Cushing's syndrome (CS) is a collection of symptoms caused by prolonged exposure to excess cortisol. Chronically elevated glucocorticoid (GC) levels contribute to hepatic steatosis. We hypothesized that histone deacetylase inhibitors (HDACi) could attenuate hepatic steatosis through glucocorticoid receptor (GR) acetylation in experimental CS. To induce CS, we administered adrenocorticotropic hormone (ACTH; 40 ng/kg/day) to Sprague-Dawley rats by subcutaneous infusion with osmotic mini-pumps. We administered the HDACi, sodium valproate (VPA; 0.71% w/v), in the drinking water. Treatment with the HDACi decreased steatosis and the expression of lipogenic genes in the livers of CS rats. The enrichment of GR at the promoters of the lipogenic genes, such as acetyl-CoA carboxylase (Acc), fatty acid synthase (Fasn), and sterol regulatory element binding protein 1c (Srebp1c), was markedly decreased by VPA. Pan-HDACi and an HDAC class I-specific inhibitor, but not an HDAC class II a-specific inhibitor, attenuated dexamethasone (DEX)-induced lipogenesis in HepG2 cells. The transcriptional activity of Fasn was decreased by pretreatment with VPA. In addition, pretreatment with VPA decreased DEX-induced binding of GR to the glucocorticoid response element (GRE). Treatment with VPA increased the acetylation of GR in ACTH-infused rats and DEX-induced HepG2 cells. Taken together, these results indicate that HDAC inhibition attenuates hepatic steatosis hrough GR acetylation in experimental CS.
Acetyl-CoA Carboxylase ; Acetylation ; Adrenocorticotropic Hormone ; Animals ; Cushing Syndrome* ; Dexamethasone ; Drinking Water ; Hep G2 Cells ; Histone Deacetylase Inhibitors ; Histone Deacetylases* ; Histones* ; Hydrocortisone ; Infusions, Subcutaneous ; Lipogenesis ; Liver ; Rats* ; Rats, Sprague-Dawley ; Receptors, Glucocorticoid ; Response Elements ; Sterol Regulatory Element Binding Protein 1 ; Valproic Acid

BACKGROUND: Flecainide is an antiarrhythmic agent that is used primarily in the treatment of cardiac arrhythmias. Some evidences also suggest that flecainide can participate in alveolar fluid clearance and inflammatory responses. This experiment was aimed to evaluate the effects of flecainide on sepsis induced acute lung injury in a rat model. METHODS: Rats were treated with subcutaneous infusion of saline or flecainide (0.1 or 0.2 mg/kg/hr) by a mini-osmotic pump. Subcutaneous infusion was started 3 hours before and continued until 8 hours after intraperitoneal injection of saline or endotoxin. Animals were sacrificed for analyses of severity of acute lung injury with wet to dry (W/D) ratio and lung injury score (LIS) in lung and inflammatory responses with level of leukocyte, polymorphonuclear neutrophils (PMNs) and inteleukin-8 (IL-8) in bronchoalveolar lavages fluid (BALF). RESULTS: Flecainide markedly improved dose dependently sepsis induced acute lung injury as analysed by W/D ratio (from 2.24 ± 0.11 to 1.76 ± 0.09, p < 0.05) and LIS (from 3 to 1, p < 0.05), and inflammatory response as determined by leukocyte (from 443 ± 127 to 229 ± 95, p < 0.05), PMNs (from 41.43 ± 17.63 to 2.43 ± 2.61, p < 0.05) and IL-8 (from 95.00 ± 15.28 to 40.00 ± 10.21, p < 0.05) in BALF. CONCLUSIONS: Flecanide improve sepsis induced acute lung injury in rats by controlling inflammatory responses.
Acute Lung Injury* ; Animals ; Arrhythmias, Cardiac ; Bronchoalveolar Lavage ; Flecainide* ; Infusions, Subcutaneous ; Injections, Intraperitoneal ; Interleukin-8 ; Leukocytes ; Lung ; Lung Injury ; Models, Animal ; Neutrophils ; Rats ; Sepsis*

