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Biomedical subjects

H-J Kim

Publications and source records attributed to H-J Kim.

At least 19 recordsLinked to original sources
PubMed2006

6-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1alpha resulting in new vessel formation.

Hypoxia-inducible factor-1alpha (HIF-1alpha) plays a central role in oxygen homeostasis. Previously, we reported that the orphan nuclear receptor Nur77 functions in stabilizing HIF-1alpha. Here, we demonstrate that 6-mercaptopurine (6-MP), an activator of the NR4A family members, enhances transcriptional activity of HIF-1. 6-MP enhanced the protein-level of HIF-1alpha as well as vascular endothelial growth factor (VEGF) in a dose- and time-dependent manner. The induction of HIF-1alpha was abolished by the transfection of either a dominant-negative Nur77 mutant or si-Nur77, indicating a critical role of Nur77 in the 6-MP action. The HIF-1alpha protein level remained up to 60 min in the presence of 6-MP when de novo protein synthesis was blocked by cycloheximide, suggesting that 6-MP induces stabilization of the HIF-1alpha protein. The fact that 6-MP decreased the association of HIF-1alpha with von Hippel-Lindau protein and the acetylation of HIF-1alpha, may explain how 6-MP induced stability of HIF-1alpha. Further, 6-MP induced the transactivation function of HIF-1alpha by recruiting co-activator cyclic-AMP-response-element-binding protein. Finally, 6-MP enhanced the expression of HIF-1alpha and VEGF, and the formation of capillary tubes in human umbilical vascular endothelial cells. Together, our results provide a new insight for 6-MP action in the stabilization of HIF-1alpha and imply a potential application of 6-MP in hypoxia-associated human vascular diseases.

Cell Line, Tumor↗
PubMed2006

Suppression of hypoxic cell death by APIP-induced sustained activation of AKT and ERK1/2.

Apaf-1-interacting protein (APIP) was previously isolated as an inhibitor of mitochondrial cell death interacting with Apaf-1. Here, we report a hypoxia-selective antiapoptotic activity of APIP that induces the activation of AKT and extracellular signal-regulated kinase (ERK)1/2. Stable expression of APIP in C2C12 (C2C12/APIP) cells suppressed cell death induced by hypoxia and etoposide. Unlike etoposide, however, APIP induces the sustained activation of AKT and ERK1/2 and the phosphorylation of caspase-9 during hypoxia. Inhibition of AKT and ERK1/2 activation by the treatments with phosphatidylinositol 3'-kinase and mitogen-activated protein kinase kinase (MEK)1/2 inhibitors sensitized C2C12/APIP cells to hypoxic cell death and abolished the hypoxia-induced phosphorylation of caspase-9. Further, overexpression of phosphorylation-mimic caspase-9 mutants (caspase-9-T125E and caspase-9-S196D), but not phosphorylation-defective caspase-9 mutants (caspase-9-T125A and caspase-9-S196A), effectively suppressed hypoxia-induced death of C2C12 cells. These results elucidate a novel Apaf-1-independent antiapoptotic activity of APIP during hypoxic cell death, inducing the sustained activation of AKT and ERK1/2 and leading to caspase-9 phosphorylation.

Animals↗
PubMed2006

Skeletal muscle and heart LKB1 deficiency causes decreased voluntary running and reduced muscle mitochondrial marker enzyme expression in mice.

LKB1 has been identified as a component of the major upstream kinase of AMP-activated protein kinase (AMPK) in skeletal muscle. To investigate the roles of LKB1 in skeletal muscle, we used muscle-specific LKB1 knockout (MLKB1KO) mice that exhibit low expression of LKB1 in heart and skeletal muscle, but not in other tissues. The importance of LKB1 in muscle physiology was demonstrated by the observation that electrical stimulation of the muscle in situ increased AMPK phosphorylation and activity in the wild-type (WT) but not in the muscle-specific LKB1KO mice. Likewise, phosphorylation of acetyl-CoA carboxylase (ACC) was markedly attenuated in the KO mice. The LKB1KO mice had difficulty running on the treadmill and exhibited marked reduction in distance run in voluntary running wheels over a 3-wk period (5.9 +/- 0.9 km/day for WT vs. 1.7 +/- 0.7 km/day for MLKB1KO mice). The MLKB1KO mice anesthetized at rest exhibited significantly decreased phospho-AMPK and phospho-ACC compared with WT mice. KO mice exhibited lower levels of mitochondrial protein expression in the red and white regions of the quadriceps. These observations, along with previous observations from other laboratories, clearly demonstrate that LKB1 is the major upstream kinase in skeletal muscle and that it is essential for maintaining mitochondrial marker proteins in skeletal muscle. These data provide evidence for a critical role of LKB1 in muscle physiology, one of which is maintaining basal levels of mitochondrial oxidative enzymes. Capacity for voluntary running is compromised with muscle and heart LKB1 deficiency.

