Construction of dentin-on-a-chip based on microfluidic technology and tissue engineering.

AIM: Three-dimensional (3D) cell culture systems perform better in resembling tissue or organism structures compared with traditional 2D models. Organs-on-chips (OoCs) are becoming more efficient 3D models. This study aimed to create a novel simplified dentin-on-a-chip using microfluidic chip technology and tissue engineering for screening dental materials. METHODOLOGY: A microfluidic device with three channels was designed for creating 3D dental tissue constructs using stem cells from the apical papilla (SCAP) and gelatin methacrylate (GelMA). The study investigated the effect of varying cell densities and GelMA concentrations on the layer features formed within the microfluidic chip. Cell viability and distribution were evaluated through live/dead staining and nuclei/F-actin staining. The osteo/odontogenic potential was assessed through ALP staining and Alizarin red staining. The impact of GelMA concentrations (5 %, 10 %) on the osteo/odontogenic differentiation trajectory of SCAP was also studied. RESULTS: The 3D tissue constructs maintained high viability and favorable spreading within the microfluidic chip for 3-7 days. A cell seeding density of 2 × 104 cells/µL was found to be the most optimal choice, ensuring favorable cell proliferation and even distribution. GelMA concentrations of 5 % and 10 % proved to be most effective for promoting cell growth and uniform distribution. Within the 5 % GelMA group, SCAP demonstrated higher osteo/odontogenic differentiation than that in the 10 % GelMA group. CONCLUSION: In 3D culture, GelMA concentration was found to regulate the osteo/odontogenic differentiation of SCAP. The study recommends a seeding density of 2 × 104 cells/µL of SCAP within 5 % GelMA for constructing simplified dentin-on-a-chip. CLINICAL SIGNIFICANCE: This study built up the 3D culture protocol, and induced odontogenic differentiation of SCAP, thus forming the simplified dentin-on-a-chip and paving the way to be used as a well-defined biological model for regenerative endodontics. It may serve as a potential testing platform for cell differentiation.

Sodium-glucose exchanger 2 inhibitor canagliflozin promotes mitochondrial metabolism and alleviates salt-induced cardiac hypertrophy via preserving SIRT3 expression.

INTRODUCTION: Excess salt intake is not only an independent risk factor for heart failure, but also one of the most important dietary factors associated with cardiovascular disease worldwide. Metabolic reprogramming in cardiomyocytes is an early event provoking cardiac hypertrophy that leads to subsequent cardiovascular events upon high salt loading. Although SGLT2 inhibitors, such as canagliflozin, displayed impressive cardiovascular health benefits, whether SGLT2 inhibitors protect against cardiac hypertrophy-related metabolic reprogramming upon salt loading remain elusive. OBJECTIVES: To investigate whether canagliflozin can improve salt-induced cardiac hypertrophy and the underlying mechanisms. METHODS: Dahl salt-sensitive rats developed cardiac hypertrophy by feeding them an 8% high-salt diet, and some rats were treated with canagliflozin. Cardiac function and structure as well as mitochondrial function were examined. Cardiac proteomics, targeted metabolomics and SIRT3 cardiac-specific knockout mice were used to uncover the underlying mechanisms. RESULTS: In Dahl salt-sensitive rats, canagliflozin showed a potent therapeutic effect on salt-induced cardiac hypertrophy, accompanied by lowered glucose uptake, reduced accumulation of glycolytic end-products and improved cardiac mitochondrial function, which was associated with the recovery of cardiac expression of SIRT3, a key mitochondrial metabolic regulator. Cardiac-specific knockout of SIRT3 not only exacerbated salt-induced cardiac hypertrophy but also abolished the therapeutic effect of canagliflozin. Mechanistically, high salt intake repressed cardiac SIRT3 expression through a calcium-dependent epigenetic modifications, which could be blocked by canagliflozin by inhibiting SGLT1-mediated calcium uptake. SIRT3 improved myocardial metabolic reprogramming by deacetylating MPC1 in cardiomyocytes exposed to pro-hypertrophic stimuli. Similar to canagliflozin, the SIRT3 activator honokiol also exerted therapeutic effects on cardiac hypertrophy. CONCLUSION: Cardiac mitochondrial dysfunction caused by SIRT3 repression is a critical promotional determinant of metabolic pattern switching underlying salt-induced cardiac hypertrophy. Improving SIRT3-mediated mitochondrial function by SGLT2 inhibitors-mediated calcium handling would represent a therapeutic strategy against salt-related cardiovascular events.