BACKGROUND: Flecainide is an antiarrhythmic agent that is used primarily in the treatment of cardiac arrhythmias. Some evidences also suggest that flecainide can participate in alveolar fluid clearance and inflammatory responses. This experiment was aimed to evaluate the effects of flecainide on sepsis induced acute lung injury in a rat model. METHODS: Rats were treated with subcutaneous infusion of saline or flecainide (0.1 or 0.2 mg/kg/hr) by a mini-osmotic pump. Subcutaneous infusion was started 3 hours before and continued until 8 hours after intraperitoneal injection of saline or endotoxin. Animals were sacrificed for analyses of severity of acute lung injury with wet to dry (W/D) ratio and lung injury score (LIS) in lung and inflammatory responses with level of leukocyte, polymorphonuclear neutrophils (PMNs) and inteleukin-8 (IL-8) in bronchoalveolar lavages fluid (BALF). RESULTS: Flecainide markedly improved dose dependently sepsis induced acute lung injury as analysed by W/D ratio (from 2.24 ± 0.11 to 1.76 ± 0.09, p < 0.05) and LIS (from 3 to 1, p < 0.05), and inflammatory response as determined by leukocyte (from 443 ± 127 to 229 ± 95, p < 0.05), PMNs (from 41.43 ± 17.63 to 2.43 ± 2.61, p < 0.05) and IL-8 (from 95.00 ± 15.28 to 40.00 ± 10.21, p < 0.05) in BALF. CONCLUSIONS: Flecanide improve sepsis induced acute lung injury in rats by controlling inflammatory responses.
Acute Lung Injury ; Animals ; Arrhythmias, Cardiac ; Bronchoalveolar Lavage ; Flecainide ; Infusions, Subcutaneous ; Injections, Intraperitoneal ; Interleukin-8 ; Leukocytes ; Lung ; Lung Injury ; Models, Animal ; Neutrophils ; Rats ; Sepsis

The diagnosis and treatment of congenital hyperinsulinism (CHI) have made a remarkable progress over the past 20 years and, currently, it is relatively rare to see patients who are left with severe psychomotor delay. The improvement was made possible by the recent developments in the understanding of the molecular and pathological basis of CHI. Known etiologies include inactivating mutations of the K(ATP) channel genes (ABCC8 and KCNJ11) and HNF4A, HNF1A, HADH, and UCP2 or activating mutations of GLUD1, GCK, and SLC16A1. The understanding of the focal form of K(ATP) channel CHI and its detection by 18F-fluoro-L-DOPA positron emission tomography have revolutionized the management of CHI, and many patients can be cured without postoperative diabetes mellitus. The incidence of the focal form appears to be higher in Asian countries; therefore, the establishment of treatment systems is even more important in this population. In addition to diazoxide or long-term subcutaneous infusion of octreotide or glucagon, long-acting octreotide or lanreotide have also been used successfully until spontaneous remission. Because of these medications, near-total pancreatectomy is less often performed even for the diazoxide-unresponsive diffuse form of CHI. Other promising medications include pasireotide, small-molecule correctors such as sulfonylurea or carbamazepine, GLP1 receptor antagonists, or mammalian target of rapamycin inhibitors. Unsolved questions in this field include the identification of the remaining genes responsible for CHI, the mechanisms leading to transient CHI, and the mechanisms responsible for the spontaneous remission of CHI. This article reviews recent developments and hypothesis regarding these questions.
Asian Continental Ancestry Group ; Carbamazepine ; Congenital Hyperinsulinism* ; Diabetes Mellitus ; Diagnosis ; Diazoxide ; Glucagon ; Humans ; Hyperinsulinism ; Hypoglycemia ; Incidence ; Infusions, Subcutaneous ; Octreotide ; Pancreatectomy ; Positron-Emission Tomography ; Remission, Spontaneous ; Sirolimus

Glucagon-like peptide 1 (GLP-1) is secreted from enteroendocrine L-cells in response to oral nutrient intake and elicits glucose-stimulated insulin secretion while suppressing glucagon secretion. It also slows gastric emptying, which contributes to decreased postprandial glycemic excursions. In the 1990s, chronic subcutaneous infusion of GLP-1 was found to lower blood glucose levels in patients with type 2 diabetes. However, GLP-1's very short half-life, arising from cleavage by the enzyme dipeptidyl peptidase 4 (DPP-4) and glomerular filtration by the kidneys, presented challenges for clinical use. Hence, DPP-4 inhibitors were developed, as well as several GLP-1 analogs engineered to circumvent DPP-4-mediated breakdown and/or rapid renal elimination. Three categories of GLP-1 analogs, are being developed and/or are in clinical use: short-acting, long-acting, and prolonged-acting GLP-1 analogs. Each class has different plasma half-lives, molecular size, and homology to native GLP-1, and consequently different characteristic effects on glucose metabolism. In this article, we review current clinical data derived from each class of GLP-1 analogs, and consider the clinical effects reported for each category in recent head to head comparison studies. Given the relatively brief clinical history of these compounds, we also highlight several important efficacy and safety issues which will require further investigation.
Blood Glucose ; Diabetes Mellitus, Type 2* ; Dipeptidyl Peptidase 4 ; Filtration ; Gastric Emptying ; Glucagon ; Glucagon-Like Peptide 1* ; Glucose ; Half-Life ; Head ; Humans ; Infusions, Subcutaneous ; Insulin ; Kidney ; Metabolism ; Peptides ; Plasma ; Venoms ; Liraglutide