AMP-Activated Protein Kinases↗
PubMed2006

Cox-2 expression on tissue microarray of breast cancer.

AIM: To measure cyclooxygenase-2 (Cox-2) expression in a series of breast cancers and evaluate its potential as a predictive marker for doxorubicin chemotherapy. PATIENTS AND METHODS: Cox-2 expression was analyzed in 178 node-positive patients treated with doxorubicin-based adjuvant chemotherapy by immunohistochemistry on tissue microarray (TMA). RESULTS: Cox-2 was over-expressed in 70 out of the 178 invasive breast cancers. Cox-2 expression was significantly increased in undifferentiated tumors. There was no significant association between Cox-2 over-expression and tumor size, histologic grade, and estrogen receptor expression. Disease-free survival and overall survival of the patients having Cox-2 expressing tumor were significantly decreased when compared with the patients having Cox-2 negative tumor (p=0.009 for DFS, p=0.011 for OS). CONCLUSION: Cox-2 expression may represent an aggressive phenotype of breast cancer which is resistant to doxorubicin.

Antibiotics, Antineoplastic↗
PubMed2006

N-(4-hydroxyphenyl)retinamide-induced apoptosis triggered by reactive oxygen species is mediated by activation of MAPKs in head and neck squamous carcinoma cells.

N-(4-hydroxyphenyl)retinamide (4HPR), a synthetic retinoid effective in cancer chemoprevention and therapy, is thought to act via apoptosis induction resulting from increased reactive oxygen species (ROS) generation. As ROS can activate MAP kinases and protein kinase C (PKC), we examined the role of such enzymes in 4HPR-induced apoptosis in HNSCC UMSCC22B cells. 4HPR increased ROS level within 1 h and induced activation of caspase 3 and PARP cleavage within 24 h. Activation of MKK3/6 and MKK4, JNK, p38 and ERK was detected between 6 and 12 h, increased up to 24 h and preceded apoptosis. 4HPR-induced activation of these kinases was abrogated by the antioxidants BHA and vitamin C. SP600125, a JNK inhibitor, suppressed 4HPR-induced c-Jun phosphorylation, cytochrome c release from mitochondria and apoptosis. Suppression of JNK1 and JNK2 using siRNA decreased, whereas overexpression of wild type-JNK1 enhanced 4HPR-induced apoptosis. PD169316, a p38, inhibitor suppressed phosphorylation of Hsp27 and apoptosis. PD98059, an MEK1/2 inhibitor, also suppressed ERK1/2 activation and apoptosis induced by 4HPR. Likewise, PKC inhibitor GF109203X suppressed ERK and p38 phosphorylation and PARP cleavage. These data indicate that 4HPR-induced apoptosis is triggered by ROS increase, leading to the activation of the mitogen-activated protein serine/threonine kinases JNK, p38, PKC and ERK, and subsequent apoptosis.

Anticarcinogenic Agents↗
PubMed2006

Drosophila homolog of APP-BP1 (dAPP-BP1) interacts antagonistically with APPL during Drosophila development.

beta-Amyloid precursor protein binding protein 1 (APP-BP1) was previously identified based on its binding to the carboxyl terminal of beta-amyloid precursor protein. In this report, we have discovered that a mutation of dAPP-BP1 (Drosophila ortholog of APP-BP1) hinders tissue development, causes apoptosis in imaginal disc cells, and blocks the NEDD8 conjugation pathway. We show that dAPP-BP1 specifically binds the intracellular domain of APP-like protein (APPL). The dAPP-BP1 mutation partially suppresses the abnormal macrochaete phenotype of Appl(d), while overexpression of dAPP-BP1 causes abnormal macrochaetes. When APPL is overexpressed, the normal bristle pattern in the fly thorax is disturbed and apoptosis is induced in wing imaginal discs. APPL overexpression phenotypes are enhanced by reducing the level of dAPP-BP1. APPL overexpression is shown to inhibit the NEDD8 conjugation pathway. APPL-induced apoptosis is rescued by overexpression of dAPP-BP1. Our data suggest that APPL and dAPP-BP1 interact antagonistically during Drosophila development.