Efficacy of a four-curvature auxiliary arch at preventing maxillary central incisor linguoclination during orthodontic treatment: a finite element analysis.

BACKGROUND: Correct torque of the incisors is beneficial in the assessment of the effects of orthodontic treatment. However, evaluating this process effectively remains a challenge. Improper anterior teeth torque angle can cause bone fenestrations and exposure of the root surface. METHODS: A three-dimensional finite element model of the maxillary incisor torque controlled by a homemade four-curvature auxiliary arch was established. The four-curvature auxiliary arch placed on the maxillary incisors was divided into four different state groups, among which 2 groups had tooth extraction space retracted traction force set to 1.15 N. Initial displacements and pressure stresses of the periodontal tissue in the maxillary incisors and molars were calculated after torque forces (0.5, 1, 1.5, and 2 N) were applied to the teeth at different stable states. RESULTS: The effect of using the four-curvature auxiliary arch on the incisors was significant but did not affect the position of the molars. Given the absence of tooth extraction space, when the four-curvature auxiliary arch was used in conjunction with absolute anchorage, the recommended force value was < 1.5 N. In the other 3 groups (i.e., molar ligation, molar retraction, and microimplant retraction groups), the recommended force value was < 1 N. The application of a four-curvature auxiliary arch did not influence the molar periodontal and displacement. CONCLUSION: A four-curvature auxiliary arch may treat severely upright anterior teeth and correct cortical fenestrations of the bone and root surface exposure.

Catheter-based adrenal ablation: an alternative therapy for patients with aldosterone-producing adenoma.

Unilateral adrenalectomy is the standard treatment for patients with aldosterone-producing adenoma (APA), but it lacks an option for patients with APA who refuse or are not suitable for surgery. In this study, we studied whether catheter-based adrenal ablation for APA is comparable to adrenalectomy. A total of 2185 hypertensive patients were screened, and 112 patients with APA were recruited and counselled on the treatment options. Fifty-two patients opted for catheter-based adrenal ablation, and 60 opted for adrenalectomy. Clinical and biochemical outcomes were assessed at 6 months after treatment. Factors associated with hypertension remission and the advantages and limitations of this approach were evaluated. According to the primary aldosteronism surgical outcome (PASO) criteria, complete and partial clinical success was achieved in 21 (40.4%) and 23 (44.2%) patients in the ablation group vs. 33 (55.0%) and 23 (38.3%) patients in the adrenalectomy group, respectively. Complete and partial biochemical success was achieved in 30 (57.7%) and 17 (32.7%) patients in the ablation group vs. 51 (85.0%) and 5 (8.3%) patients in the adrenalectomy group, respectively. The complete clinical success rate was not (P > 0.05), but the complete biochemical success rate was significantly different between the two groups (P < 0.01). Factors associated with adrenal ablation-mediated hypertension remission were hypertension duration and serum potassium level at baseline. Compared with surgery, adrenal ablation requires a shorter operating time and time to resume physical activity. Catheter-based adrenal ablation may be an alternative and feasible option for APA patients unwilling to receive surgical treatment.

Clinical Characteristics of Target Organ Damage in Primary Aldosteronism with or without Metabolic Syndrome.

The aim of this study is to investigate the prevalence of metabolic disorders in patients with primary aldosteronism (PA) and target organ damage (TOD) in different subtypes of patients with PA with or without metabolic syndrome (MS). Patients with PA were screened out from those with secondary hypertension and then subtyped via adrenal venous sampling (AVS). Baseline clinical characteristics (blood pressure, blood glucose, abdominal circumference, and lipid profile) were collected for the diagnosis of MS. Organ damage was evaluated according to cardiac and carotid ultrasound and urine microalbumin measurements. In all 261 patients with PA, 113 patients had concomitant MS and experienced more severe cardiac hypertrophy and increased intima-media thickness (IMT). The incidence of MS and diabetes mellitus (DM) had no statistic difference between the two groups, moreover, the rates of TOD were not different except microalbuminuria. However, metabolic disorders caused more remarkable TOD in PA patients with unilateral hypersecretion. It showed that cardiac hypertrophy was associated with obesity while microalbuminuria was related to plasma aldosterone concentration (PAC) in PA patients. In this retrospective study, our findings suggest that the effect of metabolic disorders on organ damage is more remarkable in patients with unilateral PA.

