Changes in left anterior descending coronary artery wall thickness detected by high resolution transthoracic echocardiography

Recently, it has been demonstrated that high-resolution transthoracic echocardiography (HRTTE) is able to detect differences in the wall thickness of the left anterior descending coronary artery (LAD) between patients with coronary artery disease (CAD) and normal volunteers. The aim of this study was to further validate this technique. One hundred ten volunteers, 58 patients with angiographically proved CAD and 52 control subjects, underwent assessments of their LADs using HRTTE. Anterior and posterior wall thicknesses differed between subjects in the CAD group and controls (1.9 +/- 0.6 vs 1.2 +/- 0.3 mm, p <0.001, and 1.8 +/- 0.5 vs 1.2 +/- 0.3 mm, p <0.001, respectively). External LAD diameter was also greater in subjects in the CAD group compared with controls (5.2 +/- 1.9 vs 4.4 +/- 0.9 mm, respectively, p = 0.01). However, there was no difference in luminal diameter between subjects in the CAD group and the controls (1.9 +/- 0.9 vs 2.1 +/- 0.8 mm, respectively, p = 0.3). In conclusion, HRTTE demonstrated that LAD wall thicknesses and external diameters in patients with CAD were significantly larger than in normal volunteers. Luminal diameter, however, was maintained in the 2 groups, indicating that subjects in the CAD group had undergone positive remodeling at the site measured. This objectively visualized evidence of coronary atherosclerosis with HRTTE would likely be undetected during coronary angiography.     

Current Antiviral Therapy of Chronic Hepatitis B: Efficacy and Safety

The treatment of chronic hepatitis B is in constant evolution. Interferon, the first agent licensed for chronic hepatitis B treatment, has been superseded by the growing popularity of nucleoside/nucleotide analogues (NA). However, resistance to these agents is a major challenge. Newer NAs, such as entecavir and tenofovir dipivoxil fumarate, have very low resistance rates and favorable safety profiles. Long-term use of these agents can effectively suppress hepatitis B virus DNA, leading to decrease in incidence of hepatitic flares, as well as in the development of cirrhosis and hepatocellular carcinoma. The efficacy and safety of various antiviral agents is discussed in this review.     

Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca²⁺/Calmodulin-dependent protein kinase II

The balance between excitatory and inhibitory synapses is crucial for normal brain function. Wnt proteins stimulate synapse formation by increasing synaptic assembly. However, it is unclear whether Wnt signaling differentially regulates the formation of excitatory and inhibitory synapses. Here, we demonstrate that Wnt7a preferentially stimulates excitatory synapse formation and function. In hippocampal neurons, Wnt7a increases the number of excitatory synapses, whereas inhibitory synapses are unaffected. Wnt7a or postsynaptic expression of Dishevelled-1 (Dvl1), a core Wnt signaling component, increases the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents (mIPSCs). Wnt7a increases the density and maturity of dendritic spines, whereas Wnt7a-Dvl1-deficient mice exhibit defects in spine morphogenesis and mossy fiber-CA3 synaptic transmission in the hippocampus. Using a postsynaptic reporter for Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII) activity, we demonstrate that Wnt7a rapidly activates CaMKII in spines. Importantly, CaMKII inhibition abolishes the effects of Wnt7a on spine growth and excitatory synaptic strength. These data indicate that Wnt7a signaling is critical to regulate spine growth and synaptic strength through the local activation of CaMKII at dendritic spines. Therefore, aberrant Wnt7a signaling may contribute to neurological disorders in which excitatory signaling is disrupted.     

Relation of addiction genes to hypothalamic gene changes subserving genesis and gratification of a classic instinct, sodium appetite

Sodium appetite is an instinct that involves avid specific intention. It is elicited by sodium deficiency, stress-evoked adrenocorticotropic hormone (ACTH), and reproduction. Genome-wide microarrays in sodium-deficient mice or after ACTH infusion showed up-regulation of hypothalamic genes, including dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa (DARPP-32), dopamine receptors-1 and -2, α-2C- adrenoceptor, and striatally enriched protein tyrosine phosphatase (STEP). Both DARPP-32 and neural plasticity regulator activity-regulated cytoskeleton associated protein (ARC) were up-regulated in lateral hypothalamic orexinergic neurons by sodium deficiency. Administration of dopamine D1 (SCH23390) and D2 receptor (raclopride) antagonists reduced gratification of sodium appetite triggered by sodium deficiency. SCH23390 was specific, having no effect on osmotic-induced water drinking, whereas raclopride also reduced water intake. D1 receptor KO mice had normal sodium appetite, indicating compensatory regulation. Appetite was insensitive to SCH23390, confirming the absence of off-target effects. Bilateral microinjection of SCH23390 (100 nM in 200 nL) into rats' lateral hypothalamus greatly reduced sodium appetite. Gene set enrichment analysis in hypothalami of mice with sodium appetite showed significant enrichment of gene sets previously linked to addiction (opiates and cocaine). This finding of concerted gene regulation was attenuated on gratification with perplexingly rapid kinetics of only 10 min, anteceding significant absorption of salt from the gut. Salt appetite and hedonic liking of salt taste have evolved over >100 million y (e.g., being present in Metatheria). Drugs causing pleasure and addiction are comparatively recent and likely reflect usurping of evolutionary ancient systems with high survival value by the gratification of contemporary hedonic indulgences. Our findings outline a molecular logic for instinctive behavior encoded by the brain with possible important translational-medical implications.     