Amino Acid Sequence↗
PubMed2006

Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin.

We investigated the cytoprotective mechanisms of flunarizine in cisplatin-induced death of auditory cells. Concomitant with an increase in viability, treatment with flunarizine resulted in a marked dissociation of Nrf2/Keap1 and subsequent intranuclear translocation of Nrf2, which was mediated by PI3K-Akt signaling. Overexpression of Nrf2 protected cells from cisplatin along with transcriptional activation of ARE to generate heme oxygenase-1 (HO-1). Pretreatment with flunarizine predominantly increased the transcriptional activity of HO-1 among Nrf2-driven transcripts, including HO-1, NQO1, GCLC, GCLM, GST micro-1, and GSTA4. Furthermore, both pharmacological inhibition and siRNA transfection of HO-1 completely abolished the flunarizine-mediated protection of HEI-OC1 cells and the primary rat (P2) organ of Corti explants from cisplatin. These results suggest that Nrf2-driven transcriptional activation of ARE through PI3K-Akt signaling augments the generation of HO-1, which may be a critically important determinant in cellular response toward cisplatin and the cytoprotective effect of flunarizine against cisplatin.

Active Transport, Cell Nucleus↗
PubMed2006

Mapping quantitative trait loci for yield components and morphological traits in an advanced backcross population between Oryza grandiglumis and the O. sativa japonica cultivar Hwaseongbyeo.

Introgression has been achieved from wild species Oryza grandiglumis (2n = 48, CCDD, Acc. No. 101154) into O. sativa subsp. japonica cv. Hwaseongbyeo as a recurrent parent. An advanced introgression (backcross) line, HG101, produced from a single plant from BC5F3 families resembled Hwaseongbyeo, but it showed differences from Hwaseongbyeo in several traits, including days to heading and culm length. To detect the introgressions, 450 microsatellite markers of known chromosomal position were used for the parental survey. Of the 450 markers, 51 (11.3%) detected O. grandiglumis segments in HG101. To characterize the effects of alien genes introgressed into HG101, an F(2:3) population (150 families) from the cross Hwaseongbyeo/HG101 was developed and evaluated for 13 agronomic traits. Several lines outperformed Hwaseongbyeo in several traits, including days to heading. Genotypes were determined for 150 F2 plants using simple sequence repeat markers. Qualitative trait locus (QTL) analysis was carried out to determine the relationship between marker genotype and the traits evaluated. A total of 39 QTL and 1 gene conferring resistance to blast isolate were identified using single-point analysis. Phenotypic variation associated with each QTL ranged from 4.2 to 30.5%. For 18 (46.2%) of the QTL identified in this study, the O. grandiglumis-derived alleles contributed a desirable agronomic effect despite the overall undesirable characteristics of the wild phenotype. Favorable wild alleles were detected for days to heading, spikelets per panicle, and grain shape traits. Grain shape QTL for grain weight, thickness, and width identified in the F(2:3) lines were further confirmed based on the F4 progeny test. The confirmed locus, tgw2 for grain weight is of particular interest because of its independence from undesirable height and maturity. Several QTL controlling amylose content and grain traits have not been detected in the previous QTL studies between Oryza cultivars, indicating potentially novel alleles from O. grandiglumis. The QTL detected in this study could be a rich source of natural genetic variation underlying the evolution and breeding of rice.

Chromosome Mapping↗
PubMed2006

Induction of leukemic-cell-specific cytotoxic T lymphocytes by autologous monocyte-derived dendritic cells presenting leukemic cell antigens.

Leukemic-dendritic cells (leukemic-DCs) have certain limitations, which include difficult generation in 30-40% of patients, and low levels of expression of several key molecules. Therefore, an alternative approach using monocyte-derived DCs pulsed with tumor antigens is required. We investigated the possibility of immunotherapy for AML using leukemic-cell-specific cytotoxic T lymphocytes that were stimulated in vitro by autologous DCs pulsed with tumor antigens. To generate DCs, CD14(+) cells were isolated from peripheral blood mononuclear cells using magnetic-activated cell sorting, and cultured in the presence of GM-CSF and IL-4. On day 6, maturation of DCs was induced by addition of cytokine cocktail (TNF-alpha, IL-1beta, IL-6, and prostaglandin E(2)) for 2 days, and then the mature DCs were pulsed with whole leukemic cell lysates or apoptotic leukemic cells. There were no differences in the phenotypic expressions of mature DCs generated by pulsing with or without leukemic antigens. The mature DCs pulsed with tumor cell lysates or apoptotic leukemic cells showed a higher allostimulatory capacity for allogeneic CD3(+) T cells as compared with mature non-pulsed DCs. Autologous CD3(+) T cells stimulated by the mature pulsed DCs showed more potent cytotoxic activities against autologous leukemic cells than those stimulated by mature non-pulsed DCs. These results suggest that use of DCs pulsed with leukemic cell lysates or apoptotic leukemic cells is a feasible alternative immunotherapeutic approach to overcome the limitations of leukemic-DCs for the treatment of AML patients.