Assessment of sublingual microcirculation for the screening of diabetic nephropathy.

OBJECTIVE: To investigate the potential of employing sublingual microcirculation as an early noninvasive screening technique for diabetic nephropathy (DN). RESEARCH DESIGN AND METHODS: We recruited 89 patients with type 2 diabetes mellitus (T2DM) and 41 healthy subjects in this cross-sectional observational study. All participants underwent fluorescein fundus angiography, vibration perception testing, 10 g (Semmes-Weinstein) monofilament examination, nerve conduction velocity, and 24-h urine microalbumin determination. HbA1c, fasting plasma glucose, blood lipid, and estimated glomerular filtration rate(eGFR) were measured. Sublingual microcirculatory images were captured using side-stream dark-field (SDF) microcirculation microscopy, and total and perfused vascular density (TVD and PVD) were calculated. RESULTS: The sublingual microcirculatory parameters denoting microvascular density and perfusion were negatively correlated with both fasting plasma glucose (TVD, r = - 0.316, P < 0.001; PVD, r = - 0.350, P < 0.001; PPV, r = - 0.279, P = 0.001) and HbA1c (TVD, r = - 0.367, P < 0.001; PVD, r = - 0.423, P < 0.001; PPV, r = - 0.399, P < 0.001). Diabetes patients already had a reduction in sublingual microcirculation compared with healthy control, and more severe reductions in TVD (7.07 ± 1.64 vs. 9.67 ± 1.94 mm/mm2, P < 0.001) and PVD (5.88 ± 1.82 vs. 8.64 ± 2.46 mm/mm2, P < 0.001) were found in those diabetes patients developed microvascular complications. Sublingual microcirculation impairment was accompanied with higher urinary albumin creatinine ratio (UACR). Receiver operating characteristic (ROC) analysis showed that TVD (area under the curve, AUC = 0.890 [0.836 0.944], P < 0.001) and PVD (AUC = 0.883 [0.826, 0.940], P < 0.001) could be indicators for DN screening. We derived a combined predictor index (CPI) considering both TVD and PVD for screening DN, and both the AUC (0.892, [0.838 0.945], P < 0.001) and cutoff point of 11.30 mm/mm2 showed great improvement (sensitivity: 95.5%, specificity: 67.4%). CONCLUSIONS: Diabetes patients experienced impaired sublingual microcirculation, which was closely correlated with UACR. Sublingual microcirculation monitoring could be used for the noninvasive early detection of DN.

Sodium-Glucose Cotransporter 2 Inhibitor Canagliflozin Antagonizes Salt-Sensitive Hypertension Through Modifying Transient Receptor Potential Channels 3 Mediated Vascular Calcium Handling.

Background Salt-sensitive hypertension is highly prevalent and associated with cardiorenal damage. Large clinical trials have demonstrated that SGLT2 (sodium-glucose cotransporter 2) inhibitors exert hypotensive effect and cardiorenal protective benefits in patients with hypertension with and without diabetes. However, the underlying mechanism remains elusive. Methods and Results Dahl salt-sensitive rats and salt-insensitive controls were fed with 8% high-salt diet and some of them were treated with canagliflozin. The blood pressure, urinary sodium excretion, and vascular function were detected. Transient receptor potential channel 3 (TRPC3) knockout mice were used to explain the mechanism. Canagliflozin treatment significantly reduced high-salt-induced hypertension and this effect was not totally dependent on urinary sodium excretion in salt-sensitive hypertensive rats. Assay of vascular function and proteomics showed that canagliflozin significantly inhibited vascular cytoplasmic calcium increase and vasoconstriction in response to high-salt diet. High salt intake increased vascular expression of TRPC3 in salt-sensitive rats, which could be alleviated by canagliflozin treatment. Overexpression of TRPC3 mimicked salt-induced vascular cytosolic calcium increase in vitro and knockout of TRPC3 erased the antihypertensive effect of canagliflozin. Mechanistically, high-salt-induced activation of NCX1 (sodium-calcium exchanger 1) reverse mode increased cytoplasmic calcium level and vasoconstriction, which required TRPC3, and this process could be blocked by canagliflozin. Conclusions We define a previously unrecognized role of TRPC3/NCX1 mediated vascular calcium dysfunction in the development of high-salt-induced hypertension, which can be improved by canagliflozin treatment. This pathway is potentially a novel therapeutic target to antagonize salt-sensitive hypertension.

