Reduced expression of glyoxalase-1 mRNA in mood disorder patients

Glyoxalase-1 (Glo1) is an antioxidant enzyme which detoxifies alpha-ketoaldehydes to prevent the accumulation of pro-oxidant compounds, such as methylglyoxal, in all cell types. Glo1 has been suggested to be involved in anxiety disorders, autism, and Alzheimer's disease. Mood disorders have a high rate of comorbidity with anxiety disorders although, to date, little is known of the involvement of Glo1 in the pathophysiology of these conditions. In the present study, we examined the expression levels of Glo1 mRNA in peripheral white blood cells of mood disorder patients to understand the role of Glo1 in mood disorders. Quantitative real-time polymerase chain reaction experiments revealed that reduced expression of Glo1 mRNA was observed in major depressive and bipolar disorder patients in a current depressive state, as compared with healthy control subjects. In contrast, the expression of Glo1 mRNA in major depressive and bipolar patients, in a remissive state, showed no significant alteration when compared with healthy control subjects. These results suggest that the aberrant expression of Glo1 might be involved in the pathophysiology of mood disorders.     

Incorporation of a matrix metalloproteinase-sensitive substrate into self-assembling peptides - a model for biofunctional scaffolds

Controlling and guiding cell behavior requires scaffolding materials capable of programming the three-dimensional (3-D) extracellular environment. In this study, we devised a new self-assembling peptide template for synthesizing nanofibrous hydrogels containing cell-responsive ligands. In particular, the insertion of a matrix metalloproteinase-2 (MMP-2) labile hexapeptide into the self-assembling building blocks of arginine-alanine-aspartate-alanine (RADA) was investigated. A series of peptides, varied by the position of the MMP-2 hexapeptide substrate and the length of RADA blocks, were prepared by parallel synthesis. Their self-assembling capabilities were characterized and compared by circular dichroism spectroscopy and dynamical mechanical analysis. Among all the different insertion patterns, the sequence comprising a centrically positioned MMP-2 substrate was flanked with three RADA units on each side self-assembled into a hydrogel matrix, with mechanical properties and nanofiber morphology comparable to the native material built with (RADA)(4) alone. Exposure of the new gel to MMP-2 resulted in peptide cleavage, as confirmed by mass spectroscopy, and a decrease in surface hardness, as detected by nanoindentor, indicating that the enzyme mediated degradation was localized to the gel surface. The new design can be used for introducing biological functions into self-assembling peptides to create scaffolding materials with potential applications in areas such as tissue engineering and regenerative medicine.     

Neuroanatomical mapping of juvenile rat brain regions with prominent basal signal in [(35)S]GTPgammaS autoradiography

[(35)S]GTPgammaS autoradiography represents a powerful functional approach to detect receptor-dependent G(i/o) protein activity in anatomically defined brain structures. Inherent to this technique, however, is the notable basal signal evident in several brain regions in the absence of receptor stimulation by exogenously added agonist. In the rat brain, much of this basal labelling derives from tonic activation of adenosine A(1) and lysophosphatidic acid LPA(1) receptors in the gray and white matter regions, respectively. Despite the elimination of the two receptor activities, prominent basal [(35)S]GTPgammaS labelling is still evident in discrete brain structures, possibly reflecting regional enrichment of G(i/o) and/or constitutive receptor activity or the presence of still unknown endogenous ligands activating their orphan receptors. Here, the anatomical distribution of the enhanced basal signal was systematically mapped in brain sections of 4-week-old male Wistar rats. Regions with prominent basal [(35)S]GTPgammaS labelling represented neuroanatomically distinct structures, in particular various thalamic and hypothalamic nuclei. For instance, the paraventricular thalamic nucleus, the bed nucleus of the stria terminalis and the subfornical organ were highly labelled, as were the periaqueductal gray and the nucleus of the solitary tract. Pre-treatment with N-ethylmaleimide (NEM), an alkylating agent preventing all known receptor-driven G protein activity in cryostat sections markedly decreased the basal binding in all examined regions. In preliminary screening, selective antagonists for various brain-enriched G(i/o)-coupled receptors failed to suppress the basal signal in any of the studied regions.     

