antibodies have been developed as therapeutic agents for the treatment of cancer, infection, and inflammation. In addition to binding activity toward the target, antibodies also exhibit effector-mediated activities through the interaction of the Fc glycan and the Fc receptors on immune cells. To identify the optimal glycan structures for individual antibodies with desired activity, we have developed an effective method to modify the Fc-glycan structures to a homogeneous glycoform. In this study, it was found that the biantennary N-glycan structure with two terminal alpha-2,6-linked sialic acids is a common and optimized structure for the enhancement of antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and antiinflammatory activities.

Metabolomic profiling reveals decreased serum cysteine levels during gestational diabetes mellitus progression.

Gestational diabetes mellitus (GDM) is a pregnancy-related metabolic disorder associated with short-term and long-term adverse health outcomes, but its pathogenesis has not been clearly elucidated. Investigations of the dynamic changes in metabolomic markers in different trimesters may reveal the underlying pathophysiology of GDM progression. Therefore, in the present study, we analysed the metabolic profiles of 75 women with GDM and 75 women with normal glucose tolerance throughout the three trimesters. We found that the variation trends of 38 metabolites were significantly changed during GDM development. Specifically, longitudinal analyses revealed that cysteine (Cys) levels significantly decreased over the course of GDM progression. Further study showed that Cys alleviated GDM in female mice at gestational day 14.5, possibly by inhibiting phosphoenolpyruvate carboxykinase to suppress hepatic gluconeogenesis. Taken together, these findings suggest that the Cys metabolism pathway might play a crucial role in GDM and Cys supplementation represents a potential new treatment strategy for GDM patients.

Histopathologic observations in a coccidiosis model of Eimeria tenella.

BACKGROUND: Species of the genus Eimeria cause coccidiosis in chickens, resulting in a huge burden to the poultry industry worldwide. Eimeria tenella is one of the most prevalent chicken coccidia in China, and E. tenella infection causes hemorrhagic cecitis. METHODS: Using an established model of coccidiosis in chickens combined with necropsy, imaging of pathological tissue sections, and other techniques, we evaluated the gross and microscopic lesions of cecal tissue within 15 days after inoculation with sporulated oocysts and described the endogenetic developmental process and relationship between E. tenella infection and enteritis development in chickens. RESULTS: We observed three generations of merogony and gamogony in E. tenella. We observed gross lesions in the cecum from 84 hpi (hours post inoculation) and microscopic lesions from 60 hpi. The lesions in the cecum mainly exhibited hemorrhagic enteritis. Their severity increased with the onset of the second generation of merogony. The lesions began to alleviate by the end of the endogenous stages of E. tenella. CONCLUSION: We show, for the first time, the complete observation of a series of changes in enteritis caused by 5 × 103 E. tenella oocysts. This study provides reference materials for E. tenella research and pathological diagnosis.

Ethanolamine as a biomarker and biomarker-based therapy for diabetic retinopathy in glucose-well-controlled diabetic patients.

Diabetic retinopathy (DR) is the leading cause of blindness among the working-age population. Although controlling blood glucose levels effectively reduces the incidence and development of DR to less than 50%, there are currently no diagnostic biomarkers or effective treatments for DR development in glucose-well-controlled diabetic patients (GW-DR). In this study, we established a prospective GW-DR cohort by strictly adhering to glycemic control guidelines and maintaining regular retinal examinations over a median 2-year follow-up period. The discovery cohort encompassed 71 individuals selected from a pool of 292 recruited diabetic patients at baseline, all of whom consistently maintained hemoglobin A1c (HbA1c) levels below 7% without experiencing hypoglycemia. Within this cohort of 71 individuals, 21 subsequently experienced new-onset GW-DR, resulting in an incidence rate of 29.6%. In the validation cohort, we also observed a significant GW-DR incidence rate of 17.9%. Employing targeted metabolomics, we investigated the metabolic characteristics of serum in GW-DR, revealing a significant association between lower levels of ethanolamine and GW-DR risk. This association was corroborated in the validation cohort, exhibiting superior diagnostic performance in distinguishing GW-DR from diabetes compared to the conventional risk factor HbA1c, with AUCs of 0.954 versus 0.506 and 0.906 versus 0.521 in the discovery and validation cohorts, respectively. Furthermore, in a streptozotocin (STZ)-induced diabetic rat model, ethanolamine attenuated diabetic retinal inflammation, accompanied by suppression of microglial diacylglycerol (DAG)-dependent protein kinase C (PKC) pathway activation. In conclusion, we propose that ethanolamine is a potential biomarker and represents a viable biomarker-based therapeutic option for GW-DR.

