Prolonged survival of end-stage AIDS patients immunized with therapeutic HIV vaccine V-1 Immunitor.

Death, rather than surrogate markers, is a single and most straightforward clinical endpoint, defining unequivocally the merit of a therapeutic intervention. As there is still neither a cure for AIDS nor a vaccine to prevent HIV infection, an AIDS diagnosis remains associated with a death sentence. V-1 Immunitor (V1) is an experimental, oral, therapeutic AIDS vaccine licensed as a dietary supplement. As part of a charity program V1 has been offered at Wat Phra Baht Nam Phu--a Buddhist hospice for end-stage AIDS patients. Out of 117 approached individuals, 53 decided to take V1 and 64 declined the treatment. Patients in both groups did not differ in age, gender, or severity of disease. All patients were in WHO terminal stage 4 at study entry and had received similar palliative care. None of the patients had received conventional antiviral drugs. At 9 weeks the last two patients in the non-V1 group died. In contrast, 56.6% (30/53) in the V1 group remained alive. Kaplan-Meier survival analysis showed that median short-term survival time for non-treated and treated patients was 4 and 10 weeks, respectively. The difference was statistically significant by Wilcoxon signed rank test (P=0.000089). Patients who remained alive were followed until the last patient died at 142 weeks. Based on the main outcome, i.e. time to death, patients on V1 had a 15.8 times longer life expectancy than the control group (P<0.000001). Observed results are encouraging and V1 needs to be tested in controlled clinical trials as a life-saving immunotherapy.     

National survey of patients with hemophilia and other congenital bleeding disorders in Thailand

A national survey of patients with hemophilia and other congenital bleeding disorders in Thailand was conducted in the years 2000 to 2002. Questionnaires were sent to physicians working at hospitals throughout the country. Although the overall response rate to the questionnaires was 19%, the two highest rates of 80% and 73.7% were found at university and regional hospitals, respectively, where most of the patients received their diagnosis and treatment. A total of 1,450 patients comprised of hemophilia 1,325 cases, von Willebrand disease, 69 cases, congenital factor VII deficiency, 15 cases, hereditary platelet dysfunction, 22 cases, and undefined causes of congenital bleeding disorders, 19 cases. Most were pediatric patients <15 years of age. Treatment was mainly given on demand for a bleeding episode, while only 8.6% received additional home treatment for early bleeding episodes. Replacement therapy primarily relied on fresh frozen plasma, cryoprecipitate and cryo-removed plasma. Factor concentrate was seldom used because of the high price. As a result, hemophilia care services in Thailand should be strengthened by providing comprehensive education for medical personnel, making available simple laboratory kits to determine hemophilia A and B, ensuring an adequate supply of blood components and affordable factor concentrate, and establishing home care treatment.     

CD99 ligation induces intercellular cell adhesion molecule-1 expression and secretion in human gingival fibroblasts

ObjectiveTo examine CD99 expression and its functional role in ICAM-1 induction in human gingival fibroblasts (HGFs) and human gingival epithelial cells (HGECs) by activating cells with anti-CD99 monoclonal antibody, MT99/3.BackgroundEngagement of CD99 with agonistic antibodies has been shown to regulate immune responses, cell adhesion and migration, and cell death in several studies. Particularly, this engagement results in transendothelial migration of leukocytes mediated by intercellular adhesion molecule-1 (ICAM-1) induction in endothelial cells.MethodsTotal mRNA and protein were isolated from HGFs and HGECs for analyses of CD99 and ICAM-1 expression. Surface expression of CD99 and ICAM-1 was analysed by flow cytometry, and the detection of soluble ICAM-1 was assayed by immunoprecipitation and ELISA.ResultsCD99 surface expression was constitutive on HGFs to a greater extent than that on HGECs. CD99 ligation with MT99/3 induced ICAM-1 mRNA expression in HGFs, but not in HGECs. Interestingly, CD99 ligation led to an increased level of soluble ICAM-1 detected in culture supernatant, whereas interleukin-1β (IL-1β) treatment induced expression of membrane-bound ICAM-1. Furthermore, ICAM-1 induction by CD99 engagement was demonstrated to involve the activation of the p50 subunit of nuclear factor-kappaB (NF-κB), extracellular signal-regulated kinase, and p46 c-Jun N-terminal kinase that differed from that by IL-1β treatment.ConclusionOur study has shown the involvement of CD99 ligation in the up-regulation of ICAM-1 expression and its secretion in gingival fibroblasts, which may be essential for better understanding of the pathogenesis of periodontal disease.     

Dichapetalin-type triterpenoids and lignans from the aerial parts of Phyllanthus acutissima

Chemical investigation of the aerial parts of Phyllanthus acutissima resulted in the isolation of five new dichapetalin-type triterpenoids, acutissimatriterpenes A-E ( 1- 5), and two new lignans, acutissimalignans A ( 6) and B ( 7), along with two known lignans and three known ellagic acid derivatives. The structures of 1- 7 were determined mainly on the basis of spectroscopic methods. The compounds obtained were evaluated for cytotoxic and anti-HIV-1 activities.     

