Possible role of D-serine in the pathophysiology of Alzheimer's disease

Several lines of evidence suggest that D-serine may function as an endogenous agonist of the glycine site on the N-methyl-D-aspartate (NMDA) receptor that has been implicated in the pathophysiology of Alzheimer's disease (AD). The purpose of the study was to determine whether serum levels of D- and L-serine in patients with AD are altered as compared with normal controls. Serum levels of D- and L-serine in patients of AD and age- and gender-matched normal controls were determined using a high-performance liquid chromatography (HPLC). Serum levels of D-serine in the patients with AD were slightly (z=-1.77, p=0.078) lower than those of normal controls. In contrast, serum levels of L-serine in the patients were slightly (z=-1.73, p=0.083) higher than those of controls. In addition, the percentage (%) of D-serine in the total (L+D) serine in the patients was significantly (z=-2.36, p=0.018) lower than that of controls. The present study suggests that the reduced activity of serine racemase, an enzyme catalyzing the formation of D-serine from L-serine may play a role in the pathophysiology of AD.     

Diurnal variation in QT dispersion in patients with chronic heart failure

QT dispersion is defined as the difference in QT interval among the different leads of the standard 12-lead electrocardiogram and reflects inhomogeneity of myocardial repolarization. Dispersion of repolarization is an important electrophysiologic feature that is considered fundamental for the initiation of ventricular fibrillation. However, no data exist regarding the diurnal variation of QT dispersion measured from simultaneous 12-lead recording in chronic heart failure patients. The aim of this study was to identify diurnal variation in QT dispersion in patients with chronic heart failure. QT dispersion was measured in the 12-lead standard electrocardiogram in 11 patients with chronic heart failure. QT dispersion in these patients was increased in the afternoon compared to the morning. It is concluded that QT dispersion has a clear diurnal variation in patients with chronic heart failure. These findings have potentially significant implications for therapy and prevention of sudden cardiac death in patients with chronic heart failure.     

Epicardial and endocardial mapping determine most successful site of ablation for ventricular tachyarrhythmias originating from left ventricular summit

A 34-year-old woman presented with idiopathic premature ventricular complex (PVC) and ventricular tachycardia (VT) originating from the area called the left ventricular summit. Radiofrequency (RF) application both through the coronary sinus and to the epicardial surface transiently suppressed the VT/PVC. Radiofrequency with sufficient energy was only applicable from the endocardial site, and the VT/PVC was successfully eliminated.     

Glycine and <Emphasis Type="SmallCaps">d</Emphasis>-serine,but not <Emphasis Type="SmallCaps">d</Emphasis>-cycloserine,attenuate prepulse inhibition deficits induced by NMDA receptor antagonist MK-801

RATIONALE: Several agents that stimulate the glycine site of N-methyl-D: -aspartate (NMDA) receptors have been reported to moderately improve both negative symptoms and cognitive dysfunctions in patients with schizophrenia. However, differences in efficacy have also been reported, and further comparative pharmacological studies are still needed. OBJECTIVES: We aimed to explore the effects of two glycine site agonists of the NMDA receptor, glycine and D: -serine, and a partial agonist, D: -cycloserine, on prepulse inhibition (PPI) deficits induced by a NMDA receptor antagonist, MK-801, in mice. Furthermore, we performed in vivo microdialysis and additional PPI measurements using a selective glycine site antagonist to verify if the beneficial effects observed after the systemic administration of glycine were due to glycine itself via its activity at the glycine site. RESULTS: High doses of glycine (1.6 g/kg) and D: -serine (1.8 and 2.7 g/kg) significantly attenuated MK-801-induced PPI deficits. In contrast, D: -cycloserine did not show any amelioration of MK-801-induced PPI deficits at doses ranging from 7.5 mg/kg to 60 mg/kg. The selective glycine site antagonist, L-701,324 (10 mg/kg), antagonized the effect of glycine on MK-801-induced PPI deficits. Furthermore, in vivo microdialysis demonstrated that intraperitoneal injection of glycine significantly increased glycine and L: -serine levels, but decreased D: -serine levels in the prefrontal cortex. CONCLUSIONS: The findings of the present study suggest that glycine and D: -serine but not D: -cycloserine could attenuate PPI deficits associated with NMDA receptor hypofunction via NMDA glycine sites in the brain.     

