Multiple Ileal Diverticula Causing an Ileovesical Fistula: Report of a Case

We report a case of multiple ileal diverticula causing an ileovesical fistula in an 85-year-old man. The patient was admitted for investigation and treatment of intractable urethrocystitis, which he had suffered for 5 years. Cystography showed an ileovesical fistula, and contrast study of the small bowel revealed about 80 diverticula in the ileum. The segment involved by diverticula was resected and a pathological diagnosis of diverticulitis leading to ileovesical fistula was confirmed. His postoperative clinical course was uneventful. Received: September 13, 2001 / Accepted: March 5, 2002     

Effect of protein-bound uraemic toxins on the thermodynamic characteristics of human albumin

The ability of albumin to bind drugs and other lipophilic organic acids is decreased in chronic renal failure by the accumulation of albumin-bound uraemic toxins such as hippuric acid, indoxyl sulphate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF). This furan acid is the most highly bound and is not removed by haemodialysis. The inhibitory effects of these three uraemic toxins on the interaction of three marker ligands sodium octanoate (for medium chain fatty acids), salicylic acid and phenol red (bilirubin site/site I) with albumin have been investigated by differential scanning microcalorimetry and flow microcalorimetry. CMPF was the most potent inhibitor and its binding site coincided with that of bilirubin (site I). Indoxyl sulphate binds to the site for medium-chain fatty acids and tryptophan (site II) and hippuric acid, the weakest inhibitor, inhibited binding to the salicylic acid site.     

Practical issues and observations on the use of foreign clinical data in drug development

The International Conference on Harmonization (ICH) has recently developed the ICH guidelines, which are the common guidelines for regulatory requirements in the ICH regions, i.e., European Union, Japan, and the United States of America. The guidelines have been successively implemented in the ICH regions, and the people involved in drug evaluation in the pharmaceutical industry, such as statisticians and pharmaceutical scientists, have referred to the guidelines during their daily work. Probably one of the most influential ICH guidelines on the drug development process in the ICH regions, especially in Japan, is the ICH-E5 guideline, which is encouraging the pharmaceutical industry to use the mountain of foreign clinical data for the registration of a new drug. In this article, we review the issues concerning the ICH-E5 guideline discussed so far, and discuss some practical issues in applying the guideline, especially the design of the study conducted in a new region. This is called a "bridging study." In addition, we introduce some statistical approaches for evaluating the acceptability of foreign clinical data.     

Energy metabolism and turnover are increased in mice lacking the cholecystokinin-B receptor

Cholecystokinin (CCK) is an important gastrointestinal hormone as well as a neurotransmitter. Two types of CCK receptors, types A and B, have been identified. The CCK-A receptor is involved in satiety, food intake and behavior, whereas the B receptor is involved in anxiety. We recently produced CCK-A, -B and AB receptor knockout mice to study the role of these receptors in energy metabolism. Daily energy intake and expenditure were significantly greater in CCK-BR(-/-) and CCK-AR(-/-)BR(-/-) mice than CCK-AR(-/-) and wild-type [CCK-AR(+/+)BR(+/+)] mice. Relative liver and kidney weights (g/kg body) were significantly greater in CCK-AR(-/-)BR(-/-) mice than in wild-type mice. Energy metabolism and energy turnover were increased in mice with a disruption of the CCK-BR gene, although the underlying mechanism is unknown.     

Medial temporal lobe activation during context-dependent relational processes in episodic retrieval: an fMRI study. Functional magnetic resonance imaging