Antigens, Neoplasm↗
PubMed2006

Usefulness of (18)F-fluorodeoxyglucose PET for radiosurgery planning and response monitoring in patients with recurrent spinal metastasis.

INTRODUCTION: With the advancement and successful treatment of metastatic spinal cord disease, newer treatments are needed for the long-term survivors of recurrent disease. The lack of a standardized re-treatment regimen and the difficulty in delineating the tumor margins among patients who have received the treatment with metallic spinal fixation and conventional radiation are two of the challenges to be faced in recurrent metastatic spinal cord disease. In these patients, we applied hypofractionated stereotactic radiosurgery by defining the tumor margin with (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET). PATIENTS AND METHODS: Three consecutive recurrent spinal metastasis patients underwent the CyberKnife treatment (Accuray, Inc., Sunnyvale, CA) from March 2004 to July 2004. A three-fraction schedule was applied at approximately 24 hour intervals. One patient had sarcoma and the other two patients had breast cancer. All patients had received previous conventional radiotherapy after operation ranging from 30 Gy to 45 Gy. CT-based planning was corrected by the FDG-PET hyperuptake area with the help of nuclear medicine. The mass responses were followed not only by MRI but also by FDG-PET, which was taken prior to treatment, and at one and six months after the treatment. The changes in standard uptake value (SUV) of serial PET were taken as a measure of response. To evaluate the relative SUV changes from different pretreatment values, we set a reduction index (RI), which represents the ratio of SUV change to pretreatment SUV. RESULTS: No significant complications were noted during treatment with a mean follow-up of 13.3 months. The tumor volume on CT-based planning was 2.2 times larger than that of the CT-PET combined planning in case 1 of paraspinal muscle invasion. But the tumor volumes showed minimal changes in the other cases, in which the metastatic tumors were confined to the vertebral bodies. The SUV one month after treatment showed variable decreases and the RI ranged from 0.07 to 0.7. However, the SUVs at 6 months were well correlated with the clinical results. One patient showed marginal failure and the other two patients showed local control of the tumor, as their RI values were 0.65 and 0.87, respectively. CONCLUSION: To our knowledge, this is the first report using FDG-PET with radiosurgery in patients with recurrent spinal metastases hidden under metallic artifacts. The mass responses measured by SUV changes in FDG-PET correlated with the clinical results.

Adult↗
PubMed2006

Differential regulation of interleukin-12 and tumour necrosis factor-alpha by phosphatidylinositol 3-kinase and ERK 1/2 pathways during Mycobacterium tuberculosis infection.

Interleukin (IL)-12 and tumour necrosis factor (TNF)-alpha are both thought to be critical factors in the defence against mycobacteria but are known to play different roles. In this study, we investigated the regulatory pathways for IL-12 and TNF-alpha expression in human monocyte-derived macrophages (MDMs) after treatment with Mycobacterium tuberculosis H37Rv or the Triton X-100 solubilized proteins (TSP) purified from M. tuberculosis. We found a rapid phosphorylation of Akt and extracellular signal-regulated kinase (ERK), albeit with differential activation kinetics, in human MDMs treated with M. tuberculosis or TSP. Studies using inhibitors selective for phosphatidylinositol 3-kinase (PI 3-K) and ERK 1/2 show that both pathway plays an essential role in the induction of TNF-alpha at both the transcriptional and translational levels in human MDMs. In contrast, blockade of the PI 3-K/Akt or ERK 1/2 pathways significantly increased M. tuberculosis- or TSP-induced IL-12 p40 and p35 mRNA and bioactive p70 protein. The enhancement of IL-12 levels by inhibition of PI 3-K and ERK 1/2 was not reversed by neutralization of TNF-alpha or addition of rhTNF-alpha, suggesting that the negative regulation of IL-12 is not mediated by concomitant TNF-alpha suppression. Further, PI 3-K activity is required for the M. tuberculosis- or TSP-induced phosphorylation of ERK 1/2 activation. TSP from M. tuberculosis shows a similar dependency on the PI 3-K and ERK 1/2 pathways to those by M. tuberculosis. Collectively, these data suggest that the Th1-driving cytokine IL-12 and proinflammatory cytokine TNF-alpha are differentially regulated by PI 3-K and ERK 1/2 pathways in human MDMs during mycobacterial infection. These results may provide therapeutic targets for precise and specific fine-tuning of cytokine responses.