Molecular mechanisms of experimental glomerulonephritis: an overview

Summary: Most glomerular diseases are autoimmune in nature with injury occurring as a consequence of antibody reacting with antigens on glomerular cell membranes or in glomerular matrix, or immune complex formation occurring on or near glomerular cell membrnes. Many of the structural and functional consequences of these events result from the response of resident glomerular cells to the injury, or may be induced by inflammatory effector cells derived from the circulation. In terms of glomerular cells, injury to the glomerular epithelial cell (GEC) may be induced by: (i) non-complement fixing antibodies which mimic the glomerular lesions of minimal change nephrotic syndrome/focal glomerular sclerosis; or (ii) by antibodies which fix complement leading to GEC attack by C5b-9 resulting in a lesion analogous to membranous nephropathy. C5b-9 also mediates antibody induced injury to the mesangial cell resulting in a mesangioproliferative glomerulonephritis (IgA nephropathy, systemic lupus erythematosus; SLE) as well as to the glomerular endothelial cell (thrombotic microangiopathy, haemolytic uraemic syndrome). the effects of C5b-9 may be lytic (mesangial cell, glomerular endothelial cell; GEN) or sublytic (GEC) resulting in stimulation of local oxident and protease production. Both lytic and sublytic effects are substantially modulated by cell-bound complement regulatory proteins such as CD59 and Crry. When fixed or planted antigens are present in larger quantities and accessible to the circulation, complement activation generates chemotactic factors leading to neutrophil infiltration and producing injury through the myeloperoxidase (MPO)-H₂-O₂-halide system, a mechanism substantially augmented by platelet-neutrophil interaction (post-infectious glomerulonephritis [GN], SLE). Macrophages may also be localized in glomeruli by either immune adherence mechanisms or as a consequence of cell mediated immune reactions in the glomerulus. Macrophages differ from neutrophils in producing large amounts of transforming growth factor-β (TGF-β) and procoagulants which contribute to crescent formation rapidly progressive glomerulonephritis (RPGN).     

Indications for an implantable cardioverter defibrillator (ICD)

Since the first clinical use of implantable defibrillator in human, the technology and the function of implantable cardioverter-defibrillator (ICD) have been much improved and now, ICD can be implanted within the chest wall. ICD is the most reliable therapy to prevent sudden cardiac death (SCD) in patients with documented VT/VF and the efficacy is most clear in patients with depressed heart function. It is now extended as a tool of the primary prevention of SCD in high risk patients after myocardial infarction. However, such beneficial effect is not applicable to DCM though patients might have depressed heart function. ICD is not free from procedure- or device-related problems which need to be resolved. From unknown causes, VT/VF might recur in an incessant form and an emergency admission is needed. Therefore, even during ICD therapy, patients often require antiarrhythmic drugs or catheter ablation.     

Effect of applying p75NTR saporin to a punctured intervertebral disc on calcitonin gene-related peptide expression in rat dorsal root ganglion neurons

Background

Recent studies have revealed that the low-affinity nerve growth factor receptor, p75 neurotrophin receptor (p75NTR), is important in inflammatory pain. Moreover, p75NTR immunoreactive sensory nerve and dorsal root ganglion (DRG) neurons have been found to innervate lumbar intervertebral discs. The purpose of the current study was to investigate the effect of p75NTR saporin, a toxin used to destroy p75NTR, on calcitonin gene-related peptide (CGRP), an inflammatory neuropeptide associated with pain, in DRG neurons innervating punctured intervertebral discs in rats.

Methods

The neurotracer fluorogold (FG) was applied to the surfaces of L5/6 discs to label their innervating DRG neurons (n = 30). Of 30 rats, 10 were in a nonpunctured disc sham surgery control group (nonpuncture group), and the other 20 were in experimental groups in which intervertebral discs were punctured with a 23-gauge needle. p75NTR saporin was applied to the discs of 10 rats (puncture + p75NTR saporin group) and the other 10 received the same volume of saline (puncture + saline group). At 14 days after surgery, DRGs from L1 to L6 were harvested, sectioned, and immunostained for CGRP, and the proportions of CGRP-immunoreactive DRG neurons was evaluated.

Results

Of the FG-labeled neurons innervating the L5/6 disc, the proportion of CGRP-immunoreactive neurons was 32% ± 6% (mean ± SE) in the nonpuncture group, 47.2% ± 8% in the puncture + saline group, and 34.6% ± 9% in the puncture + p75NTR saporin group. The proportion of CGRP-immunoreactive neurons was significantly greater in the puncture + saline group compared with the nonpuncture and puncture + p75NTR saporin groups (P < 0.01).

Conclusions

Half of the DRG neurons innervating the discs were positive for CGRP in the puncture + saline group. CGRP is important for mediating inflammatory and nerve-injured pain and may be important in discogenic pain. However, p75NTR saporin suppressed CGRP expression in DRG neurons. Therefore, p75NTR may be an important receptor for mediating discogenic pain via CGRP expression.     

Definition of MCN (mucinous cystic neoplasm of the pancreas) and a proposal for a new concept of MRN or MSN (mucinous round or spherical neoplasm)

The differential diagnosis of IPMN and MCN is very important for clinicians. MCN is reported to develop in middle-aged females (mean age 48 years) and in the body and tail of the pancreas. Some doctors insist that ovarian-like stroma is absolutely necessary for the definition of MCN. Prompt resection of MCN after diagnosis is desirable. In contrast, about 60% of cases with branch-type IPMN do not require an operation. Therefore, one of the important goals in the differential diagnosis of MCN and branch-type IPMN is to determine the surgical indications before the operation. We believe that MCN and IPMN should be defined by imaging procedures before the operation. We suggest that a neoplasm with an appearance similar to an orange should be diagnosed as MCN, while that with an appearance similar to a bunch of grapes in MRCP should be diagnosed as branch-type IPMN. Proposal of a new concept: If the term MCN is restricted to neoplasms that exhibit ovarian-like stroma, we propose that lesions which are surrounded by a very thick capsule, and which show an orange-like appearance by imaging procedures without histological ovarian-like stroma should be called MRN (mucinous round neoplasm) or MSN (mucinous spherical neoplasm).