Background Plasmodium falciparum resistance to artemisinins, the first line treatment for malaria worldwide, has been reported in western Cambodia. Resistance is characterized by significantly delayed clearance of parasites following artemisinin treatment. Artemisinin resistance has not previously been reported in Myanmar, which has the highest falciparum malaria burden among Southeast Asian countries.MethodsA non-randomized, single-arm, open-label clinical trial of artesunate monotherapy (4 mg/kg daily for seven days) was conducted in adults with acute blood-smear positive P. falciparum malaria in Kawthaung, southern Myanmar. Parasite density was measured every 12 hours until two consecutive negative smears were obtained. Participants were followed weekly at the study clinic for three additional weeks. Co-primary endpoints included parasite clearance time (the time required for complete clearance of initial parasitemia), parasite clearance half-life (the time required for parasitemia to decrease by 50% based on the linear portion of the parasite clearance slope), and detectable parasitemia 72 hours after commencement of artesunate treatment. Drug pharmacokinetics were measured to rule out delayed clearance due to suboptimal drug levels.ResultsThe median (range) parasite clearance half-life and time were 4.8 (2.1–9.7) and 60 (24–96) hours, respectively. The frequency distributions of parasite clearance half-life and time were bimodal, with very slow parasite clearance characteristic of the slowest-clearing Cambodian parasites (half-life longer than 6.2 hours) in approximately 1/3 of infections. Fourteen of 52 participants (26.9%) had a measurable parasitemia 72 hours after initiating artesunate treatment. Parasite clearance was not associated with drug pharmacokinetics.ConclusionsA subset of P. falciparum infections in southern Myanmar displayed markedly delayed clearance following artemisinin treatment, suggesting either emergence of artemisinin resistance in southern Myanmar or spread to this location from its site of origin in western Cambodia. Resistance containment efforts are underway in Myanmar.Trial RegistrationAustralian New Zealand Clinical Trials Registry ACTRN12610000896077

The spread of carbapenemase-producing Enterobacteriaceae (CPE), contributing to widespread carbapenem resistance, has become a global concern. However, the specific dissemination patterns of carbapenemase genes have not been intensively investigated in developing countries, including Myanmar, where NDM-type carbapenemases are spreading in clinical settings. In the present study, we phenotypically and genetically characterized 91 CPE isolates obtained from clinical (n = 77) and environmental (n = 14) samples in Yangon, Myanmar. We determined the dissemination of plasmids harboring genes encoding NDM-1 and its variants using whole-genome sequencing and plasmid analysis. IncFII plasmids harboring blaNDM-5 and IncX3 plasmids harboring blaNDM-4 or blaNDM-7 were the most prevalent plasmid types identified among the isolates. The IncFII plasmids were predominantly carried by clinical isolates of Escherichia coli, and their clonal expansion was observed within the same ward of a hospital. In contrast, the IncX3 plasmids were found in phylogenetically divergent isolates from clinical and environmental samples classified into nine species, suggesting widespread dissemination of plasmids via horizontal transfer. Half of the environmental isolates were found to possess IncX3 plasmids, and this type of plasmid was confirmed to transfer more effectively to recipient organisms at a relatively low temperature (25°C) compared to the IncFII plasmid. Moreover, various other plasmid types were identified harboring blaNDM-1, including IncFIB, IncFII, IncL/M, and IncA/C2, among clinical isolates of Klebsiella pneumoniae or Enterobacter cloacae complex. Overall, our results highlight three distinct patterns of the dissemination of blaNDM-harboring plasmids among CPE isolates in Myanmar, contributing to a better understanding of their molecular epidemiology and dissemination in a setting of endemicity.

The bacterial enzyme New Delhi metallo-β-lactamase hydrolyzes almost all β-lactam antibiotics, including carbapenems, which are drugs of last resort for severe bacterial infections. The spread of carbapenem-resistant Enterobacteriaceae that carry the New Delhi metallo-β-lactamase gene, blaNDM, poses a serious threat to public health. In this study, we genetically characterized eight carbapenem-resistant Escherichia coli isolates from a tertiary care hospital in Yangon, Myanmar. The eight isolates belonged to five multilocus-sequence types and harbored multiple antimicrobial-resistance genes, resulting in resistance against nearly all of the antimicrobial agents tested, except colistin and fosfomycin. Nine plasmids harboring blaNDM genes were identified from these isolates. Multiple blaNDM genes were found in the distinct Inc-replicon types of the following plasmids: an IncA/C2 plasmid harboring blaNDM-1 (n = 1), IncX3 plasmids harboring blaNDM-4 (n = 2) or blaNDM-7 (n = 1), IncFII plasmids harboring blaNDM-4 (n = 1) or blaNDM-5 (n = 3), and a multireplicon F plasmid harboring blaNDM-5 (n = 1). Comparative analysis highlighted the diversity of the blaNDM-harboring plasmids and their distinct characteristics, which depended on plasmid replicon types. The results indicate circulation of phylogenetically distinct strains of carbapenem-resistant E. coli with various plasmids harboring blaNDM genes in the hospital.