Analysis of Variance↗
PubMed2006

Characterization of a mutated Geobacillus stearothermophilus L-arabinose isomerase that increases the production rate of D-tagatose.

AIMS: Characterization of a mutated Geobacillus stearothermophilus L-arabinose isomerase used to increase the production rate of D-tagatose. METHODS AND RESULTS: A mutated gene was obtained by an error-prone polymerase chain reaction using L-arabinose isomerase gene from G. stearothermophilus as a template and the gene was expressed in Escherichia coli. The expressed mutated L-arabinose isomerase exhibited the change of three amino acids (Met322-->Val, Ser393-->Thr, and Val408-->Ala), compared with the wild-type enzyme and was then purified to homogeneity. The mutated enzyme had a maximum galactose isomerization activity at pH 8.0, 65 degrees C, and 1.0 mM Co2+, while the wild-type enzyme had a maximum activity at pH 8.0, 60 degrees C, and 1.0-mM Mn2+. The mutated L-arabinose isomerase exhibited increases in D-galactose isomerization activity, optimum temperature, catalytic efficiency (kcat/Km) for D-galactose, and the production rate of D-tagatose from D-galactose. CONCLUSIONS: The mutated L-arabinose isomerase from G. stearothermophilus is valuable for the commercial production of D-tagatose. SIGNIFICANCE AND IMPACT OF THE STUDY: This work contributes knowledge on the characterization of a mutated L-arabinose isomerase, and allows an increased production rate for D-tagatose from D-galactose using the mutated enzyme.

Aldose-Ketose Isomerases↗
PubMed2006

Ex vivo responses for interferon-gamma and proinflammatory cytokine secretion to low-molecular-weight antigen MTB12 of Mycobacterium tuberculosis during human tuberculosis.

MTB12 protein, also called CFP-2, is a major and early secreted component of Mycobacterium tuberculosis. However, its role during mycobacterial infection has been poorly characterized. In this study, we purified the native MTB12 protein and investigated the profile of MTB12-induced cytokines [interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha and interleukin (IL)-6], in early tuberculosis (TB) patients (n = 20) and healthy controls (n = 35). The cytokine profiles were compared with those induced by the 30-kDa antigen (Ag). In healthy controls, MTB12-induced IFN-gamma production was markedly decreased in peripheral blood mononuclear cells compared with 30-kDa Ag-induced IFN-gamma. In TB patients, the mean IFN-gamma level induced by MTB12 was lower than that induced by the 30-kDa Ag, albeit the difference was not significant. After 2 months of anti-TB therapy, both the MTB12- and 30-kDa-induced IFN-gamma levels were significantly increased in TB patients. MTB12-induced TNF-alpha and IL-6 levels were prominently upregulated in monocyte-derived macrophages from TB patients, but they were not significantly different from those induced by the 30-kDa Ag. Further, the activation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase was required for the induction of TNF-alpha and IL-6 by MTB12, as well as by the 30-kDa Ag. Collectively, these data suggest that the MTB12 protein plays an essential role for proinflammatory responses through the MAPK pathway during the early stages of human TB, even though its T-cell immunoreactivity is weaker than that of the 30-kDa Ag.

Antigens, Bacterial↗
PubMed2006

Apoptosis of oral epithelial cells in oral lichen planus caused by upregulation of BMP-4.

