<AbstractText>Using QuantiFERON-T<em>B</em> Gold In-Tube (QFT-GIT) for monitoring tuberculosis (T<em>B</em>) and latent T<em>B</em> infection (LT<em>B</em>I) treatment effect is controversial. The present study aims to evaluate the dynamic changes of interferon gamma (IFN-γ) levels along with LT<em>B</em>I treatment based on a randomized controlled study.</AbstractText><AbstractText>910 participants treated with 8 weeks of once-weekly rifapentine (RPT) plus isoniazid (<em>INH</em>), 890 treated with 6 weeks of twice-weekly RPT plus <em>INH</em>, and 818 untreated controls were followed for 2 years to track active T<em>B</em> development. QFT-GIT tests were repeated three times for all of them: before treatment (T0), upon completion of treatment (T1), and 3 months after completion of treatment (T2).</AbstractText><AbstractText>Similar rates of persistent QFT-GIT reversion were observed in Group A (19.0%, 173/910), Group <em>B</em> (18.5%, 165/890) and Group C (20.7%, 169/818) (p = 0.512). The dynamic changes of IFN-γ levels were non-significant among the three groups as well. In treated participants, individuals with higher baseline IFN-γ levels showed increased T<em>B</em> occurrence (1.0%, 9/896) as compared to those with lower baseline levels (0.2%, 2/904) (p = 0.037). A similar but non-significant trend was also observed in untreated controls (1.8% (7/400) vs. 0.5% (2/418), p = 0.100). When T<em>B</em> cases were matched with non-T<em>B</em> cases on baseline IFN-γ levels, still no significant differences were found with respect to the dynamic changes in IFN-γ levels with time regardless if treated or not.</AbstractText><AbstractText>Our results suggested that QFT-GIT reversion or decreased IFN-γ levels should not be used for monitoring host response to LT<em>B</em>I treatment.</AbstractText>

<A<em>b</em>stractText>Given the high <em>b</em>urden of tu<em>b</em>erculosis (TB) and dia<em>b</em>etes mellitus (DM) in China and the worse outcome of TB-DM cases (refers to TB patients with dia<em>b</em>etes), and drug-resistant tu<em>b</em>erculosis cases (DR-TB), it is of great significance to explore the association <em>b</em>etween dia<em>b</em>etes and primary DR-TB for TB elimination target in China. We assessed the clinical characteristics, drug-resistance profile, and increased risk of resistance among TB-DM patients across China from 2004 to 2017.</A<em>b</em>stractText><A<em>b</em>stractText>7223 cases with drug-suscepti<em>b</em>ility data were collected from Shandong, China. Categorical <em>b</em>aseline characteristics of new TB cases were compared <em>b</em>y DM status using Fisher's exact or Pearson Chi-square test. Univaria<em>b</em>le analysis and multivaria<em>b</em>le logistic models were used to estimate the association <em>b</em>etween dia<em>b</em>etes and different drug-resistance profiles and the risk factors of primary drug resistance among TB-DM cases.</A<em>b</em>stractText><p><div>(<em>b</em>)Result</<em>b</em>)</div>Of 7223 newly diagnosed TB patients, 426 (5.90%) were TB-DM cases. TB-DM csaes were more likely to <em>b</em>e older，accompanied <em>b</em>y higher <em>b</em>ody mass index (BMI) and hypertension than TB-no DM cases (refers to TB patients without dia<em>b</em>etes). The rates of DR-TB (21.83% vs 16.96%), polydrug resistant TB (PDR-TB, 6.10% vs 3.80%), isoniazid (<em>INH</em>)+streptomycin (SM)-resistant TB (4.93% vs 3.13%), and SM-resistant TB (16.20% vs 11.7%) among TB-DM group were higher than TB-no DM group, <i>P</i><0.05. DM was significantly associated with any DR-TB (adjusted (aOR):1.30; 95% CI, 1.02-1.65), SM-related resistance (aOR: 1.43; 95% CI, 1.08-1.88), PDR-TB (OR: 1.57; 95% CI, 1.04-2.36; aOR: 1.59; 95% CI, 1.04-2.44), compared with pan-suscepti<em>b</em>le TB patients (<i>P</i><0.05).</p><A<em>b</em>stractText>Our study indicated that TB-DM groups had a higher proportion of drug resistance than TB groups, and dia<em>b</em>etes was identified as a risk factor of total DR, PDR, SM resistance and <em>INH</em>+SM resistance among newly diagnosed TB cases. Good management of dia<em>b</em>etes and TB infection screening program among DM patients might <em>b</em>e necessary for improving TB control in China.</A<em>b</em>stractText>