Machine Learning-Based Prediction of Large-for-Gestational Age Infants in Mothers with Gestational Diabetes Mellitus.

CONTEXT: Large-for-gestational-age (LGA), one of the most common complications of gestational diabetes mellitus (GDM), has become a global concern. The predictive performance of common continuous glucose monitoring (CGM) metrics for LGA is limited. OBJECTIVE: We aimed to develop and validate an artificial intelligence (AI) based model to determine the probability of women with GDM giving birth to LGA infants during pregnancy using CGM measurements together with demographic data and metabolic indicators. METHODS: A total of 371 women with GDM from a prospective cohort at a university hospital were included. CGM was performed during 20-34 gestational weeks, and glycemic fluctuations were evaluated and visualized in women with GDM who gave birth to LGA and non-LGA infants. A convolutional neural network (CNN)-based fusion model was developed to predict LGA. Comparisons among the novel fusion model and three conventional models were made using the area under the receiver-operating characteristic curve (AUCROC) and accuracy. RESULTS: Overall, 76 (20.5%) out of 371 GDM women developed LGA neonates. The visualized 24-h glucose profiles differed at midmorning. This difference was consistent among subgroups categorized by pregestational BMI, therapeutic protocol and CGM administration period. The AI based fusion prediction model using 24-h CGM data and 15 clinical variables for LGA prediction (AUCROC 0.852, 95% CI 0.680-0.966, accuracy 84.4%) showed superior discriminative power compared with the three classic models. CONCLUSIONS: We demonstrated better performance in predicting LGA infants among women with GDM using the AI based fusion model. The characteristics of the CGM profiles allowed us to determine the appropriate window for intervention.

Sodium butyrate alleviates deoxynivalenol-induced porcine intestinal barrier disruption by promoting mitochondrial homeostasis via PCK2 signaling.

Deoxynivalenol (DON) is one of the most plentiful trichothecenes occurring in food and feed, which brings severe health hazards to both animals and humans. This study aims to investigate whether sodium butyrate (NaB) can protect the porcine intestinal barrier from DON exposure through promoting mitochondrial homeostasis. In a 4-week feeding experiment, 28 male piglets were allocated according to a 2 by 2 factorial arrangement of treatments with the main factors including supplementation of DON (< 0.8 vs. 4.0 mg/kg) and NaB (0.0 vs. 2 g/kg) in a corn/soybean-based diet. Dietary NaB supplementation mitigated the damaged mitochondrial morphology within the jejunal mucosa and the disrupted gut epithelial tight junctions irritated by DON. In IPEC-J2 cells, we found efficient recovery of the intestinal epithelial barrier occurred following NaB administration. This intestinal barrier reparation was facilitated by NaB-induced PCK2-mediated glyceroneogenesis and restoration of mitochondrial structure and function. In conclusion, we elucidated a mechanism of PCK2-mediated improvement of mitochondrial function by NaB to repair porcine intestinal barrier disruption during chronic DON exposure. Our findings highlight the promise of NaB for use in protecting against DON-induced gut epithelial tight junction disruption in piglets.

Effect of continuous glucose monitoring compared with self-monitoring of blood glucose in gestational diabetes patients with HbA1c<6%: a randomized controlled trial.

