Anatase and rutile titanium oxide nanoparticles induce acute kidney injury by coadministration with paraquat, cisplatin or 5-aminosalicylic acid.

Nanoparticles are used in a variety of fields; for example, titanium oxide nanoparticles are used in paints, food additives, cosmetics, and sunscreen materials. Although the use of titanium oxide nanoparticles is regulated, their safety has not been established. Furthermore, the interaction between titanium oxide nanoparticles and various chemical substances and pharmaceuticals is unknown. We co-administered rutile-type titanium oxide nanoparticles (nTR) or anatase-type titanium oxide nanoparticles (nTA) to mice together with paraquat (PQ), cisplatin (CDDP), or anti-5-aminosalicylic acid (5-ASA), and investigated the extent, if any, of liver and kidney injury. As a result, when nTA and nTR were administered alone, no increases were observed in aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are indicators of liver damage, or urea nitrogen (BUN), which is an indicator of kidney damage. Next, nTA and nTR were co-administered with PQ, CDDP or 5-ASA. Although no increase in ALT or AST was observed, BUN levels increased significantly and acute kidney injury was induced. The findings suggested that titanium oxide nanoparticles induce acute kidney injury through their interaction with chemicals and drugs.

Health benefits of fermented milk containing Bifidobacterium bifidum YIT 10347 on gastric symptoms in adults.

We conducted a preliminary open trial (trial 1) and a double-blind, placebo-controlled, crossover trial (trial 2) to examine how fermented milk containing the probiotic Bifidobacterium bifidum YIT 10347 affects gastric and lower abdominal symptoms in adults taking no medication. In trial 1, subjects with or without gastric and lower abdominal symptoms ingested fermented milk containing B. bifidum YIT 10347 daily for 2 wk. In trial 2, subjects with gastric symptoms ingested fermented milk containing B. bifidum YIT 10347 (active preparation) or placebo daily for 2 wk, followed by crossover for 3 wk after a washout period. Before (baseline) and 1 and 2 wk after ingestion, subjects completed a questionnaire. In trial 1 (305 subjects), the prevalence of gastric and lower abdominal symptoms was 46 and 58%, respectively, at baseline. Ingestion of B. bifidum YIT 10347 significantly decreased the prevalence of gastric and lower abdominal symptoms from 45 to 33% at 1 wk and to 28% at 2 wk, and from 57 to 40% at 2 wk, respectively. In subjects with gastric symptoms at baseline, the average gastric symptom score per subject significantly decreased by 0.9 at 1 wk and 1.2 at 2 wk. In trial 2 (27 subjects), ingestion of the active preparation significantly decreased the average gastric symptoms score per subject by 1.0 at 1 wk and 1.1 at 2 wk, but ingestion of placebo milk had no effect. No side effects were reported by any subjects in either trial. We conclude that fermented milk containing B. bifidum YIT 10347 has the potential to provide health benefits by alleviating gastric symptoms in subjects taking no medication.

Analysis of the frequency and nature of hyaline ring granulomas in inflammatory odontogenic cysts.

AIM: To determine the prevalence of hyaline ring granulomas (HRGs) in a large case series of inflammatory odontogenic cysts, and to investigate the nature of these structures. METHODOLOGY: All records from the patients diagnosed with inflammatory odontogenic cysts between January 1970 and April 2009 were reviewed. Histologic sections were evaluated by light microscopy and cases with HRGs for which sufficient biological material was available were submitted to histochemical analysis (Masson's trichrome) and immunohistochemistry (CD34, CD68 and collagen IV). RESULTS: Twenty-two (3.3%) of the 661 cases of inflammatory odontogenic cysts diagnosed during the study period presented HRGs. The relative frequency of HRGs was higher amongst residual radicular cysts (6.1%), followed by paradental cysts (5.6%) and radicular cysts (3.0%). HRGs appeared as roughly circular homogeneous/fibrillar masses in 14 (63.6%) cases and as round structures enclosing amorphous material in 3 (13.6%) cases. Most (77.8%) roughly circular homogeneous/fibrillar masses were positive for collagen, whereas all (100.0%) round structures enclosing amorphous material were negative for this protein. Immunohistochemistry showed that most mononucleated cells and all multinucleated giant cells were positive for CD68, but negative for CD34, in all cases. In addition, collagen IV immunostaining was negative in amorphous structures and weakly positive in homogeneous/fibrillar masses. CONCLUSIONS: The present results suggest a very low frequency of HRGs in inflammatory odontogenic cysts and support the hypothesis that these structures arise from the implantation of foreign material, most likely food particles of plant or vegetable origin. The diverse microscopic features of HRG possibly represent different developmental stages of this structure.

