Sodium-glucose cotransporter 2 inhibitors ameliorate ER stress-induced pro-inflammatory cytokine expression by inhibiting CD36 in NAFLD progression in vitro.

Sodium-dependent glucose cotransporter-2 (SGLT2) inhibitors, antidiabetic drugs that reduce blood sugar levels by inhibiting glucose reabsorption in the renal proximal tubules, also ameliorate nonalcoholic fatty liver disease (NAFLD). This study aimed to examine the effects of SGLT2 inhibition on hepatic steatosis and nonalcoholic steatohepatitis (NASH) using an in vitro model of NAFLD progression. HepG2 cells and a coculture of Hepa1c1c7 and Raw 264.7 cells were treated with 400 µM palmitic acid (PA), followed by treatment with or without 10 µM empagliflozin and dapagliflozin. In HepG2 cells, PA increased hepatic lipid accumulation, the expression of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß), exocytosis mediators (VAMP3 and SNAP23), and ER stress markers (GRP78, PERK, IRE1α, ATF6, ATF4, and CHOP), and the gene and protein expression of CD36. SGLT2 inhibitors reversed the effects of PA. SGLT2 inhibition via siRNA reduced proinflammatory-cytokine gene expression in thapsigargin-treated HepG2 cells. Transfection with CD36 siRNA reversed the elevated ATF4 and CHOP expression in PA-treated HepG2 cells. SGLT2 inhibition via an SGTL2 inhibitor and SGLT2 siRNA reduced CD36, Tnf-α, Il-6, Il-1ß, Vamp2, Snap23, Atf4, and Chop expression in the PA-treated Hepa1c1c7-Raw 264.7 cell coculture and suppressed Tnf-α release in the Hepa1c1c7-Raw 264.7 cell coculture treated with lipopolysaccharide and PA. These findings indicate that SGLT2 inhibitors inhibited NAFLD progression by reducing hepatic lipid accumulation and inflammation.

Long-Term Glycemic Control Improvement After the Home and Self-Care Program for Patients With Type 1 Diabetes: Real-World-Based Cohort Study.

BACKGROUND: The prevalence of type 1 diabetes (T1D) is increasing worldwide, with a much higher proportion of adult patients. However, achieving stable glycemic control is difficult in these patients. OBJECTIVE: After periodic implementation of structured education for patients with T1D through the Home and Self-Care Program, a pilot home health care project promoted by the Korean government, we evaluated the program's effects on glycemic control. METHODS: This study was conducted from April 2020 to March 2023. We analyzed 119 participants with T1D aged >15 years. Nursing and nutrition education were provided separately up to 4 times per year, with physician consultation up to 6 times per year. A distinguishing feature of this study compared with previous ones was the provision of remote support using a general-purpose smartphone communication app offered up to 12 times annually on an as-needed basis to enhance the continuity of in-person education effects. Patients were followed up on at average intervals of 3 months for up to 24 months. The primary end point was the mean difference in glycated hemoglobin (HbA1c) at each follow-up visit from baseline. For continuous glucose monitoring (CGM) users, CGM metrics were also evaluated. RESULTS: The mean HbA1c level of study participants was 8.6% at baseline (mean duration of T1D 10.02, SD 16.10 y). The HbA1c level reduction in participants who received at least 1 structured educational session went from 1.63% (SD 2.03%; P<.001; adjustment model=1.69%, 95% CI 1.24%-2.13% at the first follow-up visit) to 1.23% (SD 1.31%; P=.01; adjustment model=1.28%, 95% CI 0.78%-1.79% at the eighth follow-up visit). In the adjustment model, the actual mean HbA1c values were maintained between a minimum of 7.33% (95% CI 7.20%-7.46% at the first follow-up visit) and a maximum of 7.62% (95% CI 7.41%-7.82% at the sixth follow-up visit). Among CGM users, after at least 1 session, the mean time in the target range was maintained between 61.59% (adjusted model, 95% CI 58.14%-65.03% at the second follow-up visit) and 54.7% (95% CI 50.92%-58.48% at the eighth follow-up visit), consistently staying above 54.7% (corresponding to an HbA1c level of <7.6%). The mean time below the target range (TBR) also gradually improved to the recommended range (≤4% for TBR of <70 mg/dL and ≤1% for TBR of <54 mg/dL). CONCLUSIONS: The Home and Self-Care Program protocol for glycemic control in patients with T1D is effective, producing significant improvement immediately and long-term maintenance effects, including on CGM indexes.

