Therapeutic effect of a novel anti-parkinsonian agent zonisamide against MPTP (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine) neurotoxicity in mice

We investigated the therapeutic effect of zonisamide against 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice, using Western blot analysis, immunohistochemistry and behavioral test. Our Western blot analysis and immunohistochemical study showed that the post-treatment with zonisamide prevented significantly dopaminergic cell damage, the depletion of tyrosine-hydroxylase (TH) protein levels and the proliferation of microglia in the striatum and/or substantia nigra 8 days after MPTP treatment. Furthermore, our behavioral study showed that the post-treatment with zonisamide attenuated significantly the motor deficits 7 days after MPTP treatment. These results show that zonisamide has the therapeutic effect in the MPTP model of Parkinson’s disease (PD) in mice. Our study also demonstrates the neuroprotective effect of zonisamide against dopaminergic cell damage after MPTP treatment in mice. Thus our present findings suggest that therapeutic strategies targeted to the activation of TH protein and/or the inhibition of microglial activation with zonisamide may offer a great potential for restoring the functional capacity of the surviving dopaminergic neurons in individuals affected with PD.     

Sustained improvement in cardiac function with persistent amyloid deposition in a patient with multiple myeloma-associated cardiac amyloidosis treated with bortezomib

We describe the case of a 62-year-old man with biopsy-proven cardiac involvement of multiple myeloma-associated immunoglobulin light-chain amyloidosis, whose cardiac function improved after bortezomib therapy. Angiotensin-converting enzyme inhibitors and diuretics were initially administered, resulting in improvement of heart failure symptoms and disappearance of nonsustained ventricular tachycardia. To reduce production of amyloidogenic precursor proteins, bortezomib therapy combined with dexamethasone was subsequently started. Hematological responses were rapid and adverse events were manageable. At present, 15 months after the treatment, cardiac function of the patient showed sustained improvement, although follow-up biopsy specimens showed persistent amyloid deposition in the myocardium corresponding to echocardiogram results demonstrating no reduction in ventricular wall thickness.     

A nonradiation-containing,intermediate-dose methotrexate regimen for elderly patients with primary central nervous system lymphoma

To assess the efficacy, acute toxicity, and delayed neurotoxicity of intermediate-dose methotrexate (MTX)-containing chemotherapy without whole-brain radiotherapy in the treatment of elderly patients with primary central nervous system lymphoma (PCNSL), we conducted a retrospective analysis of elderly patients (N = 17; median age 67) with newly diagnosed PCNSL who were treated with chemotherapy alone at Tsukuba University Hospital from January 2005 to December 2009. Induction therapy consisted of intravenous intermediate-dose MTX (1 g/m²), ranimustine, procarbazine, methylprednisolone, and intrathecal MTX and cytarabine. Patients who achieved complete response (CR) or partial response (PR) received 5 cycles of maintenance therapy every 6 weeks. All patients in this study achieved CR or PR and received maintenance therapy. Overall survival (OS) and progression-free survival (PFS) were 100 and 80% at 1 year, and 61 and 43% at 2 years, respectively. The median OS and PFS were 36 and 20 months, respectively. Delayed neurotoxicity did not develop in any patient before lymphoma progression. In terms of response rate, OS, and PFS, the nonradiation-containing, intermediate-dose MTX-containing protocol used in elderly Japanese patients was comparable to previous protocols that consisted of more intensive chemotherapy. Acute and delayed toxicities were manageable and quality of life was maintained until progression.     

Drug resistance of Pseudomonas aeruginosa in four community hospitals: influence of antimicrobial use density

We investigated the relation between hospital antimirobial use density (AUD) and minimum inhibitory concentrations (MIC) for Pseudomonas aeruginosa in four community hospitals. Subjects were a total of 476 strains isolated from urine, sputum, and pus during a total of seven years since 2002, for which 50- and 90-percentile MICs were analyzed. Hospitals A, B, and C moved in 2000, 2005, and 2009, respectively, but MIC50 and MIC90 were stable. MIC values showed significance in five drugs, in which Hospital B showed maximal values in five and Hospital D showed minimal values in four drugs. AUD values were different in nine drugs, Hospital B showing the highest data in meropenem, flomoxef, and sulbactam/cefoperazone while Hospital D having the lowest data in meropenem, ceftazidime, cefotaxime, and sulbactam/cefoperazone. Thus MIC for P aeruginosa may show resistance in the presence of high AUD with wide antimicrobial spectrum.     

Bacteria isolated from surgical infections and its susceptibilities to antimicrobial agents--special references to bacteria isolated between April 2009 and March 2010

Bacteria isolated from surgical infections during the period from April 2009 to March 2010 were investigated in a multicenter study in Japan, and the following results were obtained. In this series, 671 strains including 16 strains of Candida spp. were isolated from 174 (79.1%) of 220 patients with surgical infections. Four hundred and eleven strains were isolated from primary infections, and 244 strains were isolated from surgical site infection. From primary infections, anaerobic Gram-negative bacteria were predominant, followed by aerobic Gram-negative bacteria, while from surgical site infection aerobic Gram-positive bacteria were predominant, followed by anaerobic Gram-negative bacteria. Among aerobic Gram-positive bacteria, the isolation rate of Enterococcus spp. was highest, followed by Streptococcus spp., and Staphylococcus spp. in this order, from primary infections, while Enterococcus spp. was highest, followed by Staphylococcus spp. from surgical site infection. Among aerobic Gram-negative bacteria, Escherichia coli was the most predominantly isolated from primary infections, followed by Klebsiella pneumoniae, Enterobacter cloacae and Pseudomonas aeruginosa, in this order, and from surgical site infection, E. coli was most predominantly isolated, followed by P. aeruginosa and E. cloacae. Among anaerobic Gram-positive bacteria, the isolation rate of Eggerthella lenta was the highest from primary infections, followed by Parvimonas micra, Streptococcus constellatus and Finegoldia magna, and from surgical site infection, E. lenta was most predominantly isolated. Among anaerobic Gram-negative bacteria, the isolation rate of Bilophila wadsworthia was the highest from primary infections, followed by Bacteroides fragilis, Bacteroides ovatus and Bacteroides thetaiotaomicron, and from surgical site infection, B. fragilis was most predominantly isolated, followed by B. ovatus, B. wadsworthia and B. thetaiotaomicron, in this order. In this series, we noticed no vancomycin-resistant Gram-positive cocci, nor multidrug-resistant P. aeruginosa. We should carefully follow up B. wadsworthia which was resistant to various antibiotics, and also Bacteroides spp. which was resistant to many beta-lactam antibiotics.     