Immunoexpression of REGγ and apoptosis-related proteins in oral tongue squamous cell carcinoma.

The aim of this study was to investigate the immunohistochemical expression of REGγ, p53, MDM-2, Bcl-2, and Bax in oral tongue squamous cell carcinoma (OTSCC), and to correlate the findings with clinicopathological parameters. Fifty-eight OTSCC cases were selected for the study. The percentages of nuclear (REGγ, p53, and MDM-2) and cytoplasmic (Bcl-2 and Bax) staining in epithelial cells were determined and correlated with clinicopathological parameters (regional lymph node metastasis, clinical stage, clinical outcome, and histopathological grade of malignancy). Expression of REGγ was observed in all cases studied. Significantly lower percentages were observed in tumours with lymph node metastasis (P = 0.036) and in high-grade tumours (P = 0.013). No significant differences in p53, MDM-2, or Bax expression were observed according to the clinicopathological parameters. Lower percentages of Bcl-2 staining were found in high-grade OTSCC (P = 0.040) and in cases of disease-related death (P = 0.032). The expression of REGγ showed a weak positive correlation with the expression of MDM-2 (P = 0.001) and Bcl-2 (P = 0.014). The results of this study suggest that lower expression of REGγ may contribute to the progression of OTSCC. The role of REGγ in the development of OTSCC does not appear to be primarily related to the modulation of apoptosis in neoplastic cells.

Effect of Bifidobacterium bifidum fermented milk on Helicobacter pylori and serum pepsinogen levels in humans.

Helicobacter pylori infection is an important risk factor for gastric diseases. Some probiotics are useful for suppressing H. pylori infection. Bifidobacterium bifidum YIT 4007 can improve the experimental gastric injury in rats and the disease stages on the gastric mucosa in peptic ulcer patients. We evaluated the fermented milk using a clone (BF-1) having the stronger ability to survive in the product than this parent strain to clarify the in vitro suppressive effect of BF-1 on H. pylori and the in vivo efficacy of BF-1 fermented milk on H. pylori and gastric health. In the mixed culture assay of BF-1 and H. pylori, the number of pathogens was decreased such that it was not detected after 48 h in the Brucella broth with a decrease in pH values. In the cell culture experiment with human gastric cells, the H. pylori infection-induced IL-8 secretion was suppressed by the preincubation of BF-1. In a human study of 12-wk ingestion (BF-1 group, n = 40; placebo group, n = 39) with a randomized double-blind placebo-control design, the H. pylori urease activity and gastric situation were evaluated using a urea breath test (UBT) and the serum pepsinogen (PG) levels as biomarkers for inflammation or atrophy, respectively. In the H. pylori-positive subjects, the difference (DeltaUBT) of the UBT value from the baseline value in the BF-1 group (n = 34) was lower than that in the placebo group (n = 35) at 8 wk. The baseline UBT values showed a negative correlation with DeltaUBT values at 8 and 12 wk in the BF-1 group but not in the placebo. In the PG-positive subjects classified by the PG test method, the BF-1 group was lower in DeltaUBT values than the placebo group at 8 and 12 wk. In the active gastritis class by PG levels, the BF-1 group was lower in their DeltaUBT values than the placebo at 8 and 12 wk. The PG I levels in the BF-1 group were lower than the placebo at 12 wk. The PG II levels in the BF-1 group did not change during the ingestion period, but the placebo was increased. The PG I/II ratios slightly decreased from baseline at 12 and 20 wk in the BF-1 and placebo groups. These patterns were also observed in the H. pylori-positive subjects. The improving rates of upper gastrointestinal symptomatic subjects and total symptom numbers in the BF-1 group were higher than those in the placebo. These results indicate that BF-1 fermented milk may affect H. pylori infection or its activity, gastric mucosal situation, and the emergence of upper gastrointestinal symptoms.