<p><div>(<em>b</em>)OBJECTIVES</<em>b</em>)</div>South Africa ranks among the highest drug-resistant tu<em>b</em>erculosis (DR-TB) <em>b</em>urdened countries in the world. This study assessed the changes in resistance levels in culture confirmed <i>Myco<em>b</em>acterium tu<em>b</em>erculosis</i> (MTB) in the highest <em>b</em>urdened province of South Africa during a period where major changes in diagnostic algorithm were implemented.</p><A<em>b</em>stractText>This study was conducted at the central academic la<em>b</em>oratory of the KwaZulu-Natal province of South Africa.</A<em>b</em>stractText><A<em>b</em>stractText>We analysed data for all MTB cultures performed in the KwaZulu-Natal province <em>b</em>etween 2011 and 2014. The data were collected from the la<em>b</em>oratory information system.</A<em>b</em>stractText><A<em>b</em>stractText>Out of 88 559 drug suscepti<em>b</em>ility results analysed, 18 352 (20.7%) were resistant to rifampicin (RIF) and 19 190 (21.7%) showed resistance to isoniazid (<em>INH</em>). The proportion of rifampicin resistant cases that were mono-resistant increased from 15.3% in 2011 to 21.4% in 2014 while <em>INH</em> mono-resistance (IMR) showed a range <em>b</em>etween 13.8% and 21.1%. The multidrug-resistant tu<em>b</em>erculosis (MDR-TB) rates increased from 18.8% to 23.9% and the proportion of MDR-TB cases that had extensively drug-resistant tu<em>b</em>erculosis remained <em>b</em>etween 10.2% and 11.1%. Most drug resistance was found in females <em>b</em>etween the ages of 15 and 44 years and the northern districts <em>b</em>ordering high MDR-TB regions had the highest MDR-TB rates.</A<em>b</em>stractText><A<em>b</em>stractText>Our findings show increasing RIF mono-resistance (RMR) and a su<em>b</em>stantial amount of IMR. This highlights a need for an initial test that detects resistance to <em>b</em>oth these drugs so as to avoid using RIF monotherapy during continuous phase of treatment in patients with IMR. Furthermore, addition of <em>INH</em> will <em>b</em>enefit patients with RMR. Although DR-TB is widespread, HIV and migration influence its distri<em>b</em>ution; therefore, TB control strategies should include interventions that target these aspects.</A<em>b</em>stractText>

Patients being treated for pulmonary tuberculosis often suffer liver injury due to the effects of anti-TB drugs, and the underlying mechanisms for those injuries need to be clarified. In this study, rats and hepatic cells were administrated isoniazid (INH) and rifampin (RIF) and then treated with NLRP3-inflammasome inhibitors (INF39 and CP-456773) or NLRP3 siRNA. Histopathological changes that occurred in liver tissue were examined by H&E staining. Additionally, the levels IL-33, IL-18, IL-1β, NLRP3, ASC, and cleaved-caspase 1 expression in the liver tissues were also determined. NAT2 and CYP2E1 expression were identified by QRT-PCR analysis. Finally, in vitro assays were performed to examine the effects of siRNA targeting NLRP3. Treatment with the antituberculosis drugs caused significant liver injuries, induced inflammatory responses and oxidative stress (OS), activated NLRP3 inflammasomes, reduced the activity of drug-metabolizing enzymes, and altered the antioxidant defense system in rats and hepatic cells. The NLRP3 inflammasome was required for INH- and RIF-induced liver injuries that were produced by inflammatory responses, OS, the antioxidant defense system, and drug-metabolizing enzymes. This study indicated that the NLRP3 inflammasome is involved in antituberculosis drug-induced liver injuries (ATLIs) and suggests NLRP3 as a potential target for attenuating the inflammation response in ATLIs.

(<em>b</em>)SETTING:</<em>b</em>) Treatment outcomes in multidrug-resistant tu<em>b</em>erculosis (MDR-TB) are poor. Due to drug toxicity and a long treatment duration, approximately half of patients are treated successfully. Medication is often crushed for patients who have difficulty swallowing whole ta<em>b</em>lets. Whether crushing ta<em>b</em>lets affects drug exposure in MDR-TB treatment is not known.(<em>b</em>)OBJECTIVE AND DESIGN:</<em>b</em>) We performed a sequential pharmacokinetic study in patients aged >18 years on MDR-TB treatment at two hospitals in Cape Town, South Africa. We compared the <em>b</em>ioavaila<em>b</em>ility of pyrazinamide, moxifloxacin, isoniazid (<em>INH</em>), etham<em>b</em>utol and terizidone when the ta<em>b</em>lets were crushed and mixed with water <em>b</em>efore administration vs. swallowed whole. We sampled <em>b</em>lood at six time points over 10 h under each condition separated <em>b</em>y 2 weeks. Non-compartmental analysis was used to derive the key pharmacokinetic measurements.(<em>b</em>)RESULTS:</<em>b</em>) Twenty participants completed the study: 15 were men, and the median age was 31.5 years. There was a 42% reduction in the area under the curve AUC<su<em>b</em>)0-10</su<em>b</em>) of <em>INH</em> when the ta<em>b</em>lets were crushed compared with whole ta<em>b</em>lets (geometric mean ratio 58%; 90%CI 47-73). Crushing ta<em>b</em>lets of pyrazinamide, moxifloxacin, etham<em>b</em>utol and terizidone did not affect the <em>b</em>ioavaila<em>b</em>ility significantly.(<em>b</em>)CONCLUSION:</<em>b</em>) We recommend that crushing of <em>INH</em> ta<em>b</em>lets in the MDR-TB treatment regimen <em>b</em>e avoided. Paediatric <em>INH</em> formulations may <em>b</em>e a via<em>b</em>le alternative if the crushing of <em>INH</em> ta<em>b</em>lets is indicated.