Tebuconazole Induces Mouse Fetal Testes Damage via ROS Generation in an Organ Culture Method.

The fungicide tebuconazole (TEB) poses risks to human and animal health via various exposure routes. It induces toxicity in multiple organs and disrupts reproductive health by affecting steroid hormone synthesis and fetal development. In this study, we investigated the impact of TEB on fetal testes using in vitro models, focusing on germ, Sertoli, and Leydig cells, and explored the mechanisms underlying cellular damage. The results revealed significant damage to germ cells and disruption of Leydig cell development. TEB exposure led to a decrease in germ cell numbers, as indicated by histological and immunostaining analyses. TEB induced the up- and down-regulation of the expression of fetal and adult Leydig cell markers, respectively. Additionally, TEB-treated fetal testes exhibited increased expression of oxidative-stress-related genes and proteins. However, co-treatment with the antioxidant N-acetylcysteine mitigated TEB-induced germ cell damage and prevented abnormal Leydig cell development. These findings suggest that administration of antioxidants can prevent the intratesticular damage typically caused by TEB exposure.

Anticancer Effects of Mitoquinone via Cell Cycle Arrest and Apoptosis in Canine Mammary Gland Tumor Cells.

Treating female canine mammary gland tumors is crucial owing to their propensity for rapid progression and metastasis, significantly impacting the overall health and well-being of dogs. Mitoquinone (MitoQ), an antioxidant, has shown promise in inhibiting the migration, invasion, and clonogenicity of human breast cancer cells. Thus, we investigated MitoQ's potential anticancer properties against canine mammary gland tumor cells, CMT-U27 and CF41.Mg. MitoQ markedly suppressed the proliferation and migration of both CMT-U27 and CF41.Mg cells and induced apoptotic cell death in a dose-dependent manner. Furthermore, treatment with MitoQ led to increased levels of pro-apoptotic proteins, including cleaved-caspase3, BAX, and phospho-p53. Cell cycle analysis revealed that MitoQ hindered cell progression in the G1 and S phases in CMT-U27 and CF41.Mg cells. These findings were supported using western blot analysis, demonstrating elevated levels of cleaved caspase-3, a hallmark of apoptosis, and decreased expression of cyclin-dependent kinase (CDK) 2 and cyclin D4, pivotal regulators of the cell cycle. In conclusion, MitoQ exhibits in vitro antitumor effects by inducing apoptosis and arresting the cell cycle in canine mammary gland tumors, suggesting its potential as a preventive or therapeutic agent against canine mammary cancer.

Impact of mental disorders on the risk of heart failure among Korean patients with diabetes: a cohort study.

BACKGROUND: Few studies have assessed the correlation between coexisting mental disorders in participants with diabetes mellitus (DM) and the risk of heart failure (HF). Herein, we conducted a cohort study to determine the association between the accumulation of mental disorders in participants with DM and the risk of HF. METHODS: The Korean National Health Insurance Service records were assessed. 2,447,386 adults with DM who underwent health screening between 2009 and 2012 were analyzed. Participants with major depressive disorder, bipolar disorder, schizophrenia, insomnia, or anxiety disorders were included. In addition, participants were categorized based on the number of coexisting mental disorders. Each participant was followed until December 2018 or until the onset of HF. Cox proportional hazard modelling with confounding factors adjustment was conducted. In addition, a competing risk analysis was conducted. Subgroup analysis assessed the impact of clinical variables on the association between the accumulation of mental disorders and the risk of HF. RESULTS: The median follow-up duration was 7.09 years. The accumulation of mental disorders was associated with a risk of HF (zero mental disorder (0), reference; 1 mental disorder, adjusted hazard ratio (aHR): 1.222, 95% confidence intervals (CI): 1.207-1.237; 2 mental disorders, aHR: 1.426, CI: 1.403-1.448; ≥3 mental disorders, aHR: 1.667, CI: 1.632-1.70. In the subgroup analysis, the strength of association was the strongest in the younger age group (< 40 years, 1 mental disorder, aHR 1.301, CI 1.143-1.481; ≥2 mental disorders, aHR 2.683, CI 2.257-3.190; 40-64 years, 1 mental disorder, aHR 1.289, CI 1.265-1.314; ≥2 mental disorders, aHR 1.762, CI 1.724-1.801; ≥65 years, 1 mental disorder, aHR 1.164, CI 1.145-1.183; ≥2 mental disorders, aHR 1.353, CI 1.330-1.377; Pinter<0.001). In addition, income, BMI, hypertension, chronic kidney disease, history of cardiovascular disease, insulin use, and duration of DM showed significant interactions. CONCLUSIONS: Comorbid mental disorders in participants with DM are associated with an increased risk of HF. In addition, the association was stronger in a younger age group. Participants with DM and mental disorders should be monitored with increased frequency for signs of HF; for which they have a higher risk than the general population.

