<A<em>b</em>stractText>DOG1 is a calcium-activated chloride channel that has gained attention as a promising drug target due to its involvement in several processes essential for tumor development and progression. DOG1 is overexpressed in >95% of gastrointestinal stromal tumors (GIST). The aim was to determine DOG1 <em>inh</em>i<em>b</em>ition antitumoral effects on GIST.</A<em>b</em>stractText><A<em>b</em>stractText>Human GIST (GIST-T1 and GIST882) cell lines were used to study the effect of DOG1 <em>inh</em>i<em>b</em>itors on chloride currents, via<em>b</em>ility, colony formation, and cell cycle.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>CaCC<su<em>b</em>)<em>inh</em></su<em>b</em>)-A01 decreased chloride currents. CaCC<su<em>b</em>)<em>inh</em></su<em>b</em>)-A01 and T16<su<em>b</em>)<em>inh</em></su<em>b</em>)-A01 reduced GIST cell via<em>b</em>ility and CaCC<su<em>b</em>)<em>inh</em></su<em>b</em>)-A01 affected cell cycle distri<em>b</em>ution leading to G<su<em>b</em>)1</su<em>b</em>) cell-cycle arrest. CaCC<su<em>b</em>)<em>inh</em></su<em>b</em>)-A01 also increased the su<em>b</em>-G<su<em>b</em>)1</su<em>b</em>) phase population, indicative of apoptosis, in GIST882. CaCC<su<em>b</em>)<em>inh</em></su<em>b</em>)-A01 strongly reduced the colony forming a<em>b</em>ility of the cells, whereas T16<su<em>b</em>)<em>inh</em></su<em>b</em>)-A01 did not.</p><A<em>b</em>stractText>DOG1 <em>inh</em>i<em>b</em>ition has antitumoral effects in GIST cells in vitro, and could potentially serve as a target for GIST therapy.</A<em>b</em>stractText>

<A<em>b</em>stractText>Multidrug-resistant tu<em>b</em>erculosis (MDR-TB) and extensively drug-resistant tu<em>b</em>erculosis (XDR-TB) are a major pu<em>b</em>lic health threat.</A<em>b</em>stractText><p><div>(<em>b</em>)O<em>b</em>jective</<em>b</em>)</div>This study aimed to determine resistance patterns to second line anti-TB drugs (SLDs), and to determine the frequency of extensively drug resistant <i>Myco<em>b</em>acterium tu<em>b</em>erculosis</i> (XDR-TB).</p><A<em>b</em>stractText>During the period from July 2009 to July 2010; sputum specimens were collected from TB retreatment patients; isolates were tested for sensitivity to first line anti-TB drugs <em>b</em>y the 1% proportion method; MDR strains were tested for second line anti-TB drugs sensitivity <em>b</em>y 1% proportion method and <em>b</em>y version 1. Hain GenoType MTBDRsl Assay.</A<em>b</em>stractText><A<em>b</em>stractText>One hundred and forty three myco<em>b</em>acterial isolates were successfully recovered from a total of 239 specimens (143/239; 59.8%). Fifty six strains were rifampicin resistant (RR); of these 54 were multi-drug resistant (MDR); two were RIF/<em>INH</em>-resistant myco<em>b</em>acterium other than tu<em>b</em>erculosis (MOTT). Five of MDR (5/50; 10%) showed resistance to at least one second line drug and one isolate (1/50; 2%) was XDR. The XDR strain was concordantly detected <em>b</em>y the two methods.</A<em>b</em>stractText><A<em>b</em>stractText>Initial resistance to second line anti-TB drugs among MDR-TB patients is at 10% levels and XDR-TB is prevalent at low levels (2%). Nevertheless; without great efforts from national tu<em>b</em>erculosis control program (NTP) this figure can fuel the TB epidemics in Sudan.</A<em>b</em>stractText>

