4-Aminopyridine and l-cis-diltiazem block the cGMP-activated K channels closed by light in the molluscan extra-ocular photoreceptors

The cGMP-activated K⁺ channels closed by light lead to the depolarizing photocurrent of photoreceptors in the Onchidium ganglion. Whole-cell current records showed that external application of 100–200 μM 4-aminopyridine or 200–400 μM l-cis-diltiazem completely blocked the macroscopic photocurrent at any depolarizing and hyperpolarizing potentials. Single-channel current recordings suggested that both 4-aminopyridine and l-cis-diltiazem act to block the cGMP-activated K⁺ channels in their open state from inside the cell.     

Detection of in-stent restenosis of coronary stents using 40-detector row computed tomography in vitro

OBJECTIVE: To evaluate the performance of 40-detector row computed tomography (CT) in the detection of in-stent stenosis of coronary stents. METHODS: Seven patent vascular models, 7 stenotic models, and 7 obstructed models were scanned with a 40-detector CT. We made the vascular models using 3 types of stent (Bx-Velocity, Express2, Driver) with an inner diameter of about 2.5, 3.0, or 3.5 mm. We measured the stent lumen diameter and evaluated the in-stent stenosis visually for the 21 vascular models. We evaluated attenuation values of the stent lumen of the 9 patent models of 2.5-mm diameter. RESULTS: The inner diameters of the vascular models were underestimated by CT with mean measurement errors of -1.19 to -1.49 mm. The absolute mean overall measurement error decreased as the inner diameter increased. The direct visualization of in-stent stenosis was possible for the 3.0- and 3.5-mm diameter models, but impossible for the 2.5-mm diameter models. For patent vascular models of 2.5-mm diameter, the CT attenuation inside the stent was significantly higher than that of the unstented portion (P < 0.0001). For obstructed vascular models of 2.5-mm diameter, the CT attenuation inside the stent was significantly lower than that of the unstented portion (P < 0.0001). Also for stenotic vascular models of 2.5-mm diameter, the CT attenuation inside the stent was lower than that of the unstented portion. CONCLUSIONS: Visualization of stent lumen on CT is affected by the stent diameter. Measurement of stent lumen is useful for detection of in-stent stenosis, when the direct visualization of in-stent stenosis is impossible.     

Time course of effects of venlafaxine on migraine and generalized pruritus in a patient with depression

Venlafaxine has potential as a therapeutic option for patients with depressive disorder, migraine, and pruritus unresponsive to antihistamines.     

Neuronal cell death by Alzheimer's disease-relevant insults and its rescue

Neuronal cell death accounts for the clinical manifestations in Alzheimer's disease (AD). To establish the curative therapy of AD, neuroprotection is one of the primary therapeutic targets, and the elucidation of the mechanism of neuronal cell death is mandatory. Detailed characterization of neuronal cell death caused by familial AD (FAD)-linked mutant genes revealed that different cell death pathways are evoked by different types of mutants. Humanin (HN), a newly identified neuroprotective peptide, suppresses neuronal cell death caused by all known FAD mutants and A beta, while it has no effect on neuronal cell death caused by AD-irrelevant insults. The functional target of HN is the antagonism to neuronal death, not the modulation of A beta production, suggesting that HN-based medication can be combined with other remedies targeting A beta. HN is a promising seed for a novel therapy aiming at complete cure of AD through the suppression of neuronal loss.     

Prevalence and persistence of depression in patients with implantable cardioverter defibrillator: a 2-year longitudinal study

Background: It is unclear whether depression persists in patients with implantable cardioverter defibrillators (ICDs). We evaluated the prevalence and persistence of depression in ICD patients over a 2‐year period. Methods: The study included 90 consecutively hospitalized patients. Patients underlying heart disease was 24% coronary artery disease, 29% idiopathic dilated cardiomyopathy, 24% hypertrophic cardiomyopathy, 13% idiopathic VF/long QT syndrome and miscellaneous conditions 11%. A secondary indication for ICD implantation was present in 20 patients. All patients completed the Zung Self‐Rating Depression Scale (SDS) at study baseline and at the their routine follow‐up visit 2 years after the baseline questionnaire. Delivery of ICD therapies was tracked throughout the 2 years. Results: Depression, indicated by a Zung SDS index score exceeding 60, was present in 29 (32%) of patients at study baseline. Depression was present in 11/51 (21%) patients scheduled to undergo ICD implantation, 2/2 (100%) patients whose device was upgraded to a CRT‐D, 3/14 (21%) patients who had undergone pulse generator replacement, 7/14 (50%) patients who experienced electrical storm and 6/9 (66%) patients hospitalized with acute decompensated heart failure. NYHA functional class III was significantly associated with depression at baseline (HR 6.7, 95% CI 1.68–27.2, p = 0.0007). No differences were noted for female gender, demographics, β‐blocker use, or LVEF ≤35% (p = ns). Depression was present in 25 (28%) of patients at 2 years follow‐up, persisting in 21 (72%) of patients whose Zung SDS scores were elevated at baseline. The median time from ICD shock therapy to completion of the 2 year questionnaire was 9 months (range, 1–22). Patients who were depressed (9/25, 36%) experienced more shocks than non‐depressed patients (6/65, 9%) after 2 years (p = 0.002). Conclusions: Depression is not uncommon among patients who meet criteria for ICD implantation and persists over time particularly when functional status is impaired. Depression is associated with a higher incidence shock therapy. (PACE 2010; 33:1455–1461)     

Simple method for the identification of oxidative fibers in skeletal muscle

Skeletal muscle is composed of several different types of myofiber: slow oxidative (SO), fast glycolytic oxidative and fast glycolytic. However, the classification is usually determined by myosin heavy chain typing rather than by metabolic index. In this study, the oxidative metabolic index was investigated as a possible method of myofiber typing. Myoglobin, which is involved in oxygen transport and storage in myofibers, and mitochondria, which are the central organelles for oxidative metabolism, were studied. High levels of myoglobin and mitochondria are believed to exist in SO fibers, but the current study showed that they are considerably richer in some fast type fibers. As myofiber typing using the oxidative metabolic index is important physiologically, an attempt was made to find a simple method for this purpose. Some mitochondrial proteins have been observed to auto-fluoresce but until now this effect was too faint to detect easily. Owing to the recent advances in cooling charge-coupled device technology, such auto-fluorescence can now be used for myofiber typing, and the simple and rapid method for doing so is reported here.     