Acromegaly and the long-term fracture risk of the vertebra and hip: a national cohort study.

In this national cohort study, the patients with acromegaly had significantly higher risks of clinical vertebral (HR 2.09 [1.58-2.78]) and hip (HR 2.52 [1.61-3.95]) fractures than the controls. The increased fracture risk in patients with acromegaly was time-dependent and was observed even during the early period of follow-up. PURPOSE: Acromegaly is characterized by the overproduction of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), both play important roles in regulating bone metabolism. We investigated the risk of vertebral and hip fractures in patients with acromegaly compared to age- and sex-matched controls. METHODS: This nationwide population-based cohort study included 1,777 patients with acromegaly aged 40 years or older in 2006-2016 and 8,885 age- and sex-matched controls. A Cox proportional hazards model was used to estimate the adjusted hazard ratio (HR) [95% confidence interval]. RESULTS: The mean age was 54.3 years and 58.9% were female. For approximately 8.5 years of follow-up, the patients with acromegaly had significantly higher risks of clinical vertebral (HR 2.09 [1.58-2.78]) and hip (HR 2.52 [1.61-3.95]) fractures than the controls in the multivariate analyses. There were significant differences in the risks of clinical vertebral (P < 0.0001) and hip (P < 0.0001) fractures between the patients with acromegaly and the controls in the Kaplan-Meier survival analysis. The multivariable-adjusted HRs for clinical vertebral fractures comparing the patients with acromegaly with controls during and excluding the first 7 years of observation were 1.69 [1.15-2.49] and 2.70 [1.75-4.17], respectively. The HRs for hip fractures during and excluding the first 7 years of observation were 2.29 [1.25-4.18] and 3.36 [1.63-6.92], respectively. CONCLUSIONS: The patients with acromegaly had a higher risk of hip fractures as well as clinical vertebral fractures than the controls. The increased fracture risk in patients with acromegaly was time-dependent and was observed even during the early period of follow-up.

Exposures to humidifier disinfectant and various health conditions in Korean based on personal exposure assessment data of claimants for compensation.

BACKGROUND: Humidifier disinfectants (HDs) were commonly used household chemicals to prevent microbial growth in a humidifier water tank in South Korea. A growing body of evidence has indicated that its airborne exposure can induce severe lung injury. However, there has been low awareness of other health outcomes in HD users. This study aimed to evaluate health conditions appealed by claimants for compensation in relation with an increased exposure to HD. METHODS: From survey data of personal HD exposure assessment of claimants for compensation in Korea, we included a total of 4,179 subjects [cases in each dataset were defined by nine reported health conditions, i.e., pneumonia, asthma, cardiovascular disease, respiratory disease, otorhinolaryngologic disease, brain disease (including cerebrovascular disease), dermatological disease, lung cancer, and all cancers]. HD exposures was considered as the following exposure criteria: exposure duration, exposure proximity, exposure direction, chemical type, cumulative exposure time, indoor air concentration, and cumulative exposure level. Logistic regression models were used to evaluate the associations between HD exposure and health conditions. RESULTS: After adjusting for sociodemographic and health behavioral factors and other chemical exposures (households, environmental, and occupational exposures), an increase in cumulative HD exposure time was significantly associated with risks of all nine diseases (all p-trends < 0.05). An increase in HD exposure duration was associated with asthma, respiratory disease, otorhinolaryngologic disease, dermatological disease, all cancers, and lung cancer (p-trends < 0.05). Indoor HD concentration was associated with only pneumonia (p-trend = 0.015). CONCLUSIONS: Our findings suggest that cumulative exposures to airborne HD might potentially increase the risk of various reported health outcomes.

