Mutation in Smek2 regulating hepatic glucose metabolism causes hypersarcosinemia and hyperhomocysteinemia in rats.

Suppressor of mek1 (Dictyostelium) homolog 2 (Smek2), was identified as one of the responsible genes for diet-induced hypercholesterolemia (DIHC) of exogenously hypercholesterolemic (ExHC) rats. A deletion mutation in Smek2 leads to DIHC via impaired glycolysis in the livers of ExHC rats. The intracellular role of Smek2 remains obscure. We used microarrays to investigate Smek2 functions with ExHC and ExHC.BN-Dihc2BN congenic rats that harbor a non-pathological Smek2 allele from Brown-Norway rats on an ExHC background. Microarray analysis revealed that Smek2 dysfunction leads to extremely low sarcosine dehydrogenase (Sardh) expression in the liver of ExHC rats. Sarcosine dehydrogenase demethylates sarcosine, a byproduct of homocysteine metabolism. The ExHC rats with dysfunctional Sardh developed hypersarcosinemia and homocysteinemia, a risk factor for atherosclerosis, with or without dietary cholesterol. The mRNA expression of Bhmt, a homocysteine metabolic enzyme and the hepatic content of betaine (trimethylglycine), a methyl donor for homocysteine methylation were low in ExHC rats. Results suggest that homocysteine metabolism rendered fragile by a shortage of betaine results in homocysteinemia, and that Smek2 dysfunction causes abnormalities in sarcosine and homocysteine metabolism.

Randomized controlled trial of daily teriparatide, weekly high-dose teriparatide, or bisphosphonate in patients with postmenopausal osteoporosis: The TERABIT study.

PURPOSE: The effects of daily teriparatide (20 µg) (D-PTH), weekly high-dose teriparatide (56.5 µg) (W-PTH), or bisphosphonates (BPs) on areal bone mineral density (aBMD), bone turnover markers (BTMs), volumetric BMD (vBMD), microarchitecture, and estimated strength were investigated in postmenopausal osteoporosis patients. METHODS: The study participants were 131 women with a history of fragility fractures. They were randomized to receive D-PTH, W-PTH, or BPs (alendronate or risedronate) for 18 months. Dual-energy X-ray absorptiometry (DXA), BTMs, and high-resolution peripheral quantitative CT (HR-pQCT) parameters were evaluated at baseline and after 6 and 18 months of treatment. The primary endpoint was the change (%) in cortical thickness (Ct.Th) after 18 months' treatment compared with baseline. RESULTS: DXA showed that D-PTH, W-PTH, and BPs increased lumbar spine aBMD (+12.0%, +8.5%, and +6.8%) and total hip aBMD (+3.0%, +2.1%, and +3.0%), but D-PTH and W-PTH decreased 1/3 radius aBMD (-4.1%, -3.0%, -1.4%) after 18 months. On HR-pQCT, D-PTH increased trabecular vBMD (Tb.vBMD) at the distal radius and tibia after 18 months (+6.4%, +3.7%) compared with the BPs group, decreased cortical volumetric tissue mineral density (Ct.vTMD) (-1.8%, -0.9%) compared with the other groups, increased Ct.Th (+1.3%, +3.9%), and increased failure load (FL) (+4.7%, +4.4%). W-PTH increased Tb.vBMD (+5.3%, +1.9%), maintained Ct.vTMD (-0.7%, +0.2%) compared with D-PTH, increased Ct.Th (+0.6%, +3.6%), and increased FL (+4.9%, +4.5%). The BPs increased Tb.vBMD only in the radius (+2.0%, +0.2%), maintained Ct.vTMD (-0.6%, +0.3%), increased Ct.Th (+0.5%, +3.4%), and increased FL (+3.9%, +2.8%). CONCLUSIONS: D-PTH and W-PTH comparably increased Ct.Th, the primary endpoint. D-PTH had a strong effect on trabecular bone. Although D-PTH decreased Ct.vTMD, it increased Ct.Th and total bone strength. W-PTH had a moderate effect on trabecular bone, maintained Ct.vTMD, and increased Ct.Th and total bone strength to the same extent as D-PTH.

