Acquired bedaquiline resistance in Karakalpakstan, Uzbekistan.

BACKGROUND: The WHO recommends the use of bedaquiline (BDQ) in longer, as well as shorter, multidrug-resistant TB (MDR-TB) treatment regimens. However, resistance to this new drug is now emerging. We aimed to describe the characteristics of patients in Karakalpakstan, Uzbekistan, who were treated for MDR-TB and acquired BDQ resistance during treatment.METHODS: We performed a retrospective study of routinely collected data for patients treated for MDR-TB in Karakalpakstan between January 2015 and December 2020. We included patients on BDQ-containing regimens with baseline susceptibility to BDQ who developed BDQ resistance at any point after treatment initiation. Patients resistant to BDQ at baseline or with no confirmed susceptibility to BDQ at baseline were excluded.RESULTS: Of the 523 patients who received BDQ-containing regimens during the study period, BDQ resistance was detected in 31 patients (5.9%); 20 patients were excluded-16 with no prior confirmation of BDQ susceptibility and 4 who were resistant at baseline. Eleven patients with acquired BDQ resistance were identified. We discuss demographic variables, resistance profiles, treatment-related variables and risk factors for unfavourable outcomes for these patients.CONCLUSION: Our programmatic data demonstrated the acquisition of BDQ resistance during or subsequent to receiving a BDQ-containing regimen in a patient cohort from Uzbekistan. We highlight the need for individualised treatment regimens with optimised clinical and laboratory follow up to prevent resistance acquisition.

Challenges of smokeless tobacco use in Myanmar.

Myanmar Tobacco Control Law of 2006 covers the control of all forms of tobacco use. After 7-year, tobacco use among adults did not see a decrease. The paper aimed to study the prevalence, details of the products, trade, legislation, tax, marketing, advertising and evidence on morbidity and mortality, and to make recommendations for policy options. Personal communications by authors and colleagues, and searches by keywords in PubMed and on Google, literature review and research from published reports, and various studies and surveys conducted in Myanmar and other countries. Smokeless tobacco use in Myanmar is the highest among ASEAN countries. A variety of SLT products used together with betel chewing poses a challenge; betel quid chewing has been accepted as a cultural norm in both rural and urban areas. Betel quid chewing usually starts at younger ages. Sale, marketing, and advertising of SLT are not under control and thus, road-side kiosks selling betel quid with SLT are mushrooming. Considerable trade of SLT products by illegal and legal means created an increase in access and availability. Low cost of SLT product enables high volume of use, even for the poor families. Taxation for raw tobacco and tobacco products is half the values of the tax for cigarettes. Effective enforcement, amendment of the law, and action for social change are needed.

Induction of matrix metalloproteinase-1 in in vitro experimental wound model using a novel three-dimensional culture system.

The aim of this study was to determine whether experimentally punched wounds may influence the connective tissue metabolism of human fibroblast in a three dimensional culture supplemented with L-ascorbic acid. This culture was designed for human dermal fibroblasts to organize a three-dimensional dermis-like structure by accumulating self-produced extracellular matrixes. In order to examine the effects of the wound, mRNA expression and production of type I collagen, matrix metalloproteinase-1 (MMP-1) and tissue inhibitors of metalloproteinase-1 (TIMP-1) were sequentially examined up to 72 hrs after the wound was created. The levels of mRNA expression of MMP-1 were higher at 12 and 24 hrs compared with the initial level and then gradually decreased in studies both with and without wounds. However, the levels of mRNA expression of MMP-1 between 6 to 48 hrs were higher in wounds than in non-wounds. The production of proMMP-1 was also significantly enhanced. There were no significant differences in the levels of mRNA expression or the production of type I collagen and TIMP-1 with the presence or absence of a wound. These results indicate that MMP-1 is synthesized to initiate the tissue restoration in response to the disruption of the three dimensional structure. Thus, this culture system provides a new experimental tool with which to examine the direct effect of mechanical changes on connective tissue metabolism in human dermal fibroblasts.

Differential effect of etretinate on proliferation and extracellular matrix metabolism of human dermal fibroblasts from elderly and young individuals in a novel three-dimensional culture.

The effect of etretinate on proliferation and biosynthesis of collagens and glycosaminoglycans (GAGs) were investigated using human dermal fibroblasts in a novel three-dimensional culture supplemented with L-ascorbic acid 2-phosphate. Fibroblasts from two young and two elderly individuals were studied at different concentrations of etretinate, 0.25, 1.0 and 2.5 microg/ml. Collagens (hydroxyproline) and GAGs (disaccharide units) extracted from the cell layer were analyzed and quantified biochemically by high-performance liquid chromatography (HPLC). Etretinate showed no significant effect on fibroblast proliferation either in the monolayer or the three-dimensional culture. Etretinate increased the collagen or GAGs content in the cell layer, which was prominent at etretinate concentrations of 1.0 and 2.5 or 0.25 microg/ml, respectively in fibroblasts from the elderly (P < 0.05). This effect was not seen in dermal fibroblast from the young. These results suggest that etretinate may have the differential effect on collagen and GAG metabolisms depending on the donor age of the cultured fibroblasts.

The presence of anti-basement membrane zone antibodies in the sera of patients with non-bullous lupus erythematosus.

We performed indirect immunofluorescence (IF) studies using 1 mol/l sodium chloride split skin to determine whether or not a positive IF is specific to patients with bullous lupus erythematosus (LE). We examined the sera from 21 patients with systemic LE (SLE), three of which were obtained from two SLE patients and one subacute cutaneous LE (SCLE) patient with bullous eruptions. As a comparison, we also studied the sera from patients with discoid LE (DLE, n = 7), SCLE (n = 1), systemic sclerosis (SSc, n = 20), bullous pemphigoid (n = 2) and normal individuals (n = 10). Sera from 16 SLE, four DLE and two SSc revealed a linear deposition of IgG isotype antibody at the epidermal side and/or the dermal side on indirect IF of split skin. The sera from three patients with bullous eruption and from 12 patients of SLE, SCLE, DLE without bullous eruption or SSc were further analysed by immunoblotting using five defined antigens, i.e. dermal extract, epidermal extract, three fusion proteins of 230 kDa bullous pemphigoid antigen (BPAG). 180 kDa BPAG, and human epidermolysis bullosa acquisita (EBA) antigen. Two SLE sera as well as one of the SCLE and the DLE serum reacted with 230 kDa BPAG in epidermal extract, and one of the SCLE and the DLE serum also reacted with the fusion protein of 180 kDa BPAG. No serum reacted with the dermal extract or the fusion protein of 230 kDa BPAG or EBA antigen. There was no consistent correlation between split-skin IF results and immunoblotting results. These results may suggest that even non-bullous LE patients often have autoantibodies to the basement membrane zone antigens, most of which are less pathogenic. Although we rarely examine the sera from non-bullous LE patients, we should keep this phenomenon in mind to avoid overestimating the results of split-skin test and immunoblotting.