Streptococcus thermophilus fermented milk reduces serum MDA-LDL and blood pressure in healthy and mildly hypercholesterolaemic adults.

Low-density lipoprotein (LDL)-cholesterol, malondialdehyde-modified low-density lipoprotein (MDA-LDL), MDA-LDL/LDL-cholesterol in serum, and blood pressure are considered useful risk markers of cardiovascular diseases. This study aimed to examine whether a fermented milk containing Streptococcus thermophilus YIT 2001 (ST), which has high anti-oxidative activity, would benefit healthy and mildly hyper-LDL-cholesterolaemic adults via a randomised, double-blind, placebo-controlled trial. ST-fermented milk or non-fermented placebo milk (PC) was consumed once a day for 12 weeks by 29 and 30 subjects, respectively, with average serum LDL-cholesterol levels of about 140 mg/dl. Serum levels of LDL-cholesterol and MDA-LDL and blood pressure were analysed before (baseline) and after consumption. Comparisons of the responses between both groups were assessed using analysis of covariance (ANCOVA, with the baseline value as the covariate). ANCOVA demonstrated that the ST group had significant reductions in MDA-LDL, MDA-LDL/LDL-cholesterol, systolic blood pressure (SBP), and diastolic blood pressure (DBP) compared with the PC group during the consumption period (P<0.05). Moreover, stratified analysis revealed that there were significant reductions in MDA-LDL, MDA-LDL/LDL-cholesterol, SBP, and DBP in the ST group compared with the PC group during the consumption period in subjects who had above median (65 U/l) levels of oxidative stress marker MDA-LDL at baseline (P<0.05), but not in subjects with levels below the median. These findings suggest that daily consumption of ST-fermented milk may be beneficial in healthy or mildly hyper-LDL cholesterolaemic subjects through reductions in risk marker values of oxidative stress and/or cardiovascular diseases. The benefits were particularly remarkable in subjects who had higher levels of MDA-LDL.

Immunoexpression of VEGFR-3, but not the immunoexpression of VEGF-C or lymphatic density, is correlated with metastasis in lower lip squamous cell carcinoma.

The purpose of this study was to evaluate the immunoexpression of vascular endothelial growth factor C (VEGF-C) and VEGF receptor 3 (VEGFR-3) and their correlation with intratumoural lymphatic density (ILD) and peritumoural lymphatic density (PLD) in metastatic and non-metastatic lower lip squamous cell carcinoma (LLSCC). Twenty-five LLSCC with regional nodal metastasis and 25 LLSCC without metastasis were selected. The percentages of VEGF-C and VEGFR-3 staining in each tumour core and at the deep invasive front were assessed. PLD and ILD were determined using anti-podoplanin antibody. Immunohistochemical findings were correlated with nodal metastasis, clinical staging, local recurrence, clinical outcome, and histological grade. Cytoplasmic immunoexpression of VEGFR-3 in the tumour core was associated with metastasis (P=0.009), patient death (P=0.008), and histological grade (P<0.005). PLD, ILD, and VEGF-C expression showed no significant associations with clinicopathological parameters (P>0.05). PLD and ILD were not significantly correlated with the immunoexpression of VEGF-C or VEGFR-3 (P>0.05). There was a significant positive correlation between PLD and ILD (P=0.004), and between cytoplasmic immunoreactivity of VEGF-C and VEGFR-3 (P=0.011). These results suggest an important role for VEGFR-3 in the progression of LLSCC, and highlight the possible influence of its expression on the prognosis of these tumours. ILD and PLD may not be associated with lymph node metastasis in LLSCC.

Citrus juice fermented with Lactobacillus plantarum YIT 0132 alleviates symptoms of perennial allergic rhinitis in a double-blind, placebo-controlled trial.