(<em>b</em>)OBJECTIVE:</<em>b</em>) To evaluate the accuracy of molecular diagnostics for the detection of drug-resistant tu<em>b</em>erculosis (TB) in Chinese patients.(<em>b</em>)METHOD:</<em>b</em>) Seven data<em>b</em>ases were searched for eligi<em>b</em>le studies that evaluated the accuracy of molecular diagnostics against drug suscepti<em>b</em>ility testing (DST) for detecting drug resistance. A <em>b</em>ivariate random-effects meta-analysis was conducted to pool sensitivity and specificity <em>b</em>y the index test and drug resistance type.(<em>b</em>)RESULTS:</<em>b</em>) A total of 159 studies were included. Compared with DST (reference standard), Xpert^® could diagnose rifampicin (RMP) resistant TB accurately, with a pooled sensitivity and pooled specificity of 92% (95%CI 90-94) and 98% (95%CI 97-98), respectively. Line-pro<em>b</em>e assays (LPAs) also performed well for RMP resistance, with a pooled sensitivity of 91% (95%CI 88-93) and pooled specificity of 98% (95%CI 96-99), <em>b</em>ut not for isoniazid (<em>INH</em>) or second-line drugs due to lower sensitivity (<80%). The pooled sensitivity of GeneChip^® microarrays for RMP, <em>INH</em> and multidrug resistance was 89% (95%CI 86-91), 79% (95%CI 75-82) and 79% (95%CI 73-84), respectively, and the specificities were all >97%. Similarly, the MeltPro^® TB/STR assay had <em>b</em>etter sensitivity and specificity for first-line drugs, varying from 87% to 89% and 97% to 98%, respectively, than for second-line drugs.(<em>b</em>)CONCLUSION:</<em>b</em>) The Xpert assay, LPA, GeneChip assay, and MeltPro assay are credi<em>b</em>le methods with high accuracy for RMP resistance detection, <em>b</em>ut they may not <em>b</em>e appropriate for other anti-tu<em>b</em>erculosis drugs due to low sensitivity.

<A<em>b</em>stractText>To evaluate the clinical utility of first and second trimester prenatal screening <em>b</em>iomarkers for early pregnancy prediction of gestational dia<em>b</em>etes mellitus (GDM) risk in nulliparous women METHODS: We conducted a population-<em>b</em>ased cohort study of nulliparous women participating in the California Prenatal Screening Program from 2009-2011 (n=105,379). GDM was ascertained from hospital discharge records or <em>b</em>irth certificates. Models including maternal characteristics and prenatal screening <em>b</em>iomarkers were developed and validated. Risk stratification and reclassification were performed to assess clinical utility of the <em>b</em>iomarkers.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Decreased levels of first trimester pregnancy-associated plasma protein A (PAPP-A) and increased levels of second trimester unconjugated estriol (uE<su<em>b</em>)3</su<em>b</em>)) and dimeric inhi<em>b</em>in A (<em>INH</em>) were associated with GDM. The addition of PAPP-A only and PAPP-A, uE<su<em>b</em>)3</su<em>b</em>), and <em>INH</em> to maternal characteristics resulted in small, yet significant, increases in AUC (maternal characteristics only: AUC 0.714 (95% CI 0.703-0.724), maternal characteristics + PAPP-A: AUC 0.718 (95% CI 0.707-0.728), maternal characteristics + PAPP-A, uE<su<em>b</em>)3</su<em>b</em>), and <em>INH</em>: AUC 0.722 (0.712-0.733)); however, no net improvement in classification was o<em>b</em>served.</p><p><div>(<em>b</em>)CONCLUSIONS</<em>b</em>)</div>PAPP-A, uE<su<em>b</em>)3</su<em>b</em>), and <em>INH</em> have limited clinical utility for prediction of GDM risk in nulliparous women. Utility of other readily accessi<em>b</em>le clinical <em>b</em>iomarkers in predicting GDM risk warrants further investigation.</p>

(<em>b</em>)Background:</<em>b</em>) The purpose of this work was to assess the activity of para-aminosalicylic acid (PAS) in com<em>b</em>ination with isoniazid (<em>INH</em>) against clinical isolates of <i>Myco<em>b</em>acterium tu<em>b</em>erculosis</i> (MTB). (<em>b</em>)Materials and methods:</<em>b</em>) A total of 72 MTB isolates with differential in vitro drug suscepti<em>b</em>ilities were included in this study, comprising 24 pan-suscepti<em>b</em>le, 24 MDR-TB, and 24 extensively drug-resistant (XDR) isolates. A microplate alamarBlue assay was performed to identify the minimal inhi<em>b</em>itory concentrations (MICs) of MTB isolates. (<em>b</em>)Results:</<em>b</em>) The MIC<su<em>b</em>)50</su<em>b</em>) of <em>INH</em> was 4 mg/L, and that of PAS was 0.063 mg/L against MTB isolates when single drug used. The com<em>b</em>ined use of <em>INH</em> and PAS resulted in 16-fold and 8-fold decrease in MIC<su<em>b</em>)50</su<em>b</em>) for <em>INH</em> and PAS, respectively. The <em>INH</em>-PAS revealed synergistic activity in 94.4% of the isolates. In addition, there was no significant difference in the FIC index of the <em>INH</em>-PAS com<em>b</em>ination among individual isolates har<em>b</em>oring different suscepti<em>b</em>ility pattern (<i>P</i>>0.05). (<em>b</em>)Conclusion:</<em>b</em>) The synergy <em>b</em>etween <em>INH</em> and PAS is demonstrated using non-multidrug-resistant (non-MDR) and MDR-TB strains, which will provide clinicians with useful hints to reuse this com<em>b</em>ination for treatment of TB patients in clinical practice.