Ethanol is a tumor promoter and may promote metastasis of breast cancer. However, the underlying cellular/molecular mechanisms remain unknown. Overexpression and high activity of matrix metalloproteinase-2 (MMP-2) are frequently associated with metastatic breast cancers and serve as a prognostic indicator of clinical outcome. MMP-2 is predominantly expressed in stromal fibroblasts and plays a pivotal role in regulating the invasive behavior of breast tumor cells. We hypothesized that ethanol may enhance the invasion of breast tumor cells by modulating the activity of fibroblastic MMP-2. With in vitro models (HS68 and CCD1056SK human fibroblasts), we showed that ethanol at physiologically relevant concentrations (50 -200 mg/dl) activated MMP-2; conversely, at a higher concentration (400 mg/dl), it inhibited the MMP-2 activity. Consistently, conditioned medium collected from ethanol ( Key words: alcohol; ErbB; metastasis; proteinases; signal transductionBreast cancer is a leading cause of morbidity and mortality in women. 1 The endogenous and environmental factors that contribute to its etiology remain elusive. Despite being responsive to hormonal manipulation and chemotherapy, relapse after treatment is common, particularly in patients presenting with metastatic disease. 2 The metastatic process involves the degradation of different macromolecular components of the extracellular matrix (ECM) and basement membranes and is regulated by intrinsic properties of the tumor cells as well as microenvironmental factors. Alcohol is a tumor promoter; there is a positive correlation between alcohol intake and the risk of several human cancers, including mouth/oropharyngeal cancer, oesophageal cancer, liver cancer and breast cancer. [3][4][5][6][7][8][9][10][11] Epidemiologic studies indicate that alcohol consumption is associated with advanced and invasive breast tumors, [12][13][14] suggesting that alcohol may enhance tumor development and metastasis. These epidemiologic results are supported by experimental studies using animal models and cell culture systems, which show that ethanol promotes mammary tumorigenesis and stimulates proliferation as well as invasion of breast cancer cells. [15][16][17][18][19][20][21] The molecular mechanisms underlying ethanol action, however, remain to be determined.Abnormal communication between the mammary epithelium and stromal cells promotes tumorigenesis and development of breast carcinomas. 22 Cancer-stroma interaction is mediated at least in part through the matrix metalloproteinases (MMPs). MMPs are a family of zinc-dependent endopeptidases that collectively are capable of degrading all components of the ECM. MMPs have been implicated in normal matrix remodeling events such as development of the mammary gland 23 and in pathologic conditions, including tumor invasion and metastasis. 24 Coupled with their function in metastasis, the MMPs also have a role in carcinogenesis. 25,26 High levels of MMP-2 and MMP-9 have been found to correlate with enhanced metastasis and poor prognosis in ...

Although brain lesions have been described in some cases with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), little is known about the nature of brain lesion and its relation to the spinal cord lesion. In the present study, we performed histopathological analysis of the brain and the spinal cord of four autopsied cases with HAM/TSP to clarify the relationship between the brain and the spinal cord lesions. In two cases with active-chronic inflammation in the spinal cord, perivascular inflammatory infiltration was also seen in the brain, and the composition of cell subsets was similar both in the spinal cord and in the brain. No active inflammatory change was seen in the brain in two cases with inactive-chronic spinal cord lesions. Inflamed vessels were distributed mainly in the deep white matter and in the area between cerebral cortex and white matter of the brain. In the spinal cord inflamed vessels were mainly seen in the bilateral lateral and the ventral posterior columns. Parenchymal infiltration was diffused in the spinal cord but very sparse in the brain, suggesting the importance of parenchymal infiltration in the destruction of tissues. These results suggest that inflammatory changes occurred simultaneously in the spinal cord and in the brain, and that distribution of inflamed vessels closely correlated with the characteristics of vascular architecture of the brain and the spinal cord, which lead to a slow blood flow. This study may help promote a better understanding of the pathogenesis of HAM/TSP.