T-2 mycotoxin Induces male germ cell apoptosis by ROS-mediated JNK/p38 MAPK pathway.

T-2 mycotoxin, a type A trichothecene toxin that, specifically, causes male and female reproductive toxicity. We evaluated T-2 toxin toxicity in testes from neonatal testes after in vitro tissue cultured. Additionally, current study focuses on the molecular mechanism of toxicity and germ cell damage in GC-1 spermatogonial cells. Mouse testicular fragments were subjected to T-2 toxin (0-20 nM) during days 5 of in vitro culture. Testicular germ cell number were reduced and downregulated the expression of corresponding markers depending on the exposure concentration of T-2 toxin; however, Sertoli cell markers and steroidogenic enzyme expression increased when treated with 20 nM T-2 toxin. The cell viability decreased, apoptosis increased, and pro-apoptotic protein expression increased in 5-20 nM T-2 toxin-exposed spermatogonia. Moreover, T-2 toxin generated reactive oxygen species (ROS) and induced mitochondrial dysfunction, indicating that activation of p38 MAPK signaling triggered by ROS is involved in the apoptotic molecular mechanism of T-2 toxin. T-2 toxin induced the phosphorylation of ERK1/2, c-Jun, JNK/SAPK, p38, and p53, and the subsequent inhibition of AKT phosphorylation. The upregulation of genes related to apoptosis and MAPK/JNK signaling was consistently observed in cells exposed to T-2 toxin. These results indicate that T-2 toxin triggers apoptotic cell death in germ cells through the triggering of ROS-mediated JNK/p38-MAPK signaling pathways.

Outcomes of Arthroscopic All-Inside Repair Are Improved Compared to Transtibial Pull-Out Repair of Medial Meniscus Posterior Root Tears.

PURPOSE: The purpose of the present study was to compare the clinical outcomes of patients who underwent an all-inside repair (with a bony trough) versus transtibial pull-out repair in medial meniscus posterior root tears (MMPRTs). METHODS: We retrospectively investigated consecutive patients who underwent MMPRT repairs in nonacute tears in age over 40 from November 2015 to June 2019. All patients were divided into a transtibial pull-out repair group and an all-inside repair group. Different surgical techniques were used during different time frames. All patients were followed-up for a minimum of 2 years. The data collected included the International Knee Documentation Committee (IKDC) Subjective, Lysholm, and Tegner activity scores. Magnetic resonance imaging (MRI) was performed at the 1-year follow-up to assess meniscus extrusion, signal intensity, and healing. RESULTS: The final cohort consisted of 28 patients in the all-inside repair group and 16 in the transtibial pull-out repair group. In the all-inside repair group, the IKDC Subjective, Lysholm, and Tegner scores improved significantly at the 2-year follow-up. In the transtibial pull-out repair group, the IKDC Subjective, Lysholm, and Tegner scores did not improve significantly at the 2-year follow-up. Postoperative extrusion ratio increased in both groups, and patient-reported outcomes at follow-up did not differ between the two groups The change in the extrusion ratio was significantly less in the all-inside repair group (P = .009), as was the postoperative meniscus signal (P = .011). Postoperative MRI revealed significantly better healing in the all-inside group (P = .041). CONCLUSION: All-inside repair improved the functional outcome scores. Radiologically, all-inside repair was better than transtibial pull-out repair. All-inside repair may be a viable MMPRT treatment option. LEVEL OF EVIDENCE: III, retrospective cohort study.

Reprint of: Outcomes of Arthroscopic All-Inside Repair Are Improved Compared to Transtibial Pull-Out Repair of Medial Meniscus Posterior Root Tears.

