Combination therapy of exercise and angiotensin-converting enzyme inhibitor markedly improves insulin sensitivities in hypertensive patients with insulin resistance.

The contraction of muscle enhances the release of bradykinin (BK) and improves glucose uptake by the muscle. Angiotensin-converting enzyme inhibitor (ACEI) slows the breakdown of BK, thus the effect of BK is augmented in the presence of ACEI. The present study investigated whether the combination of exercise (increased production of BK) and ACEI (delay in breakdown of BK) might further improve insulin sensitivity in hypertensive patients with insulin resistance (HOMA-R>1.8). Patients were assigned either to increased walking distance (Walking group) or taking 2 mg temocapril, an ACEI, daily (ACEI group) for 8 weeks. Then both interventions were given to all patients for 8 weeks (ACEI+Walking group). Blood concentrations of triglycerides were slightly lower in the ACEI+Walking group than at baseline, although there were no significant differences in total cholesterol or high density lipoprotein-cholesterol among the 2 groups. Blood glucose was not significantly different with each treatment, but blood concentrations of insulin and HOMA-R were significantly lower in the Walking and ACEI groups compared with the Control group. The combination of walking and ACEI further lowered blood concentrations of insulin and HOMA-R, which suggests that this treatment is beneficial for hypertensive patients with insulin resistance.     

Minireview: recent developments in the regulation of glucose transporter-4 traffic: new signals, locations, and partners

Glucose transporter (GLUT) 4 is the major glucose transporter of muscle and adipose cells, exquisitely regulated by insulin through posttranslational events. Twenty years after the seminal observations that GLUT4 levels rapidly rise at the plasma membrane (PM) and drop in endomembranes in response to an acute insulin challenge, we are still mapping the intracellular traffic of the transporter and the regulatory events that insulin unleashes. Newly synthesized GLUT4 enters an insulin-responsive compartment aided by GGA2 (an Arf-binding protein). In cultured adipocytes and myocytes, GLUT4 concentrates in a perinuclear pole through participation of microtubules and the EHD1 Eps15 homology domain-containing protein 1. In the absence of stimuli, GLUT4 distributes between recycling endosomes and the insulin-responsive compartment. A handful of proteins that bind to GLUT4 appear to regulate its half-life (e.g. Ubc9) and tethering within endomembranes (e.g. TUG). Insulin-derived signals promote not only GLUT4 mobilization toward the PM but also its traffic between endosomal compartments and internalization from the PM. Class IA phosphatidylinositol (PI) 3-kinase plays a pivotal role at several steps of GLUT4 mobilization. The PI 3-kinase --> atypical PKC and --> Akt/PKB --> AS160 signaling cascades are major regulators of GLUT4 exocytosis aided by small GTPases. At the cell periphery, GLUT4-containing vesicles tether, dock, and fuse with the PM assisted by the exocyst complex followed by engagement of a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex [with vesicle-associated membrane protein (VAMP)2 as the vesicular (v)-SNARE and soluble NSF-attachment protein (SNAP)23 and syntaxin4 as target (t)-SNAREs] regulated by the accessory proteins Munc18c, Synip and Tomosyn. Vesicle tethering and fusion are regulated by insulin through input from class IA PI 3-kinase.     

Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis

BACKGROUND/AIMS: The presence of antibodies to the 210-kDa glycoprotein of the nuclear pore complex (gp210) is highly indicative of primary biliary cirrhosis (PBC). However, the significance of anti-gp210 antibody titers for monitoring PBC remains unresolved. METHODS: We used an ELISA with a gp210 C-terminal peptide as an antigen to assess serum antibody titers in 71 patients with PBC. RESULTS: Patients were classified into three groups: Group A in whom anti-gp210 titers were sustained at a high level, Group B in whom anti-gp210 status changed from positive to negative under ursodeoxycholic acid (UDCA) therapy, Group C in whom anti-gp210 antibodies were negative at the time of diagnosis. The rate of progression to end-stage hepatic failure was significantly higher in group A (60%) as compared to groups B (0%) and C (4.2%). The sustained antibody response to gp210 was closely associated with the severity of interface hepatitis. The significance of anti-gp210 antibody was confirmed by National Hospital Organization Study Group for Liver Disease in Japan. CONCLUSIONS: The serial quantitation of serum anti-gp210-C-terminal peptide antibodies is useful for monitoring the effect of UDCA and for the early identification of patients at high risk for end-stage hepatic failure.     

Factor XI deficiency with a novel homozygous mutation Trp599Arg near the C-terminal region

We identified a novel mutation in an asymptomatic 72-year old Japanese woman with severe factor XI (FXI) deficiency. Sequence analysis showed a homozygous missense mutation Trp599Arg (g.234T-->C according to Genbank accession number M20218). This residue belongs to a region conserved in human FXI and the FXI of several animals. Molecular modeling showed that the Trp599 residue is positioned in an alpha helix in the C-terminal region of the FXI molecule.     