Glucagon-like peptide 1 (GLP-1) is secreted from enteroendocrine L-cells in response to oral nutrient intake and elicits glucose-stimulated insulin secretion while suppressing glucagon secretion. It also slows gastric emptying, which contributes to decreased postprandial glycemic excursions. In the 1990s, chronic subcutaneous infusion of GLP-1 was found to lower blood glucose levels in patients with type 2 diabetes. However, GLP-1's very short half-life, arising from cleavage by the enzyme dipeptidyl peptidase 4 (DPP-4) and glomerular filtration by the kidneys, presented challenges for clinical use. Hence, DPP-4 inhibitors were developed, as well as several GLP-1 analogs engineered to circumvent DPP-4-mediated breakdown and/or rapid renal elimination. Three categories of GLP-1 analogs, are being developed and/or are in clinical use: short-acting, long-acting, and prolonged-acting GLP-1 analogs. Each class has different plasma half-lives, molecular size, and homology to native GLP-1, and consequently different characteristic effects on glucose metabolism. In this article, we review current clinical data derived from each class of GLP-1 analogs, and consider the clinical effects reported for each category in recent head to head comparison studies. Given the relatively brief clinical history of these compounds, we also highlight several important efficacy and safety issues which will require further investigation.
Blood Glucose ; Diabetes Mellitus, Type 2* ; Dipeptidyl Peptidase 4 ; Filtration ; Gastric Emptying ; Glucagon ; Glucagon-Like Peptide 1* ; Glucose ; Half-Life ; Head ; Humans ; Infusions, Subcutaneous ; Insulin ; Kidney ; Metabolism ; Peptides ; Plasma ; Venoms ; Liraglutide

BACKGROUND: The robot-assisted transaxillary approach to thyroid surgery is a novel method that has recently been used to improve patient safety and cosmetic outcomes. We evaluated post-operative pain, following robot-assisted endoscopic transaxillary thyroid surgery, and pain relief using a continuous wound perfusion system with local anesthetics. METHODS: In a control group of 25 female patients who underwent robot-assisted endoscopic transaxillary thyroidectomy, the post-operative pain scores and characteristics as well as analgesic use were monitored. Fifty female patients undergoing robot-assisted endoscopic transaxillary thyroidectomy were given the On-Q system. They were then randomly assigned to receive one of two different local anesthetic doses: Group I (0.25% Ropivacaine, n = 25); and Group II (0.375% Ropivacaine, n = 25). The pain score, pain site, analgesic requirements and side effects of each group were recorded during the 48 hour period post-surgery. RESULTS: Post-operative pain scores and analgesic demand were lower in the On-Q groups than in the control group. No difference was found between Group I and Group II. Until 6-12 hours after surgery, pain was mainly located in the axilla, while after 6-12 hours, the primary location of pain had a tendency to move to the neck. Pain scores gradually decreased in time for all patients. CONCLUSIONS: Patients who underwent robot-assisted endoscopic transaxillary thyroidectomy with an On-Q system injecting 0.25% ropivacaine had lower pain scores, showing the effectiveness of the system. As a potential pain blocker, continuous wound perfusion with the On-Q system attenuates side effects. This could lead to shortened hospital stays after robot-assisted endoscopic transaxillary thyroidectomy.
Amides ; Anesthetics, Local ; Axilla ; Female ; Humans ; Infusions, Subcutaneous ; Length of Stay ; Methods ; Neck ; Pain Management* ; Patient Safety ; Perfusion ; Robotics ; Thyroid Gland ; Thyroidectomy* ; Wounds and Injuries