PURPOSE: The purpose of the present study was to compare the clinical outcomes of patients who underwent an all-inside repair (with a bony trough) versus transtibial pull-out repair in medial meniscus posterior root tears (MMPRTs). METHODS: We retrospectively investigated consecutive patients who underwent MMPRT repairs in nonacute tears in age over 40 from November 2015 to June 2019. All patients were divided into a transtibial pull-out repair group and an all-inside repair group. Different surgical techniques were used during different time frames. All patients were followed-up for a minimum of 2 years. The data collected included the International Knee Documentation Committee (IKDC) Subjective, Lysholm, and Tegner activity scores. Magnetic resonance imaging (MRI) was performed at the 1-year follow-up to assess meniscus extrusion, signal intensity, and healing. RESULTS: The final cohort consisted of 28 patients in the all-inside repair group and 16 in the transtibial pull-out repair group. In the all-inside repair group, the IKDC Subjective, Lysholm, and Tegner scores improved significantly at the 2-year follow-up. In the transtibial pull-out repair group, the IKDC Subjective, Lysholm, and Tegner scores did not improve significantly at the 2-year follow-up. Postoperative extrusion ratio increased in both groups, and patient-reported outcomes at follow-up did not differ between the two groups The change in the extrusion ratio was significantly less in the all-inside repair group (P = .009), as was the postoperative meniscus signal (P = .011). Postoperative MRI revealed significantly better healing in the all-inside group (P = .041). CONCLUSION: All-inside repair improved the functional outcome scores. Radiologically, all-inside repair was better than transtibial pull-out repair. All-inside repair may be a viable MMPRT treatment option. LEVEL OF EVIDENCE: III, retrospective cohort study.

A 10-Bit 400-KS/s Low Noise Asynchronous SAR ADC with Dual-Domain Comparator for Input-Referred Noise Reduction.

This paper presents a low noise 0.6-V 400-kS/s asynchronous successive approximation register (SAR) analog-to-digital converter (ADC) for input-referred noise reduction. A dual-domain comparator is proposed to optimize the power, noise, and sampling rate of the ADC in the 10-bit conversion. In order to optimize the figure of merits (FoM) of the ADC, the 10-bit conversion consists of a 7-bit coarse conversion with the double-tail dynamic comparator and a 3-bit fine conversion with the VCDL-based time-domain comparator. An asynchronous timing controller is also proposed to improve the ADC sampling rate and optimize the power consumption of the dual-domain comparator. The proposed SAR ADC is fabricated in 180-nm CMOS technology with an area of 0.836 mm2. At a 0.6-V supply voltage and a 400-kS/s sampling rate, the implemented SAR ADC achieves a signal-to-noise and distortion ratio (SNDR) of 56.59 dB and an effective number of bits (ENOB) of 9.16 bits. The peak values of DNL and INL are +0.47/-0.53 LSB and +0.92/-0.64 LSB, respectively. The FoM is 10.31 fJ/conversion step with a power consumption of 2.36 µW.

Efficient Integrity-Tree Structure for Convolutional Neural Networks through Frequent Counter Overflow Prevention in Secure Memories.

Advancements in convolutional neural network (CNN) have resulted in remarkable success in various computing fields. However, the need to protect data against external security attacks has become increasingly important because inference process in CNNs exploit sensitive data. Secure Memory is a hardware-based protection technique that can protect the sensitive data of CNNs. However, naively applying secure memory to a CNN application causes significant performance and energy overhead. Furthermore, ensuring secure memory becomes more difficult in environments that require area efficiency and low-power execution, such as the Internet of Things (IoT). In this paper, we investigated memory access patterns for CNN workloads and analyzed their effects on secure memory performance. According to our observations, most CNN workloads intensively write to narrow memory regions, which can cause a considerable number of counter overflows. On average, 87.6% of total writes occur in 6.8% of the allocated memory space; in the extreme case, 93.9% of total writes occur in 1.4% of the allocated memory space. Based on our observations, we propose an efficient integrity-tree structure called Countermark-tree that is suitable for CNN workloads. The proposed technique reduces overall energy consumption by 48%, shows a performance improvement of 11.2% compared to VAULT-128, and requires a similar integrity-tree size to VAULT-64, a state-of-the-art technique.

