A 45-Year-Old Woman With Unexplained Iron Deficiency Anemia and No Respiratory Symptoms.

CASE PRESENTATION: A 45-year-old Japanese woman was diagnosed with anemia in a work place medical check-up and came to our hospital for further investigations. She had experienced general fatigue and orthostatic dizziness for 6 months without fever or respiratory symptoms, including cough, sputum, hemoptysis, or dyspnea. She had undergone annual medical check-ups previously, which had shown no abnormalities, including anemia. She had no history of weight loss, epimenorrhagia, hematuria, or melena. She had no significant positive medical history and was not on any regular medication or supplements. She had no history of alcohol abuse or smoking.

Inhibition of BACE1 and amyloid ß aggregation by polyketide from Streptomyces sp.

Alzheimer's disease (AD) causes cognitive impairment in the elderly and is a severe problem worldwide. One of the major reasons for the pathogenesis of AD is thought to be due to the accumulation of amyloid beta (Aß) peptides that result in neuronal cell death in the brain. In this study, bioassay-guided fractionation was performed to develop seed compounds for anti-AD drugs that can act as dual inhibitors of BACE1 and Aß aggregation from secondary metabolites produced by Streptomyces sp. To improve the solubility, the crude extracts were methylated with trimethylsilyl (TMS) diazomethane and then purified to yield polyketides 1-5, including the new compound 1. We synthesized the compounds 6 and 7 (original compounds 2 and 3, respectively), and their activities were evaluated. KS-619-1, the demethylated form of 4 and 5, was isolated and evaluated for its inhibitory activity. The IC50 values for BACE1 and Aß aggregation were found to be 0.48 and 1.1 µM, respectively, indicating that KS-619-1 could be a lead compound for the development of therapeutic agents for AD.

Semisynthesis and biological evaluation of prenylated resveratrol derivatives as multi-targeted agents for Alzheimer's disease.

A series of prenylated resveratrol derivatives were designed, semisynthesized and biologically evaluated for inhibition of ß-secretase (BACE1) and amyloid-ß (Aß) aggregation as well as free radical scavenging and neuroprotective and neuritogenic activities, as potential novel multifunctional agents against Alzheimer's disease (AD). The results showed that compound 4b exhibited good anti-Aß aggregation (IC50 = 4.78 µM) and antioxidant activity (IC50 = 41.22 µM) and moderate anti-BACE1 inhibitory activity (23.70% at 50 µM), and could be a lead compound. Moreover, this compound showed no neurotoxicity along with a greater ability to inhibit oxidative stress on P19-derived neuronal cells (50.59% cell viability at 1 nM). The neuritogenic activity presented more branching numbers (9.33) and longer neurites (109.74 µm) than the control, and was comparable to the quercetin positive control. Taken together, these results suggest compound 4b had the greatest multifunctional activities and might be a very promising lead compound for the further development of drugs for AD.

[Anesthetic Management of an Infant with Rapidly Developed Hyponatremia due to Bowel Perforation during Enema Reduction Using Diluted Contrast Medium].

A 7-kg 8-month-old boy was transferred to our institution after failed enema reduction of intussusception elsewhere. During the redo intervention using a 6-fold-diluted solution of Gastrografin with water as contrast medium, the bowel was perforated. Urgent surgical repair was planned and preoperative examination revealed serum sodium of 137 mEq x l(-1). On arrival in the operating room, the patient presented abdominal distension, drowsiness and tachypnea. His trachea was intubated and anesthesia was maintained with sevoflurane. Arterial blood examination immediately before the surgery (approximate by 80 minutes after the previous blood test) showed the following findings: pH 7.27, base excess -8.5 mEq x l(-1) and sodium 122 mEq x l(-1). Watery ascites estimated at 450 ml was evacuated upon a peritoneal incision. At termination of anesthesia, serum sodium recovered to 133 mEq x l(-1), resulting from replenishment of electrolytes and sodium bicarbonate administration. The patient became fully awake and his trachea was extubated in the operating room. Gastrografin has osmolarity of 1,900 mOsm x l(-1), containing sodium of 158 mEq x l(-1). Massive intraperitoneal accumulation of diluted Gastrografin is a rational explanation for the rapidly developed hyponatremia, which can lead to hyponatremic encephalopathy, especially in infants. Prompt surgical intervention is therefore essential for successful management of such cases.

[Possibility of the natural product extracted from Calophyllum Brasiliense].

During our search for cancer chemopreventing compounds derived from plant sources, we discovered that the natural product GUT-70, isolated from the stem bark of Calophyllum Brasiliense collected in Brazil, significantly inhibited the growth of leukemic cells via the induction of caspase-mediated and p53-independent apoptosis. Furthermore, we synthesized BNS-22 as a derivative of GUT-70, which showed more antiproliferative activity against human cancer cells than GUT-70. GUT-70 and BNS-22 commonly inhibited ubiquilin-1, suggesting that a GUT-70 derivative might become a First in Class agent. In addition, GUT-70 and BNS-22 inhibited HSP90 and topoisomerase II, respectively. Recently, we also found that GUT-70 inhibited HIV replication. These findings indicated that GUT-70 could serve as a lead compound to develop novel therapeutic agents against cancer and HIV-1 infection.