This study aimed to examine whether citrus juice fermented with Lactobacillus plantarum YIT 0132 (LP0132), which was pasteurised after fermentation, could alleviate the symptoms of perennial allergic rhinitis in a double-blind, placebo-controlled, parallel-group trial. Subjects with perennial allergic rhinitis consumed LP0132-fermented juice (n=17) or unfermented citrus juice (placebo; n=16) once a day for 8 weeks. During the pre-intervention and intervention periods, the subjects recorded nasal symptoms (number of sneezing attacks, number of nose-blowing incidents, and stuffy nose score). The primary endpoint, nasal symptoms score (NSS), was scored from 0 to 4 according to the 'Practical Guideline for the Management of Allergic Rhinitis in Japan 2009' using a combination of the three nasal symptom items. Blood samples were collected at pre-intervention and at 8 weeks after commencing the intervention. There were several significant improvements not only in the LP0132 group but also in the placebo group because of potential anti-allergic effects of citrus. Compared with the placebo group, the LP0132 group showed a significant reduction in the NSS and stuffy nose score during the intervention period. Also, the LP0132 group, but not the placebo group, showed significant attenuation of type 2 helper T cells (Th2 cells)/helper T cells, serum total immunoglobulin E (IgE), and eosinophil cationic protein (ECP), and showed significant augmentation of type 1 helper T cells (Th1 cells)/Th2 cells at 8 weeks of intervention compared with baseline. It is suggested that daily intake of fermented citrus juice containing heat-killed LP0132 has beneficial effects on symptoms of perennial allergic rhinitis, and these benefits may be associated with the attenuation of Th2 cells, total IgE, and ECP via the immunomodulating activities of LP0132.

Living cells of probiotic Bifidobacterium bifidum YIT 10347 detected on gastric mucosa in humans.

The probiotic strain Bifidobacterium bifidum YIT 10347 has been demonstrated to inhibit Helicobacter pylori activity, prevent injury to the gastric mucosa, and improve general gastric malaise symptoms in H. pylori positive patients. This study aimed to investigate the adhering activity and localisation of B. bifidum YIT 10347 to gastric cells and tissue in vitro, and in human in vivo to clarify the mechanism of its beneficial effects on the stomach. The in vitro study found the adhesion rate of B. bifidum YIT 10347 to human gastric epithelial cells was about 10 times higher than that of lactic acid bacteria and other bifidobacteria. In the human study, 5 H. pylori negative and 12 H. pylori positive subjects ingested milk fermented with B. bifidum YIT 10347. B. bifidum YIT 10347 cells were measured by RT-qPCR for in gastric biopsy samples. Living B. bifidum YIT 10347 cells were detected in the biopsy samples in H. pylori negative subjects (105 cells/g and 104 cells/g at 1 h and 2 h after ingestion, respectively) and H. pylori positive subjects (104 cells/g at 1 h after the ingestion). Moreover, immunostaining analysis of tissue sections found that B. bifidum YIT 10347 cells were located at the interstitial mucin layer of the stomach. These results suggest that cells of probiotic B. bifidum YIT 10347 adhered to the human gastric mucosa in a live state, and that the higher adhering activity of B. bifidum YIT 10347 to the gastric mucosa may be involved in its beneficial effects on the human stomach.

Differential effects of picrotoxin- and pentylenetetrazol-induced convulsions on the secretion of luteinizing hormone and follicle-stimulating hormone in rats.

A single subcutaneous (sc) injection of picrotoxin in a dose ranging from 3 to 40 mg/kg to proestrous female rats produced sustained clonic-tonic convulsions and resulted in a significant elevation of serum LH levels. FSH release was not stimulated. Serum calcium levels increased, with a positive correlation with the increment of serum LH increase in these animals. Similarly, 5 mg/kg of picrotoxin was effective in inducing an increase in serum LH and calcium, but not FSH, in adult male rats. Pentylenetetrazol in a dose of 120 mg/kg induced sustained clonic-tonic convulsions and stimulated the release of LH, but not of FSH, in both adult male and female rats. An increase in serum calcium levels also was evident. These results suggest that sustained convulsions induce overall excitation of the central nervous system and result in the enhancement of LH release from the pituitary. The mechanism responsible for the differential stimulation of LH and FSH release remains to be clarified.

Positron emission tomography in systemic lupus erythematosus: relation of cerebral vasculitis to PET findings.

