Randomized placebo-controlled clinical trial of immunoglobulin Y as adjunct to standard supportive therapy for rotavirus-associated diarrhea among pediatric patients

This study aims to evaluate the effect of hyperimmune immunoglobulin Y (IgY) against human rotavirus (HRV) among pediatric patients receiving standard supportive treatment for rotavirus-associated diarrhea mostly with an enteric non-cholera co-pathogen in a hospital setting. Two natural HRV reassortant clinical strains ATCC VR 2273 and ATCC VR 2274 were used as mixed immunizing antigens in poultry hens to generate anti-HRV IgY (Rotamix IgY). The Rotamix IgY was used in laboratory and clinical studies against control or placebo IgY. The control or placebo IgY was prepared using tissue culture medium from mock-infected MA104 cell line as antigen for poultry immunization. In vitro, Rotamix IgY exhibited multi-serotypic cross neutralization activities along with synergistic effects against major global serotypes G1, G2, G3, G4 and other human or animal rotavirus strains when compared with mono-specific IgY. Suckling mice (ICR strain) pre-treated orally once with Rotamix IgY and then challenged with rotavirus 3h later showed a significant dose-dependent reduction in frequency (p<0.05) and duration (p<0.05) of diarrhea compared to placebo IgY-treated mice. Out of 114 children aged between 3 and 14 months and with diarrhea upon admission in a Myanmar hospital, 54 dehydrated and rotavirus-positive children were randomized into Rotamix IgY group and placebo IgY group. Of these, only 52 children had complete data with n=26 children per study group. Ninety-two percent of patients in each of these groups were positive for co-infecting enteric non-cholera pathogen and all patients received standard supportive therapy for diarrhea. The patients were monitored for volume and duration of oral rehydration fluid (ORF) and intravenous fluid (IVF) intake, daily stool frequency and overall duration of diarrhea, and frequency and duration of rotavirus shedding. Compared to placebo IgY group, the Rotamix IgY group had statistically significant reduction in mean ORF intake (p=0.004), mean duration of intravenous fluid administration (p=0.03), mean duration of diarrhea from day of admission (p<0.01) and mean duration of rotavirus clearance from stool from day of admission (p=0.05). Overall, our novel approach using oral Rotamix IgY for rotavirus-infected children mostly with non-cholera enteric pathogen co-infection appears to be a promising, safe and effective adjunct to management of acute diarrhea in pediatric patients.     

Prevalence and persistence of certain serologic types of Streptococcus pyogenes in metropolitan Tokyo

M-typing was conducted for Streptococcus pyogenes strains isolated within 1 week of admission from patients admitted to the Tokyo Metropolitan Toshima Hospital for scarlet fever in the 23-year period between 1956 and 1978. M12 was detected in the largest number of patients, followed by M6, M4, M3, and M1. T-typing was also conducted for Streptococcus pyogenes strains isolated from healthy schoolchildren in three different parts of the 20-year period between 1977 and 1998. T12 was detected in the largest number of children, followed by T28, T1, T4, and T6. These results suggested that strains of similar types are prevalent in scarlet fever patients and healthy carriers, that these strains become prevalent at intervals of several years, and that they are detected every year, albeit in a small number of persons, indicating that they are endemic. Isolated strains were typed by M-typing and T-typing. The results of typing were identical in more than 90% of cases. Comparison of major Streptococcus pyogenes strains isolated in Tokyo and three other major cities abroad showed that M12 was detected in the largest number of persons in Tokyo and New York and that major types were similar in the four cities.     

A Phase 2/3 Trial of Pabinafusp Alfa,IDS Fused with Anti-Human Transferrin Receptor Antibody,Targeting Neurodegeneration in MPS-II

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Further investigation of the modifying effect of various chemopreventive agents on apoptosis and cell proliferation in human colon cancer cells

PURPOSE: Recent preclinical assays using animal models have shown that naturally-occurring and synthetic chemicals such as auraptene (AUR), nobiletin (NOB), hesperidin (HE), diosmin (DIO), indole-3-carbinol (I3C), 1'-acetoxychavicol acetate (ACA), 2,5-di-O-acetyl-D-1,4-glucaro-6,3-dilactone (ACE), D-glucuronic acid gamma-lactone (GL), chlorogenic acid (CGA), protocatechuic acid (PA), and sinigrin (SIN) are possible preventive agents against the development of cancer. However, the mode of action of such preventive agents remains to be elucidated. The current study, therefore, was conducted to analyze whether these agents induce apoptosis and/or inhibit DNA synthesis in human colorectal cancer cell lines. METHODS: We performed an 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay to evaluate the modifying effects of the chemicals on cell viability as the first screening. Then, induction of apoptosis was detected by means of a DNA fragmentation assay, a quantitative enzyme immunoassay, and morphological analysis using 4-diamidino-2-phenylindole staining. In addition, the modulating effects of the compounds on DNA synthesis of the cells with fixed doses of the compounds were analyzed by scoring the 5-bromo-2'-deoxyuridine labeling index. RESULTS: AUR, NOB, I3C, ACA, and ACE had apoptosis-inducing effects in a concentration- and time-dependent manner, some of which were followed by a reduction in replicating DNA synthesis. CGA, PA, SIN, GL, DIO, and HE had little modulating effect on cell viability, apoptosis, and DNA synthesis in this cell system. CONCLUSIONS: Our results suggest that AUR, I3C, ACA, NOB, and ACE might exert tumor-preventive action through apoptosis- and/or cell proliferation-dependent mechanisms and, on the other hand, CGA, PA, SIN, HE, DIO, and GL might be apoptosis- and cell proliferation-independent. These assays provided an initial tool for further mechanical studies of tumor-preventive agents and future applications to mechanism-based chemopreventive studies.     