Metformin, resveratrol, and exendin-4 inhibit high phosphate-induced vascular calcification via AMPK-RANKL signaling.

Vascular calcification increases the risk of developing cardiovascular disease, and it is closely associated with metabolic disorders such as diabetes mellitus and non-alcoholic fatty liver disease. We investigated whether the activators of AMP-activated protein kinase (AMPK), metformin, resveratrol, and exendin-4, improved inorganic phosphate (Pi)-induced vascular calcification in rat vascular smooth muscle cells (VSMCs) and whether these effects were via AMPK. Pi increased calcium deposition in a dose-dependent manner, and metformin, resveratrol, and exendin-4 significantly decreased calcium deposition in the Pi-treated VSMCs. Moreover, metformin and exendin-4 increased the expression of a SMC marker gene, α-smooth muscle actin, and Ampk and reduced the receptor activator of nuclear factor kappa-Β ligand (Rankl)/osteoprotegerin ratio. Metformin, resveratrol, and exendin-4 reduced the expression of osteoblast differentiation-associated factors, such as runt-related transcription factor 2, bone morphogenic protein-2, p-small mothers against decapentaplegic 1/5/8, and Rankl. Inhibition of AMPK by siRNA adversely affected the anti-calcification effects of metformin, resveratrol, and exendin-4 and reversed the reduction of the expression of Rankl by metformin and exendin-4 in the Pi-treated VSMCs. These data suggest that metformin, resveratrol, and exendin-4 ameliorate Pi-induced vascular calcification by inhibiting osteoblast differentiation of VSMCs, which is mediated by AMPK.

C1q/TNF-α-Related Protein 1 (CTRP1) Maintains Blood Pressure Under Dehydration Conditions.

RATIONALE: Circulating CTRP1 (C1q/TNF-α [tumor necrosis factor-α]-related protein 1) levels are increased in hypertensive patients compared with those in healthy subjects. Nonetheless, little is known about the molecular and physiological function of CTRP1 in blood pressure (BP) regulation. OBJECTIVE: To investigate the physiological/pathophysiological role of CTRP1 in BP regulation. METHODS AND RESULTS: CTRP1 production was increased to maintain normotension under dehydration conditions, and this function was impaired in inducible CTRP1 KO (knockout) mice (CTRP1 ΔCAG). The increase in CTRP1 under dehydration conditions was mediated by glucocorticoids, and the antagonist mifepristone prevented the increase in CTRP1 and attenuated BP recovery. Treatment with a synthetic glucocorticoid increased the transcription, translation, and secretion of CTRP1 from skeletal muscle cells. Functionally, CTRP1 increases BP through the stimulation of the AT1R (Ang II [angiotensin II] receptor 1)-Rho (Ras homolog gene family)/ROCK (Rho kinase)-signaling pathway to induce vasoconstriction. CTRP1 promoted AT1R plasma membrane trafficking through phosphorylation of AKT and AKT substrate of 160 kDa (AS160). In addition, the administration of an AT1R blocker, losartan, recovered the hypertensive phenotype of CTRP1 TG (transgenic) mice. CONCLUSIONS: For the first time, we provide evidence that CTRP1 contributes to the regulation of BP homeostasis by preventing dehydration-induced hypotension.

Ankle strength is not strongly associated with postural stability in patients awaiting surgery for chronic lateral ankle instability.

PURPOSE: (1) To describe ankle strength and postural stability in patients with chronic lateral ankle instability and (2) to analyse the correlation between deficits in ankle strength and postural stability. METHODS: Results of preoperative isokinetic and balance tests in 203 patients whose contralateral ankle was normal were retrospectively reviewed. Isokinetic peak torque values of eversion and inversion at 2 angular velocities (30°/s and 120°/s) were measured in the injured and normal ankles. In the balance test, the percent differences of 3 actual scores (overall, anterior-posterior, and medial-lateral) between the injured and normal ankles were calculated. Additional statistical analyses were performed to evaluate weakness of ankle strength, postural stability deficits, and their correlation. RESULTS: Significant differences in 4 peak torque values and 4 relative peak torque values (peak torque/body weight) were found between the injured and normal ankles. All 8 values were significantly lower in the injured ankles. Weakness was severe during inversion and at 30°/s. In the balance test, 49 subjects (24.1%) had significant deficits in postural stability and 109 (53.7%) had favourable results. No strong association was found between weakness of ankle strength and deficits in postural stability. CONCLUSIONS: Strength measurement alone is insufficient to evaluate preoperative functional deficits, and other functional tests are required to measure postural stability. The results of this study provide further evidence for a rehabilitation programme consisting of proprioceptive training as well as strengthening. The proprioceptive training must be an integral part of the rehabilitation programme in addition to strengthening exercise. LEVEL OF EVIDENCE: Case series, Level IV.