Previous studies have reported that the medial temporal lobe (MTL) structures contribute to the processing of relations among multiple stimuli in episodic encoding. There have been few studies, however, on the episodic retrieval requiring processing of relations among multiple components that was involved in our events. We used functional magnetic resonance imaging (fMRI) to investigate neural activities during the retrieval of relations within an organized episode and the recognition of an episodic component. Healthy, normal participants memorized 50 four-scene comic strips before fMRI scanning. In the retrieval phase with fMRI scanning, participants were engaged in three tasks: a visual identification (VI) task, a story recall (SR) task, and a picture recognition (PRe) task. In the VI task, participants were asked to judge whether they could identify at least one female character in the two scenes presented vertically. In the SR task, participants were shown the first and last scenes from strips memorized previously and asked to judge whether or not the two scenes were from the same strip. In the PRe task, participants were shown two scenes and asked to judge whether they both belonged to the memorized scenes. The two contrasts of SR with VI and PRe with VI demonstrated some commonly activated areas, such as the bilateral middle frontal gyrus and cerebellum. More importantly, the SR task differentially activated the bilateral parahippocampal gyrus, whereas the PRe task differentially activated right prefrontal areas, including the inferior frontal and precentral gyri. The results suggest that the activity of the MTL structures may be strongly associated with episodic memory retrieval requiring context-dependent relational processing.     

In vivo immunogenicity of osteosarcoma cells that express B7-1a,an alternatively spliced form of B7-1

BACKGROUND: B7 family members play a central costimulatory role in T cell activation. We have previously identified B7-1a, an alternatively spliced form of B7-1. The function of B7-1a in induction of anti-tumor immunity remains uncertain. MATERIALS AND METHODS: The cDNAs of murine B7-1, B7-1a and B7-2 were introduced into a murine osteosarcoma cell line, LM8. The ability of B7 transfectants to elicit in vivo anti-tumor immunity was comparatively analyzed with respect to tumorigenecity, pulmonary metastasis and survival time. RESULTS: LM8 cells expressing B7-1, B7-1a, or B7-2 all elicited immunological responses in immunocompetent C3H/He mice. Notably, the anti-tumor effects were most obvious in mice inoculated with B7-1a-transfected LM8 cells. Such a difference among B7-transfectants became indistinguishable in immunodeficient nude mice. CONCLUSION: These findings indicate that B7-1a serves as a more efficacious costimulatory molecule than B7-1 or B7-2 in the induction and maintenance of anti-tumor immune responses against a poorly immunogenic osteosarcoma cell line.     

Cationic charge determines the distribution of liposomes between the vascular and extravascular compartments of tumors

Tumor vessels possess unique physiological features that might be exploited for improving drug delivery. In the present study, we investigate the possibility of modifying polyethylene glycol-ylated liposome cationic charge of polyethylene glycol coated liposomes to optimize delivery to tumor vessels using biodistribution studies and intravital microscopy. The majority of liposomes accumulated in the liver, and increasing charge resulted in lower retention in the spleen and blood. Although overall tumor uptake was not affected by charge in the biodistribution studies, intravital microscopy showed that increasing the charge content from 10 to 50 mol % doubled the accumulation of liposomes in tumor vessels, suggesting a change in intratumor distribution; no significant effect of charge on interstitial accumulation could be detected, possibly attributable to spatial heterogeneity. Increased vascular accumulation of cationic liposomes was similar in two different tumor types and sites. Our results suggest that optimizing physicochemical properties of liposomes that exploit physiological features of tumors and control the intratumor distribution of these drug carriers should improve vascular-specific delivery.     