<A<em>b</em>stractText>To explore the prevalence, risk and genetic characteristics of drug-resistant tu<em>b</em>erculosis (T<em>B</em>) from a tertiary care T<em>B</em> hospital in China.</A<em>b</em>stractText><p><div>(<em>b</em>)Patients and methods</<em>b</em>)</div>We carried out a retrospective study including isolates from 189 patients with pulmonary T<em>B</em> at Fuzhou Pulmonary Hospital. All isolates from these patients were su<em>b</em>jected to drug suscepti<em>b</em>ility testing and genotyping. For drug-resistant isolates, DNA sequencing was used to investigate mutations in 12 loci, including <i>katG</i>, <i>inhA</i>, <i>oxyR-ahpC</i>, <i>rpo<em>B</em></i>, <i>rpsL</i>, <i>rrs</i><su<em>b</em>)1</su<em>b</em>) (nucleotides 388-1084 of rrs), <i>em<em>b</em><em>B</em></i>, <i>tlyA</i>, <i>eis</i>, <i>rrs</i><su<em>b</em>)2</su<em>b</em>) (nucleotides 1158-1674 of rrs), <i>gyrA</i> and <i>gyr<em>B</em></i>.</p><p><div>(<em>b</em>)Results</<em>b</em>)</div>Among 189 isolates, 28.6% were resistant to at least one of the seven anti-T<em>B</em> drugs, including isoniazid (<em>INH</em>), rifampin (RIF), streptomycin (STR), etham<em>b</em>utol (EM<em>B</em>), capreomycin (CAP), kanzmycin (KAN) and ofloxacin (OFX). The proportion of multidrug-resistant T<em>B</em> and extensively drug-resistant T<em>B</em> isolates was 9.5% and 1.1%, respectively. Patients in rural areas as well as previously treated patients showed a significantly increased risk of developing drug resistance. In addition, among these isolates, 111 (58.7%) were <em>B</em>eijing genotype strains, 84 (75.7%) of which <em>b</em>elonged to modern <em>B</em>eijing su<em>b</em>lineage. There was no association <em>b</em>etween genotype and drug resistance. The most common mutations were <i>katG</i>315, <i>rpo</i><i><em>B</em></i>531 <i>rpsL</i>43, <i>em<em>b</em><em>B</em></i>306, <i>rrs</i>1401 and <i>gyrA</i>94.</p><A<em>b</em>stractText>These findings provided additional information of drug-resistant T<em>B</em> in China. Previously treated patients and patients in rural areas should receive greater attention owing to their higher risk of developing drug resistance.</A<em>b</em>stractText>

(<em>b</em>)Background and o<em>b</em>jectives</<em>b</em>): Bradykinin-mediated angioedema (AE) induced <em>b</em>y antihypertensive drugs primarily affect the head and neck region and may occur even after several years of uneventful treatment. Many facts a<em>b</em>out the clinical course remain unknown. Diagnosis is not easy, as the clinical appearance resem<em>b</em>les allergic AE. No specific diagnostic markers are known and no officially approved treatment is currently availa<em>b</em>le. (<em>b</em>)Methods</<em>b</em>): All patients who presented to the ORL department <em>b</em>etween 2010 and 2016 with acute AE were included. Those with a history of renin-angiotensin-aldosterone system (RAAS) <em>b</em>locker intake were defined as RAE and their pathophysiological characteristics and clinical course of the disease were analyzed. (<em>b</em>)Results</<em>b</em>): A total of 84 patients (median age of 71 years) with RAE was identified. The majority (80%) was on ACE inhi<em>b</em>ition. The oral cavity was most often affected. Nearly 60% were medicated for more than 1 year <em>b</em>efore AE occurred. RAE occurred more often during the morning hours. The necessity for emergency intu<em>b</em>ation and/or tracheostomy was nine times higher in patients with acute RAE compared to patients with AE due to other reasons. (<em>b</em>)Conclusions</<em>b</em>): Event-free, long-term therapy with an RAAS <em>b</em>locker <em>b</em>efore the first development of edema does not exclude RAE. RAE is associated with an increased risk for emergency airway management. (<em>b</em>)A<em>b</em><em>b</em>reviations</<em>b</em>) ACE: Angiotensin Converting Enzyme; ACEi AE: ACE inhi<em>b</em>itor-induced angioedema; AE: Angioedema; ARB: Angiotensin II receptor 1 <em>b</em>locker; C1 <em>INH</em>: C1 Inhi<em>b</em>itor; CI: Confidence Interval; CRP: C-reactive protein; DPP IV: Dipeptidyl peptidase IV; ENT: Ear, Nose and Throat; HAE: Hereditary Angioedema; ICD 10: International Statistical Classification of Diseases and Related Health Pro<em>b</em>lems, 10th Edition; OR: Odds Ratio; ORL: Otorhinolaryngology; RAAS: Renin-Angiotensin-Aldosterone System; RAE: RAAS-<em>b</em>locker-induced angioedema.