Repair of only anterior talofibular ligament resulted in similar outcomes to those of repair of both anterior talofibular and calcaneofibular ligaments.

PURPOSE: To compare the surgical outcomes of the two different ankle stabilization techniques. METHODS: This randomized controlled trial aimed to compare the outcomes of the modified Broström procedure with [calcaneofibular ligament (CFL) group] or without CFL repair [anterior talofibular ligament (ATFL) only group]. Of the 50 patients randomly assigned to two groups, 43 were followed up prospectively for ≥ 2 years (CFL group: 22 patients, 36.6 ± 13.1 months; ATFL Only group: 21 patients, 35.3 ± 11.9 months). Functional outcomes were assessed using the Karlsson-Peterson and Tegner activity level scoring systems. Anterior talar translation (ATT), talar tilt angle (TTA), and degrees of displacement of the calcaneus against the talus on stress radiographs were measured. All parameters were compared between the two groups. Multiple regression analysis setting the postoperative Karlsson-Peterson score as the dependent variable was performed to determine the significant variable. RESULTS: There were no significant differences between the two groups in functional (Karlsson-Peterson and Tegner activity level) scores at the last follow-up and their changes. There were no significant differences between the two groups in the ATT, TTA, their differences compared with the contralateral ankles, and degrees of displacement of the calcaneus against the talus at the last follow-up. Osteochondral lesion of the talus rather than CFL repair was the significant variable related to functional outcome. CONCLUSION: The modified Broström procedure with additional CFL repair did not result in a significant advantage in any measured outcome at 3 years. LEVEL OF EVIDENCE: Randomized controlled trial, Level I.

Toxic Effects of Nonylphenol on Neonatal Testicular Development in Mouse Organ Culture.

Nonylphenol (NP) is an alkylphenol that is widely used in chemical manufacturing. Exposure to this toxic environmental contaminant has been shown to negatively affect the reproductive system. Herein, we evaluated the toxicity of NP in mouse testes, while using in vitro organ culture. Mouse testicular fragments (MTFs), derived from five-day postpartum neonatal mouse testes, were exposed to different concentrations of NP (1-50 µM) for 30 days. The results showed that NP impaired germ cell development and maintenance. Furthermore, NP significantly downregulated the transcript levels of both undifferentiated and differentiated germ cell marker genes relative to those in controls. In particular, a high dose of NP (50 µM) led to complete germ cell depletion and resulted in spermatogenic failure, despite the presence of Sertoli and Leydig cells. In addition, the mRNA expression of steroidogenic enzymes, such as steroidogenic acute regulatory protein (STAR), Cytochrome P450 Family 11 Subfamily A Member 1 (Cyp11α1), Cytochrome P450 17A1 (Cyp17α1), and androgen receptor (AR), increased with increasing concentration of NP. Conversely, the expression of estrogen receptor alpha (ESR1) and Cytochrome P450 family 19 subfamily A member 1 (Cyp19α1) in NP-exposed MTFs decreased when compared to that of the control. Taken together, this study demonstrates that NP has a negative effect on prepubertal spermatogenesis and germ cell maintenance and it disrupts steroidogenesis and induces hormonal imbalance in MTFs.

QSAR Model for Predicting the Cannabinoid Receptor 1 Binding Affinity and Dependence Potential of Synthetic Cannabinoids.

