Development and efficacy of a clinician-targeted refresher course for treating nonpneumonia respiratory tract infections.

BACKGROUND: In 2017, the Japanese government published an evidence-based manual describing the appropriate use of antibiotics in outpatient settings to tackle the problem of antimicrobial resistance. To fill the evidence-practice gap, we developed a clinician-targeted course aimed at improving clinician skills in the daily clinical practice of treating acute respiratory tract infections (RTIs) based on the manual. The aim of this study was to evaluate the efficacy of the course. METHODS: This course consisted of lectures using illness scripts and checklists, as well as interactive communication skills training using role-playing. We performed a vignette-based evaluation of the changes in the knowledge and attitudes of the course participants toward prescribing antibiotics for nonpneumonia RTIs, using pre- and postcourse questionnaires. The questionnaires also included course feedback via the use of a 5-point Likert scale. RESULTS: Thirty-eight clinicians were included in the analyses, and 90% of these participants had graduated ≥20 years ago. We found statistically significant reductions in the intention to prescribe antibiotics for four of the six nonpneumonia RTI vignettes: acute bronchitis (-47.2%; 95% confidence interval [CI] -66.3 to -28.1%), common cold (-16.2%; 95% CI -30.8 to -1.6%), acute pharyngitis (-27.0%; 95% CI -49.0 to -5.0%), and acute rhinosinusitis (-33.3%; 95% CI -53.3 to -13.3%). The course seemed to be satisfactory for experienced doctors who were the relevant target population of such a workshop. CONCLUSIONS: The refresher course was helpful for reducing the participants' intensions to prescribe antibiotics for nonpneumonia RTIs.

Severe demyelination in a patient with a late infantile form of Niemann-Pick disease type C.

Niemann-Pick disease type C (NPC) is a cholesterol storage disease caused by defective cellular cholesterol transportation. The onset and progression of NPC are variable, and autopsy findings have mainly been reported for the adult and juvenile forms of this disease. Here we report the clinical and pathological findings from a 9-year-old female patient with the late infantile form of NPC due to NPC1 gene mutation. She had notable splenomegaly at 4 months of age. She lost the ability to speak at 18 months of age. She learned to walk, but often fell and could no longer walk after 30 months. At 3 years of age, she was diagnosed with NPC. Sequence analysis of the NPC1 gene revealed compound heterozygous mutation of T2108C (F703S) and C2348G (S813X) (both novel). Thereafter, the patient suffered repeated respiratory infections and died of respiratory failure at 9 years of age. Pathological findings included cerebral atrophy (particularly of white matter), severe demyelination, and the loss of neurons from the cerebrum and from the nuclei of the brain stem. Remnant neuronal cells and microglia in the cerebrum, cerebellum, and brain stem had become swollen and foamy. Neurons of the hippocampal CA1 and Purkinje cells were relatively spared, and senile plaques and axonal spheroids were not present. Foamy cells were also observed in other organs, especially the spleen and bone marrow. The F703S mutation in this patient was localized in a sterol-sensing domain (SSD). Severe neurological phenotypes have been previously reported in patients with missense mutations in an SSD. It is considered that the combination of a nonsense mutation and missense mutation in an SSD was responsible for the severe neurological phenotype of our present patient. While pathological findings of adult/juvenile forms of NPC have included swollen neurons and glia, neuronal cell loss, and NFTs, demyelination may be a predominant finding in the infantile form of NPC.

An Infant With Medulloepithelioma Successfully Treated by High-dose Chemotherapy Followed by Autologous Peripheral Blood Stem Cell Transplantation Without Radiotherapy.

Medulloepithelioma of the central nervous system (CNS) is a rare primitive neuroectodermal tumor characterized by highly malignant behavior occurring in early childhood. Few cases have been reported and optimal management remains unknown. Here, we report a case of CNS medulloepithelioma successfully treated with high-dose chemotherapy (HDCTX) followed by autologous stem cell transplantation (auto-SCT) without radiotherapy. At the last follow-up, 3.0 years after onset, the patient was alive with no sign of relapse and normal development. To the best of our knowledge, this is the first reported case of long-term survival of CNS medulloepithelioma treated by HDCTX/auto-PBSCT without radiotherapy.

Aberrant aneurysm of adult-type pulmonary sequestration: report of a case.