A 12-year-old Japanese girl with systemic lupus erythematosus is described. Positron emission tomography (PET) showed low attenuation in the right frontotemporal area at relapse, which disappeared at remission. Findings on electroencephalography coincided with those on PET. On x-ray CT there were no specific findings. The PET findings were thought to be due to cerebral vasculitis.

Acute and delayed neurologic reaction to inoculation with attenuated live measles virus.

A Japanese boy developed a high fever and a prolonged convulsion 11 days after inoculation with live measles vaccine. He had 4 more seizures during the next 6 mos. His EEG became transiently abnormal 14 mos later. Antimeasles complement fixation, hemagglutination, and neutralization titers were elevated.

[Clinical studies on cefteram pivoxil in the field of pediatrics].

Cefteram pivoxil (CFTM-PI) was administered to 37 patients with acute febrile upper or lower respiratory infections and 3 patients with urinary tract infections at 10 mg/kg/day divided into 3 portions. Good clinical effects were observed in all the cases. As for the bacteriological effect, the evaluable 24 strains (60.0%) were eradicated among 43 strains identified in 37 cases with the treatment with CFTM-PI. Only 2 strains were eradicated among 9 strains of Staphylococcus aureus. Among 3 patients with urinary tract infections with Escherichia coli, 2 strains were eradicated from urine after the administration of CFTM-PI. Four cases showed mild diarrhea among 40 cases. It was not clear whether the diarrhea was due to the administration of CFTM-PI.

[A preclinical and clinical study of cefmenoxime in newborns].

1. Cefmenoxime (CMX) was administered with a dosage regimen of 20-25 mg/kg, 2-3 times daily (40-75 mg/kg/day) by intravenous drip over 30 minutes to 9 neonates with bacterial infections including purulent meningitis and septicemia. Clinical responses to the treatment were excellent in 7 and poor in 2. Bacteriological responses were "eradication of pathogens" from 8 of them except another patient with an infection due to Staphylococcus aureus. 2. Adverse reactions to CMX were observed in 6 of 18 neonates treated with the drug: diarrhea, oral thrush, and the elevation of S-GOT, S-GPT, LDH and alkaline phosphatase. None of the reactions, however, necessitated the discontinuation of the treatment. 3. Changes in blood concentrations of CMX in neonates with ages between 0 and 30 days were followed. These subjects included 16 mature neonates and 10 neonates with low birth weights. Intravenous drip infusion of 20 mg/kg of CMX over 30 minutes was immediately followed by peak blood CMX concentrations of 34.6-72.7 mcg/ml (mean +/- S.D.: 50.4 +/- 11.3 mcg/ml) in the mature neonates, and 22.3-78.2 mcg/ml (55.5 +/- 16.5 mcg/ml) in the neonates with low birth weight. Blood half-lives of the drug in the mature neonates were in the range from 1.7 to 20.7 hours (5.9 +/- 6.6 hours) in subjects with ages of 0-3 days, and 1.1-3.5 hours (2.0 +/- 0.8 hours) in subjects of 4-25 days. In neonates with low birth weight, they were 3.4-10.2 hours (7.2 +/- 2.7 hours) in subjects of 0-2 days, and 1.4-5.5 hours (3.0 +/- 1.5 hours) in subjects of 4-30 days. In other words, the blood half-lives of the drug tended to be longer in younger subjects. 4. Concentration of CMX in cerebrospinal fluid (CSF) were determined in a patient in acute stage with purulent meningitis caused by Mycoplasma hominis. Intravenous drip infusion of 80 mg/kg of CMX over 30 minutes was followed by CSF concentrations of 7.7-15.5 mcg/ml. 5. MICs of CMX for clinical isolates were determined. The drug was proved to have excellent antibacterial activities against Escherichia coli (3 strains) and group B hemolytic streptococci (2 strains) and these MICs were comparable to those of cefotaxime. The MIC of CMX for S. aureus (1 strain) was high at 25 mcg/ml with an inoculum size of 10(8) CFU/ml. This MIC value of CMX was higher than that of cefmetazole.

[Clinical evaluation of norfloxacin in children].