In recent years, there have been frequent reports on the adverse effects of synthetic cannabinoid (SC) abuse. SCs cause psychoactive effects, similar to those caused by marijuana, by binding and activating cannabinoid receptor 1 (CB1R) in the central nervous system. The aim of this study was to establish a reliable quantitative structure-activity relationship (QSAR) model to correlate the structures and physicochemical properties of various SCs with their CB1R-binding affinities. We prepared tetrahydrocannabinol (THC) and 14 SCs and their derivatives (naphthoylindoles, naphthoylnaphthalenes, benzoylindoles, and cyclohexylphenols) and determined their binding affinity to CB1R, which is known as a dependence-related target. We calculated the molecular descriptors for dataset compounds using an R/CDK (R package integrated with CDK, version 3.5.0) toolkit to build QSAR regression models. These models were established, and statistical evaluations were performed using the mlr and plsr packages in R software. The most reliable QSAR model was obtained from the partial least squares regression method via Y-randomization test and external validation. This model can be applied in vivo to predict the addictive properties of illicit new SCs. Using a limited number of dataset compounds and our own experimental activity data, we built a QSAR model for SCs with good predictability. This QSAR modeling approach provides a novel strategy for establishing an efficient tool to predict the abuse potential of various SCs and to control their illicit use.

Synthesis of silver-loaded ZnO nanorods and their enhanced photocatalytic activity and photoconductivity study.

Herein, we synthesized ZnO nanorods using a solvothermal reaction technique at 200 °C for 24 h, and the prepared ZnO nanorods were decorated with silver (Ag) nanoparticles to enhance their photocatalytic activity. The Ag nanoparticles were photochemically deposited on the ZnO rods with varying molar concentrations (from 0.5 to 10 mol%), and their various physicochemical properties were studied. The prepared material was characterised using different spectroscopic techniques. XRD revealed the formation of a highly crystalline hexagonal phase of ZnO. For a higher silver loading (>5 mol%), separate peaks corresponding to cubic silver were observed in the XRD pattern. The photoluminescence spectra of the Ag/ZnO nanostructures show two distinct peaks at 390 and 500 nm; interestingly, the PL intensity of the ZnO emission peak at 500 nm decreases with an increase in the silver concentration. The diffuse reflectance spectra of Ag/ZnO indicate absorbance at 380 nm due to ZnO and a slight hump at 440 nm that corresponds to silver nanoparticles. The FE-SEM and TEM analysis indicates the formation of a hexagonal rod-like morphology, with the lengths of the rods ranging from around 50 to 200 nm and a diameter of around 30 nm. TEM also confirms the presence of Ag nanoparticles with sizes in the range of 20 to 30 nm on the surface of the ZnO nanorods. The photocatalytic activity of the Ag/ZnO nanostructures was evaluated by following the degradation of methylene blue (MB) dye under a 400 W mercury vapour lamp. ZnO with 10 mol% Ag loading shows the highest photocatalytic activity as compared to the 0.5, 1 & 5 mol% Ag-ZnO catalysts. The observed apparent rate constant for the photocatalytic MB degradation using 10 mol% Ag-ZnO (Kapp = 6.01 × 10-2 min-1) was six times that of pure ZnO (Kapp = 1.09 × 10-2 min-1). A gradual increase in the photocatalytic activity of Ag/ZnO was observed with an increase in the silver concentration. The photocurrent response of the prepared Ag-ZnO nanostructures was examined by a photoconductivity study. Moreover, the photocatalytic performance of the sample was correlated with the photoconductivity of the samples. The photoconductivity of the samples was stable, and the photoconductivity of 10 mol% Ag-ZnO was almost 20 times that of pure ZnO, resulting in a higher photocatalytic activity.

Production of human tissue-type plasminogen activator (htPA) using in vitro cultured transgenic pig mammary gland cells.

Tissue plasminogen activator (tPA) is a protein involved in the breakdown of blood clots. We have previously produced a human tPA (htPA)-overexpressing transgenic pig using a mammary gland-specific promoter. In this study, we have established a transgenic pig mammary gland cell line that produces recombinant htPA. The mammary gland cells grew well and retained their character over long periods of culture. There was no difference in the extent of apoptosis in transgenic cells compared to wild-type mammary gland cells. In addition, the transgenic mammary gland cells expressed and secreted htPA into the conditioned media at a concentration similar to that in milk. This transgenic cell line represents a simple and ethical method for recombinant htPA production.