Combining shock reduction strategies to enhance ICD therapy: a role for computer modeling

Combining Shock Reduction Strategies to Enhance ICD Therapy . Objectives: To develop a computer model to test shock reduction strategies such as antitachycardia pacing and shock withholding for supraventricular rhythms, oversensing, and nonsustained ventricular tachycardia. Background: While the implantable cardioverter defibrillator (ICD) can reduce mortality, inappropriate ICD shocks remain a limitation. Randomized trials provide evidence of efficacy, but they are not always practical. Computer models provide an alternative approach, and are particularly useful when evaluating multiple interventions. Methods: A computer model was developed using clinical data and validated in a large ICD data set (EMPIRIC). After validation, the model was applied to 736 adjudicated clinical episodes from the ICD arm of Sudden Cardiac Death Heart Failure Trial (SCD‐HeFT). Results: The shock reduction strategies hypothetically reduced the number of VT/VF shocked episodes in SCD‐HeFT by an estimated 59% (from 952 observed to 395 modeled shocks, probability of >0.999) at detection duration settings (18 of 24 intervals). The percentage of patients experiencing inappropriate shocks over 5 years was decreased by 15% (23.5–8.4%), and the number of shocks for non‐VT/VF episodes was decreased from 423 to 77 (82% reduction). The percentage of patients receiving shocks for VT/VF was reduced from 30.7% (SCD‐HeFT) to 26.1% with the addition of ATP. Extended detection (24 of 32 or 30 of 40 intervals) showed modest additional improvement compared to 18 of 24 intervals. Conclusion: Computer modeling is able to predict the results of a known clinical trial and demonstrate that shock reduction strategies have the potential to significantly reduce inappropriate and unnecessary ICD shocks versus the mandated programming used in SCD‐HeFT. (J Cardiovasc Electrophysiol, Vol. 22, pp. 280‐289, March 2011)     

Normal expiratory flow rate and lung volumes in patients with combined emphysema and interstitial lung disease: a case series and literature review

Pulmonary function tests in patients with idiopathic pulmonary fibrosis characteristically show a restrictive pattern including small lung volumes and increased expiratory flow rates resulting from a reduction in pulmonary compliance due to diffuse fibrosis. Conversely, an obstructive pattern with hyperinflation results in emphysema by loss of elastic recoil, expiratory collapse of the peripheral airways and air trapping. When the diseases coexist, pulmonary volumes are compensated, and a smaller than expected reduction or even normal lung volumes can be found. The present report describes 10 patients with progressive breathlessness, three of whom experienced severe limitation in their quality of life. All patients showed lung interstitial involvement and emphysema on computed tomography scan of the chest. The 10 patients showed normal spirometry and lung volumes with severe compromise of gas exchange. Normal lung volumes do not exclude diagnosis of idiopathic pulmonary fibrosis in patients with concomitant emphysema. The relatively preserved lung volumes may underestimate the severity of idiopathic pulmonary fibrosis and attenuate its effects on lung function parameters.     

Polymorphisms within Fas gene are not associated with occult hepatitis B virus infection: Polymorphisms within Fas gene in occult HBV infection

Background

Occult hepatitis B infection (OBI) is a form of hepatitis in which there is an absence of detectable HBsAg, despite the presence of HBV-DNA in the peripheral blood of patients. It seems that non-effective or attenuated immune system responses against HBV lead to the development of OBI. Previous studies showed that the Fas/Fas ligand (FasL) system is an important death signaling pathway that is used by cytotoxic T lymphocytes to eradicate HBV from the liver.

Objectives

To investigate polymorphisms in the -670 region of the Fas gene in those with OBI.

Patients and Methods

The plasma samples from 3700 blood donors were tested for HBsAg and anti-HBs by ELISA. The HBsAg-/anti-HBc(+) samples were selected and screened for HBV-DNA by PCR. Those with HBV-DNA were diagnosed as OBI and PCR-RFLP technique was performed to examine polymorphisms within their Fas gene.

Results

352 (9.5%) of 3700 blood samples were HBsAg-/anti-HBc(+). HBV-DNA was detected in 57 (16.1%) of 352 HBsAg-/anti-HBc(+) samples. Therefore, 57 HBsAg-/anti-HBc+/HBV-DNA(+) patients were diagnosed as OBI. Patient and control groups had no significant differences in terms of the studied polymorphisms.

Conclusions

The functional polymorphisms in the promoter region of Fas gene are not associated with OBI. Therefore, it may be concluded that polymorphisms at the -670 position of the Fas gene do not have any critical effects on the immune response against HBV in OBI.     

Inducible nitric oxide synthase (iNOS) in muscle wasting syndrome, sarcopenia, and cachexia

Muscle atrophy-also known as muscle wasting-is a debilitating syndrome that slowly develops with age (sarcopenia) or rapidly appears at the late stages of deadly diseases such as cancer, AIDS, and sepsis (cachexia). Despite the prevalence and the drastic detrimental effects of these two syndromes, there are currently no widely used, effective treatment options for those suffering from muscle wasting. In an attempt to identify potential therapeutic targets, the molecular mechanisms of sarcopenia and cachexia have begun to be elucidated. Growing evidence suggests that inflammatory cytokines may play an important role in the pathology of both syndromes. As one of the key cytokines involved in both sarcopenic and cachectic muscle wasting, tumor necrosis factor α (TNFα) and its downstream effectors provide an enticing target for pharmacological intervention. However, to date, no drugs targeting the TNFα signaling pathway have been successful as a remedial option for the treatment of muscle wasting. Thus, there is a need to identify new effectors in this important pathway that might prove to be more efficacious targets. Inducible nitric oxide synthase (iNOS) has recently been shown to be an important mediator of TNFα-induced cachectic muscle loss, and studies suggest that it may also play a role in sarcopenia. In addition, investigations into the mechanism of iNOS-mediated muscle loss have begun to reveal potential therapeutic strategies. In this review, we will highlight the potential for targeting the iNOS/NO pathway in the treatment of muscle loss and discuss its functional relevance in sarcopenia and cachexia.