Analysis of Social Mission Commitment at Dental, Medical, and Nursing Schools in the US.

Importance: The COVID-19 pandemic and calls for racial justice have highlighted the need for schools to promote social mission. Measuring social mission engagement and performance in health professions education may encourage institutional efforts to advance health equity and social justice commitments. Objective: To describe the current state of social mission commitment within dental, medical, and nursing schools in the US and to examine how social mission performance compares across school types. Design, Setting, and Participants: This cross-sectional survey study invited all US dental and medical schools and a subset of baccalaureate- and master's degree-conferring nursing schools to participate in a self-assessment to measure their school's social mission commitment from January 29 through October 9, 2019. The survey measured 79 indicators (with indicators defined as responses to specific scored questions that indicated the state or level of social mission commitment) across 18 areas in 6 domains of school functioning (educational program, community engagement, governance, diversity and inclusion, institutional culture and climate, and research) that have potential to enhance social mission engagement and performance. Individual health professions schools were the unit of analysis, and 689 dental, medical, and nursing schools were invited to participate. School deans and program directors were the primary target respondents because of their broad insight into their school's programs and policies and their ability to request data from various internal sources. Demographic information from respondents was not collected because multiple respondents from an institution could complete different sections of the survey. Main Outcomes and Measures: Survey responses were analyzed to create indicator scores, standardized area scores, and an overall social mission score for each school. Using descriptive analyses, frequency and contingency tables of specific indicators within each area were created, and schools were compared based on ownership status (private or public), Carnegie Classification of Institutions of Higher Education research classification group (doctoral university with very high research activity [R1], doctoral university with high [R2] or moderate [R3] research activity, baccalaureate or master's nursing college or university, or special focus institution), and discipline group (dental school, medical school granting doctor of osteopathic medicine [DO] degrees, medical school granting doctor of medicine [MD] degrees, nursing school granting baccalaureate-level degrees, or nursing school granting master's-level degrees). Results: Among 689 invited schools, 242 schools (35.1%) completed the self-assessment survey. Of those, 133 (55.0%) were nursing schools, 83 (34.3%) were medical schools, and 26 (10.7%) were dental schools. Response rates ranged from 133 of 420 invited nursing schools (31.7%) to 83 of 203 invited medical schools (40.9%). Most schools included social determinants of health in their curriculum in either required courses (233 of 242 schools [96.3%]) or elective courses (4 of 242 schools [1.7%]), but only 116 of 235 schools (49.4%) integrated social determinants of health across all years of study. Most schools also included health disparities in either their required courses (232 of 242 [95.9%]) or elective courses (6 of 242 [2.5%]); however, only 118 of 235 schools (50.2%) integrated health disparities across all years of study. In several areas of social mission, public schools performed better than private schools (eg, curriculum: mean [SE] standardized area score, 0.13 [0.07] points vs -0.14 [0.09] points, respectively), and R1 doctoral universities and special focus institutions performed better than R2 and R3 doctoral universities and baccalaureate and master's nursing colleges and universities (eg, extracurricular activities: mean [SE] standardized area score, 0.25 [0.09] points for R1 doctoral universities and 0.20 [0.12] points for special focus institutions vs -0.05 [0.12] points for R2 and R3 doctoral universities and - 0.30 [0.12] points for baccalaureate and master's nursing colleges and universities. Different areas of strength emerged for dental, medical, and nursing schools. For example, in the curriculum area, MD-granting medical schools had a mean (SE) standardized area score of 0.38 (0.08) points, which was significantly higher than the standardized area scores of dental schools (mean [SE], -0.21 [0.14] points), DO-granting medical schools (mean [SE], -0.22 [0.13] points), graduate nursing schools (mean [SE], -0.21 [0.19] points), and undergraduate nursing schools (mean [SE], -0.05 [0.10] points). Conclusions and Relevance: In this study, there was widespread interest from health professions educational leaders in understanding and enhancing social mission commitment. Future work may focus on identifying and promoting best practices using the framework described, providing schools with continued opportunities for self-assessment, and further validating the self-assessment survey.