Leader (L) and L* proteins of Theiler's murine encephalomyelitis virus (TMEV) and their regulation of the virus' biological activities

Theiler's murine encephalomyelitis virus (TMEV) is divided into two subgroups on the basis of their different biological activities. GDVII subgroup strains produce fatal poliomyelitis in mice without virus persistence or demyelination. In contrast, TO subgroup strains induce demyelinating disease with virus persistence in the spinal cords of weanling mice. Two proteins, whose open reading frames are located in the N-terminus of the polyprotein, recently have been reported to be important for TMEV biological activities. One is leader (L) protein and is processed from the most N-terminus of the polyprotein; its function is still unknown. Although the homology of capsid proteins between DA (a representative strain of TO subgroup) and GDVII strains is over 94% at the amino acid level, that of L shows only 85%. Therefore, L is thought to be a key protein for the subgroup-specific biological activities of TMEV. Various studies have demonstrated that L plays important roles in the escape of virus from host immune defenses in the early stage of infection. The second protein is a 17–18 kDa protein, L*, which is synthesized out-of-frame with the polyprotein. Only TO subgroup strains produce L* since GDVII subgroup strains have an ACG rather than AUG at the initiation site and therefore do not synthesize L*. 'Loss and gain of function' experiments demonstrate that L* is essential for virus growth in macrophages, a target cell for TMEV persistence. L* also has been demonstrated to be necessary for TMEV persistence and demyelination. Further analysis of L and L* will help elucidate the pathomechanism(s) of TMEV-induced demyelinating disease.     

Therapeutic versus neuroinflammatory effects of passive immunization is dependent on Aβ/amyloid burden in a transgenic mouse model of Alzheimer's disease

Background

Passive immunization with antibodies directed to Aβ decreases brain Aβ/amyloid burden and preserves memory in transgenic mouse models of Alzheimer's disease (AD). This therapeutic strategy is under intense scrutiny in clinical studies, but its application is limited by neuroinflammatory side effects (autoimmune encephalitis and vasogenic edema).

Methods

We intravenously administered the monoclonal Aβ protofibril antibody PFA1 to aged (22 month) male and female 3 × tg AD mice with intermediate or advanced AD-like neuropathologies, respectively, and measured brain and serum Aβ and CNS cytokine levels. We also examined 17 month old 3 × tg AD female mice with intermediate pathology to determine the effect of amyloid burden on responses to passive immunization.

Results

The 22 month old male mice immunized with PFA1 had decreased brain Aβ, increased serum Aβ, and no change in CNS cytokine levels. In contrast, 22 month old immunized female mice revealed no change in brain Aβ, decreased serum Aβ, and increased CNS cytokine levels. Identical experiments in younger (17 month old) female 3 × tg AD mice with intermediate AD-like neuropathologies revealed a trend towards decreased brain Aβ and increased serum Aβ accompanied by a decrease in CNS MCP-1.

Conclusions

These data suggest that passive immunization with PFA1 in 3 × tg AD mice with intermediate disease burden, regardless of sex, is effective in mediating potentially therapeutic effects such as lowering brain Aβ. In contrast, passive immunization of mice with a more advanced amyloid burden may result in potentially adverse effects (encephalitis and vasogenic edema) mediated by certain proinflammatory cytokines.     

Undercarboxylated osteocalcin concentration in postmenopausal women receiving hormone therapy daily and on alternate days

OBJECTIVE: Undercarboxylated osteocalcin (ucOC) is a sensitive marker of vitamin K status. The authors examined the difference in serum ucOC concentrations in postmenopausal women receiving hormone therapy (HT) daily and on alternate days, and assessed the association between ucOC and triglyceride concentrations, which are related to the transport of vitamin K. DESIGN: Seventy-three postmenopausal women were recruited for this study. Thirty-seven women received 0.625 mg of conjugated equine estrogens (CEE) and 2.5 mg of medroxyprogesterone acetate (MPA) daily, and 36 women received 0.625 mg of CEE and 2.5 mg of MPA on alternate days. The concentrations of serum ucOC, bone turnover markers, lipid profiles, and hormones were measured before and after 12 months of HT. RESULTS: The ucOC concentration in women taking HT daily was significantly (P < 0.01) lower than that in women taking HT on alternate days. Serum ucOC concentrations during HT showed a significant (P < 0.01) inverse correlation with estradiol concentrations during HT. Serum estradiol concentrations during HT showed a significant (P < 0.01) positive correlation with triglyceride concentrations during HT. Furthermore, ucOC concentrations during HT showed a significant (P < 0.05) inverse correlation with triglyceride concentrations in women receiving HT. CONCLUSIONS: The effect of HT on alternate days on ucOC concentration was weaker than the effect of HT daily. In addition, ucOC concentration after 12 months of HT daily might be decreased due to the conversion of ucOC to carboxylated OC by the effect of vitamin K through increased triglyceride levels induced by oral CEE.