Clinicopathological findings in fulminant-type pneumococcal infection: report of three autopsy cases

Reported herein are three autopsy cases of fulminant-type pneumococcal sepsis with disseminated intravascular coagulation (DIC) resulting in death within a few days of onset of symptoms. Two of the three patients had previously had a splenectomy because of a hematological disorder. None of the patients had received pneumococcal vaccination. On post-mortem every organ had congestion as well as bleeding. Interestingly, severe inflammation of the alveoli was absent despite the sepsis. The cause of death was rapidly progressive pneumococcal sepsis leading to DIC and circulatory failure, which appeared to cause pulmonary congestion and hemorrhage without pneumonia. It is important to understand the pathogenesis of fulminant-type pneumococcal infection because it is life-threatening for compromised hosts.     

A surgical (right lobectomy) case of liver metastasis of colon cancer after chemotherapy using mFOLFIRI and cetuximab

A man in his early seventies underwent low anterior resection and partial resection of the liver for the rectal cancer and liver metastasis. However, 4 months after the surgery, he was found to have a liver tumor at S5 and S7 by abdominal CT scan. Then, he underwent chemotherapy (mFOLFOX6), but the metastatic tumor was progressive. We selected FOLFIRI + cetuximab regimen for second-line therapy to resect the metastatic tumor. As the metastatic lesion was become smaller after 4-course of the regimen including cetuximab, we decided to perform a radical resection. We conducted a right lobectomy of the liver, and the tumor was completely resected.     

Suppressed protein expression of the death-associated protein kinase enhances 5-fluorouracil-sensitivity but not etoposide-sensitivity in human endometrial adenocarcinoma cells

Targeted knockdown of the death-associated protein kinase (DAPK) expression in the endometrial adenocarcinoma HHUA cells reportedly induces cell death by enhancing the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in an autocrine/paracrine manner. This suggests that endogenous DAPK is a potential candidate for a molecularly targeted anticancer therapy for patients with endometrial adenocarcinoma. To investigate the role of endogenous DAPK in anticancer drug sensitivity, we examined effects on cellular anticancer drug sensitivities of transfections with 5 different specific DAPK small-interfering RNAs (siRNAs) into HHUA cells. DAPK siRNA transfections strongly enhanced 5-fluorouracil (5FU)-sensitivity, but not etoposide-sensitivity, of HHUA cells compared with control siRNA-transfected cells. These results indicate that etoposide-stimulated cell death signals may share or include TRAIL-mediated apoptotic signals, and that 5FU-stimulated cell death signals may be independent from TRAIL-mediated apoptotic signals induced by DAPK siRNA transfections. Moreover, 5FU-combined chemotherapy with DAPK siRNA transfection may show stronger anticancer effects on patients with endometrial adenocarcinoma than does chemotherapy alone.     

Osteoblast differentiation is impaired in SOCS-1-deficient mice

The suppressor of cytokine signaling-1 (SOCS-1) is a cytokine-inducible intracellular molecule that inhibits excessive activation of the JAK-STAT-mediated signal cascade initiated by various stimuli. The smaller size of SOCS-1 knockout (KO) mice suggests the presence of skeletal abnormality caused by the disruption of the regulatory system in JAK-STAT signaling. In addition to macroscopic examination, peripheral quantitative computed tomography (pQCT), bone histomorphometrical analysis, and in situ hybridization were used to examine the skeletal properties of SOCS-1 KO mice. Moreover, differentiation of primary cultured osteoblasts was investigated. Distinct phosphorylation of STAT1 was detected in the SOCS-1 KO calvarial cells but was hardly detectable in wild-type (WT) mice. Undercalcified areas in the skulls and sternum, as well as comparatively thinner calcified areas of cortical bone, were found in SOCS-1 KO mice. pQCT analysis showed a marked decrease in salt content, whereas the mineralization activity of primary cultured calvarial cells strongly suggested significant impairment in osteoblasts of SOCS-1 KO mice. In situ hybridization analysis demonstrated that these mice expressed the early markers [type I collagen (COL-1) and osteonectin (ON)] and the mid-marker [osteopontin (OP)] at levels comparable with those seen in WT mice. However, a dramatic decrease was observed in the expression level of the late marker [osteocalcin (OC)] of osteoblasts. Our findings thus demonstrate that SOCS-1 regulates osteoblast differentiation in the later stage.     

Phylogenetic, ontogenetic, and pathological aspects of the urine-concentrating mechanism

The urine-concentrating mechanism is one of the most fundamental functions of avian and mammalian kidneys. This particular function of the kidneys developed as a system to accumulate NaCl in birds and as a system to accumulate NaCl and urea in mammals. Based on phylogenetic evidence, the mammalian urine-concentrating mechanism may have evolved as a modification of the renal medulla's NaCl accumulating system that is observed in birds. This qualitative conversion of the urine-concentrating mechanism in the mammalian inner medulla of the kidneys may occur during the neonatal period. Human kidneys have several suboptimal features caused by the neonatal conversion of the urine-concentrating mechanism. The urine-concentrating mechanism is composed of various functional molecules, including water channels, solute transporters, and vasopressin receptors. Abnormalities in water channels aquaporin (AQP)1 and AQP2, as well as in the vasopressin receptor V2R, are known to cause nephrogenic diabetes insipidus. An analysis of the pathological mechanism involved in nephrogenic diabetes insipidus suggests that molecular chaperones may improve the intracellular trafficking of AQP2 and V2R, and, in the near future, such chaperones may become a new clinical tool for treating nephrogenic diabetes insipidus.     