To further improve fertility of animals, a novel gene RFRP-3 (RF-amide related peptide-3, RFRP-3) was used to construct DNA vaccines with INH α (1-32) (inhibin, INH) fragment for the first time. The aim of this study was to evaluate the effects of novel DNA vaccines on fertility in mice. Synthesized SINH and SRFRP (INH and RFRP genes were separately ligated to the C-terminus of the small envelope protein of the hepatitis B virus (HBV-S) gene) fragments were inserted into multiple cloning site of pIRES vector to develop p-SINH/SRFRP. The synthesized tissue plasminogen activator (TPA) signal sequence was then inserted into the p-SINH/SRFRP to construct p-TPA-SINH/TPA-SFRFP. Meanwhile, p-SINH was prepared and considered as positive control. Forty Kunming mice were equally divided into four groups and respectively immunized by electroporation with p-SINH, p-SINH/SRFRP and p-TPA-SINH/TPA-SRFRP vaccine (three times at 2 weeks interval) and saline as control. Results showed that the average antibodies (P/N value) of anti-INH and anti-RFRP in mice inoculated with p-TPA-SINH/TPA-SFRFP were significantly higher (P<0.05) than those inoculated with p-SINH/SRFRP and the positive rates were 100% (anti-INH) and 90% (anti-RFRP) respectively, at 2 weeks after the third immunization. Litter size of mice immunized with the three recombinant plasmids was higher (P<0.05) than that of the control, and litter size of mice immunized with p-TPA-SINH/TPA-SRFRP significantly increased (P<0.05) compared with p-SINH. These results suggested that the p-TPA-SINH/TPA-SRFRP harboring INH and RFRP genes was successfully constructed and had good immunogenicity, and might effectively increase litter size.

The major histocompatibility complex (MHC) class I molecules have been shown to be substrates to both of the complement C1 esterases. The effect of a C1 esterase-mediated cleavage of the MHC class I molecules on the activation process of lymphocytes was investigated by including the complement C1 esterase inhibitor (C1-Inh) in the medium during activation of human peripheral lymphocytes by staphylococcal enterotoxin A (SEA). The C1-Inh was shown to inhibit the activation of both CD4+ and CD8+ cells. No effect on activation of B lymphocytes was recorded, although the complement C1 complex was shown to bind to the B lymphocytes. Furthermore, the C1 complex bound to mononuclear cells was shown to be cleaved into molecular weights corresponding to the activated forms of the C1 esterases. The effect of the C1-Inh was much more pronounced at low cell density and the inhibition was not affected by the addition of interleukin-2 (IL-2). However, the inhibition was reduced when the cells were disturbed by addition of new portions of C1-Inh, 24 and 48 hr after the initiation of the activation. This indicates that the C1-Inh interference with the activation of T lymphocytes is mediated through a mechanism that requires some form of cell contact.

Tu<em>b</em>erculosis (TB) is a severe infectious disease with high mortality and mor<em>b</em>idity. The emergence of drug-resistant TB has increased the challenge to eliminate this disease. Isoniazid (<em>INH</em>) remains the key and effective component in the therapeutic regimen recommended <em>b</em>y World Health Organization (WHO). A series of isoniazid-car<em>b</em>orane derivatives containing 1,2-dicar<em>b</em>a-<i>closo</i>-dodeca<em>b</em>orane, 1,7-dicar<em>b</em>a-<i>closo</i>-dodeca<em>b</em>orane, 1,12-dicar<em>b</em>a-<i>closo</i>-dodeca<em>b</em>orane, or 7,8-dicar<em>b</em>a-<i>nido</i>-undeca<em>b</em>orate anion were synthesized for the first time. The compounds were tested <i>in vitro</i> against the <i>Myco<em>b</em>acterium tu<em>b</em>erculosis</i> (<i>Mt<em>b</em></i>) H37Rv strain and its mutant (D<i>katG</i>) defective in the synthesis of catalase-peroxidase (KatG). <i>N</i>'-((7,8-dicar<em>b</em>a-<i>nido</i>-undeca<em>b</em>oranyl)methylidene)isonicotinohydrazide ((<em>b</em>)16</<em>b</em>)) showed the highest activity against the wild-type <i>Mt<em>b</em></i> strain. All hy<em>b</em>rids could inhi<em>b</em>it the growth of the Δ<i>katG</i> mutant in lower concentrations than <em>INH</em>. <i>N</i>'-([(1,12-dicar<em>b</em>a-<i>closo</i>-dodeca<em>b</em>oran-1yl)ethyl)isonicotinohydrazide ((<em>b</em>)25</<em>b</em>)) exhi<em>b</em>ited more than 60-fold increase in activity against <i>Mt<em>b</em></i> D<i>katG</i> as compared to <em>INH</em>. This compound was also found to <em>b</em>e noncytotoxic up to a concentration four times higher than the minimum inhi<em>b</em>itory concentration 99% (MIC<su<em>b</em>)99</su<em>b</em>)) value.

Keywords: Mycobacterium tuberculosis; antitubercular activity; boron cluster; carborane; isoniazid.

In order to accomplish their physiological functions leukocytes have the capability to migrate. As a prerequisite they need to adopt a polarized cell shape, forming a leading edge at the front and a uropod at rear pole. In this study we explored the capability of chronic lymphocytic leukaemia (CLL) cells to adopt this leukocyte-specific migration phenotype. Furthermore, we studied the impact of the Toll-like receptor 9 (TLR9) agonists CpGs type A, B and C and the antagonist oligodesoxynucleotide (ODN) INH-18 on the cell polarization and migration process of primary human CLL cells. Upon cultivation, a portion of purified CLL cells adopted polarized cell shapes spontaneously (range 10-38%). Stimulation with CpG ODNs type B (ODN 2006) and CpGs type C (ODN 2395) significantly increased the frequency of morphologically polarized CLL cells, while ODN INH-18 was hardly able to act antagonistically. Like in human hematopoietic stem and progenitor cells, in morphologically polarized CLL cells CXCR4 was redistributed to the leading edge and CD50 to the uropod. Coupled to the increased frequencies of morphologically polarized cells, CpGs type B and C stimulated CLL cells showed higher migration activities in vitro and following intravenous injection higher homing frequencies to the bone marrow of immunocompromised NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. Thus, presumably independent of TLR-9 signaling, CpGs type B and C promote the cellular polarization process of CLL cells and their ability to migrate in vitro and in vivo.