Asymptomatic carriers of toxigenic Staphylococcus aureus are potential source of diseases, including food poisoning. Toxigenic potential and genetic traits of colonizing S. aureus were investigated for 563 healthy food handlers in Myanmar. Carriage of S. aureus was found in 110 individuals (19.5%), and a total of 144 S. aureus isolates were recovered from nasal cavities (110 isolates) and hands (34 isolates). Panton-Valentine leucocidin genes (pvl) were detected in 18 isolates (12.5%), among which 11 isolates were classified into coa-VIa, agr type III, and ST1930 (CC96) that had been also detected in pvl-positive clinical isolates in Myanmar. A pvl-positive, ST2250 nasal isolate was identified as S. argenteus, a novel coagulase-positive staphylococcus species. Toxic shock syndrome toxin-1 (TSST-1) gene was detected in five pvl-negative isolates. All of the 144 isolates harbored at least one of the 21 enterotoxin(-like) gene(s). The most prevalent enterotoxin(-like) gene was selw (98%), followed by selx (97%), sei (28%), sely (28%), sem (26%), sel (24%), and sea and sec (22% each). Considerable genetic diversity with five groups was detected for selw. The present study revealed the relatively high rate of pvl, as well as the wide distribution of enterotoxin(-like) genes among colonizing S. aureus in Myanmar.

The spread of carbapenemase-producing Enterobacteriaceae (CPE) poses a serious threat to clinical practice and public health. These bacteria are present both in clinical settings and non-clinical environments. The presence of CPE in food stuffs has been reported, but sporadically so. Here, we screened for CPE in meat, seafood, and vegetable samples from local markets of Yangon, Myanmar. We obtained 27 CPE isolates from 93 food samples and identified 13 as Escherichia coli, six as Klebsiella pneumoniae, seven as Enterobacter cloacae complex, and one as Serratia marcescens. All except the E. cloacae complex harboured the carbapenemase genes blaNDM-1 or blaNDM-5, while all Enterobacter isolates carried the carbapenemase gene blaIMI-1. The blaIMI-1 gene was located in putative mobile elements EcloIMEX-2, -3, or -8. Using multi-locus sequence typing, E. coli, K. pneumoniae, and E. cloacae complex isolates were classified into 10, six, and five different sequence types, respectively. Our results demonstrate that diverse organisms with various carbapenemase genes are widespread in the market foods in Yangon, highlighting the need for promoting proper food hygiene and effective measures to prevent further dissemination.

Human T-cell leukemia virus type 1 (HTLV-1) infection is prevalent in native Americans living in the Andes. Some of their malignant lymphomas (ML) show a peculiar histology suggestive of adult T-cell leukemia/lymphoma (ATLL). To determine whether ML resembling ATLL are indeed ATLL, re-analysis of 34 cases occurring in Jujuy, a province of Argentina, was conducted, concentrating on immunological phenotype, integration of HTLV-1 proviral DNA, expression of HTLV-1 p40Tax and p27Rex, and infection of Epstein-Barr virus (EBV). The ML were 22 cases of mature peripheral T-cell and natural killer (NK)-cell neoplasm (mT/NKN), 11 B-cell malignant neoplasms and one Hodgkin's lymphoma. Polymerase chain reaction against the HTLV-1 proviral DNA, using DNA extracted from paraffin sections, indicated integration of the HTLV-1 proviral DNA in three cases of eight mT/NKN. Two other cases of mT/NKN were positive for anti-HTLV-1 antibodies. Expression of p40Tax and p27Rex was detected in all five of these mT/NKN cases associated with HTLV-1. As such, these five mT/NKN were rediagnosed as ATLL. In situ hybridization signals for EBV-encoded small nuclear early region-1 were detected in nine cases of mT/NKN, of which five cases of NK-cell lymphoma were found to have cytoplasmic CD3 expression, a CD56 phenotype and positivity of TIA1. According to the new World Health Organization classification, the mT/NKN class includes five cases of ATLL and five cases of NK-cell lymphomas. The five cases of ATLL were of native American extraction from an HTLV-1-endemic area around Jujuy, north-west Argentina.