Disseminated Nocardiosis caused by Nocardia concava with acute respiratory failure and central nervous system involvement treated with linezolid.

Nocardia concava was identified as a new species in 2005; however, the clinical manifestations of Nocardia concava infection have yet to be clarified. We herein present the case of an immunosuppressed patient who developed disseminated nocardiosis caused by N. concava with multiple abscesses in the lungs, cutis, subcutaneous tissue, skeletal muscles and kidneys accompanied by central nervous system involvement, including meningitis and ventriculitis. The patient was cured with appropriate treatment including linezolid after testing for susceptibility. Linezolid should be considered as an alternative agent for treating disseminated nocardiosis because of its effective distribution to multiple sites.

AT-9283, a small-molecule multi-targeted kinase inhibitor for the potential treatment of cancer.

AT-9283 has been identified and developed by Astex Therapeutics via structure-based optimization of a ligand-efficient pyrazole-benzimidazole fragment. AT-9283 inhibits several important kinases, including the Aurora kinase A, Aurora kinase B, Janus kinase (Jak)2, Jak3 and Abl kinase. Studies using multiple solid tumor and leukemia cell lines have demonstrated the ability of AT-9283 to inhibit growth and survival of tumor cells, and the direct inhibition of these kinases has been demonstrated in cell-based systems. The in vivo antitumor activity of AT-9283 has also been demonstrated in human tumor xenograft models. Based on these preclinical studies, several clinical trials have been conducted in patients with hematological malignancies, such as leukemias, myelodysplastic syndrome, myeloproliferative disease, chronic myeloid leukemia, lymphomas and multiple myeloma, and also in patients with solid tumors. Although phase II clinical trials have not been completed, AT-9283 demonstrated good safety and efficacy in phase I clinical trials. Thus, AT-9283 has potential as a therapeutic agent in several patient populations through its different inhibitory activities.

Zoledronic acid inhibits proliferation of human fibrosarcoma cells with induction of apoptosis, and shows combined effects with other anticancer agents.

Third-generation bisphosphonates are known to inhibit bone resorption and also appear to exhibit direct anti-tumour activity. We previously reported that third-generation bisphosphonates such as zoledronic acid (ZOL) have a direct antitumour effect, and synergistically augment the effects of antitumor agents in osteosarcoma cells. There has been no report on the antitumor effect of ZOL against soft tissue sarcoma. The aim of this study was to evaluate the antitumor effect of this drug on a human fibrosarcoma cell line, in terms of proliferation and apoptosis, and, moreover, to evaluate the combined effects of ZOL with other antitumor drugs against the human fibrosarcoma cell line. HT1080 cells were treated with ZOL at various concentrations up to 10 microM, and then cell proliferation, cell cycle, nuclear morphology, and Western blot analyses were performed to study the antitumor effects of ZOL alone, and, moreover, HT1080 cells were treated with ZOL and other anticancer drugs such as paclitaxel, docetaxel, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, cisplatin, or methotrexate to investigate the combined effects using proliferation and cell cycle analyses. We found that ZOL strongly inhibited in vitro proliferation, arrested the cell cycle between S and G2/M phases, and induced the apoptosis of human fibrosarcoma cells. Moreover, ZOL augmented the effect of antitumor agents when administered concurrently with paclitaxel, docetaxel, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, and cisplatin in human fibrosarcoma cells. The treatment of fibrosarcoma with ordinary antitumor drugs is not fully effective. These findings suggest that ZOL directly affects the proliferation and survival of fibrosarcoma cells, and that the combined administration of ZOL with other antitumor agents may improve the efficacy of fibrosarcoma treatment. These results support the possibility that their combined use could be beneficial in the treatment of patients not only with various types of cancer or osteosarcoma, but also with soft tissue sarcoma.

ABT-737 is a useful component of combinatory chemotherapies for chronic myeloid leukaemias with diverse drug-resistance mechanisms.

The effect of ABT-737, a BH3-mimicking inhibitor for anti-apoptotic Bcl-2 and Bcl-X(L), but not Mcl-1, against Bcr-Abl-positive (Bcr-Abl(+)) leukaemic cells was examined. ABT-737 potently induced apoptosis in Bcr-Abl(+) chronic myeloid leukaemia (CML) cell lines and primary CML samples in vitro and prolonged the survival of mice xenografted with BV173 cells, a CML cell line. Higher expression of anti-apoptotic Bcl-2 proteins reduced cell killing by ABT-737 in each cell line, but there was no correlation between the sensitivities to ABT-737 and the specific expression patterns of Bcl-2 family proteins among cell lines. Thus, the cell killing effect of ABT-737 must be determined not only by the expression patterns of Bcl-2 family proteins but also by other mechanisms, such as high expression of Bcr-Abl, or a drug-efflux pump, in CML cells. ABT-737 augmented the cell killing effect of imatinib in Bcr-Abl(+) cells with diverse drug-resistance mechanisms unless leukaemic cells harboured imatinib-insensitive Abl kinase domain mutations, such as T315I. The combination of homoharringtonine that reduces Mcl-1 enhanced the killing by ABT-737 strongly in Bcr-Abl(+) cells even with T315I mutation. These results suggest that ABT-737 is a useful component of chemotherapies for CML with diverse drug-resistance mechanisms.