The Predominant Contribution of Oligopeptide Transporter PepT1 to Intestinal Absorption of β-Lactam Antibiotics in the Rat Small Intestine

Although recent evidence suggests that certain β-lactam antibiotics are absorbed via a specific transport mechanism, its nature is unclear. To confirm whether peptide transport in the rat can be largely ascribed to the intestinal oligopeptide transporter PepT1, the transporter has been functionally characterized and its significance in the intestinal absorption of β-lactam antibiotics was evaluated. For evaluation of transport activity complementary RNA (cRNA) of rat PepT1 was synthesized in-vitro and expressed in Xenopus laevis oocytes. cRNA induced uptake of several β-lactam antibiotics and the dipeptide [¹⁴C]glycylsarcosine; this was specifically inhibited by various dipeptides and tripeptides but not by their constituent amino acids or by terra- or pentapeptides. The transport activity of PepT1 for β-lactam antibiotics correlated well with their in-vivo intestinal transport and absorption. Furthermore, mutual inhibitory effects on uptake were observed between glycylsarcosine and β-lactam antibiotics. Hybrid depletion of the functional expression of rat PepT1 in oocytes injected with rat intestinal epithelial total mRNA was studied using an antisense oligonucleotide corresponding to the 5′-coding region of PepT1. In oocytes injected with rat mRNA pre-hybridized with the antisense oligonucleotide against rat PepT1, the uptake of [¹⁴C]glycylsarcosine was almost completely abolished, whereas its uptake was not influenced by a sense oligonucleotide for the same region of PepT1. Similarly, the uptake of β-lactam antibiotics was also reduced by the antisense oligonucleotide against rat PepT1. These results demonstrate that the intestinal proton-coupled oligopeptide transporter PepT1 plays a predominant role in the carrier-mediated intestinal absorption of β-lactam antibiotics and native oligopeptides in the rat.     

The safety of a nitric oxide inhalation system with high frequency oscillatory ventilation

Nitric oxide (NO) inhalation and high frequency oscillatory ventilation (HFOV) has been indicated in infants with severe respiratory failure. The purpose of the present study was to evaluate the safety of an NO inhalation system with HFOV in terms of nitrogen dioxide (NO₂) production. The NO inhalation system consisted of a high frequency oscillatory ventilator, a neonatal circuit and a test lung. The NO concentration was changed from 0 to 19 p.p.m. At each level of NO, the oxygen (O₂) concentration was changed from 21 to 100%. The NO and NO₂ concentrations were measured with a chemiluminescence analyzer using a molybdenum converter. The NO₂ concentration was increased when either the O₂ or the NO concentration was increased. The interposition of the endotracheal tubes increased NO₂ concentrations at 4 p.p.m. NO. The high stroke volume and high mean airway pressure produced a significant increase in NO₂ production at 4 p.p.m. NO. The increase in NO₂ production was prevented by placing a one-way valve at the joint of the NO gas line to the inspired limb. It was concluded that the NO inhalation system with HFOV can be safely used when a one-way valve is placed at the joint of the NO gas line to the inspired limb and when inhaled NO is at a relatively low concentration.     

Diagnostic Accuracy of Laparoscopic Liver Biopsy in Chronic Liver Diseases,Comparison of Laparoscopic and US-Guided Liver Biopsy Results

Liver biopsies were carried out using three different needles, a Vim-Silverman needle 2.5 mm in outer caliber, an 18-Gauge (18G) Majima needle, and a 17-Gauge (17G) Majima needle. The biopsies were obtained from nearby locations on the liver surface under laparoscopic observation, to ascertain differences in histological diagnosis according to the size of the biopsy specimen. The biopsy specimens obtained with the Vim-Silverman needle were wider than those obtained with the other two needles. The agreement in histological diagnoses of the liver, obtained with the Vim-Silverman needle versus the 18G Majima needle, was 26.0%, while that between the Vim-Silverman needle and the 17G Majima needle was 40.0%. Histological diagnosis tended to be underestimated in small biopsy specimens in advanced chronic liver diseases. A questionnaire survey, conducted in 92 hospitals affiliated with Okayama University Medical School, revealed US-guided liver biopsy to be the practice of choice in 57 of 92 (62.0%) hospitals, and 18G needles were used in US-guided liver biopsy in 35 of 78 (45.2%) hospitals.     