Aberrant pulmonary artery exposed by high-blood pressure over a long period in adult-type pulmonary sequestration can be susceptible to arteriosclerotic change and aneurysmal formation. Dividing this aneurysmal artery has a risk of stump leakage and aneurysm. We herein report a 64-year-old man with an aberrant aneurysm of intralobar pulmonary sequestration. Thoracoscopic resection of the sequestrated lung was performed uneventfully by prior endovascular occlusion of the aberrant aneurysm.

Successful treatment with pulse cyclophosphamide of a steroid-refractory hepatitic variant of liver acute graft-vs.-host disease in a child.

A 13-yr-old boy with recurrent acute myeloid leukemia underwent HSCT using cells from an unrelated donor who matched all HLA antigens except one. Forty-two days later, the patient developed a steroid-refractory hepatitic variant of liver GVHD with peak ALT and T.Bil values of 1406 mU/mL and 10.4 mg/dL, respectively. He was successfully treated with pulse Cy (1000 mg/dose × one day) without a change in chimerism being observed or acquiring an infection. All immunosuppressant therapies could be discontinued 12 months after HSCT. Two yr after HSCT, the patient remains in CR without chronic GVHD. This single case report suggests that pulse Cy may be a promising therapy for steroid-refractory GVHD, especially hepatitic GVHD, but needs to be further tested in clinical trials.

Resolution of anti-neutrophil cytoplasmic antibody-associated vasculitis after resection of gastric cancer.

We report a case of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis in a 62-year-old patient with gastric cancer. The myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) level was threefold above normal preoperatively. Vasculitis was seen on renal biopsy. Gastric resection revealed well-differentiated adenocarcinoma and vasculitis. The MPO-ANCA level returned to normal post-operatively. Although ANCA-associated vasculitis occasionally accompanies malignant tumors, this is the first documented case of concurrent gastric cancer-associated and ANCA-associated vasculitis, with post-operative resolution of the vasculitis.

Refractory kaposiform hemangioendothelioma that expressed vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3: a case report.

This report describes the case of a 10-month-old boy who was diagnosed to have kaposiform hemangioendothelioma (KHE) with Kasabach-Merritt syndrome (KMS), which is a rare pediatric vascular tumor with a high mortality rate. Although both KHE with KMS were resistant to various therapies, such as oral prednisolone, sclerotherapy, and chemotherapy, repeated radiation therapy with methylprednisolone pulse therapy did reduce the volume of KHE and improved the symptoms of KMS. Unfortunately, a regrowth of KHE with KMS was observed 4 months after the cessation of treatment and the patient thereafter died from an intracranial hemorrhage and Pneumocystis carinii pneumonia, which is a complication related to repetitive radiation and steroid therapy. A histopathologic examination of autopsy specimens confirmed a diagnosis of KHE and immunohistologic staining was positive for vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3. These findings may provide the rationale to further investigate the role of VEGFRs in the pathogenesis of KHE and also to elucidate its prognostic value, along with the application of inhibitors for VEGFRs for the treatment of refractory KHE.

Prognostic significance of intragastric pressure for the occurrence of aspiration pneumonia in the patients with percutaneous endoscopic gastrostomy (PEG).

BACKGROUND/AIMS: Patients who have undergone a percutaneous endoscopic gastrostomy have been increasing. However, complications in serious patients are encountered more frequently. We attempted to examine the simple and new technique for the purpose of preventing complications in percutaneous endoscopic gastrostomy patients. By using our method of measuring of the intragastric pressure during the fasting period, the aspiration pneumonia of percutaneous endoscopic gastrostomy patient could be estimated. METHODOLOGY: From January 2003 to December 2005, one hundred and thirty-two consecutive patients were examined. The intragastric pressure is measured by using a percutaneous endoscopic gastrostomy tube. This method is referenced as the technique for measuring the intra-abdominal pressure which is measured in the case of the abdominal compartment syndrome and the central venous pressure. RESULTS: The mean intragastric pressure of patients with complicated pneumonia was 10.4 +/- 7.1 cm H2O, and 4.7 +/- 4.5 cm H2O with non-complicated pneumonia (p=0.0001). In cases of the patients in whom the tube immediately becomes dirty, the mean intragastric pressure was higher than in clean cases (p=0.0005). CONCLUSIONS: There is a relationship between the intragastric pressure and the incidence of complications such as aspiration pneumonia. Our simple and easy technique can estimate the aspiration pneumonia.