Dopaminergic involvement in the estrogen-induced suppression of frequency of pulsatile luteinizing hormone secretion in the ovariectomized rat

This experiment examined whether various catecholaminergic synthesis inhibitors and receptor blockers affect the inhibitory effect on the frequency of pulsatile luteinizing hormone (LH) secretion induced by local application of estradiol benzoate (EB) into the preoptic suprachiasmatic area (POSC) of ovariectomized rats. Ovariectomized rats were pretreated with either alpha-methyl-p-tyrosine (AMPT; tyrosine hydroxylase inhibitor), AMPT plus threo-dihydroxyphenylserine (DOPS; norepinephrine precursor), diethyldithiocarbamate (DDC; dopamine-beta-hydroxylase inhibitor), pimozide (dopaminergic receptor blocker), phenoxybenzamine (alpha-adrenergic receptor blocker), propranolol (beta-adrenergic receptor blocker), or their vehicles. EB implantation into the POSC reduced the frequency of existing pulsatile LH secretion in vehicle-treated rats. Pretreatment of the rat with AMPT, AMPT plus DOPS, or pimozide did not affect the basal pulsatile LH secretion but eliminated the suppressive effect of EB implantation on the LH pulse frequency. In rats pretreated with DDC or phenoxybenzamine, basal pulsatile LH secretion was significantly inhibited, and EB implantation did not lower serum LH further in these rats. Propranolol had no obvious effect on either basal pulsatile LH secretion or EB-induced suppression of LH pulse frequency. These findings suggest that, in addition to the alpha-adrenergic involvement in maintaining the basal pulsatile LH secretion, the intact dopaminergic system is required for the suppression of the frequency of LH pulses induced by estrogen.     

Questionnaire survey on lower urinary tract symptoms (LUTS) for patients attending general practice clinics

OBJECTIVES: We investigated the incidence of lower urinary tract symptoms (LUTS) in people consulting a general practice (GP) clinics. MATERIALS AND METHODS: The questionnaire included 7 questions regarding LUTS and 1 question regarding QOL (QOL index) based on the International Prostate Symptom Score (I-PSS), 3 questions on the Overactive Bladder Symptom Score (OABSS) and 4 questions on the International Conference of Incontinence Questionnaire Short-form (ICIQ-SF) and the survey was conducted among 1,120 people aged 50 or older who consulted a GP clinic. RESULTS: Questionnaires were collected from 958 persons (86%) and the data from 822 (73%) who completed all the above questions were analyzed. There were 364 men (mean age: 67 year-old) and 458 women (68 year-old). Moderate or severe grades on I-PSS and OABSS were indicated in 99 (27%) and 43 (12%), respectively, for men, and 55 (12%) and 40 (9%) for women. Moderately or severely impaired QOL was indicated in 206 (57%) men and 193 (42%) women. Fifty-five (15%) men and 185 (40%) women indicated that they had some type of urinary incontinence. There were 138 (38%) men and 165 (36%) women showing both moderate or severe I-PSS and moderate or severe impairment of QOL, and/or with an ICIQ-SF score greater than 1. CONCLUSION: When I-PSS and QOL score were used for LUTS screening, 38% of men and 36% of women aged over 50, consulting a GP clinic, had some LUTS which should be assessed to determine whether they need treatment.     

Frequent presence of HBV in the sera of HBsAg-negative, anti-HBc-positive blood donors

BACKGROUND: Recent studies have revealed that HBV may not be cleared even after the disappearance of serum HBsAg. The purpose of this study was to investigate whether the replication of HBV persists in HBsAg-negative blood donors who lack apparent liver disease. STUDY DESIGN AND METHODS: Serum HBV was examined by using PCR coupled with Southern blotting in 50 blood donors who were identified to be HBsAg negative but anti-HBc positive. RESULTS: HBV DNA was detected in the sera from 19 (38%) of 50 donors. In 11 of the 19, HBV existed exclusively as immune complexes, while HBV presumably did not exist as immune complexes in the remaining eight. The levels of HBV DNA were similar to those in patients who had recovered from acute HBV. Some nucleotide substitutions, which did not confer amino acid changes in the major epitope of HBsAg, were found in the preS-S regions. CONCLUSION: The replication of HBV is ongoing in a substantial proportion of healthy blood donors who have anti-HBc. Blood from such donors may contain very low levels of HBV free of immune complex formation and should be excluded for transfusion. The fact that such blood donors apparently lacked liver disease suggests no pathogenicity of such "occult" HBV.     