Asprosin induces vascular endothelial-to-mesenchymal transition in diabetic lower extremity peripheral artery disease.

BACKGROUND: Altered adipokine secretion in dysfunctional adipose tissue facilitates the development of atherosclerotic diseases including lower extremity peripheral artery disease (PAD). Asprosin is a recently identified adipokine and displays potent regulatory role in metabolism, but the relationship between asprosin and lower extremity PAD remains uninvestigated. METHODS: 33 type 2 diabetes mellitus (T2DM) patients (DM), 51 T2DM patients with PAD (DM + PAD) and 30 healthy normal control (NC) volunteers were recruited and the blood samples were collected for detecting the circulatory asprosin level and metabolomic screening. RNA sequencing was performed using the aorta tissues from the type 2 diabetic db/db mice and human umbilical vein endothelial cells (HUVECs) were treated with asprosin to determine its impact on the endothelial-to-mesenchymal transition (EndMT). RESULTS: The circulating levels of asprosin in DM + PAD group were significantly higher than that of NC group and the DM group. Circulating asprosin level was remarkably negatively correlated with ankle-brachial index (ABI), even after adjusting for age, sex, body mass index (BMI) and other traditional risk factors of PAD. Logistic regression analysis revealed that asprosin is an independent risk factor for PAD and receiver-operator characteristic (ROC) curve determined a good sensitivity (74.5%) and specificity (74.6%) of asprosin to distinguish PAD. Data from metabolomics displayed a typical characteristics of de novo amino acid synthesis in collagen protein production by myofibroblasts in patients with PAD and activation of TGF-ß signaling pathway appeared in the aortic tissue of db/db mice. Asprosin directly induces EndMT in HUVECs in a TGF-ß-dependent manner as TGF-ß signaling pathway inhibitor SB431542 erased the promotional effect of asprosin on EndMT. CONCLUSIONS: Elevated circulatory asprosin level is an independent risk factor of lower extremity PAD and might serve as a diagnostic marker. Mechanistically, asprosin directly induces EndMT that participates in vascular injury via activation of TGF-ß signaling pathway. Trial registration This trial was registered at clinicaltrials.gov as NCT05068895.

Salt-Induced Hepatic Inflammatory Memory Contributes to Cardiovascular Damage Through Epigenetic Modulation of SIRT3.

BACKGROUND: High salt intake is the leading dietary risk factor for cardiovascular diseases. Although clinical evidence suggests that high salt intake is associated with nonalcoholic fatty liver disease, which is an independent risk factor for cardiovascular diseases, it remains elusive whether salt-induced hepatic damage leads to the development of cardiovascular diseases. METHODS: Mice were fed with normal or high-salt diet for 8 weeks to determine the effect of salt loading on liver histological changes and blood pressure, and salt withdrawal and metformin treatment were also conducted on some high-salt diet-fed mice. Adeno-associated virus 8, global knockout, or tissue-specific knockout mice were used to manipulate the expression of some target genes in vivo, including SIRT3 (sirtuin 3), NRF2 (NF-E2-related factor 2), and AMPK (AMP-activated protein kinase). RESULTS: Mice fed with a high-salt diet displayed obvious hepatic steatosis and inflammation, accompanied with hypertension and cardiac dysfunction. All these pathological changes persisted after salt withdrawal, displaying a memory phenomenon. Gene expression analysis and phenotypes of SIRT3 knockout mice revealed that reduced expression of SIRT3 was a chief culprit responsible for the persistent inflammation in the liver, and recovering SIRT3 expression in the liver effectively inhibits the sustained hepatic inflammation and cardiovascular damage. Mechanistical studies reveal that high salt increases acetylated histone 3 lysine 27 (H3K27ac) on SIRT3 promoter in hepatocytes, thus inhibiting the binding of NRF2, and results in the sustained inhibition of SIRT3 expression. Treatment with metformin activated AMPK, which inhibited salt-induced hepatic inflammatory memory and cardiovascular damage by lowering the H3K27ac level on SIRT3 promoter, and increased NRF2 binding ability to activate SIRT3 expression. CONCLUSIONS: This study demonstrates that SIRT3 inhibition caused by histone modification is the key factor for the persistent hepatic steatosis and inflammation that contributes to cardiovascular damage under high salt loading. Avoidance of excessive salt intake and active intervention of epigenetic modification may help to stave off the persistent inflammatory status that underlies high-salt-induced cardiovascular damage in clinical practice.