Experimental periodontal breakdown in the dog

abstract – This paper describes a method for inducing rapidly progressing and reproducible periodontal lesions around selected teeth in dogs. The experiments were performed on 10 beagles which were fed a diet favoring gross formation of plaque. Approximately 1 mm of the marginal alveolar bone around ₄P and P₄ was removed and a notch prepared in the root. A ligature of cotton floss was placed around ₄P and P₄ at the cemento-enamel junction. Radiographs and sections prepared 230 d later revealed that a progressive breakdown of the periodontal tissues had occurred. The average bone loss was 2.4 mm and the distance between the apical cells of the pocket epithelium and the notch was 854μm.     

Nucleotide sequence of a hepatitis B virus genome of subtype adw isolated from a Philippine: Comparison with the reported three genomes of the same subtype

The complete nucleotide sequence was determined for a hepatitis B virus genome of subtype adw (pFDW294) isolated and cloned from the plasma sample of a Philippino. The genome was 3221 base-pair long with a point mutation at the 1376th nucleotide that affected the coding capacity of the P and X genes. There was a wide range of sequence divergence among pFDW294 and the reported three genomes of the same subtype (1.1–9.9%), occurring more often in the pre-S region and the S gene than in the pre-C region and the C gene.     

Developmental Toxicity of Aspirin Prenatally Given to Rats: Assessment in Slc: Wistar-KY Rats

ABSTRACT  Slc:Wistar-KY rats were administered orally with 62.5, 125, 187.5 or 250mg/kg aspirin suspended with 0.5 % CMC-Na on days 9–11 of gestation (plug += day 0). Suppression of maternal weight gain and food consumption during treatment was observed at and over 187.5 mg/kg. At term, the fetal mortality increased at and over 187.5 mg/kg and the fetal weight was lowered at and over 125 mg/kg. Among 15 live fetuses at 250 mg/kg, 4 had external malformations. In the skeletal examination (double staining), skeletal anomalies increased at and over 187.5 mg/kg. The skeletal variations such as vertebral anomalies, fused costal cartilages and increased presacral vertebrae were often encountered and delayed ossification was also found at and over 125 mg/kg. The internal anomalies tended to increase at and over 187.5 mg/kg. The live birth rate was significantly lower at 187.5 mg/kg than that in controls, and all pups, except for 3 from a dam, died before weaning. At 125 mg/kg, the pivoting locomotion on day 7 post partum was poorer as compared with controls. The physical and functional development at 62.5 mg/kg was not changed. There were no significant effects on male offspring in the open-field, rotarod, under-water T-maze and avoidance learning tests. However, in the Biel T-maze test (9–10 weeks of age), the aspirin-treated groups showed more errors and the increased elapsed time on the 1st trial day than controls. These results indicate that aspirin may induce a slight learning defect on rat offspring even at the non-teratogenic dose and the Biel T-maze test is more sensitive than any other learning tests given in this study.     

Localization of HIV-1 in human thymic implant in SCID-hu mice after intravenous inoculation

Human immunodeficiency virus type 1 (HIV-1) was immunohistochemically and ultrastructurally localized in human thymus implants in SCID-hu mice 3 weeks after intravenous (i.v.) inoculation of the virus. A viral antigen (gp120) was predominantly distributed in and around the epithelial cells in Hassall's corpuscles as demonstrated by fluorescence immunohistochemistry. Occasional solitary round cells positive for the viral antigen but negative for cytokeratin were detected in the perivascular areas. Ultrastructural examinations clearly revealed a number of mature viral particles in the intercellular spaces of the Hassall's corpuscles. Thus the present study indicates the possibility that thymic epithelial cells in Hassall's corpuscles act as a target and/or reservoir in an early stage of HIV infection.     