OBJECTIVE

Polycystic ovary syndrome (PCOS) is a common endocrine problem in adolescents with an increasing prevalence of 30%. Pursuing new biomarkers with high specificity and sensitivity in the diagnosis of PCOS in adolescents is currently an active area of research. We aimed to investigate the diagnostic value of anti-Müllerian hormone (AMH), insulin-like peptide-3 (INSL3), inhibin-A (INH-A), and inhibin-B (INH-B) in adolescents with PCOS and also to determine the association, if any, between these hormones and clinical/laboratory findings related with hyperandrogenism.

METHODS

The study group comprised 53 adolescent girls aged between 14.5 and 20 years who were admitted to our outpatient clinic with symptoms of hirsutism and/or irregular menses and diagnosed as having PCOS in accordance with the Rotterdam criteria. Twenty-six healthy peers, eumenorrheic for at least two years and body mass index-matched, constituted the controls. Fasting blood samples for hormones [luteinizing hormone (LH), follicle-stimulating hormone (FSH), dehydroepiandrosterone-sulfate (DHEAS), androstenedione (D4-A), total/free testosterone (T/fT), sex hormone binding globulin (SHBG), AMH, INSL3, INH-A, INH-B] were drawn after an overnight fast.

RESULTS

In the PCOS group, 83% of the subjects were oligomenorrheic/amenorrheic and 87% had hirsutism. The LH, LH/FSH ratio, total T, fT, free androgen-index (FAI), DHEAS levels were significantly higher (p=0.005, p=0.042, p=0.047, p<0.001, p=0.007, p=0.014, respectively) and SHBG was significantly lower (p=0.004) in PCOS patients as compared to the controls. Although the INSL-3 and INH-B levels showed no difference between the groups (p>0.05), AMH and INH-A levels were found to be significantly higher in the PCOS group compared to the controls (p<0.001, p<0.001, respectively). In multiple linear regression analysis, WC SDS (p=0.028), logD4-A (p=0.033), logSHBG (p=0.031), and total ovarian volume (p=0.045) had significant effects on AMH levels, and LH (p=0.003) on INH-A levels. In receiver-operating characteristic analysis, the cut-off values for AMH and INH-A were 6.1 ng/mL (sensitivity 81.1%) and 12.8 pg/mL (sensitivity 86.8%), respectively, to diagnose PCOS. When AMH and INH-A were used in combination, the sensitivity (96.2%) increased.

CONCLUSIONS

INSL3 and INH-B were not found to have diagnostic value in adolescents with PCOS. On the other hand, it was shown that INH-A could be used as a new diagnostic biomarker in addition to AMH.