A survey of cancer care institutions in Nepal to inform design of a pain management mobile application.

BACKGROUND: One way to improve the delivery of oncology palliative care in low and middle-income countries (LMICs) is to leverage mobile technology to support healthcare providers in implementing pain management guidelines (PMG). However, PMG are often developed in higher-resourced settings and may not be appropriate for the resource and cultural context of LMICs. OBJECTIVES: This research represents a collaboration between the University of Virginia and the Nepalese Association of Palliative Care (NAPCare) to design a mobile health application ('app') to scale-up implementation of existing locally developed PMG. METHODS: We conducted a cross-sectional survey of clinicians within Nepal to inform design of the app. Questions focused on knowledge, beliefs, and confidence in managing cancer pain; barriers to cancer pain management; awareness and use of the NAPCare PMG; barriers to smart phone use and desired features of a mobile app. FINDINGS: Surveys were completed by 97 palliative care and/or oncology healthcare providers from four diverse cancer care institutions in Nepal. 49.5% (n = 48) had training in palliative care/cancer pain management and the majority (63.9%, n = 62) reported high confidence levels (scores of 8 or higher/10) in managing cancer pain. Highest ranked barriers to cancer pain management included those at the country/cultural level, such as nursing and medical school curricula lacking adequate content about palliative care and pain management, and patients who live in rural areas experiencing difficulty accessing healthcare services (overall mean = 6.36/10). Most nurses and physicians use an Android Smart Phone (82%, n = 74), had heard of the NAPCare PMG (96%, n = 88), and reported frequent use of apps to provide clinical care (mean = 6.38/10, n = 92). Key barriers to smart phone use differed by discipline, with nurses reporting greater concerns related to cost of data access (70%, n = 45) and being prohibited from using a mobile phone at work (61%; n = 39). CONCLUSIONS: Smart phone apps can help implement PMG and support healthcare providers in managing cancer pain in Nepal and similar settings. However, such tools must be designed to be culturally and contextually congruent and address perceived barriers to pain management and app use.

Activation of Glucagon-Like Peptide-1 Receptor Ameliorates Cognitive Decline in Type 2 Diabetes Mellitus Through a Metabolism-Independent Pathway.

Background Patients with hypertension and diabetes mellitus are susceptible to dementia, but regular therapy fails to reduce the risk of dementia. Glucagon-like peptide-1 receptor agonists have neuroprotective effects in experimental studies. We aimed to assess the effect of liraglutide, a glucagon-like peptide-1 receptor agonist, on cognitive function and whether its effect was associated with metabolic changes in patients with type 2 diabetes mellitus. Methods and Results Fifty patients with type 2 diabetes mellitus were recruited in this prospective study. All patients underwent cognitive assessment and brain activation monitoring by functional near-infrared spectroscopy. At 12 weeks, patients in the glucagon-like peptide-1 group acquired better scores in all cognitive tests and showed remarkable improvement in memory and attention (P=0.040) test compared with the control group after multivariable adjustment. Compared with the control group, liraglutide significantly increased activation of the dorsolateral prefrontal cortex and orbitofrontal cortex brain regions (P=0.0038). After liraglutide treatment, cognitive scores were significantly correlated with changes in these activating brain regions (P<0.05), but no correlation was observed between the changes in cognitive function and changes of body mass index, blood pressure, and glycemic levels. Conclusions We concluded that liraglutide improves cognitive decline in patients with type 2 diabetes mellitus. This beneficial effect is independent of its hypoglycemic effect and weight loss. The optimal intervention should be targeted to cognitive decline in the early stages of dementia. Registration URL: https://www.ClinicalTrials.gov; Unique identifier: NCT03707171.