Molecular mechanisms involved in the adaptive response to cadmium-induced apoptosis in human myelomonocytic lymphoma U937 cells

We examined the molecular mechanisms involved in the adaptive response to cadmium (Cd)-induced apoptosis in human myelomonocytic lymphoma U937 cells. When U937 cells were treated with 50 μM cadmium chloride (CdCl₂) for 12 h, significant apoptosis occurred. This was associated with an increase in intracellular reactive oxygen species (ROS), sustained phosphorylation of JNK, activation of caspase-3, a decrease in Mcl-1 (anti-apoptotic Bcl-2 proteins), and increases in Bim, Noxa and tBid (a pro-apoptotic protein under the Bcl-2 family). No apoptosis occurred when the cells were treated with 1 μM CdCl₂ for 72 h. However, pretreatment with low-dose CdCl₂ dramatically altered the sensitivity of the cells to 50 μM CdCl₂ with inhibition of apoptosis. Concomitantly, there were significant decreases in the generation of intracellular ROS and the activation of JNK. Pretreatment with 1 μM CdCl₂ also attenuated the decrease in Mcl-1 and the increases in Bim, Noxa and tBid induced by 50 μM CdCl₂. In conclusion, pretreatment with low-dose Cd inhibited apoptosis induced by high-dose Cd. The mechanism involves inhibition of intracellular ROS generation and JNK activation, and modulating the balance between the expression of Mcl-1 and its binding partners, Bim, Noxa and tBid.     

Innovative preparation of curcumin for improved oral bioavailability

Curcumin is a polyphenol that is commonly used for its perceived health benefits. However, the absorption efficacy of curcumin is too low to exhibit beneficial effects. We have successfully developed a highly absorptive curcumin dispersed with colloidal nano-particles, and named it THERACURMIN. The absorption efficacy of THERACURMIN was investigated and compared with that of curcumin powder. The area under the blood concentration-time curve (AUC) after the oral administration of THERACURMIN was found to be more than 40-fold higher than that of curcumin powder in rats. Then, healthy human volunteers were administered orally 30 mg of THERACURMIN or curcumin powder. The AUC of THERACURMIN was 27-fold higher than that of curcumin powder. In addition, THERACURMIN exhibited an inhibitory action against alcohol intoxication after drinking in humans, as evidenced by the reduced acetaldehyde concentration of the blood. These findings demonstrate that THERACURMIN shows a much higher bioavailability than currently available preparations. Thus, THERACURMIN may be useful to exert clinical benefits in humans at a lower dosage.     

Rapid typing of influenza viruses using super high-speed quantitative real-time PCR

The development of a rapid and sensitive system for detecting influenza viruses is a high priority for controlling future epidemics and pandemics. Quantitative real-time PCR is often used for detecting various kinds of viruses; however, it requires more than 2h per run. Detection assays were performed with super high-speed RT-PCR (SHRT-PCR) developed according to a newly designed heating system. The new method uses a high-speed reaction (18s/cycle; 40 cycles in less than 20min) for typing influenza viruses. The detection limit of SHRT-PCR was 1 copy/reaction and 10(-1) plaque-forming unit/reaction for viruses in culture supernatants during 20min. Using SHRT-PCR, 86 strains of influenza viruses isolated by the Tokyo Metropolitan Institute of Public Health were tested; the results showed 100% sensitivity and specificity for each influenza A and B virus, and swine-origin influenza virus. Twenty-seven swabs collected from the pharyngeal mucosa of outpatients were also tested, showing positive signs for influenza virus on an immunochromatographic assay; the results between SHRT-PCR and immunochromatography exhibited 100% agreement for both positive and negative results. The rapid reaction time and high sensitivity of SHRT-PCR makes this technique well suited for monitoring epidemics and pre-pandemic influenza outbreaks.     

Lipopolysaccharide-Mediated Induction of Calprotectin in the Submandibular and Parotid Glands of Mice

S100A8 and S100A9 constitute a heterodimeric protein, calprotectin. The mRNAs of S100A8 and S100A9, being expressed at minimal levels in the submandibular and parotid glands (SMG and PG, respectively) of C3H/HeN mice, were induced strongly and transiently by lipopolysaccharide (LPS). Among the mRNAs of members of the S100 protein family examined, those of S100A8 and S100A9 were specifically induced by LPS in the salivary glands. The induction was assumed to be mediated via toll-like receptor 4 (TLR4), since their elevation was limited in C3H/HeJ mice, a TLR4-mutant strain. These proteins became expressed in the granular convoluted tubular cells and striated duct cells in the SMG, and in both acinar and duct cells in the PG (all in the cytoplasm). The salivary calprotectin level was not increased by LPS treatment, implying that elevated calprotectin was not secreted into the saliva and that they may function in microcellular environment of the salivary gland.