Effects of monthly intravenous ibandronate on bone mineral density and microstructure in patients with primary osteoporosis after teriparatide treatment: The MONUMENT study.

PURPOSE: To investigate the effects of sequential therapy with monthly intravenous ibandronate on bone mineral density (BMD) and microstructure in patients with primary osteoporosis who received teriparatide treatment. METHODS: Sixty-six patients with primary osteoporosis who had undergone teriparatide treatment for more than 12 months (mean 18.6 months) received sequential therapy with 1 mg/month intravenous ibandronate for 12 months. The patients were evaluated using dual-energy X-ray absorptiometry (DXA), quantitative ultrasound, bone turnover markers, and high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and 6 and 12 months after beginning administration. RESULTS: At 12 months after beginning sequential therapy, the bone resorption marker, tartrate-resistant acid phosphatase-5b, decreased by 39.5%, with 82.3% of the patients exhibiting levels within the normal limit. DXA revealed that the BMD of the lumbar spine increased by 3.2%, with 79.0% of the patients exhibiting a response, and 40.3% experiencing an increase in BMD over 5%. HR-pQCT revealed that the cortical thickness of the distal tibia was increased by 2.6%. The cortical area increased by 2.5%, and the buckling ratio (an index of cortical instability) decreased by 2.5%. Most parameters of the trabecular bone showed no significant changes. These changes in the cortical bone were observed in both the distal radius and tibia and appeared beginning 6 months after treatment initiation. CONCLUSIONS: Sequential therapy with monthly intravenous ibandronate increased the BMD and improved the cortical bone microstructure of osteoporotic patients who had undergone teriparatide treatment.

Examination of pain relief effect of Goreisan for glossodynia.

BACKGROUND: Pain in glossodynia may be severe; it may prevent patients from working, interfere with daily life activities, and necessitate a patient's visit to a medical institution for consultation and treatment. The pain may be described as persistent and burning (tingling, tingling) or stinging. Patients may complain of dry mouth (dryness), which is thought to cause inflammation of the tongue and gingival mucous membranes and increased pain. Medications are prescribed based on the symptoms of glossodynia, and the therapeutic effect is confirmed. However, each drug has side effects, for example, pain may reduce, but drowsiness and dizziness may occur; further, there is always a tendency of drowsiness.On the other hand, Goreisan, a Chinese herbal medicine, has already been used by physicians to treat pain in the oral and maxillofacial regions resulting from rapid changes in air pressure. However, the lack of high-quality clinical research has been of concern, and a randomized clinical trial to investigate the efficacy and safety of Goreisan for treatment of pain in glossodynia is warranted. METHODS/DESIGN: This multicenter, randomized, controlled study will involve patients treated for glossodynia-related pain. In the experimental group, Goreisan will be taken for 12 weeks in combination with conventional treatment. Participants in the control group will not take any Kampo medicine; only the standard treatment will be taken. Subsequently, the degree of pain will be assessed, and saliva tests of all the patients on their first visit will be performed. Goreisan will be taken at a dose of 7.5 g/d (minute 3) for 12 consecutive weeks. Twelve weeks later, the degree of pain of each patient will be assessed. DISCUSSION: The purpose of this study is to investigate the efficacy of Goreisan for pain reduction in patients undergoing treatment for glossodynia-related pain. If pain in glossodynia patients can be reduced by the administration of Goreisan, its candidacy as an alternative treatment for pain in glossodynia can be further supported by more reliable research. TRIAL REGISTRATION: The study was registered in the jRCTs071200017. URL https://jrct.niph.go.jp/latest-detail/jRCTs071200017.