Oral new quinolone, norfloxacin (NFLX, AM-715), was evaluated for its safety, efficacy and pharmacokinetics in children. 1. NFLX was effective in 88.0% of 25 cases infected with Haemophilus influenzae, Pseudomonas aeruginosa, Escherichia coli, Campylobacter jejuni, Staphylococcus aureus including methicillin-resistant strains, and other bacteria. 2. After single oral administration of 50 mg and 100 mg NFLX tablet at fasting, mean peak values of serum concentration were 0.35, 0.48 microgram/ml and T1/2 values were 2.2, 2.7 hours, respectively. 3. No adverse reactions suggestive for arthropathy were encountered with NFLX therapy with daily doses of 4.6-35.7 mg/kg (maximum 600 mg per day) and duration of 3 to 19 days. From these preliminary data, NFLX seems to have a place in the treatment of pediatric infectious diseases.

[Clinical evaluation of cefminox, a new cephamycin antibiotic, in the pediatric infections].

Cefminox (CMNX, MT-141) was evaluated for its safety and efficacy in children. Fifteen cases of bacterial infections were treated with intravenous bolus injections of 30 to 100 mg/kg/day of CMNX. Each 5 cases of acute respiratory tract, urinary tract, and gastrointestinal infections were included. All the cases were cured after the CMNX therapy. No adverse reactions were encountered with the therapy. The serum half-life was approximately 1.5 to 2 hours after intravenous bolus injection in children. The data suggest that CMNX is a safe and effective antibiotic when used in children with susceptible bacterial infections.

[Clinical evaluation of ceftizoxime in the pediatric infections (author's transl)].

Ceftizoxime (FK 749, CZX) was evaluated in 24 children with a suspicion of bacterial infection. Of the 17 confirmed bacterial infections, 16 were shown to be effective (effective rate, 94.1%). The diagnosis included acute pharyngitis (2), pneumonia (6), staphylococcal empyema (1), cervical purulent lymphadenitis (2), acute enterocolitis (2), acute pyelonephritis (1), SSSS (1) and suspected septicemia (2). The etiological pathogens recovered were Streptococcus anginosus (1), Streptococcus pneumoniae (1), Staphylococcus aureus (2), Haemophilus influenzae (3), enteropathogenic Escherichia coli (1) etc. A case of suspected Pseudomonas aeruginosa septicemia was not effectively treated with CZX. The serum half-life of CZX was 1.36 hours after intravenous bolus infection. A cerebrospinal fluid level of CZX was 6.2 mcg/ml 1 hour after intravenous bolus injection of 1 g (23.8 mg/kg) in a child with inflamed meninges. No severe adverse reaction was encountered with the CZX therapy. The data suggest that CZX is an excellent candidate for the first choice parenteral antibiotic in the pediatric infections.

[Clinical evaluation of sulbactam/cefoperazone in the pediatric infections].

Sulbactam/cefoperazone (SBT/CPZ), a fifty-fifty combination of a beta-lactamase inhibitor, SBT, and an already marketed broad spectrum cephalosporin, CPZ, was evaluated for its efficacy and safety in 25 children. The diagnoses included purulent lymphadenitis, pneumonia, acute UTI, bacteremia and purulent meningitis. SBT/CPZ was effective in all the 20 cases with bacterial infections, but strains highly resistant to CPZ were not isolated in this study. The serum and cerebrospinal-fluid levels of SBT were grossly parallel with those of CPZ, and the half-life of the serum SBT was 0.754 hour. Although severe adverse reactions were not encountered with SBT/CPZ therapy, loose stools in 20% and diarrhea in 16% of the cases were observed.

[Clinical and pharmacokinetic study of ceftriaxone in pediatric bacterial infections].

Ceftriaxone (Ro 13-9904, CTRX) was evaluated for its safety and efficacy in 33 children with various bacterial infections including 10 cases of bacterial meningitis. CTRX was effective in all but 1 case who had acute mucositis due to a resistant strain of Enterobacter cloacae. The serum half-life (T1/2 beta) was 4.5 +/- 1.6 hours after an intravenous bolus injection in children. Cerebrospinal fluid levels of CTRX in the acute phase of bacterial meningitis were 7.69 +/- 4.75 mcg/ml. The only side effect was mild to moderate diarrhea observed in 10 of the 33 cases, but in no case was it necessary to discontinue the drug.