Objective: This study evaluated the effect of continuous glucose monitoring (CGM) versus self-monitored blood glucose (SMGB) in gestational diabetes mellitus (GDM) with hemoglobin A1c (HbA1c) <6%. Methods: From January 2019 to February 2021, 154 GDM patients with HbA1c<6% at 24-28 gestational weeks were recruited and assigned randomly to either SMBG only or CGM in addition to SMBG, with 77 participants in each group. CGM was used in combination with fingertip blood glucose monitoring every four weeks until antepartum in the CGM group, while in the SMBG group, fingertip blood glucose monitoring was applied. The CGM metrics were evaluated after 8 weeks, HbA1c levels before delivery, gestational weight gain (GWG), adverse pregnancy outcomes and CGM medical costs were compared between the two groups. Results: Compared with patients in the SMBG group, the CGM group patients had similar times in range (TIRs) after 8 weeks (100.00% (93.75-100.00%) versus 99.14% (90.97-100.00%), p=0.183) and HbA1c levels before delivery (5.31 ± 0.06% versus 5.35 ± 0.06%, p=0.599). The proportion with GWG within recommendations was higher in the CGM group (59.7% versus 40.3%, p=0.046), and the newborn birth weight was lower (3123.79 ± 369.58 g versus 3291.56 ± 386.59 g, p=0.015). There were no significant differences in prenatal or obstetric outcomes, e.g., cesarean delivery rate, hypertensive disorders, preterm births, macrosomia, hyperbilirubinemia, neonatal hypoglycemia, respiratory distress, and neonatal intensive care unit admission >24 h, between the two groups. Considering glucose monitoring, SMBG group patients showed a lower cost than CGM group patients. Conclusions: For GDM patients with HbA1c<6%, regular SMBG is a more economical blood glucose monitoring method and can achieve a similar performance in glycemic control as CGM, while CGM is beneficial for ideal GWG.

RAB7A GTPase Is Involved in Mitophagosome Formation and Autophagosome-Lysosome Fusion in N2a Cells Treated with the Prion Protein Fragment 106-126.

Failed communication between mitochondria and lysosomes causes dysfunctional mitochondria, which may induce mitochondria-related neurodegenerative diseases. Here, we show that RAB7A, a small GTPase of the Rab family, mediates the crosstalk between these two important organelles to maintain homeostasis in N2a cells treated with PrP106-126. Specifically, we demonstrate that mitophagy deficiency in N2a cells caused by PrP106-126 is associated with dysregulated RAB7A localization in mitochondria. Cells lacking RAB7A display decreased mitochondrial colocalization with lysosomes and significantly increased mitochondrial protein expression, resulting in inhibited mitophagy. In contrast, overexpression of GTP-bound RAB7A directly induces lysosome colocalization with mitochondria. Further study revealed that GTP-bound RAB7A protects mitochondrial homeostasis by supporting autophagosome biogenesis. Moreover, we suggest that depletion of RAB7A leads to gross morphological changes in lysosomes, which prevents autophagosome-lysosome fusion and interferes with the breakdown of autophagic cargo within lysosomes. Overexpression of GTP-bound RAB7A can also alleviate PrP106-126-induced morphological damage and dysfunction of mitochondria, reducing neuronal apoptosis. Collectively, our data demonstrate that RAB7A successfully drives mitochondria to the autophagosomal lumen for degradation, suggesting that the communication of proteotoxic stress from mitochondria to lysosomes requires RAB7A, as a signaling molecule, to establish a link between the disturbed mitochondrial network and its remodeling. These findings indicate that small molecules regulating mitophagy have the potential to modulate cellular homeostasis and the clinical course of neurodegenerative diseases. Proposed model of mitophagy regulated by RAB7A. (1) Accumulating PrP106-126 induced mitophagy. (2) RAB7A is recruited to mitochondria. (3) ATG5-12 and ATG9A (5) vesicles are recruited to the autophagosome formation sites in a RAB7A-dependent manner. The ATG5-12 complex recruits and anchors LC3-I to form active LC3-II (4), accelerating mitophagosomal formation. The ATG9A vesicles are thought to be a source of membranes for autophagosome assembly. The recruitment of proteins and lipids induces membrane expansion and subsequent closure to form the mitophagosome. (6) Maintenance of the normal low lysosomal PH depends on active (GTP-bound) RAB7A. (7) RAB7A recruits effector molecules responsible for tight membrane interactions, and directly or indirectly, the subsequent autophagosome merges with the lysosome, and the cargo is completely degraded.

Consistently Low Levels of Osteocalcin From Late Pregnancy to Postpartum Are Related to Postpartum Abnormal Glucose Metabolism in GDM Patients.