(<em>b</em>)O<em>b</em>jective:</<em>b</em>) With the aim of surmounting the severe hepatotoxicity induced <em>b</em>y antitu<em>b</em>erculosis drug isoniazid (<em>INH</em>), a novel cocrystal of <em>INH</em> with hepatoprotective nutraceutical syringic acid (SYA), namely <em>INH</em>-SYA, was designed and prepared through cocrystallization strategy, which is an intriguing attempt to reduce the toxic side effects of <em>INH</em>.(<em>b</em>)Significance:</<em>b</em>) The studies of this paper not only provides new thinking for inhi<em>b</em>iting toxic side effects of drugs through cocrystallization strategy, <em>b</em>ut also opens a new pathway for the application of nutraceuticals in the pharmacy.(<em>b</em>)Methods:</<em>b</em>) <em>INH</em> and SYA were successfully crystallized into the same crystal lattice through com<em>b</em>ining volatilization with solvent assisted methods. The resulting cocrystal was structurally characterized <em>b</em>y single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC).(<em>b</em>)Results:</<em>b</em>) The SCXRD analysis for the present cocrystal revealed that it has a 1:1 ratio of <em>INH</em> to SYA with two molecules <em>INH</em> homodimers and two SYA molecules, in which they are arranged alternately linked <em>b</em>y hydrogen <em>b</em>onds to form a six molecules ring structure (R⁶<su<em>b</em>)6</su<em>b</em>)(40)) in crystal. The systematic evaluation of the <i>in vitro/vivo</i> suggested that, owing to the formation of cocrystal, the dissolution efficiency of SYA was increased 5.85-fold compared with that of coarse SYA, and the oral <em>b</em>ioavaila<em>b</em>ility of the cocrystal in rats was enhanced <em>b</em>y 3.66 times. As a result, the present <em>INH</em>-SYA cocrystal almost removed <em>INH</em> induced serious hepatotoxicity, which was further demonstrated <em>b</em>y the hepatotoxicity studies in rats.(<em>b</em>)Conclusion:</<em>b</em>) <em>INH</em>-SYA cocrystal could effectively reducing the hepatotoxicity of isoniazid.

Alzheimer's disease (AD) in the elderly is frequently accompanied by chronic cerebral hypoperfusion (CCH), which impairs the clearance of amyloid beta (Aβ) due to the dysfunction of the blood-brain barrier (BBB) and accelerates the AD pathology. Since the coagulation and complement cascades are associated with BBB dysfunction and AD pathology, we investigated the expression changes of coagulation (fibrinogen alpha chain-FGA, coagulation factor XIII A chain-Factor XIIIα) and complement (plasma protease C1 inhibitor-C1-INH, Complement component 3-C3) factors in the brain of novel AD model (APP23) mice with CCH at 12 months of age. Immunohistochemical and immunofluorescent analysis showed that the expressions of FGA, Factor XIIIα, C1-INH and C3 were significantly increased in cerebral neocortex, hippocampus, and thalamus of APP23 + CCH group (n = 12) as compared with wild type (WT, n = 10) and APP23 (n = 10) groups (^⁎P < .05 and ^⁎⁎P < .01 vs WT; ^#P < .05 and ^##P < .01 vs APP23), especially near and inside of neurovascular unit. The present study suggests that CCH activated both the coagulation and complement cascades in a novel AD model mice brain accompanied by the acceleration of AD pathology.

Data regarding prevalence of multi-drug resistant tuberculosis (MDR-TB) and associated common mutations is scarce from Punjab region. The study was designed to determine rate of MDR-TB among presumptive MDR-TB from Punjab and mutation patterns using GenoType MTBDRplus assay. Total of 812 consecutive sputum samples were received from January 2012 to July 2013, from 14 districts of Punjab at the National Reference Laboratory at New Delhi for diagnosis of MDR-TB as hand holding activity. Presumptive MDR-TB patients were identified on basis of criterion B defined by the programme. Smear positive and negatives patients were found to be 636/798 (79.7%) and 162/ 798 (20.3%) respectively. Total of 606 GenoType MTBDRplus tests were conducted and mutations in rpoB, kat G and inhA genes analyzed. Total of 94/606 (15.5%), 43/606 (7.1%) and 40/606 (6.6%) were found to be RIF and INH resistant, mono-RIF resistant and 40/606 (6.6%) mono-INH resistant respectively. Commonest known mutation for RIF in rpoB gene and INH in kat G gene was S531L (80/ 137; 58.4%) and S315T1 (119/134; 88.8%) respectively. Mutations in inhA were found in 21/134 (15.7%) strains. Average turn-around time (TAT) for dispatch of result toPunjab was 4.6days. Prevalence of RIF resistance in Punjab was found to be 22.6%. Common mutations for RIF and INH were similar to that in other regions of country. GenoType MTBDRplus was found to be useful assay for rapid detection of MDR-TB, responsible for determining better management of MDR-TB patients under the programme.