Suppression of epidermal growth factor-induced phospholipase C activation associated with actin rearrangement in rat hepatocytes in primary culture

Hepatocytes maintained in primary culture for periods of 1 to 24 hours exhibited a rapid decline in epidermal growth factor (EGF)-induced activation of phospholipase C (PLC), as was evident in a loss of EGF-induced inositol 1,4,5-trisphosphate (IP(3)) formation and mobilization of Ca(2+) from intracellular Ca(2+) stores. The loss of PLC activation was not the result of a decrease in EGF receptor or phospholipase C-gamma1 (PLCgamma1) protein levels, nor the result of a loss of tyrosine phosphorylation of these proteins, but was associated with a decrease in EGF-induced translocation of PLCgamma1 to the Triton-insoluble fraction, presumably reflecting binding to the actin cytoskeleton. Disruption of F-actin by treatment of cultured hepatocytes with cytochalasin D recovered the EGF-induced IP(3) formation and Ca(2+) mobilization to the same level and with the same dose-response relationship as was obtained in freshly isolated cells. Analysis of PLCgamma1 colocalization with F-actin by confocal microscopy showed that PLCgamma1 was mostly distributed diffusely in the cytosol, both in freshly plated cells and in cells in culture for 24 hours, despite marked differences in actin structures. EGF stimulation caused a modest redistribution of PLCgamma1 and a detectable increase in colocalization with cortical actin structures in freshly plated cells or in cytochalasin D-treated cells, but in cells that had been maintained and spread in culture only a limited PLCgamma1 relocation was detected to specific actin-structure associated with lamellipodia and membrane ruffles. We conclude that actin cytoskeletal structures can exert negative control over PLCgamma1 activity in hepatocytes and the interaction of the enzyme with specific actin structures dissociates PLCgamma1 tyrosine phosphorylation from activation of its enzymatic activity.     

Mucosal lesions may be a minor complication of SAPHO syndrome: a study of 11 Japanese patients with SAPHO syndrome

Since the term synovitis–acne–pustulosis–hyperostosis–osteitis (SAPHO) syndrome was proposed by Chamot et al. (Rev Rhum Mal Osteoartic 54:187–196, 1987), clinical reviews concerning this syndrome have been mainly reported from Europe. We carried out a retrospective analysis of 11 Japanese patients with SAPHO syndrome, and reviewed the clinical features of our series in comparison with those in a European large case study. In this study the major features of SAPHO syndrome were chronic osteitis of the anterior chest wall and pustulotic arthro-ostitis with middle age onset, and mucosal lesions seemed to be a minor complication of SAPHO syndrome. The non-erosive peripheral large joints arthritis and the particular HLA types (HLA-B51, B52, or A26), which had been reported to be increased in Behcet’s disease, were frequently seen in SAPHO syndrome with mucosal lesions. This study also suggests that SAPHO syndrome with mucosal lesions may be part of a broader disease spectrum including Behcet’s disease.     

Association of serum antioxidant capacity with coronary artery disease in middle-aged men

The possible involvement of oxidative damage in the progression of atherosclerosis has been suggested. There is some evidence that antioxidant therapy may be beneficial for the prevention of coronary heart disease. In this study, we investigated the relationship between coronary artery disease (CAD) and serum antioxidative status by measuring the total antioxidant status (TAS). Other relevant antioxidants, such as retinol, alpha, gamma-tocopherol, ascorbic acid, alpha, beta-carotenoids, erythrocyte glutathione peroxidase (GSH-Px) and oxidative products, were also determined in 31 male CAD patients with angiographically defined CAD and 66 male controls, aged 40-70 years, in a case-control study. The TAS levels, ratio and the concentrations of retinol, albumin, total protein and HDL cholesterol were significantly lower in the CAD patients than in the controls (p<0.01), and alpha-tocopherol and alpha/gamma-tocopherol were significantly higher in the CAD patients than in the controls. The TAS level correlated positively with gamma-GTP, GPT, GOT and uric acid (p<0.01). A multiple regression analysis in the CAD patients revealed that the TAS levels correlated most negatively with the number of diseased vessels. The concentrations of carotenoids and GSH-Px, as well as the alpha/gamma-tocopherol ratio were also significantly associated. Although conditional logistic regression analysis suggested low levels of HDL-cholesterol to be a significant coronary risk factor (OR=5.1, 95% CI=1.09-24.3), the TAS level showed no significant independent contribution to CAD. This study demonstrated an association of antioxidant parameters with the atherosclerosis progression, however, it did not confirm antioxidants as an independent risk factor for CAD event.