Objective: Increasing evidence suggests that osteocalcin (OC), a marker of bone formation, plays an important role in glucose homoeostasis. Few studies have investigated the relationship between OC levels in gestational diabetes mellitus (GDM) patients and their postpartum glucose metabolism. This study evaluated the relationship between OC levels in late pregnancy, their longitudinal changes, and postpartum glucose metabolism among GDM patients. Measures: Serum OC was measured in late pregnancy and the postpartum period for 721 GDM patients. All patients underwent a 75-g oral glucose tolerance test (OGTT) at 6-8 weeks postpartum. According to postpartum OGTT outcomes, patients were categorized into abnormal glucose metabolism (AGM) (n=255) and normal glucose tolerance (NGT) groups (n=466). Glucose metabolism-related indices were measured and calculated. Logistic regression analysis and linear mixed-effects model were used to assess the association between OC and postpartum AGM. Results: In late pregnancy, OC levels were lower in the AGM group than in the NGT group (13.93 ± 6.90 vs 15.33 ± 7.63 ng/ml, P=0.015). After delivery, OC levels increased in both groups. However, OC levels remained lower in the AGM group than in the NGT group (23.48 ± 7.84 vs 25.65 ± 8.37 ng/ml, P=0.001). Higher OC levels in late pregnancy were associated with decreased risk of progressing to postpartum AGM (OR:0.96, 95%CI:0.94-0.99). Linear mixed-effects analysis showed that postpartum AGM patients exhibited consistently lower OC levels than NGT group from late pregnancy to the postpartum period after adjustment for cofactors (ß=-1.70, 95% CI: -2.78- -0.62). Conclusions: In GDM patients, consistently low levels of OC from late pregnancy to postpartum were associated with increased postpartum AGM risk. The increase in serum OC may act as a protective factor to curb the progression of AGM at postpartum for GDM patients.

A stratified analysis of a deep learning algorithm in the diagnosis of diabetic retinopathy in a real-world study.

BACKGROUND: The aim of our research was to prospectively explore the clinical value of a deep learning algorithm (DLA) to detect referable diabetic retinopathy (DR) in different subgroups stratified by types of diabetes, blood pressure, sex, BMI, age, glycosylated hemoglobin (HbA1c), diabetes duration, urine albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR) at a real-world diabetes center in China. METHODS: A total of 1147 diabetic patients from Shanghai General Hospital were recruited from October 2018 to August 2019. Retinal fundus images were graded by the DLA, and the detection of referable DR (moderate nonproliferative DR or worse) was compared with a reference standard generated by one certified retinal specialist with more than 12 years of experience. The performance of DLA across different subgroups stratified by types of diabetes, blood pressure, sex, BMI, age, HbA1c, diabetes duration, UACR, and eGFR was evaluated. RESULTS: For all 1674 gradable images, the area under the receiver operating curve, sensitivity, and specificity of the DLA for referable DR were 0.942 (95% CI, 0.920-0.964), 85.1% (95% CI, 83.4%-86.8%), and 95.6% (95% CI, 94.6%-96.6%), respectively. The DLA showed consistent performance across most subgroups, while it showed superior performance in the subgroups of patients with type 1 diabetes, UACR ≥ 30 mg/g, and eGFR < 90 mL/min/1.73m2 . CONCLUSIONS: This study showed that the DLA was a reliable alternative method for the detection of referable DR and performed superior in patients with type 1 diabetes and diabetic nephropathy who were prone to DR.

SARM1 participates in axonal degeneration and mitochondrial dysfunction in prion disease.

Prion disease represents a group of fatal neurogenerative diseases in humans and animals that are associated with energy loss, axonal degeneration, and mitochondrial dysfunction. Axonal degeneration is an early hallmark of neurodegeneration and is triggered by SARM1. We found that depletion or dysfunctional mutation of SARM1 protected against NAD+ loss, axonal degeneration, and mitochondrial functional disorder induced by the neurotoxic peptide PrP106-126. NAD+ supplementation rescued prion-triggered axonal degeneration and mitochondrial dysfunction and SARM1 overexpression suppressed this protective effect. NAD+ supplementation in PrP106-126-incubated N2a cells, SARM1 depletion, and SARM1 dysfunctional mutation each blocked neuronal apoptosis and increased cell survival. Our results indicate that the axonal degeneration and mitochondrial dysfunction triggered by PrP106-126 are partially dependent on SARM1 NADase activity. This pathway has potential as a therapeutic target in the early stages of prion disease.