<A<em>b</em>stractText>Micro<em>b</em>ial tetracycline (TC) pastes have <em>b</em>een employed to treat oral <em>b</em>acterial infection. In the present study, we investigated the kinetic radical-scavenging and pro-/anti-inflammatory activity of TC with or without visi<em>b</em>le light irradiation (VLI).</A<em>b</em>stractText><p><div>(<em>b</em>)MATERIALS AND METHODS</<em>b</em>)</div>The radical-scavenging activity of TC and minocycline (MC) was determined <em>b</em>y differential scanning calorimetry (DSC). The stoichiometric factor (n) and the rate constant of <em>inh</em>i<em>b</em>ition and propagation (k<su<em>b</em>)<em>inh</em></su<em>b</em>)/k<su<em>b</em>)p</su<em>b</em>)) were determined. The levels of cyclooxygenase-2 (Cox2), tumor necrosis factor-α (Tnfα) or nitric oxide synthase 2 (Nos2) mRNA in RAW264.7 cells stimulated with lipopolysaccharide (LPS) were investigated using real-time reverse transcriptase-polymerase chain reaction.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>The n and k<su<em>b</em>)<em>inh</em></su<em>b</em>)/k<su<em>b</em>)p</su<em>b</em>) values for 1 mM TC in 2,2'-azo<em>b</em>isiso<em>b</em>utyronitrile and <em>b</em>enzoyl peroxide systems were 0.1-0.2 and 119-250, respectively, whereas the corresponding values for quercetin (QU) and resveratrol (RE) were 2-4 and 7-15, respectively. In RAW264.7 cells stimulated with LPS, Cox2 and Tnfα mRNA were over-expressed in the presence of TC. MC down-regulated only the expression of Cox2 <em>b</em>y a<em>b</em>out 50% in LPS-stimulated cells. The anti-inflammatory activity determined on the <em>b</em>asis of Cox2 <em>inh</em>i<em>b</em>ition declined in the order QU>RE>MC>TC. Upon application of VLI, only TC down-regulated the expression of LPS-stimulated Cox2 and Tnfα mRNA. After exposure to VLI, TC, <em>b</em>ut not MC, markedly up-regulated hemoxygenase-1 (Ho-1) expression.</p><p><div>(<em>b</em>)CONCLUSION</<em>b</em>)</div>TC is a chain-<em>b</em>reaking antioxidant with a large k<su<em>b</em>)<em>inh</em></su<em>b</em>) Upon activation <em>b</em>y VLI, TC may undergo degradation and its degradation products affect pleiotropic mediators such as Cox2, Tnfα and Ho-1. TC may <em>b</em>e useful as a local photodynamic therapy for periodontal diseases.</p>

Although proteases found in neutrophil extracellular traps (NETs) have antimicrobial properties, they also stimulate collagen type 1 (COL1) production by the mare endometrium, contributing for the development of endometrosis. Cathepsin G (CAT), a protease present in NETs, is inhibited by specific inhibitors, such as cathepsin G inhibitor I (INH; β-keto-phosphonic acid). Matrix metallopeptidases (MMPs) are proteases involved in the equilibrium of the extracellular matrix. The objective of this study was to investigate the effect of CAT and INH (a selective CAT inhibitor) on the expression of MMP-2 and MMP-9 and on gelatinolytic activity. In addition, the putative inhibitory effect of INH on CAT-induced COL1 production in mare endometrium was assessed. Endometrial explants retrieved from mares in follicular phase or midluteal phase were treated for 24 or 48 h with CAT, inhibitor alone, or both treatments. In explants, transcripts (quantitative polymerase chain reaction) of COL1A2, MMP2, and MMP9, as well as the relative abundance of COL1 protein (Western blot), and activity of MMP-2 and MMP-9 (zymography) were evaluated. The protease CAT induced COL1 expression in explants, at both estrous cycle phases and treatment times. The inhibitory effect of INH was observed on COL1A2 transcripts in follicular phase at 24-h treatment, and in midluteal phase at 48 h (P < 0.05), and on the relative abundance of COL protein in follicular phase and midluteal phase explants, at 48 h (P < 0.001). Our study suggests that MMP-2 might also be involved in an earlier response to CAT, and MMP-9 in a later response, mainly in the follicular phase. While the use of INH reduced CAT-induced COL1 endometrial expression, MMPs might be involved in the fibrogenic response to CAT. Therefore, in mare endometrium, the use of INH may be a future potential therapeutic means to reduce CAT-induced COL1 formation and to hamper endometrosis establishment.