An Armrest is Effective for Reducing Hand Tremble in Neurosurgeons

Experienced neurosurgeons reduce hand tremble by placing their hand beside the operative field when performing microneurosurgery conventionally. Another solution to reduce hand tremble is an armrest. However, the reduction of hand tremble by using an armrest or finger-placing technique has not been rigorously measured in microneurosurgery. This study was performed to provide a quantitative assessment of the efficacy of an armrest to reduce hand tremble in comparison with the finger-placing technique. Hand tremble was evaluated in 11 board-certified neurosurgeons in a simulated microneurosurgery. The loci of surgical forceps handled by neurosurgeons were measured by a three-dimensional optical coordinate measuring machine. A static task was performed under four conditions: with/without the finger-placing technique and/or an armrest. The radius of an imaginative sphere including 95% of each locus was calculated and reviewed according to the four conditions. Hand tremble was significantly larger when the finger-placing technique was not implemented compared to when the technique was used (P < 0.05). The armrest also reduced hand tremble (P < 0.05) similar to the finger-placing technique. Non-inferiority was retained between the finger-placing technique and the armrest. Concomitant use of the armrest and the finger-placing technique did not interfere with the efficacy of the technique to reduce neurosurgeon’s hand tremble. The finger-placing technique was confirmed to reduce hand tremble. Resting the neurosurgeon’s forearm on an armrest also reduced the hand tremble. An armrest is a device that reduces hand tremble in neurosurgeons like the finger-placing technique.     

SYNTHESIS OF SUBSTRATES SPECIFIC FOR HUMAN SPLEEN FIBRINOLYTIC PROTEINASE (SFP)

Two peptide anilides, Suc-Tyr-Leu-Val-pNA (III) and Ac-Ser-His-I.eu-Val-pNA (V) were synthesized by the conventional method with the object of obtaining specific substrates for human spleen fibrinolytic proteinase (SFP). The K_cat/K_m values for hydrolysis of HI and V by SFP were 22 64 7 and 2 700, respectively. On the contrary, the K_cat/K_m values for hydrolysis of III and V by porcine pancreatic elastase were 21 and 9, respectively.     

A lower starting dose of eltrombopag is efficacious in Japanese patients with previously treated chronic immune thrombocytopenia

Background:  Eltrombopag is an oral, non‐peptide thrombopoietin receptor agonist that has shown efficacy and safety in chronic immune thrombocytopenia (ITP). However, ethnic differences in eltrombopag exposure have been reported: area under the curve exposure to eltrombopag was 87% greater among ITP patients of East Asian descent than among ITP patients of non‐East Asian ITP descent. Objectives:  To evaluate the efficacy and safety of eltrombopag by using, in Japanese ITP patients, lower starting (12.5 mg) and maximum (50 mg) doses of eltrombopag than the standard starting (50 mg) and maximum (75 mg) doses approved in the USA and Europe. Patients:  We examined 23 Japanese patients with previously treated chronic ITP with a platelet count of < 30 000 μL^?1 in a multicenter study comprising a randomized, double‐blind, placebo‐controlled phase for 6‐week evaluation (15 eltrombopag, and eight placebo) and an open‐label phase for 6‐month evaluation (23 eltrombopag). Results and Conclusions:  The response rate (platelet count of ≥ 50 000 μL^?1) at week 6 of the 6‐week double‐blind phase was 60% in eltrombopag‐treated patients and 0% in placebo‐treated patients. Ten of 23 patients (43.5%) responded for ≥ 75% of predefined assessment visits during the 6‐month open‐label phase. Notably, 22% (5/23) of patients responded to 12.5 mg of eltrombopag, which was administered within the first 3 weeks of eltrombopag treatment. Bleeding decreased with eltrombopag treatment as compared with baseline. Eltrombopag was generally well tolerated; one patient experienced a transient ischemic attack on day 9. Eltrombopag (12.5–50 mg) is effective for the management of Japanese patients with chronic ITP (NCT00540423).