PINK1-parkin-mediated neuronal mitophagy deficiency in prion disease.

A persistent accumulation of damaged mitochondria is part of prion disease pathogenesis. Normally, damaged mitochondria are cleared via a major pathway that involves the E3 ubiquitin ligase parkin and PTEN-induced kinase 1 (PINK1) that together initiate mitophagy, recognize and eliminate damaged mitochondria. However, the precise mechanisms underlying mitophagy in prion disease remain largely unknown. Using prion disease cell models, we observed PINK1-parkin-mediated mitophagy deficiency in which parkin depletion aggravated blocked mitochondrial colocalization with LC3-II-labeled autophagosomes, and significantly increased mitochondrial protein levels, which led to inhibited mitophagy. Parkin overexpression directly induced LC3-II colocalization with mitochondria and alleviated defective mitophagy. Moreover, parkin-mediated mitophagy was dependent on PINK1, since PINK1 depletion blocked mitochondrial Parkin recruitment and reduced optineurin and LC3-II proteins levels, thus inhibiting mitophagy. PINK1 overexpression induced parkin recruitment to the mitochondria, which then stimulated mitophagy. In addition, overexpressed parkin and PINK1 also protected neurons from apoptosis. Furthermore, we found that supplementation with two mitophagy-inducing agents, nicotinamide mononucleotide (NMN) and urolithin A (UA), significantly stimulated PINK1-parkin-mediated mitophagy. However, compared with NMN, UA could not alleviate prion-induced mitochondrial fragmentation and dysfunction, and neuronal apoptosis. These findings show that PINK1-parkin-mediated mitophagy defects lead to an accumulation of damaged mitochondria, thus suggesting that interventions that stimulate mitophagy may be potential therapeutic targets for prion diseases.

The silent occurrence of cerebral small vessel disease in nonelderly patients with type 2 diabetes mellitus.

BACKGROUND: The prevalence of cerebral small vessel disease (SVD) increases in elderly patients with type 2 diabetes (T2DM), exacerbating cognitive decline. However, the prevalence and the severity of SVD in dementia-free nonelderly T2DM patients were largely unknown. Our primary aim is to investigate SVD in such patients, with a specific focus on the correlation between SVD and diabetic peripheral sensorimotor polyneuropathy (DSP). METHODS: We recruited 180 young and middle-aged subjects without cognitive impairment (106 with T2DM, 74 controls). Signs of cerebral SVD on magnetic resonance image were investigated, and the overall SVD burden was evaluated by a combined score. Patients with T2DM underwent further detailed DSP assessment. Regression models were used to investigate the association of SVD with the presence of T2DM, and the associations of the prevalence and severity of SVD and DSP were also explored in patients with T2DM. RESULTS: The prevalence of microbleeds and overall burden of SVD were significantly higher in T2DM patients than in the controls. Further, the presence of DSP related to an increased risk of SVD after adjustment in diabetic group. Moreover, Toronto Clinical Scoring System values were positively associated with the increased SVD scores, and bilateral sural sensory nerve conduction velocities were negatively associated with increasingly severity of SVD scores. CONCLUSION: The current findings extended the increasing prevalence of SVD to dementia-free nonelderly patients with T2DM, suggesting that the time for cognitive screening and prevention might be moved forward in T2DM patients, especially for those with DSP.

Decreased Microstructural Integrity of the Central Somatosensory Tracts in Diabetic Peripheral Neuropathy.