Study on prevention of hypercapnia by nasal high flow in patients undergoing endoscopic retrograde cholangiopancreatography during intravenous anesthesia.

BACKGROUND: For relatively invasive upper gastrointestinal endoscopy procedures, such as an endoscopic retrograde cholangiopancreatography (ERCP), and also lower gastrointestinal endoscopy procedures, intravenous anesthesia is routinely used to reduce patient anxiety. However, with the use of intravenous anesthesia, even at mild to moderate depth of anesthesia, there is always a risk of upper airway obstruction due to a relaxation of the upper airway muscles.With the advent of nasal high flow (NHF) devices that allow humidified high flow air through the nasal cavity, can be used as a respiratory management method in the context of anesthesia. AIRVO is commonly used for patients with obstructive sleep apnea and other respiratory disorders. This device uses a mild positive pressure load (several cmH2O) that improves carbon dioxide (CO2) washout and reduces rebreathing to improve respiratory function and therefore is widely used to prevent hypoxemia and hypercapnia.This study aims to maintain upper airway patency by applying NHF with air (AIRVO) as a respiratory management method during intravenous anesthesia for patients undergoing an ERCP. In addition, this study investigates whether the use of an NHF device in this context can prevent intraoperative hypercapnia and hypoxemia. METHODS/DESIGN: This study design employed 2 groups of subjects. Both received intravenous anesthesia while undergoing an ERCP, and 1 group also used a concurrent nasal cannula NHF device. Here we examine if the use of an NHF device during intravenous anesthesia can prevent hypoxemia and hypercapnia, which could translate to improved anesthesia management.Efficacy endpoints were assessed using a transcutaneous CO2 monitor (TCM). This device measured the changes in CO2 concentration during treatment. Transcutaneous CO2 (PtcCO2) concentrations of 60 mm Hg or more (PaCO2 > 55 mm Hg) were considered marked hypercapnia. PtcCO2 concentrations of 50 to 60 mm Hg or more (equivalent to PaCO2 > 45 mm Hg) were considered moderate hypercapnia.Furthermore, the incidence of hypoxemia with a transcutaneous oxygen saturation value of 90% or less, and whether the use of NHF was effective in preventing this adverse clinical event were evaluated. DISCUSSION: The purpose of this study was to obtain evidence for the utility of NHF as a potential therapeutic device for patients undergoing an ERCP under sedation, assessed by determining if the incidence rates of hypercapnia and hypoxemia decreased in the NHF device group, compared to the control group that did not use this device. TRIAL REGISTRATION: The study was registered in the jRCTs 072190021.URL https://jrct.niph.go.jp/en-latest-detail/jRCTs072190021.

Study on prevention of hypercapnia by Nasal High Flow in patients with endoscopic submucosal dissection during intravenous anesthesia.