BACKGROUND: The robot-assisted transaxillary approach to thyroid surgery is a novel method that has recently been used to improve patient safety and cosmetic outcomes. We evaluated post-operative pain, following robot-assisted endoscopic transaxillary thyroid surgery, and pain relief using a continuous wound perfusion system with local anesthetics. METHODS: In a control group of 25 female patients who underwent robot-assisted endoscopic transaxillary thyroidectomy, the post-operative pain scores and characteristics as well as analgesic use were monitored. Fifty female patients undergoing robot-assisted endoscopic transaxillary thyroidectomy were given the On-Q system. They were then randomly assigned to receive one of two different local anesthetic doses: Group I (0.25% Ropivacaine, n = 25); and Group II (0.375% Ropivacaine, n = 25). The pain score, pain site, analgesic requirements and side effects of each group were recorded during the 48 hour period post-surgery. RESULTS: Post-operative pain scores and analgesic demand were lower in the On-Q groups than in the control group. No difference was found between Group I and Group II. Until 6-12 hours after surgery, pain was mainly located in the axilla, while after 6-12 hours, the primary location of pain had a tendency to move to the neck. Pain scores gradually decreased in time for all patients. CONCLUSIONS: Patients who underwent robot-assisted endoscopic transaxillary thyroidectomy with an On-Q system injecting 0.25% ropivacaine had lower pain scores, showing the effectiveness of the system. As a potential pain blocker, continuous wound perfusion with the On-Q system attenuates side effects. This could lead to shortened hospital stays after robot-assisted endoscopic transaxillary thyroidectomy.
Amides ; Anesthetics, Local ; Axilla ; Female ; Humans ; Infusions, Subcutaneous ; Length of Stay ; Methods ; Neck ; Pain Management* ; Patient Safety ; Perfusion ; Robotics ; Thyroid Gland ; Thyroidectomy* ; Wounds and Injuries

The safety of accelerated schedules of allergen immunotherapy (ASAI) in patients with bronchial asthma (BA) has been reported but there are little data on the safety of ASAI for patients with atopic dermatitis (AD). In this study, we investigated the safety of ASAI in patients with AD. Sixty patients with AD and 18 patients with BA sensitized to house dust mites (HDM) were studied. A maximum maintenance dose of HDM extract, adsorbed to aluminum hydroxide, was administered to patients by subcutaneous injection with either a 3-day protocol (rush immunotherapy) or 1-day protocol (ultra-rush immunotherapy). Systemic reactions were observed 4 of 15 patients (26.7%) with AD during rush immunotherapy, 13 of 45 patients (28.9%) with AD during ultra-rush immunotherapy, and 4 of 18 patients (22.2%) with BA during rush immunotherapy (P > 0.05). No severe or near fatal systemic reactions occurred in 78 subjects of this study. Systemic reactions developed within 4 hr after administration of the maximum allergen dose in 20 of 21 patients (95.2%) with AD and BA who showed systemic reactions during rush or ultra-rush immunotherapy. In conclusion, ASAI was safe and well tolerated in patients with AD. ASAI can be a useful therapeutic option for AD.
Adolescent ; Adult ; Allergens/*therapeutic use ; Aluminum Hydroxide/chemistry ; Animals ; Asthma/therapy ; Dermatitis, Atopic/immunology/*therapy ; Desensitization, Immunologic/*methods ; Drug Administration Schedule ; Female ; Humans ; Infusions, Subcutaneous ; Male ; Pyroglyphidae/*immunology/metabolism

BACKGROUND: Insulin assays are affected by varying degrees of interference from anti-insulin antibodies (IAs) and by cross-reactivity with recombinant insulin analogues. We evaluated the usefulness of the E170 insulin assay by assessing IA effects and cross-reactivity with 2 analogues. METHODS: Sera were obtained from 59 type 2 diabetes patients receiving continuous subcutaneous insulin infusion and 18 healthy controls. Insulin levels were determined using an E170 analyzer. To investigate the effects of IAs, we performed IA radioimmunoassays, and analyzed the differences between directly measured insulin (direct insulin) and polyethylene glycol (PEG)-treated insulins (free, IA-unbound; total, IA-bound and unbound insulin). We performed in-vitro cross-reactivity tests with insulin aspart and insulin glulisine. RESULTS: In IA-positive patients, E170 free insulin levels measured using the E170 analyzer were significantly lower than the direct insulin levels. The mean value of the direct/free insulin ratio and IA-bound insulin, which were calculated as the difference between total and free insulin, increased significantly as endogenous IA levels increased. The E170 insulin assay showed low cross-reactivities with both analogues (< 0.7%). CONCLUSIONS: IAs interfered with E170 insulin assay, and the extent of interference correlated with the IA levels, which may be attributable to the increase in IA-bound insulin, and not to an error in the assay. The E170 insulin assay may measure only endogenous insulin since cross-reactivity is low. Our results suggest that the measurement of free insulin after PEG pre-treatment could be useful for beta cell function assessment in diabetic patients undergoing insulin therapy.
Adult ; Aged ; Aged, 80 and over ; Cross Reactions ; Diabetes Mellitus, Type 2/blood/immunology ; Female ; Humans ; Infusions, Subcutaneous ; Insulin/analogs & derivatives/*blood/chemistry/immunology ; Insulin Antibodies/*blood ; Male ; Middle Aged ; Polyethylene Glycols/chemistry ; Radioimmunoassay/instrumentation/*methods ; Recombinant Proteins/analysis/immunology/metabolism