WT1 peptide vaccine for the treatment of cancer

Wilms' tumor gene WT1 is expressed in various kinds of cancers. Human WT1-specific cytotoxic T lymphocytes (CTLs) were generated, and mice immunized with WT1 peptide rejected challenges by WT1-expressing cancer cells without auto-aggression to normal organs. Furthermore, WT1 antibodies and WT1-specific CTLs were detected in cancer patients, indicating that WT1 protein was immunogenic. These findings provided us with the rationale for cancer immunotherapy targeting WT1. Clinical trials of WT1 peptide vaccination for cancer patients were started, and WT1 vaccination-related immunological responses and clinical responses, including reduction of leukemic cells, reduction of M-protein amount in myeloma, and shrinkage of solid cancer, were observed. Valuable information about immune responses against tumor antigens can be obtained by the analysis of samples from the vaccinated patients, which should lead to further improvement of cancer vaccine.     

A technique for simultaneous needle insertion in prostate seed implantation

The purpose was to develop a fast needle insertion system to shorten the implantation time and to restrain prostate swelling during the implantation, thus reducing the seed setup error. The basic idea is to insert all the needles simultaneously using ultrasound guidance. The developed system consists of two similar templates that are connected. All the needles are set and locked to a moveable rear template according to the dose plan. The needle pack is then pushed into position, the lock released and seeds implanted needle by needle. A test and training phantom was also built.     

The contribution of quasi-joint stiffness of the ankle joint to gait in patients with hemiparesis

Background

The role of ankle joint stiffness during gait in patients with hemiparesis has not been clarified. The purpose of this study was to determine the contribution of quasi-joint stiffness of the ankle joint to spatiotemporal and kinetic parameters regarding gait in patients with hemiparesis due to brain tumor or stroke and healthy individuals.

Methods

Spatiotemporal and kinetic parameters regarding gait in twelve patients with hemiparesis due to brain tumor or stroke and nine healthy individuals were measured with a 3-dimensional motion analysis system. Quasi-joint stiffness was calculated from the slope of the linear regression of the moment–angle curve of the ankle joint during the second rocker.

Findings

There was no significant difference in quasi-joint stiffness among both sides of patients and the right side of controls. Quasi-joint stiffness on the paretic side of patients with hemiparesis positively correlated with maximal ankle power (r = 0.73, P < 0.01) and gait speed (r = 0.66, P < 0.05). In contrast, quasi-joint stiffness in controls negatively correlated with maximal ankle power (r = − 0.73, P < 0.05) and gait speed (r = − 0.76, P < 0.05).

Interpretation

Our findings suggested that ankle power during gait might be generated by increasing quasi-joint stiffness in patients with hemiparesis. In contrast, healthy individuals might decrease quasi-joint stiffness to avoid deceleration of forward tilt of the tibia. Our findings might be useful for selecting treatment for increased ankle stiffness due to contracture and spasticity in patients with hemiparesis.     

Hypomagnesemia in type 2 diabetic nephropathy: a novel predictor of end-stage renal disease

OBJECTIVE

There is now growing evidence that magnesium (Mg) deficiency is implicated in type 2 diabetes and its complications. However, it has not been fully elucidated whether hypomagnesemia is a predictor of end-stage renal disease (ESRD) in type 2 diabetic nephropathy.

RESEARCH DESIGN AND METHODS

This retrospective cohort study included 455 chronic kidney disease (CKD) patients (144 with type 2 diabetic nephropathy and 311 with nondiabetic CKD) who were hospitalized at Osaka General Medical Center for a CKD educational program between April 2001 and December 2007. The primary outcome was progression to renal replacement therapy. Participants were categorized based on serum Mg level into Low-Mg (serum Mg level ≤1.8 mg/dL) and High-Mg (serum Mg level >1.8 mg/dL) groups with the previously published normal lower limit chosen as the cutoff point.