A case of adult Wilms' tumor --review of the Japanese literature

The patient was a 23-year-old-woman who was referred to our hospital with chief complaints of right flank pain and macroscopic hematuria. Right radical nephrectomy was performed with the diagnosis of right renal cancer. Histopathological examination revealed Wilms' tumor of favorable histology, stage I according to the National Wilms Tumor Study classification. She received adjuvant chemotherapy consisting of actinomycin D and vincristine at another hospital. One year and three months later, she developed lung metastasis. She underwent partial pulmonary resection, and then received chemotherapy. She is presently disease-free more than forty months after the initial operation. Wilms' tumor is rare in adults and has a poor prognosis compared with that in children. We analyzed 112 cases in the Japanese literature from 1981 to 2004. The mean age was 36.9 years, with males and females equally affected. No difference was found between the left and right sides in frequency of tumor. We also examined the relationship between histological features and prognosis based on 43 Japanese reports. Twenty-two of the 43 (51%) cases had unfavorable histology. The 2-year survival rate with unfavorable histology was 18%, while that with favorable histology was 87%. The 2-year survival rates for stages under II and over III were 67% and 27%, respectively. Based on these findings, we conclude that the prognosis of adult Wilms' tumor is very poor since many patients have unfavorable histology and no effective treatment guidelines have been established.     

Tissue-engineered approach for the treatment of steroid-induced osteonecrosis of the femoral head: transplantation of autologous mesenchymal stem cells cultured with beta-tricalcium phosphate ceramics and free vascularized fibula

Autologous mesenchymal stem cells (MSCs) cultured with beta-tricalcium phosphate (beta-TCP) ceramics and with a free vascularized fibula were transplanted into three patients with steroid-induced osteonecrosis of the femoral head. The average follow-up period was 34 months and the average patient age at the time of surgery was 28 years old. Fifteen milliliters of bone marrow was obtained from the patients 4 weeks before surgery, and was used for in vitro proliferation of MSCs. beta-TCP granules were immersed in the MSC suspension and the cells were further cultured for 2 weeks. Cultured MSCs/beta-TCP composite granules were implanted into the cavity that remained after curettage of necrotic bone; and finally, a free vascularized fibula was grafted. All hips showed preoperative collapse and radiographic progression was observed in two hips postoperatively. Osteonecrosis did not progress any further and early bone regeneration was observed. This tissue-engineered approach has potentials for the treatment of osteonecrosis. However, our results suggested that the present procedure could not be used for cases with severe preoperative collapse.     

Survey of current conditions regarding awareness of the nutritional role of supplements for pharmacy students

Various nutritional supplements have become available in recent years. However, health problems resulting from the misuse of these supplements are on the rise, and have been attributed to a lack of knowledge among consumers. In addition, a survey of university students revealed that approximately 20% of students erroneously considered nutritionally balanced supplements as substitutes for meals. Given this background, we conducted a questionnaire survey of first- and fourth-year students at the Faculty of Pharmaceutical Sciences at Kobe Gakuin University with the objective of elucidating factors such as the awareness of supplements among pharmacy students and whether these students had a superior understanding of supplements compared to the general student population. Awareness of supplements among students was determined in terms of the degrees of emphasis on meals and supplements in nutritional intake. The proportion of students who essentially believed that "nutritionally balanced supplements can be used as substitutes for meals" did not significantly differ between pharmacy students and the general student population. In addition, only 30% of students had an accurate understanding of supplements. Following graduation, pharmacy students may become pharmacists and thus be responsible for providing directions regarding usage of supplements. These findings suggest that in order to nurture professional pharmacists, it is necessary to first implement practical nutrition education and consumer education to promote healthier dietary habits among the students themselves.     

Cardiovascular malformations induced by prenatal exposure to phenobarbital in rats

The effects of prenatal exposure to phenobarbital (PB) on the cardiovascular system were examined in rat fetuses and pups. PB was administered at a dose of 80 or 120 mg/kg/day by gavage to Sprague Dawley (SD) rats on two consecutive gestational days (GD): 7-8, 8-9, 9-10, or 10-11. Fetuses were examined for cardiovascular malformations on GD 20. In addition, pups were examined for PB-induced cardiovascular malformations. Incidences of ventricular septal defect (VSD), overriding aorta, double outlet right ventricle and transposition of great arteries were significantly increased in the fetuses whose dams were administered PB at 120 mg/kg on GD 8-9, 9-10 or 10-11. GD 8-11 was the critical period for the cardiovascular malformations associated with administration of PB in rats. Various types of cardiovascular malformations were detected in pups from the PB-administered dam. Severe cardiovascular malformations induced by PB caused deaths on early postnatal days. However, slight malformations such as isolated VSD persisted until weaning, and did not affect postnatal viability.