Keywords: cathepsin G; cathepsin G inhibitor; endometrosis; fibrosis; metallopeptidases.

A heteroporous metal-organic framework, [Cd<su<em>b</em>)2</su<em>b</em>)(2,2'-DSB)<su<em>b</em>)2</su<em>b</em>)(<em>INH</em>)<su<em>b</em>)2</su<em>b</em>)(H<su<em>b</em>)2</su<em>b</em>)O)<su<em>b</em>)2</su<em>b</em>)]<su<em>b</em>)n</su<em>b</em>) ((<em>b</em>)1</<em>b</em>)), is fa<em>b</em>ricated <em>b</em>y the reaction of CdI<su<em>b</em>)2</su<em>b</em>), 2-mercapto<em>b</em>enzoic acid (2-MBAH), and isoniazid (<em>INH</em>). The X-ray structure of the compound (<em>b</em>)1</<em>b</em>) shows the <em>b</em>ridging <em>INH</em> and 2,2'-disulfanediyldi<em>b</em>enzoic acid (H<su<em>b</em>)2</su<em>b</em>)2,2'-DSBA) around the Cd(II) ion center. 2-MBAH has <em>b</em>een <i>in situ</i> dimerized to the formation of 2,2'-DSB^2- (S-S-<em>b</em>onded dianion), which has further extended to form the 2D network. However, supramolecular assem<em>b</em>ly via π···π and hydrogen <em>b</em>onds strengthens the structural motif within the 3D array. Optical stimulation generated the thiol radical under an argon environment followed <em>b</em>y the electron paramagnetic resonance (EPR) study, <em>b</em>ut upon exposure to air, the EPR signal gradually disappeared <em>b</em>y the formation of the S-S <em>b</em>ond, which was commonly known as a self-healing property. Again, compound (<em>b</em>)1</<em>b</em>) exhi<em>b</em>ited as a semiconducting material with a <em>b</em>and gap of 3.7 eV. The <i>I-V</i> characteristics of (<em>b</em>)1</<em>b</em>) show that the conductivity is intensified <em>b</em>y an optical response. The Schottky diode property of (<em>b</em>)1</<em>b</em>) shows a lower <em>b</em>arrier height, a lower resistance, and a higher conductivity upon illumination at 360 nm.

Urea is the major nitrogen-containing product of protein metabolism, and the urea cycle is intrinsically linked to nitric oxide (NO) production via the common substrate L-arginine. Urea accumulates in the brain in neurodegenerative states, including Alzheimer's and Huntington's disease. Urea transporter B (UT-B, SLC14A1) is the primary transport protein for urea in the CNS, identified most abundantly in astrocytes. Moreover, enhanced expression of the Slc14a1 gene has been reported under neurodegenerative conditions. While the role of UT-B in disease pathology remains unclear, UT-B-deficient mice display behavioural impairment coupled with urea accumulation, NO disruption and neuronal loss. Recognising the role of inflammation in neurodegenerative disease pathology, the current short study evaluates the role of UT-B in regulating inflammatory responses. Using the specific inhibitor UTB_inh-14, we investigated the impact of UT-B inhibition on LPS-induced changes in BV2 microglia and N2a neuroblastoma cells. We found that UTB_inh-14 significantly attenuated LPS-induced production of TNFα and IL-6 from BV2 cells, accompanied by reduced release of NO. While we observed a similar reduction in supernatant concentration of IL-6 from N2a cells, the LPS-stimulated NO release was further augmented by UTB_inh-14. These changes were accompanied by a small, but significant downregulation in UT-B expression in both cell types following incubation with LPS, which was not restored by UTB_inh-14. Taken together, the current evidence implicates UT-B in regulation of inflammatory responses in microglia and neuronal-like cells. Moreover, our findings offer support for the further investigation of UT-B as a novel therapeutic target for neuroinflammatory conditions.