BACKGROUND: For relatively invasive upper gastrointestinal endoscopy procedures, such as an endoscopic submucosal dissection (ESD), intravenous anesthesia is routinely used to reduce patient anxiety. However, with the use of intravenous sedation, even at mild to moderate depth of anesthesia, there is always a risk of upper airway obstruction due to a relaxation of the upper airway muscles.With the advent of Nasal High Flow (NHF) devices that allow humidified high flow air through the nasal cavity, can be used as a respiratory management method in the context of anesthesia. AIRVO is commonly used for patients with obstructive sleep apnea and other respiratory disorders. This device uses a mild positive pressure load (several cmH2O) that improves carbon dioxide (CO2) washout and reduces rebreathing to improve respiratory function and therefore is widely used to prevent hypoxemia and hypercapnia.This study aims to maintain upper airway patency by applying NHF with air (AIRVO) as a respiratory management method during intravenous anesthesia for patients undergoing an ESD. In addition, this study investigates whether the use of an NHF device in this context can prevent intraoperative hypercapnia and hypoxemia. METHODS/DESIGN: This study design employed 2 groups of subjects. Both received intravenous anesthesia while undergoing an ESD, and 1 group also used a concurrent nasal cannula NHF device. Here we examine if the use of an NHF device during intravenous anesthesia can prevent hypoxemia and hypercapnia, which could translate to improved anesthesia management.Efficacy endpoints were assessed using a transcutaneous CO2 monitor. This device measured the changes in CO2 concentration during treatment. Transcutaneous CO2 (PtcCO2) concentrations of 60 mmHg or more (PaCO2 > 55 mmHg) were considered marked hypercapnia. PtcCO2 concentrations of 50 to 60 mmHg or more (equivalent to PaCO2 > 45 mmHg) were considered moderate hypercapnia.Furthermore, the incidence of hypoxemia with a transcutaneous oxygen saturation value of 90% or less, and whether the use of NHF was effective in preventing this adverse clinical event were evaluated. DISCUSSION: The purpose of this study was to obtain evidence for the utility of NHF as a potential therapeutic device for patients undergoing an ESD under anesthesia, assessed by determining if the incidence rates of hypercapnia and hypoxemia decreased in the NHF device group, compared to the control group that did not use of this device. TRIAL REGISTRATION: The study was registered the jRCTs 072190022.URL https://jrct.niph.go.jp/en-latest-detail/jRCTs072190022.

Determination of the Kinetic Parameters for 123I Uptake by the Thyroid, Thyroid Weights, and Thyroid Volumes in Present-day Healthy Japanese Volunteers.

The purpose of this study was to evaluate the kinetic parameters that determine the uptake rate of radioiodide in the thyroid over 24 h after administration and to estimate thyroid volumes/masses of present-day Japanese. Methods: We determined the thyroid uptake rate of I in healthy male Japanese after oral administration (4.5-8.0 MBq) without iodine restriction. Masses of thyroid glands were collected in 2012-2016 during autopsies of 7,651 male and 3,331 female subjects. Volumes of thyroid glands were estimated by ultrasonography and magnetic resonance imaging in 52 male subjects. Results: The thyroid uptake rate of I for 24 h was 16.1 ± 5.4%. Kinetic model analysis was conducted to obtain the clearances (L h) for thyroid uptake and urinary excretion of I (0.499 ± 0.258 and 2.10 ± 0.39 L h, respectively). The masses of thyroid glands were on average 19.8 g (95% confidence interval of 18.3-19.5 g) and 15.5 g (95% confidence interval of 14.7-16.2 g) in male and female subjects aged 19-52 y, respectively. Volumes of thyroid glands estimated by ultrasonography and magnetic resonance imaging were 17.5 ± 5.2 and 14.2 ± 5.3 mL, respectively. In healthy Japanese, there has been no significant change for at least 50 y in the thyroid uptake of radioiodide over 24 h or in its kinetic parameters. These Japanese-specific kinetic parameters will allow quantitative estimation of the radiation exposure from the Fukushima accident and its variance during the individual's evacuation from or stay in Fukushima.

Dietary pine bark extract reduces atherosclerotic lesion development in male ApoE-deficient mice by lowering the serum cholesterol level.

Pine bark extract (PBE) mainly contains proanthocyanidin in oligomers. It has many physiological effects, including antioxidant, anti-inflammatory, and so on. In this study, we investigated whether PBE has an anti-atherogenic effect on apoE-deficient mice. Male and female mice were fed a diet based on an AIN-76 formula (control diet), and that diet supplemented with 2% PBE (the PBF diet). The PBE diet, compared with the control diet, resulted in lowering the body weight gain and the adipose tissue weight in both male and female mice. The lesion area of the valve and the levels of serum and liver cholesterol in the male mice decreased on the PBE diet. The PBE diet had no significant effect on the levels of urinary isoprostanes or serum thiobarbituric acid reactive substances. These results indicate that dietary PBE can have beneficial effects on atherosclerosis development in male apoE-deficient mice by lowering the serum cholesterol level.