RESULTS

Of the subjects with type 2 diabetic nephropathy, 102 progressed to ESRD during follow-up (median, 23 months). A multivariate Cox proportional hazards model showed that after adjustment for various demographic factors and laboratory data, the Low-Mg group had a 2.12-fold higher risk of ESRD than the High-Mg group (95% CI 1.28–3.51; P = 0.004). In contrast, 135 of the nondiabetic CKD subjects progressed to ESRD during follow-up (median, 44 months). No significant difference in outcome was found between the Low- and High-Mg groups of this population (adjusted hazard ratio, 1.15; 95% CI 0.70–1.90; P = 0.57).

CONCLUSIONS

Hypomagnesemia is a novel predictor of ESRD in patients with type 2 diabetic nephropathy.Magnesium (Mg) is the fourth most abundant cation in the human body and plays a key role in many fundamental biological processes, including energy metabolism and DNA synthesis. Mg deficiency has been shown to cause endothelial cell dysfunction, inflammation, and oxidative stress, which are major contributors to atherosclerosis (1–3). Some epidemiologic studies have reported associations between low Mg intake or serum Mg level and hypertension, coronary artery disease, and ischemic stroke (4–6).Mg and type 2 diabetes have a close relationship. Approximately one-third of patients with type 2 diabetes have hypomagnesemia, mainly caused by enhanced renal excretion (7). Mg deficiency is associated with poor glycemic control, and Mg supplementation improves insulin sensitivity (8). Moreover, there is substantial evidence of associations between hypomagnesemia and various complications of type 2 diabetes, including neuropathy, retinopathy, foot ulcers, and albuminuria (9–12). The relationship between Mg deficiency and advanced type 2 diabetic nephropathy, however, remains to be fully elucidated. Pham et al. (13) reported that serum Mg level was significantly associated with the slope of inverse serum creatinine (SCr) in type 2 diabetes with near-normal renal function. However, they failed to show a significant association between hypomagnesemia and hard renal outcome (doubling of SCr and initiation of renal replacement therapy [RRT]), probably due to low statistical power (14). Therefore, the aim of the current study was to determine whether hypomagnesemia is a predictor of end-stage renal disease (ESRD) in patients with advanced type 2 diabetic nephropathy. We also compared the impact of hypomagnesemia on renal outcome in type 2 diabetic nephropathy with that in nondiabetic chronic kidney disease (CKD).     

Effects of chromium and nitrogen content on the microstructures and mechanical properties of as-cast Co-Cr-Mo alloys for dental applications

The microstructure and mechanical properties of as-cast Co-(20-33)Cr-5Mo-N alloys were investigated to develop ductile Co-Cr-Mo alloys without Ni addition for dental applications that satisfy the requirements of the type 5 criteria in ISO 22674. The effects of the Cr and N contents on the microstructure and mechanical properties are discussed. The microstructures were evaluated using scanning electron microscopy with energy-dispersive X-ray spectroscopy (EDS), X-ray diffractometry (XRD), and electron back-scattered diffraction pattern analysis. The mechanical properties were evaluated using tensile testing. The proof strength and elongation of N-containing 33Cr satisfied the type 5 criteria in ISO 22674. ε-phase with striations was formed in the N-free (20-29)Cr alloys, while there was slight formation of ε-phase in the N-containing (20-29)Cr alloys, which disappeared in N-containing 33Cr. The lattice parameter of the γ-phase increased with increasing Cr content (i.e. N content) in the N-containing alloys, although the lattice parameter remained almost the same in the N-free alloys because of the small atomic radius difference between Co and Cr. Compositional analyses by EDS and XRD revealed that in the N-containing alloys Cr and Mo were concentrated in the cell boundary, which became enriched in N, stabilizing the γ-phase. The mechanical properties of the N-free alloys were independent of the Cr content and showed low strength and limited elongation. Strain-induced martensite was formed in all the N-free alloys after tensile testing. On the other hand, the proof strength, ultimate tensile strength, and elongation of the N-containing alloys increased with increasing Cr content (i.e. N content). Since formation of ε-phase after tensile testing was confirmed in the N-containing alloys the deformation mechanism may change from strain-induced martensite transformation to another form, such as twinning or dislocation slip, as the N content increases. Thus the N-containing 33Cr alloy with large elongation is promising for use in dentures with adjustable clasps through one piece casting.