CONTEXT: Although diabetic peripheral neuropathy (DPN) is predominantly considered a disorder of the peripheral nerves, some evidence for central nervous system involvement has recently emerged. However, whether or to what extent the microstructure of central somatosensory tracts may be injured remains unknown. OBJECTIVE: This work aimed to detect the microstructure of central somatosensory tracts in type 2 diabetic patients and to correlate it with the severity of DPN. METHODS: A case-control study at a tertiary referral hospital took place with 57 individuals with type 2 diabetes (25 with DPN, 32 without DPN) and 33 nondiabetic controls. The fractional anisotropy (FA) values of 2 major somatosensory tracts (the spinothalamic tract and its thalamocortical [spino-thalamo-cortical, STC] pathway, the medial lemniscus and its thalamocortical [medial lemnisco-thalamo-cortical, MLTC] pathway) were assessed based on diffusion tensor tractography. Regression models were further applied to detect the association of FA values with the severity of DPN in diabetic patients. RESULTS: The mean FA values of left STC and left MLTC pathways were significantly lower in patients with DPN than those without DPN and controls. Moreover, FA values of left STC and left MLTC pathways were significantly associated with the severity of DPN (expressed as Toronto Clinical Scoring System values) in patients after adjusting for multiple confounders. CONCLUSION: Our findings demonstrated the axonal degeneration of central somatosensory tracts in type 2 diabetic patients with DPN. The parallel disease progression of the intracranial and extracranial somatosensory system merits further attention to the central nerves in diabetic patients with DPN.

Postpartum Follow-Up of Patients with Subclinical Hypothyroidism During Pregnancy.

Background: Subclinical hypothyroidism (SCH) in pregnancy is associated with adverse pregnancy and perinatal outcomes. However, few studies have investigated the evolution of postpartum thyroid function in these women. This study aimed to determine the postpartum outcomes of SCH during pregnancy and the clinical and biochemical factors related to the evolution of long-term hypothyroidism. Methods: A total of 393 women diagnosed with SCH during pregnancy (defined as thyrotropin [TSH] >4.0 µIU/mL with normal free thyroxine levels according to the 2017 American Thyroid Association guidelines) were prospectively followed up after delivery. Among them, 216 underwent long-term follow-up [median (interquartile range) follow-up time: 11 (7-19) months] postpartum. The clinical and biochemical characteristics of the women with long-term postpartum hypothyroidism and euthyroidism were compared. Linear mixed model (LMM) was used to explore the risk factors for longitudinal changes of TSH, and logistic regression analysis was employed to identify the independent predictors of long-term postpartum hypothyroidism. Results: The probability of long-term hypothyroidism after delivery in SCH during pregnancy was 38.9%. Among the subjects with normal thyroid function 6-week postpartum, 28.2% developed hypothyroidism during long-term follow-up. The LMM showed that gestational age at the time of SCH diagnosis (estimate: -0.018, p = 0.004) and thyroid peroxidase antibodies (TPOAb) (estimate: 0.001, p = 0.020) were significantly associated with longitudinal changes of TSH. The logistic regression model showed that TPOAb positive both during pregnancy and six-week postpartum was a risk factor for long-term hypothyroidism after delivery (odds ratio = 4.686 [95% confidence interval 1.242 to 17.680], p = 0.023). Conclusions: More than one-third of patients with SCH during pregnancy had persistent hypothyroidism after delivery. We recommend that patients with TPOAb positive both during pregnancy and six-week postpartum undergo close follow-up to detect persistent hypothyroidism, especially before the next pregnancy.

A Combined Systemic Strategy for Overcoming Cisplatin Resistance in Head and Neck Cancer: From Target Identification to Drug Discovery.

Cisplatin is the first-line chemotherapy agent for head and neck cancer (HNC), but its therapeutic effects are hampered by its resistance. In this study, we employed systemic strategies to overcome cisplatin resistance (CR) in HNC. CR cells derived from isogenic HNC cell lines were generated. The CR related hub genes, functional mechanisms, and the sensitizing candidates were globally investigated by transcriptomic and bioinformatic analyses. Clinically, the prognostic significance was assessed by the Kaplan-Meier method. Cellular and molecular techniques, including cell viability assay, tumorsphere formation assay, RT-qPCR, and immunoblot, were used. Results showed that these CR cells possessed highly invasive and stem-like properties. A total of 647 molecules was identified, and the mitotic division exhibited a novel functional mechanism significantly related to CR. A panel of signature molecules, MSRB3, RHEB, ULBP1, and spindle pole body component 25 (SPC25), was found to correlate with poor prognosis in HNC patients. SPC25 was further shown as a prominent molecule, which markedly suppressed cancer stemness and attenuated CR after silencing. Celastrol, a nature extract compound, was demonstrated to effectively inhibit SPC25 expression and reverse CR phenotype. In conclusion, the development of SPC25 inhibitors, such as the application of celastrol, maybe a novel strategy to sensitize cisplatin for the treatment of refractory HNC.