BDNF Release Is Required for the Behavioral Actions of Ketamine

Background:

Recent studies demonstrate that the rapid antidepressant ketamine increases spine number and function in the medial prefrontal cortex (mPFC), and that these effects are dependent on activation of glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and brain-derived neurotrophic factor (BDNF). In vitro studies also show that activation of AMPA receptors stimulates BNDF release via activation of L-type voltage-dependent calcium channels (VDCC).

Methods:

Based on this evidence, we examined the role of BDNF release and the impact of L-type VDCCs on the behavioral actions of ketamine.

Results:

The results demonstrate that infusion of a neutralizing BDNF antibody into the mPFC blocks the behavioral effects of ketamine in the forced swim test (FST). In addition, we show that pretreatment with nifedipine or verapamil, two structurally-different L-type calcium channel antagonists, blocks the behavioral effects of ketamine in the FST. Finally, we show that ketamine treatment stimulates BDNF release in primary cortical neurons and that this effect is blocked by inhibition of AMPA receptors or L-type VDCCs.

Conclusions:

Taken together, these results indicate that the antidepressant effects of ketamine are mediated by activation of L-type VDCCs and the release of BDNF. They further elucidate the cellular mechanisms underlying this novel rapid-acting antidepressant.     

Liver Injury Among Japanese Patients Treated Using Prophylactic Enoxaparin After Colorectal Surgery

Digestive Diseases and Sciences - Enoxaparin, a low molecular weight heparin, has been used to prevent thrombotic events during major surgery without increasing the rate of hemorrhage. On the other...     

Health-related quality of life of outpatients with systolic and isolated diastolic dysfunction

Background The impact of isolated diastolic dysfunction (IDD) and systolic dysfunction (SD) on health-related quality of life (HRQOL) is unknown. Methods and Results To evaluate HRQOL in patients with IDD and SD under treatment, information on outpatients aged 60-84 years was extracted from the records of 4,500 consecutive individuals who underwent echocardiographic examination at Sado General Hospital. The medical records of these patients were reviewed and a questionnaire, including the Medical Outcome Study Short Form 36, was mailed to 71 IDD and 99 SD patients; answers were obtained from 66 and 91 patients, respectively. The HRQOL of patients with cardiac dysfunction was impaired even when echocardiographic parameters improved with treatment. Patients with IDD showed an impairment of HRQOL similar to those with SD. Compared with males, female patients had a larger and more significant reduction in the physical and mental components of the HRQOL score. These scores correlated positively with exercise capacity in patients with IDD or SD. Conclusions Impaired HRQOL, in both its mental and physical components, is a serious problem for IDD and SD patients under treatment. Because exercise intolerance may underlie the reduced HRQOL, improving exercise capacity could be an important target for managing outpatients with heart failure. (Circ J 2008; 72: 1436 - 1442).     

Comparison of laparoscopic Toupet and laparoscopic Nissen fundoplications in neurologically normal children

Introduction

We compared laparoscopic Toupet fundoplication (LTF) and laparoscopic Nissen fundoplication (LNF) in neurologically normal children.

Methods

Forty neurologically normal children who were followed up for more than 3 years after LTF (n = 22) or LNF (n = 18) were reviewed retrospectively. LTF and LNF were performed between 2006 and 2012.

Results

There were no significant differences in gender (LTF, 15 male and 7 female patients; LNF:, 12 male and 6 female patients), mean age at surgery (LTF vs LNF: 2.5 vs 2.3 years), mean weight at surgery (LTF vs LNF: 9.6 vs 8.9 kg), preoperative symptoms, preoperative pH monitoring (pH <4) (LTF vs LNF: 26.7% vs 21.8%), mean operative time (LTF vs LNF: 117 vs 126 min), postoperative recommencement of enteral feeding (LTF vs LNF: 3.7 vs 3.8 days), or duration of hospitalization (LTF vs LNF: 5.5 vs 6.3 days). Intraoperative complications were esophageal trauma (LTF; n = 1; 4.5%) and liver trauma (LNF; n = 1; 5.6%) (P = 0.70). Post‐LTF complications were wrap stenosis (n = 1; 4.5%), and post‐LNF complications were wrap stenosis (n = 1; 5.5%) and gastric outlet obstruction (n = 1; 5.5%) (P = 0.43); all were managed conservatively. No case required conversion to open repair. There was no recurrence after LTF, but there were three cases (16.7%) after LNF (P = 0.08). Reoperation was performed at 4, 11, and 13 months, respectively.

Conclusion

Despite LTF and LNF appearing to be equally effective, three LNF cases required reoperation.