FDG-PET after radiotherapy is a good prognostic indicator of rectal cancer

In the management of rectal cancer after the combined therapy of the radiation and surgical operation, the evaluation of the prognosis is important. Although fluoro- 18-deoxyglucose positron emission tomography (FDG-PET) is considered as a useful tool for evaluation of therapeutic effect of this cancer as well as the other cancers, however, there are few articles that clearly describe the appropriate procedure of the FDG-PET in order to obtain the best prognostic value. The purpose of the present study is to compare several variations of a semi-quantification method, the Standardized Uptake Values (SUV) and to determine the most appropriate parameter, for the prognostic prediction and to propose the quantitative guideline of the FDG-PET. Especially, the authors focused on the SUV after radiotherapy, which had not been considered as a key quantitative value, as it was rather taken as a mere indicator of the therapeutic (radiotherapeutic) effect, not a direct indicator of the prognosis for the cancer itself. METHODS: Forty patients with rectal cancer in the lower rectal region underwent two series of FDG-PET study before and after pre-operative radiotherapy. Their SUVs were calculated from FDG-PET data and compared with the results of the long-term follow-up of the patients as well as with histopathological outcomes. Results: All 40 patients had high FDG uptake before radiotherapy. The mean value of SUV before radiotherapy (SUV1) was 7.6. After radiotherapy, the mean value of SUV (SUV2) decreased to 4.2. There was a significant difference in SUV2 between the groups with and without recurrence (p < 0.05), however, SUVI or SUV ratio (SUV2/SUV1) displayed no significant difference with the incidence of recurrence. CONCLUSION: SUV2 was considered to be a good prognostic indicator for long-term prognosis of rectal cancer patients. SUV1 nor SUV ratio SUV2/SUV1 did not have the equivalent prognostic usefulness. Subsets of patients with SUV2 greater than 3.2 should be observed closely.     

Interobserver variation in diagnosis of dementia by brain perfusion SPECT

Brain perfusion SPECT (BP-SPECT) has characteristic patterns of abnormality, enabling the differential diagnosis of dementia. The purpose of this study was to measure interobserver variations in the diagnosis of dementia using BP-SPECT. BP-SPECT images of 57 cases, 19 of Alzheimer's disease (AD), eight of multi-infarct dementia (MID), three of Pick's disease, five of other dementias, and 22 normal controls, were interpreted by ten nuclear medicine physicians with varying levels of experience. Brain MR images of the cases were then interpreted apart from SPECT. The physicians independently rated all of the diagnoses listed beforehand according to a five-point scale, with clinical information provided. Receiver-operating characteristic (ROC) curves and the area under the ROC curve (Az) were calculated. Az varied from 0.48 to 0.87. Mean Az's were significantly larger (p<0.05) in the diagnosis by SPECT than in that by MRI (0.715 and 0.629 for dementia vs. normal, 0.670 and 0.560 for AD or MID vs. normal, 0.610 and 0.416 for AD vs. normal, and 0.672 and 0.412 for AD vs. MID, respectively). Considerable interobserver variation was present in BP-SPECT interpretation. BP-SPECT may be more effective for the evaluation of dementia than MRI when the same nuclear medicine physicians interpret both images.     

Imaging by Atomic Force Microscopy of the Plasma Membrane of Prestin-Transfected Chinese Hamster Ovary Cells

The high sensitivity of mammalian hearing is achieved by amplification of the motion of the cochlear partition. This cochlear amplification is thought to be generated by the elongation and contraction of outer hair cells (OHCs) in response to acoustical stimulation. This motility is made possible by a membrane protein embedded in the lateral membrane of OHCs. Although a fructose transporter, GLUT-5, was initially proposed to be this protein, a later study identified the gene of the motor protein distributed throughout the OHC plasma membrane. This protein has been named “prestin.” However, although previous morphological studies by electron microscopy and atomic force microscopy (AFM) found the lateral wall of OHCs to be covered with 10-nm particles, believed to be motor proteins, it is unknown whether such particles consist only of prestin or are a complex of GLUT-5 and prestin molecules. To determine if the 10-nm particles are indeed constituted only of prestin, plasma membranes of prestin-transfected and untransfected Chinese hamster ovary (CHO) cells, which do not express GLUT-5, were observed by AFM. First, the cells attached to a substrate were sonicated so that only the plasma membrane remained on the substrate. The cytoplasmic face of the cell was observed by the tapping mode of the AFM in liquid. As a result, particle-like structures were recognized on the plasma membranes of both the prestin-transfected and untransfected CHO cells. Comparison of the difference in the frequency distribution of these structures between those two cells showed approximately 75% of the particle-like structures with a diameter of 8–12 nm in the prestin-transfected CHO cells to be possibly constituted only by prestin molecules. Our data suggest that the densely packed 10-nm particles observed on the OHC lateral wall are likely to be constituted only of prestin molecules.