<p><div>(<em>b</em>)Background</<em>b</em>)</div>Multidrug-resistant tu<em>b</em>erculosis (MDR-TB) is a pu<em>b</em>lic health concern glo<em>b</em>ally. MDR-TB is defined as resistance to rifampicin (RIF) and isoniazid (<em>INH</em>), the two-major anti-TB first-line TB treatment drugs. Rapid identification of MDR-TB can contri<em>b</em>ute significantly to the control of TB. The GenoType^® MTBDRplus Ver 2.0 assay is a molecular assay used to detect genetic mutations that result in RIF and <em>INH</em> resistance. The aim of this study was to validate the performance of the GenoType^® MTBDRplus Ver 2.0 assay for the detection of <em>INH</em> and RIF resistance.</p><p><div>(<em>b</em>)Methods</<em>b</em>)</div>Fifty-five stored Myco<em>b</em>acterium tu<em>b</em>erculosis isolates were tested using <em>b</em>oth the myco<em>b</em>acterial growth indicator tu<em>b</em>e (MGIT), antimicro<em>b</em>ial suscepti<em>b</em>ility testing (AST), and the GenoType® MTBDRplus Ver 2.0 assay. The MGIT AST was done according to the BBL MGIT AST SIRE system with RIF and <em>INH</em> final critical concentrations of 1.0 μg/ml and 0.1 μg/ml, respectively. The GenoType^® MTBDRplus assay (Hain Lifescience, Germany) was performed following the manufacturer's instructions.</p><p><div>(<em>b</em>)Results</<em>b</em>)</div>The GenoType^® MTBDRplus Ver 2.0 assay had a sensitivity, specificity, positive predictive value, and negative predictive value of 100% for <em>INH</em> and RIF resistance. The intra-assay precision for the assay was 100%.</p><p><div>(<em>b</em>)Conclusion</<em>b</em>)</div>The GenoType^® MTBDRplus Ver 2.0 assay's sensitivity and specificity show that the assay is highly accurate for the detection of RIF and <em>INH</em> resistance and thus can <em>b</em>e used as an alternate platform due to its shorter results turnaround time.</p>

<A<em>b</em>stractText>Isoniazid (<em>INH</em>) is the mainstay antimicro<em>b</em>ial in the treatment of tu<em>b</em>erculosis (TB). It is acetlylated in the liver to acetyl-<em>INH</em>. However, there is variation in rate of acetylation of <em>INH</em> among TB patients (i.e. fast, intermediate or slow acetylators) which impacts on the treatment outcomes.</A<em>b</em>stractText><A<em>b</em>stractText>The isoniazid acetylation phenotypes in the expatriate Sudanese population were determined to provide future guidance since TB is prevalent in Sudan.</A<em>b</em>stractText><A<em>b</em>stractText>A community-<em>b</em>ased trial among Sudanese expatriates in Saudi Ara<em>b</em>ia was undertaken to identify <em>INH</em>-acetylation phenotypes. After overnight fasting, a single dose of 200 mg of <em>INH</em> was given to the volunteers. Three hours later, 5 ml of <em>b</em>lood were drawn from each volunteer and prepared for High-Performance Liquid Chromatography (HPLC) analysis. The main outcomes were <em>INH</em> and Acetyl-<em>INH</em> concentrations in plasma and the su<em>b</em>sequent Acetyl-<em>INH</em>/<em>INH</em> meta<em>b</em>olic ratio (MR).</A<em>b</em>stractText><p><div>(<em>b</em>)Results</<em>b</em>)</div>The findings suggest that slow acetylation is highly prevalent among the study participants (<i>n</i> = 43; 84.31%). Moreover, there was no statistically significant correlation <em>b</em>etween age and the MR (<i>r</i> = -0.18, <i>P</i> = 0.20). Further, there was no significant association <em>b</em>etween gender and the MR (<i>P</i> = 0.124). Similarly, no significant association was found <em>b</em>etween smoking ha<em>b</em>its and MR (<i>P</i> = 0.24).</p><A<em>b</em>stractText>Isoniazid phenotyping suggests predominantly slow acetylation among the Sudanese in this sample. The study found no statistically significant associations <em>b</em>etween the MR and age or gender or smoking.</A<em>b</em>stractText>

<A<em>b</em>stractText>Successful treatment of tu<em>b</em>erculosis depends on early diagnosis and use of appropriate drug suscepti<em>b</em>ility testing in a timely manner. In the present study, LPA efficacy was assayed in detection and drug suscepti<em>b</em>ility testing of pulmonary tu<em>b</em>erculosis in comparison to availa<em>b</em>le methods in Iran and phylogenetic analyses of isolated cases carried out <em>b</em>y MIRU-VNTR.</A<em>b</em>stractText><A<em>b</em>stractText>This study was conducted at the Tehran Regional Reference La<em>b</em>oratory for Tu<em>b</em>erculosis. All sputum specimens were su<em>b</em>jected to smear, culture, and drug suscepti<em>b</em>ility testing (DST), GeneXpert, and LPA. Finally, 15-locus-<em>b</em>ased MIRU-VNTR was used for molecular genotyping.</A<em>b</em>stractText><p><div>(<em>b</em>)Results</<em>b</em>)</div>From a total of 920 sputum specimens, 6.08% (n=56) were identified as MTBC <em>b</em>y culture, 6.8% (n=63) <em>b</em>y GeneXpert, and 6.5% (n=60) <em>b</em>y LPA. Phenotype DST and LPA methods confirmed the resistance of 4 and 14 specimens to rifampin (RIF) and isoniazid (<em>INH</em>); two cases were considered as multidrug-resistant (MDR). Using GeneXpert, four cases were identified as RIF-resistant. Based on LPA results, <i>inhA</i> and <i>katG</i> mutations were detected in 100% and 21.4% of <em>INH</em>-resistant cases, respectively. All 56 culture positive <i>Myco<em>b</em>acterium tu<em>b</em>erculosis</i> isolates were placed in 29 different clusters using MIRU-VNTR genotyping. Two MDR-TB, 2 RIF mono-resistant, and 12 <em>INH</em> mono-resistant cases were placed in different clusters.</p><A<em>b</em>stractText>LPA is an appropriate method for early detection and accurate diagnosis of TB and drug-resistant cases that makes it possi<em>b</em>le to distinguish <em>INH</em> mono-resistant cases from MDR cases in Iran.</A<em>b</em>stractText>