Clinical features and molecular analysis in Thai patients with HbH disease

We studied the α-globin gene abnormalities, the clinical features, hematologic values, growth assessment, transfusion therapy, and serum ferritin levels of patients with hemoglobin H (HbH) disease in southern Thailand. HbH disease in 83 of the 147 patients was the deletional type of HbH. The remaining 64 patients was the nondeletional type of HbH disease. All 83 patients with the deletional type were double heterozygotes of α⁰-thalassemia and α⁺-thalassemia. The Southeast Asian type of α⁰-thalassemia accounted for 98% of the Thai patients with HbH disease and the Thai type of α⁰-thalassemia made up the rest. A 3.7-kb deletion accounted for 91% of α⁺-thalassemia, and a 4.2-kb deletion made up the rest of the deletional type. In patients with nondeletional type of HbH disease, the Constant Spring variant was the majority of the disease. Newborns with a nondeletional genotype had higher mean corpuscular volume, had higher mean corpuscular hemoglobin, had higher red blood cell distribution width, had lower mean corpuscular hemoglobin concentration, and had higher proportions of Hb Bart's than those with a deletional genotype. Twenty-one percent of children with HbH disease had growth deficiency. A genotype–phenotype correlation was found; patients with the nondeletional type of HbH disease had more symptoms at a younger age, more severe hemolytic anemia, more growth deficiency, more dysmorphic facial features, larger spleens, larger livers, and higher serum ferritin levels and required more transfusions than patients with deletional HbH disease.     

Growth patterns and final height of survivors of childhood leukemia

Growth patterns of 85 survivors of childhood leukemia were analyzed retrospectively. All patients remained in first remission with no central nervous system involvement. The mean age at diagnosis was 5.8 +/- 3.6 years. The diagnoses were acute lymphoblastic leukemia (ALL) in 68 patients (80%) and acute non-lymphoblastic leukemia (ANLL) in 17 patients (20%). All except two patients received cranial irradiation: 51 patients with 1,800 cGy and 32 patients with 2,400 cGy. Mean height SDS was -0.7 +/- 1.36 at the time of diagnosis, which decreased to -0.92 +/- 1.31 by the end of treatment, and further decreased to -1.14 +/- 1.38 at 6 years after cessation of treatment. Mean weight SDS was -0.55 +/- 1.13 at the time of diagnosis, increasing slightly to -0.39 +/- 1.02 at the end of treatment, and decreasing to -0.46 +/- 1.65 at 6 years after cessation of treatment. Of these survivors, 51 patients (26 boys and 25 girls) reached a final height that was 1.04 SDS or 5.3 cm less than their target height. There was no difference of height and weight SDS between patients with ALL and ANLL. Girls and boys had different growth patterns. Girls had a slightly increased height SDS and gained more weight after cessation of treatment, resulting in less final height deficit and overweight for height, whereas boys had further height and weight reduction resulting in more deficit of final height.     

Synergistic cytotoxicity and apoptosis induced in human cholangiocarcinoma cell lines by a combined treatment with tumor necrosis factor-alpha (TNF-alpha) and triptolide

Cholangiocarcinoma is known to be relatively resistant to chemotherapy. One alternative approach is to use a combination of an immunomodulating agent with an anticancer drug. Here we studied the synergistic actions of TNF-alpha and triptolide (a diterpene epoxide prepared from Tripterygium wilfordii), previously shown to have antitumor activity against hamster cholangiocarcinoma (CCA) cells. Three human CCA cell lines (HuCCA-1, HubCCA-1, KKU-100 cell lines) were subjected to a combined treatment of TNF-alpha (0.1-10 ng/ml) and triptolide (5-50 ng/ml) for 24 hours in microculture plates. The combination of TNF-alpha and triptolide had a significantly increased cytotoxic activity over that of triptolide alone (p < 0.05). Under the same conditions, TNF-alpha by itself was not cytotoxic to these cell lines. Similarly, the combined treatment could also accelerate apoptotic cell death in all three human cholangiocarcinoma cell lines. The combined treatment of TNF-alpha at 10 ng/ml and triptolide at 50 ng/ml for 6-10 hours achieved a percentage of apoptotic cells shown by DAPI staining of 18-65%, compared to only 6-20% apoptotic cells for triptolide alone. Analyzing the possible mechanisms of the combined treatment, we found by Western blot that at 6 hours, there was a poly (ADP-ribose) polymerase (PARP) cleavage which was not detectable by the treatment of either TNF-alpha or triptolide alone. The cleavage of PARP was inhibited when the cells were pretreated with the enzyme inhibitor AC-DEVD-CMK, suggesting that apoptosis induced by the combination of TNF-alpha and triptolide involved activation of caspase 3. These results indicate that apoptosis of human cholangiocarcinoma cell lines as induced by a combination of TNF-alpha and triptolide is mediated through caspase 3 activation.