Th1/Th2 xenogenic antibody responses are associated with recipient dendritic cells.

We characterized dendritic cells (DC) phenotypically and functionally between C57BL/6 (Th1-prone) and BALB/c (Th2-prone) mouse recipients in an in vivo sensitization model. Two strains of mice were presensitized with Lewis rat splenocytes as xenogeneic antigens. We found that BALB/c recipients mounted a significantly higher total IgG response to the xeno-antigens when compared with C57BL/6 recipients, 10 days after rat splenocyte infusion. A Th2-mediated antibody response with high ratio of IgG1/IgG2a was seen in the BALB/c recipients, while a Th1 antibody response with low ratio of IgG1/IgG2a was detected in C57BL/6 recipients. CD11c(+)DC isolated from C57BL/6 recipients possessed increased expression of CD8alpha(+) (DC-1 type). The administration of bone marrow derived-DC from IL-12 knockout mice into C57BL/6 recipients induced a shift of Th-mediated anti-xenogeneic antibody responses from Th1 to Th2 domain. Our findings suggest that DC could play an important role to regulate the balance of Th1/Th2 cytokine profiles and rejection patterns in xenotransplantation.

Distinct subsets of dendritic cells regulate the pattern of acute xenograft rejection and susceptibility to cyclosporine therapy.

We determined whether distinct subclasses of dendritic cells (DC) could polarize cytokine production and regulate the pattern of xenograft rejection. C57BL/6 recipients, transplanted with Lewis rat hearts, exhibited a predominantly CD11c(+)CD8alpha(+) splenic DC population and an intragraft cytokine profile characteristic of a Th1-dominant response. In contrast, BALB/c recipients of Lewis rat heart xenografts displayed a predominantly CD11c(+)CD8alpha(-) splenic DC population and IL-4 intragraft expression characteristic of a Th2 response. In addition, the CD11c(+)IL-12(+) splenic DC population in C57BL/6 recipients was significantly higher than that in BALB/c recipients. Adoptive transfer of syngeneic CD8alpha(-) bone marrow-derived DC shifted a Th1-dominant, slow cell-mediated rejection to a Th2-dominant, aggressive acute vascular rejection (AVR) in C57BL/6 mice. This was associated with a cytokine shift from Th1 to Th2 in these mice. In contrast, transfer of CD8alpha(+) bone marrow-derived DC shifted AVR to cell-mediated rejection in BALB/c mice and significantly prolonged graft survival time from 6.0 +/- 0.6 days to 14.2 +/- 0.8 days. CD8alpha(+) DC transfer rendered BALB/c mice susceptible to cyclosporine therapy, thereby facilitating long-term graft survival. Furthermore, CD8alpha(+) DC transfer in IL-12-deficient mice reconstituted IL-12 expression, induced Th1 response, and attenuated AVR. Our data suggest that the pattern of acute xenogeneic rejection can be regulated by distinct DC subsets.

[Incidence of benign and malignant lesions of eyelid and conjunctival tumors].

PURPOSE: To examine the incidence of benign and malignant eyelid lesions and conjunctival tumors. SUBJECTS AND METHODS: One-hundred-and twenty-eight cases (131 eyes) which were treated during the period from January 1990 to February 2004 were histopathologically diagnosed for eyelid or conjunctival tumors (87 cases of eyelid tumors and 41 cases of conjunctival tumors) in retrospective evaluations. The incidence of benign or malignant lesions, the pathological classification, age, sex, and clinical diagnostic accuracy were all investigated. RESULTS: Sixty-four (73%) of the tumors were found to be benign eyelid tumors. The common benign eyelid tumors were 14 nevocellular nevi, 9 seborrheic keratosis, 7 epidermoid cysts, and 6 papillomas. Twenty-four (27%) eyelid tumors were malignant. These included 9 basal cell carcinomas, 9 sebaceous gland carcinomas, 4 malignant lymphomas, and 2 metastatic tumors. Thirty-four (79%) conjunctival tumors were benign, and the common benign conjunctival tumors were 9 nevocellular nevi and 7 papillomas. Nine (21%) conjunctival tumors were malignant, comprising 7 malignant lymphomas and 2 squamous cell carcinomas. The mean ages of malignant eyelid and conjunctival tumor patients were significantly older than those of benign tumor patients. Clinical accuracy in predicting basal cell carcinoma and sebaceous gland carcinoma was 11.1% and 44.4%, respectively. CONCLUSIONS: Approximately 70 approximately 80% of all eyelid and conjunctival tumors are benign. Clinicians should suspect that the lesions are malignant when seeing elderly patients with eyelid or conjunctival tumors. Excised eyelid lesions should be submitted for histopathologic confirmation because there are some cases where clinical diagnosis does not match pathological diagnosis.