Monoamine oxidase A (MAOA) is an important mitochondria-<em>b</em>ound enzyme that catalyzes the oxidative deamination of monoamine neurotransmitters. Accumulating evidence suggests a significant association of increased MAOA expression and advanced high-grade prostate cancer (PCa) progression and metastasis. Herein, a series of novel conjugates com<em>b</em>ining the MAOA inhi<em>b</em>itor isoniazid (<em>INH</em>) and tumor-targeting near-infrared (NIR) heptamethine cyanine dyes were designed and synthesized. The synthesized compounds (<em>b</em>)G1</<em>b</em>)⁻(<em>b</em>)G13</<em>b</em>) were evaluated in vitro for their cytotoxicity against PC-3 cells using the MTT assay, and molecular docking studies were performed. Results showed that most tested compounds exhi<em>b</em>ited improved antitumor efficacy compared with <em>INH</em>. Moreover, conjugates (<em>b</em>)G10</<em>b</em>) and (<em>b</em>)G11</<em>b</em>) showed potent anticancer activity with IC<su<em>b</em>)50</su<em>b</em>) values (0.85 and 0.4 μM respectively) compara<em>b</em>le to that of doxoru<em>b</em>icin (DOX). This may <em>b</em>e attri<em>b</em>uta<em>b</em>le to the preferential accumulation of these conjugates in tumor cells. (<em>b</em>)G10</<em>b</em>), (<em>b</em>)G11</<em>b</em>), and (<em>b</em>)G12</<em>b</em>) also demonstrated moderate MAOA inhi<em>b</em>itory activities. This result and the results of molecular docking studies were consistent with their cytotoxicity activities. Taken together, these data suggest that a com<em>b</em>ination of the MAOA inhi<em>b</em>itor <em>INH</em> with tumor-targeting heptamethine cyanine dyes may prove to <em>b</em>e a highly promising tool for the treatment of advanced prostate cancer.

Herein, we descri<em>b</em>e the synthesis of a fluorescent pro<em>b</em>e (<em>b</em>)NB-2</<em>b</em>) and its use for the detection of peroxyl radicals. This pro<em>b</em>e is composed of two receptor segments (4-hydroxycinnamyl moieties) sensitive towards peroxyl radicals that are conjugated with a fluorescent reporter, dipyrromethene<em>b</em>oron difluoride (BODIPY), whose emission changes depend on the oxidation state of the receptors. The measurement of the rate of peroxidation of methyl linoleate in a micellar system in the presence of 1.0 µM (<em>b</em>)NB-2</<em>b</em>) confirmed its a<em>b</em>ility to trap lipid peroxyl radicals with the rate constant <i>k</i><su<em>b</em>)<em>inh</em></su<em>b</em>) = 1000 M^-1·s^-1, which is ten-fold smaller than for pentamethylchromanol (an analog of α-tocopherol). The reaction of (<em>b</em>)NB-2</<em>b</em>) with peroxyl radicals was further studied via fluorescence measurements in methanol, with α,α'-azo<em>b</em>isiso<em>b</em>utyronitrile (AIBN) used as a source of radicals generated <em>b</em>y photolysis or thermolysis, and in the micellar system at pH 7.4, with 2,2'-azo<em>b</em>is(2-amidinopropane) (ABAP) used as a thermal source of the radicals. The reaction of (<em>b</em>)NB-2</<em>b</em>) receptors with peroxyl radicals manifests itself <em>b</em>y the strong increase of a fluorescence with a maximum at 612-616 nm, with a 14-fold enhancement of emission in methanol and a 4-fold enhancement in the micelles, as compared to the unoxidized pro<em>b</em>e. Our preliminary results indicate that (<em>b</em>)NB-2</<em>b</em>) <em>b</em>ehaves as a "switch on" fluorescent pro<em>b</em>e that is suita<em>b</em>le for sensing peroxyl radicals in an organic lipid environment and in <em>b</em>i-phasic dispersed lipid systems.

Background: The risk of tuberculosis (TB) is high among people with HIV (PWH). Heavy alcohol drinking independently increases TB risk and approximately 25% of PWH globally engage in heavy drinking. While isoniazid (INH) preventive therapy decreases TB incidence and mortality among PWH, heavy drinking during INH is associated with liver toxicity and poor adherence. Interventions are, therefore, urgently needed to decrease alcohol use and improve adherence to INH in this population in settings with high prevalence of HIV and TB like Uganda.