Determination of adrenal hypersecretion in primary Aldosteronism without aldosterone-production adenomas.

BACKGROUND: Primary aldosteronism (PA) is highly prevalent in hypertensive population. Adrenal vein sampling (AVS) is the only procedure to assess adrenal aldosterone hypersecretion in PA. PA patients without aldosterone-producing adenomas (APA) frequently have unilateral aldosterone hypersecretion (UAH). These patients could bear inappropriate adrenalectomy without AVS. This study aims to identify which clinical characteristics should be recommended to perform AVS in these PA patients. METHODS: This study was performed from January 2018 to July 2019 at a center for hypertension and metabolic diseases. Adrenal computed tomography (CT) scan, biochemical evaluation, and AVS were performed. RESULTS: Total 141 patients were included in this study. Aldosterone to renin ratio (ARR) after confirmatory test is highly associated with adrenal laterality. The specificity of ARR > 10 (ng/dL)/(mU/L) after confirmatory test is 100%. After confirmatory test, patients with ARR > 10 (ng/dL)/(mU/L) had higher plasma aldosterone concentration and incidences of ischemic heart diseases and renal damage(p < 0.05). CONCLUSIONS: After confirmatory tests, ARR > 10 (ng/dL)/(mU/L) indicates adrenal laterality, with increasingly cardiorenal damage in PA patients without APA. Thus, AVS should be recommended in these patients before surgery. TRIAL REGISTRATION: NCT03398785 , Date of Registration: December 24, 2017.

Achieving blood pressure targets and antihypertensive effects through metabolic surgery in type 2 diabetes patients with hypertension.

AIMS: The effect of metabolic surgery compared with that of conventional therapy on target blood pressure (BP)and defined daily dose (DDD) of antihypertensive drugs in type 2 diabetes (T2DM) patients with hypertension remains unclear. This study aimed to investigate the differences in target BP and DDD between metabolic surgery and conventional treatment in T2DM patients with hypertension. MATERIALS AND METHODS: This was a prospective study of 535 diabetes patients who underwent metabolic surgery (n = 112) and medical treatment (n = 423). Changes in the target BP from baseline to every follow-up were analysed. RESULTS: Metabolic surgery decreased both office systolic and diastolic BP (DBP) and also significantly reduced ambulatory systolic BP (SBP; 132 ± 2 vs. 119 ± 1 mmHg, p < 0.0001), but not DBP (78 ± 1 vs. 76 ± 1 mmHg, p = 0.177). Patients maintained their SBP at <120 mmHg after 2 years (50% vs. 1.9%, p < 0.0001). Moreover, the rate of achieving the target SBP of 130 and 140 mmHg was also significantly higher in the surgery group, and this started from the initial 6 months after commencing treatment to the end of follow-up. The dosage (DDD: 1.44 ± 0.65 vs. 0.32 ± 0.05, p < 0.001) of antihypertensive medication was significantly decreased after metabolic surgery. Furthermore, metabolic surgery, but not medical treatment, markedly improved the risks of atherosclerotic cardiovascular disease. CONCLUSIONS: Metabolic surgery can effectively achieve the BP target and reduce the usage of antihypertensive medications as well as improve multiple metabolic dysfunction in T2DM patients with hypertension. This study provides an alternative approach to antagonize the metabolic related hypertension.

[Prenatal diagnosis of a fetus with Miller-Dieker syndrome].

OBJECTIVE: To carry out genetic diagnosis for a fetus. METHODS: Chromosome G-banding and chromosomal microarray analysis (CMA) were carried out for a fetus with abnormal morphology of lateral cerebral fissure. RESULTS: The karyotype of the fetus was normal, but CMA showed that it has carried a 1.4 Mb deletion at 17p13.3 region, which suggested a diagnosis of Miller-Dieker syndrome (MDS). CONCLUSION: Familiarity with clinical features and proper selection of genetic testing method are crucial for the diagnosis of MDS. Attention should be paid to microdeletions and microduplications which can be missed by conventional chromosomal karyotyping.