Aggressive G-CSF-producing gastric cancer complicated by lung and brain abscesses, mimicking metastases.

A 57-year-old Japanese man had type II c gastric cancer with marked lymph node metastases associated with leukocytosis and elevated granulocyte colony-stimulating factor (G-CSF). Total gastrectomy and distal pancreatectomy with lymph node dissection were performed. Although the primary lesion was negative for G-CSF by histopathological immunostaining, a highly increased G-CSF m-RNA level, measured using reverse transcriptase-polymerase chain reaction in frozen sections, led to a diagnosis of G-CSF-producing gastric cancer. The leukocytes and G-CSF decreased immediately after surgery. He then had an intraabdominal recurrence, and was diagnosed with multiple tumors in his lung and brain, with abnormally elevated leukocytes and greatly increased G-CSF; he died 4 months after the surgery. Autopsy showed intraabdominal recurrence of cancer, with no metastases to the lung or brain, but with multiple brain and lung abscesses. We speculate that the excessively increased neutrophils induced by G-CSF infiltrated the lung and brain and formed abscesses, mimicking metastases.

Reconstitution and replacement of bacteriochlorophyll a molecules in photosynthetic reaction centers.

Reaction centers (RCs) of the photosynthetic bacterium Rhodobacter sphaeroides R-26 were reconstituted in liposomes after release of pigments (bacteriochlorophyll a (BChla) and bacteriopheophytin a (BPhea)) by treatment with acetone. As shown by absorption and circular dichroism spectroscopies, the reconstituted RCs had the same arrangement of pigments as the native RC and exhibited photoactivity of the special pair. The recovery yield of RCs of up to 30% was achieved by addition of 7.8-fold excess of BChla in the acetone treatment. Furthermore BChla was partially replaced with Zn-BChla by addition of the pigments during the acetone treatment. About 30% and 50% of the special pair and accessory pigments can be replaced with Zn-BChla, respectively. From this rate, an oxidation-reduction potential of 520 mV (vs. the normal hydrogen electrode NHE) was derived by the simulation of the experimental data, which is 35 mV higher than that of the native RC (484 mV vs. NHE).

[Systemic lupus erythematosus with steroid induced non-alcoholic steatohepatitis: a case report].

A 56-year old Japanese female was admitted to our hospital because of the increased levels of serum AST, ALT, and gamma-GTP. She was diagnosed with systemic lupus erythematosus in September, 1996 and had been on a regular glucocorticoid therapy since then. Abdominal ultrasonography showed the mild fatty liver, and hepatic histopathology revealed a typical and remarkable steatohepatitis, a remarkable neutrophil infiltration, and Mallory bodies. Because she had no history of alcohol-drinking, diagnosis of non-alcoholic steatohepatitis (NASH) was made. Treatment was started with a low-calorie diet, bed-rest, and an oral administration of alpha-tocopherol and bezafibrate with favorable effects on her serum levels of AST, ALT, gamma-GTP, and LDH. When a patient on a glucocorticoid therapy shows signs of fatty liver, diabetes mellitus, hyperlipidemia, an insulin resistance, NASH should be considered as one of the differential diagnosis. This is particularly important since proper therapy with a low-calorie diet and drugs with anti-oxidant activities improve this potentially progressive disease before resulting in liver cirrhosis and hepatic carcinoma.

Sporadic acute hepatitis E of a 47-year-old man whose pet cat was positive for antibody to hepatitis E virus.