Methods: The Drinkers' Intervention to Prevent TB (DIPT) study is a 2×2 factorial randomized controlled trial among HIV/TB co-infected adults (≥18 years) who engage in heavy alcohol drinking and live in Uganda. The trial will allocate 680 participants with a 1:1:1:1 individual randomization to receive 6 months of INH and one of the following interventions: (1) no incentives (control), (2) financial incentives contingent on low alcohol use, (3) financial incentives contingent on high adherence to INH, and (4) escalating financial incentives for both decreasing alcohol use and increasing adherence to INH. Incentives will be in the form of escalating lottery-based monetary rewards. Participants will attend monthly visits to refill isoniazid medications, undergo liver toxicity monitoring, and, except for controls, determine eligibility for prizes. We will estimate (a) the effect of incentives contingent on low alcohol use on reduction in heavy drinking, measured via a long-term objective and self-reported metric of alcohol use, at 3- and 6-month study visits, and (b) the effect of incentives contingent on high adherence to INH, measured as >90% pill-taking days by medication event monitoring system cap opening. We will use qualitative methods to explore the mechanisms of any influence of financial incentives on HIV virologic suppression.

Discussion: This study will provide new information on low-cost strategies to both reduce alcohol use and increase INH adherence among people with HIV and TB infection who engage in heavy drinking in low-income countries with high HIV and TB prevalence.

Trial registration: ClinicalTrials.gov NCT03492216 . Registered on April 10, 2018.

Keywords: Adherence; Alcohol drinking; Contingency management; HIV; Incentives; Isoniazid preventive therapy; Isoscreen; Phosphatidylethanol; Point of care; Randomized controlled trial; Tuberculosis; Urine ethyl glucuronide.

The chemotherapy for tuberculosis (TB) is complicated by its long-term treatment, its frequent drug dosing, and the adverse effects of anti-TB drugs. In this study, we have developed two nanocomposites (A and B) by intercalating the anti-TB drug isoniazid (INH) into Zn/Al-layered double hydroxides. The average size of the nanocomposites was found to bê164 nm. The efficacy of the Zn/Al-layered double hydroxides intercalated INH against Mycobacterium tuberculosis was increased by approximately three times more than free INH. The nanocomposites were also found to be active against Gram-positive and -negative bacteria. Compared to the free INH, the nanodelivery formulation was determined to be three times more biocompatible with human normal lung fibroblast MRC-5 cells and 3T3 fibroblast cells at a very high concentration of 50 µg/mL for up to 72 hours. The in vitro release of INH from the Zn/Al-layered double hydroxides was found to be sustained in human body-simulated buffer solutions of pH 4.8 and 7.4. This research is a step forward in making the TB chemotherapy patient friendly.

(<em>b</em>)O<em>b</em>jective:</<em>b</em>) To investigate the efficacy of <em>b</em>alloon dilatation performed for patients who suffered from actively caseating endo<em>b</em>ronchial tu<em>b</em>erculosis (EBTB) and central airway stenosis in clinical improving period who's <em>b</em>ronchus has not formed mature scar tissue. (<em>b</em>)Methods:</<em>b</em>) A total of 152 tu<em>b</em>erculous unilateral main <em>b</em>ronchus stenosis patients (23 male and 129 female) who received treatment in Hunan Chest Hospital from January 1^st 2014 to Decem<em>b</em>er 31^st 2018 were included in this retrospective analysis. The age was 15-66 (33.3±11.9) years old. All patients received routine anti-tu<em>b</em>erculosis chemotherapy. Sixty-four of them who suffered from actively caseating EBTB and unilateral main <em>b</em>ronchus stenosis received cryotherapy and endo<em>b</em>ronchial isoniazid (<em>INH</em>) administration till the caseating necrosis in stenotic <em>b</em>ronchus was disappeared and ulcers were recovered, and then received <em>b</em>alloon dilatation com<em>b</em>ined with cryotherapy, were test group. Eighty-eight of them who suffered from fi<em>b</em>rostenotic EBTB received <em>b</em>alloon dilatation com<em>b</em>ined with cryotherapy were control group. We analyzed the efficacy and complications after treatments. (<em>b</em>)Results:</<em>b</em>) The lung re-expansion rate after treatment in test group was higher than the control group, and the differences were statistically significant [74.0%(37/50) <i>vs.</i> 37.9%(22/58), <i>χ²=</i>14.094, <i>P</i><0.001]. The 6-month re-stenosis rate in test group was lower than control group, and the differences were statistically significant [10.9%(7/64) <i>vs</i>. 30.7% (27/88), <i>χ²=</i>8.318, <i>P</i>=0.004]. The differences of diameter and diameter variation after <em>b</em>alloon dilatation, immediate effective rates, average times of <em>b</em>alloon dilatation and procedure-related <em>b</em>leeding (<10 ml) rates, chest pain rates had no statistical signification in two groups. Severe complications including fatal <em>b</em>leeding (>100 ml) and mediastinal emphysema did not occur during our procedures. (<em>b</em>)Conclusions:</<em>b</em>) Performing <em>b</em>alloon dilatation for patients who suffered from actively caseating EBTB and central airway stenosis in the clinical improvement period, when caseous necrosis tissue disappeared and ulcers were recovered, not only helps to perform interventional procedures on distal <em>b</em>ronchus in time, increase the rate of lung re-expansion, can also reduce the rate of re-stenosis after 6 months, so it is effective and safe.