BACKGROUND: Bone morphogenic protein (BMP-4) is a member of transforming growth factor (TGF-beta) family and involved in various functions including apoptosis during neural ectoderm development. The objective of this study is to determine whether BMP-4 is involved in apoptosis, one characteristic, of human oral lichen planus (OLP). METHODS: Immunohistochemistry and in situ hybridization for BMP-4 were carried out in OLP (n = 21) and normal human oral mucosa (NOM, n = 31). Five tissue samples from NOM and OLP were underwent reverse transcriptase-polymerase chain reaction (RT-PCR). In vitro organ culture of oral mucosa was carried out with beads soaked with various concentration of BMP-4 (0.1, 1, and 10 microg/ml). The samples from in vitro organ culture were undergone haematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labelling technique (TUNEL) assay, and immunohistochemical study with p53, matrix metalloproteinases (MMP)-1, and MMP-3. Involucrin expression was determined by western blot analysis after treatment with BMP-4 or TGF-beta1 on human oral keratinocytes. RESULTS: In immunohistochemical analysis, expression of BMP-4 was higher in OLP than NOM. BMP-4 mRNA expression was also detected in epithelial cells of both NOM and OLP together with underlying T-lymphocytes by in situ hybridization and RT-PCR. In oral mucosa organ culture, BMP-4 soaked beads induced apoptosis of epithelial cells. Acantolysis combined with apoptosis in oral epithelium was observed at 1 microg/ml of BMP-4 beads and it was due in part to the induction of p53 and MMP-1. Even MMP-3 induction was found in lower concentration of BMP-4 (0.1 and 1 microg/ml). Moreover, the expression of MMP-1 and MMP-3 was also observed in OLP. Recombinant BMP-4 or TGF-beta1 increased involucrin expression in human oral keratinocytes cell line. CONCLUSIONS: Expression of BMP-4 of epithelial cells was higher in OLP than NOM. High concentration of BMP-4 caused an apoptosis of oral epithelial cells in oral mucosa organ culture. Therefore, over-expression of BMP-4 is one causing factor for apoptosis of oral epithelial cells through upregulation of p53, MMP1 and MMP3 in OLP.

Adult↗
PubMed2006

C-arm-guided pudendal nerve block: a new technique.

Pudendal nerve block (PNB) is an effective diagnostic and/or treatment method for perineal pain. Various approach techniques, such as transperineal, transvaginal, computerised tomography (CT)- or sono-guided approach, have been suggested for this block. However, they have some limitations, such as high cost, difficulty to perform in practice, inaccurate and unreliable results and inconvenience. To overcome these limitations, we first tried C-arm-guided approach for accomplishing PNB in the prone position. Under the optimal ischial spine view of C-arm fluoroscopy, the block needle was placed on the tip of the ischial spine. Then a mixed solution for the block was administered. All of the 25 patients enrolled in this study were blocked successfully using this method. No side-effects or complications were observed in relation to the block. We concluded that the C-arm-guided approach for PNB is an effective alternative to the existing techniques, which can overcome their limitations.

Adult↗
PubMed2006

Global health inequalities: an international comparison.

OBJECTIVE: To study cross-national inequalities in mortality of adults and of children aged <5 years using a novel approach, with clustering techniques to stratify countries into mortality groups (better-off, worse-off, mid-level) and to examine risk factors associated with inequality. DESIGN, SETTING AND PARTICIPANTS: Analysis of data from the World Development Indicators 2003 database, compiled by the World Bank. MAIN OUTCOME MEASURES: Adult and child mortality among countries placed into distinct mortality categories by cluster analysis. RESULTS: 29 countries had a high adult mortality (mean 584/1000; range 460/1000 to 725/1000) and 23 had a high child mortality (mean 207/1000, range 160/1000 to 316/1000). All these countries were in western and sub-Saharan Africa and Afghanistan. Bivariate analyses showed that relative to countries with low child mortality, those with high child mortality had significantly higher rates of extreme poverty (p<0.001), populations living in rural areas (p<0.001) and female illiteracy (p<0.001), significantly lower per capita expenditure on healthcare (p<0.001), outpatient visits, hospital beds and doctors, and lower rates of access to improved water (p<0.001), sanitation (p<0.001) and immunisations. In multivariate analyses, countries with high adult mortality had a higher prevalence of HIV infection (odds ratio per 1% increase 18.6; 95% CI 0.3 to 1135.5). Between 1960 and 2000, adult male mortality in countries with high mortality increased at >4 times the rate in countries with low mortality. For child mortality, the worse-off group made slower progress in reducing <5 mortality than the better-off group. CONCLUSIONS: Inequalities in child and adult mortality are large, are growing, and are related to several economic, social and health sector variables. Global efforts to deal with this problem require attention to the worse-off countries, geographic concentrations, and adopt a multidimensional approach [corrected] to development.

Adolescent↗