We encountered a patient with sporadic acute hepatitis E who had not traveled to areas endemic for hepatitis E virus (HEV) infection and may have been infected in Japan. The patient was a 47-year-old male who had no history of blood transfusion or contact with travelers to hepatitis E-endemic regions or unspecified individuals. The disease presented with general malaise, fever, and brown urine as chief complaints in April 2002. Various hepatitis virus markers were negative, but IgM class antibodies to hepatitis E virus (anti-HEV) and HEV RNA were positive, and the patient was diagnosed with acute hepatitis E. The entire nucleotide sequence (7240 bases) of HEV (HE-JK4) isolated from this patient was determined and compared with known HEV strains. HE-JK4 belonged to genotype IV and exhibited higher similarities to genotype IV HEV strains previously isolated in Japan than to those isolated in China, Taiwan, and Vietnam. The patient's family members living with him were negative for anti-HEV IgG and IgM, but their pet cat was anti-HEV IgG-positive. This finding suggests a potential route of infection of sporadic cases of hepatitis E in Japan. Since the presence of HEV indigenous to Japan is predicted, HEV infection should be considered in the diagnosis of acute hepatitis of unknown cause, even for patients who have not traveled abroad.

Monotherapy with LF 15-0195, an analogue of 15-deoxyspergualin, significantly prolongs renal allograft survival in monkeys.

BACKGROUND: LF 15-0195 is a novel, more potent, and less toxic analogue of 15-deoxyspergualin, an antibiotic used as an immunosuppressive agent to prevent rejection of organ transplants. This study was undertaken to determine whether LF 15-0195 monotherapy would prevent renal allograft rejection in a nonhuman primate model. METHODS: In the study groups, recipients received LF 15-0195 monotherapy at doses of 0.065 mg/kg per day (group 2, n=4), 0.13 mg/kg per day (group 3, n=4), or 0.2 mg/kg per day (group 4, n=4), administered subcutaneously, on postoperative days 0 to 14. RESULTS: Group 1 consisted of untreated control recipients, all of which developed advanced graft rejection after surviving for an average of 6.5+/-0.6 days. LF 15-0195 treatment significantly prolonged graft survival in groups 2, 3, and 4, to 20+/-20 days, 49+/-5 days, and 39+/-4 days, respectively. Animals in groups 3 and 4 demonstrated no evidence of rejection during LF 15-0195 treatments. The animals maintained stable renal function for 2 weeks after LF 15-0195 withdrawal but gradually developed rejection at 5 to 6 weeks. Pathologic studies demonstrated that vascular graft rejection was attenuated in LF 15-0195-treated allografts, compared with control specimens. These groups also demonstrated transient reductions in lymphocyte counts during treatment, which returned to normal levels 2 weeks after LF 15-0195 withdrawal. Total serum concentrations of IgM and IgG decreased by a mean of 20.4% and a mean of 31.4%, respectively, at the end of LF 15-0195 treatment (postoperative day 14). LF 15-0195 did not significantly alter thrombocyte counts or hemoglobin levels. Necropsy studies showed no evidence of drug toxicity in the heart, liver, spleen, intestines, stomach, or colon. CONCLUSIONS: LF 15-0195 monotherapy significantly prolonged renal allograft survival in monkeys. These encouraging data suggest that this novel agent may be of future value in clinical transplantation.

The sharing of target-epitopes between human anti-ABO hemagglutinating and anti-Pig (xeno) endothelium or anti-Pig thyroglobulin antibodies.

To select congenial pairs between donor-pig and recipient-human for the future xenotransplantation, the levels of xeno-IgM natural antibodies (NAb) were analyzed in healthy subjects and hemodialysis patients by ELISA tests, which target swine-derived crude endothelial cells (P16N) or proteins (thyroglobulin; TG). The total IgM concentration was lower in hemodialysis patients than in healthy subjects, but there was no difference in IgM NAb titer between the two groups. Individuals with non-B blood types (A, O) exibited significantly higher IgM NAb titer compared with those with B blood types (B, AB). A blood type individuals showed higher killing activity against P16N than those with B, AB or O types with a statistical significance. Sera from A blood type, after being absorbed with red blood cells (RBC) from B blood type, decreased their IgM titer against TG to the level of sera from B blood type. Meanwhile, sera from A blood type significantly decreased hemagglutinin titer against B-RBC after passage through a TG-coated affinity column. We conclude that human anti-B-RBC and anti-Pig xeno NAb have certain common binding epitopes, which might be a branched B carbohydrate structure.