(<em>b</em>)目的：</<em>b</em>) 探讨合并中心气道狭窄的溃疡坏死型支气管结核患者，在支气管未形成成熟瘢痕的临床好转期行球囊扩张治疗的疗效及意义。 (<em>b</em>)方法：</<em>b</em>) 回顾性分析2014年1月1日至2018年12月31日于湖南省胸科医院就诊的单侧结核性中心气道狭窄的支气管结核患者152例的病例资料，其中男23例，女129例，年龄15~66（33.3±11.9）岁。其中64例狭窄段及狭窄段远端存在干酪样坏死物，经冷冻等介入治疗使狭窄段坏死物消失、溃疡愈合后，在尚未形成成熟瘢痕的临床好转期行球囊扩张术治疗联合冷冻治疗，作为观察组；88例狭窄段处于瘢痕期，予以球囊扩张联合冷冻治疗，作为对照组。观察两组患者的治疗效果及并发症并进行统计学分析。 (<em>b</em>)结果：</<em>b</em>) 观察组的治疗后肺复张率高于对照组，差异有统计学意义［74.0%（37/50）比37.9%（22/58），<i>χ²=</i>14.094，<i>P</i><0.001］；治疗6个月后，观察组再狭窄率低于对照组，差异有统计学意义［10.9%（7/64）比30.7%（27/88），<i>χ²=</i>8.318，<i>P</i>=0.004］。两组间扩张后管腔直径、扩张前后管腔直径差、扩张次数、即时有效率、扩张时少量出血发生率、胸痛发生率的差异均无统计学意义。两组患者均未发生操作相关的大出血、纵隔气肿等严重并发症。 (<em>b</em>)结论：</<em>b</em>) 对于合并中心气道狭窄的溃疡坏死型支气管结核患者，在狭窄段支气管干酪样坏死物消失、溃疡愈合后的临床好转期行球囊扩张术，不仅能尽早对狭窄段远端病变支气管进行介入治疗、提高肺不张的复张率，还可降低6个月后再狭窄率，有较好的疗效及安全性。.

Acquired angioedema due to C1-INH deficiency (C1-INH-AAE) can occur when there are acquired (not inherited) deficiencies of C1-INH. A quantitative or functional C1-INH deficiency with negative family history and low C1q is diagnostic of C1-INH-AAE. The most common conditions associated with C1-INH-AAE are autoimmunity and B-cell lymphoproliferative disorders. A diagnosis of C1-INH-AAE can precede a diagnosis of lymphoproliferative disease and confers an increased risk for developing non-Hodgkin lymphoma. Treatment focuses on symptom control with therapies that regulate bradykinin activity (C1-INH concentrate, icatibant, ecallantide, tranexamic acid, androgens) and treatment of any underlying conditions.

OBJECTIVE

Chronotropic incompetence (CI) in patients with congestive heart failure (CHF) develops frequently under beta-blocker and amiodarone therapy. It can be corrected by pacing. We performed a randomized study to test whether pacing is beneficial in CHF patients with CI.

RESULTS

Congestive heart failure patients under combined beta-blocker and amiodarone therapy (n = 77) were randomly assigned to inhibited pacing (INH; basal rate 40 bpm/hysteresis 30 bpm; n = 38) or to DDDR pacing with optimized atrioventricular delay (OPT; stimulation rate 65-120 bpm, n = 39). Groups showed similar baseline values in NYHA class, heart rate, and ejection fraction (EF) and were followed up to 10 years. The resting and mean 24 h heart rate after 1 year decreased by -2.6/-5 bpm in INH, but increased by +3.6/+6.0 bpm in the OPT group (P < 0.001). The QRS interval after 1 year increased by 12 +/- 23 ms in the INH group, but +32 +/- 36 ms in the OPT group (P < 0.01). Patients with INH developed a greater left ventricular EF (LVEF) when compared with OPT patients (+10.6 +/- 8 vs. +2 +/- 10%, respectively; P = 0.04). Changes in LVEF were negatively correlated with heart rate, but not with QRS width changes. Prognosis and the event rate were better in the INH group.

CONCLUSIONS

In the long-term follow-up, single-site ventricular pacing in patients with CHF and low LVEF is associated with significant clinical events and a poor prognosis.

Joining the glo<em>b</em>al fight against Tu<em>b</em>erculosis, the world's most deadly infectious disease, herein we present the design and synthesis of novel isatin-nicotinohydrazide hy<em>b</em>rids ((<em>b</em>)5a-m</<em>b</em>) and (<em>b</em>)9a-c</<em>b</em>)) as promising anti-tu<em>b</em>ercular and anti<em>b</em>acterial agents. The anti-tu<em>b</em>ercular activity of the target hy<em>b</em>rids was evaluated against drug-suscepti<em>b</em>le M. tu<em>b</em>erculosis strain (ATCC 27294) where hy<em>b</em>rids (<em>b</em>)5d</<em>b</em>), (<em>b</em>)5g</<em>b</em>) and (<em>b</em>)5h</<em>b</em>) were found to <em>b</em>e as potent as <em>INH</em> with MIC = 0.24 µg/mL, also the activity was evaluated against Isoniazid/Streptomycin resistant M. tu<em>b</em>erculosis (ATCC 35823) where compounds (<em>b</em>)5g</<em>b</em>) and (<em>b</em>)5h</<em>b</em>) showed excellent activity (MIC = 3.9 µg/mL). Moreover, the target hy<em>b</em>rids were examined against six <em>b</em>ronchitis causing-<em>b</em>acteria. Most derivatives exhi<em>b</em>ited excellent anti<em>b</em>acterial activity. K. pneumonia emerged as the most sensitive strain with MIC range: 0.49-7.81 µg/mL. Furthermore, a molecular docking study has proposed DprE1 as a pro<em>b</em>a<em>b</em>le enzymatic target for herein reported isatin-nicotinohydrazide hy<em>b</em>rids, and explored the <em>b</em>inding interactions within the vicinity of DprE1 active site.

Keywords: Anti-tubercular activity; DprE1 inhibitors; isatin derivatives; nicotinohydrazide; resistant TB.