Adrenal Artery Ablation for the Treatment of Hypercortisolism Based on Adrenal Venous Sampling: A Potential Therapeutic Strategy.

AIM: Hypercortisolism is characterized by metabolic disorders and high mortality rates. Adrenalectomy and medical therapies are considered major treatment options. However, some patients, especially young patients, are strongly against undergoing surgery in case of secondary hypocortisolism or relapses that require replacement supplements or pharmacological interventions. In such cases, alternative therapies are needed to treat hypercortisolism. METHODS: We report a 27-year-old Chinese female with adrenal cortisol-producing adenoma. The patient's circadian rhythm and concentrations of cortisol were abnormal, accompanying with an increased 24-hour urinary cortisol level. Computed tomography (CT) revealed a nodular soft-tissue mass in the right adrenal gland. RESULTS: Cortisol hypersecretion from the right adrenal gland was verified by adrenal venous sampling (AVS). Adrenal artery ablation was performed. After ablation, long-term follow-up showed that the patient's symptoms subsided and abnormal laboratory test results returned to normal without pharmacological treatment. CONCLUSION: AVS might be a promising method to aid the diagnosis of cortisol-producing adenoma. Adrenal artery ablation is minimally invasive and may be useful for the treatment of adrenal adenoma or nodular diseases, especially in patients who cannot undergo surgery.

Reducing NADPH Synthesis Counteracts Diabetic Nephropathy through Restoration of AMPK Activity in Type 1 Diabetic Rats.

Diabetic nephropathy (DN) is a major complication of diabetes mellitus and a primary cause of end-stage renal failure. Clinical studies indicate that metabolic surgery improves DN; however, the mechanism remains unclear. Here, we report that Roux-en-Y Gastric Bypass (RYGB) surgery significantly blocked and reversed DN without affecting the insulin signaling pathway. This protective role of RYGB surgery is almost blocked by either inhibition or knockout of 5'AMP-activated protein kinase (AMPK) in podocytes. Furthermore, mRNA microarray data reveal that RYGB surgery obviously reduced the gene expression involved in nicotinamide adenine dinucleotide phosphate (NAPDH) synthesis. The expression of a key NADPH synthase, hexose-6-phosphate dehydrogenase (H6PD), was inhibited by the low plasma corticosterone level after surgery. In addition, blocking NAPDH synthesis by knocking down H6PD mimicked the beneficial role of RYGB surgery through activation of AMPK in podocytes. Therefore, this study demonstrates that reducing NADPH production is critical for renal AMPK activation in response to RYGB surgery.

Adrenal artery ablation for primary aldosteronism without apparent aldosteronoma: An efficacy and safety, proof-of-principle trial.

Primary aldosteronism (PA) is associated with resistant hypertension and cardiovascular events. There are some limitations of current medical and surgical therapies for PA. To determine the efficacy and safety of catheter-based adrenal artery ablation for treatment of PA patients who refused both surgery and medical therapy, we performed this prospective cohort study. Thirty-six PA patients without apparent aldosteronoma were treated by adrenal artery ablation. Primary outcome was postoperative blood pressure and defined daily dose (DDD) of antihypertensive medications after adrenal ablation. Secondary outcome was biochemical success. We assessed outcomes based on Primary Aldosteronism Surgical Outcome (PASO) criteria. Adrenal CT scan, biochemical evaluation, adrenal artery ablation and adrenal venous sampling (AVS) were underwent. After adrenal ablation, complete clinical success (normotension without antihypertensive medication) was achieved in 9/36 (25.0%) patients and partial clinical success (reduction in blood pressure or less antihypertensive medication) in 13/36 (36.1%) patients. Complete biochemical success (correction of hypokalemia and normalization of aldosterone-to-renin ratio) was achieved in 16/36 (44.4%) patients. Office-based and ambulatory blood pressures were reduced by 17/7 and 11/2 mmHg at 6 months after ablation, respectively. The plasma cortisol level in the ablation group decreased slightly, but no patient developed hypoadrenocorticism. Catheter-based adrenal ablation appears to produce substantial and sustained blood pressure reduction and biochemical improvement, with only minor adverse events in PA patients without apparent aldosteronoma. This therapy could be an important supplement for current PA treatments.