Keywords: Cytokine; Microglia; Nitric oxide; SLC14A1; UT-B; UTBinh-14.

METHODS

Distal sensory polyneuropathy (DSP) may manifest in human immunodeficiency virus (HIV) infected individuals before or after antiretroviral therapy (ART). DSP can also occur in response to isoniazid (INH); this can be prevented by pyridoxine supplementation. N-acetyltransferase 2 (NAT2) polymorphisms influence drug acetylation and possibly the risk for INH-associated DSP.

OBJECTIVE

To investigate the relationship between previous/current TB, pyridoxine deficiency and DSP in HIV-infected individuals enrolled in a government-sponsored HIV programme.

METHODS

Neuropathy assessments were performed among 159 adults pre-ART and 12 and 24 weeks thereafter. DSP was defined as ⩾1 neuropathic symptom and sign. NAT2 genotypes predicted acetylation phenotype. Serum pyridoxine levels (PLP) were quantified at baseline and week 12.

RESULTS

DSP was present in 16% of individuals pre-ART and was associated with previous/current TB (P = 0.020). Over 50% were pyridoxine deficient (PLP < 25 nmol/l), despite supplementation with vitamin B complex supplements (2-4 mg/day pyridoxine). Those with a history of TB and pre-ART DSP were more likely to be pyridoxine deficient (P = 0.029), and slow/intermediate NAT2 phenotypes impacted on their PLP levels. Incident/worsening DSP after ART developed in 21% of the participants. PLP levels remained low after ART, particularly among those with prior TB, but without an association between DSP or NAT2 phenotypes.

CONCLUSIONS

Adequate pyridoxine supplementation before ART initiation should be prioritised, particularly in those with a history of TB or current TB.

Mutations in one C1 INH allele result in the autosomal dominant disease, hereditary angioedema. The plasma antigenic level of C1 INH in this disease may be low, normal, or high, while the functional level is uniformly depressed. Investigation of the mutations in the C1 INH gene reveal several key features about the DNA itself as well as protein structure-function relationships. The largest single group of mutations with a defined mechanism are recombinations associated with Alu repetitive DNA elements. Current data suggest that there may be an increased number of mutations within the region encoding the reactive center which, like some other serpins, contains both primary and secondary structure DNA polymerase pause sites. These sites may enhance the rates of mutation and evolution in the reactive center region. Some of the dysfunctional C1 INH proteins that result from hinge region mutations support models for reactive center loop interaction with beta sheet A during complex formation. The analysis of the dysfunctional mutants, therefore, suggest regions of the molecule that are important for inhibitor function.

To shed some light on the potential value of rifampicin in the treatment of tuberculous meningitis (TBM) in adults, a retrospective analysis has been made of 143 medical records from 4 hospitals for the period 1967-80. Treatment of TBM with rifampicin and other antituberculous drugs in combination (Group B) was compared to other regimes which did not include rifampicin (Group A). There were 64 patients in Group B and 79 in Group A. The two groups of patients did not differ significantly in their prognostic characteristics. The total mortality was 14.7%: it was higher among patients not treated with rifampicin (24%; Group A) than amongst those given rifampicin (3.1%; Group B; chi 2 = 10.74; p less than 0.005). The difference was also statistically significant (chi 2 = 6.88; p less than 0.01) if patients who died during the first 48 h after the institution of treatment were excluded. No significant difference in mortality rate was found when patients treated with rifampicin plus isoniazid (INH) 8-10 mg/kg (1 death out of 41 patients) were compared to patients treated with INH 15 mg/kg (2 deaths out of 20 patients). Neurological sequelae recorded during a 6 month follow-up period were more severe among patients not treated with rifampicin.

To study the relationship between the concentrations of <em>INH</em> <em>B</em> (Inhibin <em>B</em>), ACT A (Activin A), and FSH (Follicle stimulating hormone) in blood plasma and fecundity, Dazu black goat with high productivity and Sannen dairy goat with low productivity were used as experiment objects in this research. The concentrations of <em>INH</em> <em>B</em>, ACT A, and FSH in blood plasma were measured by enzyme-linked immunosorbent assay (ELISA) in order to study the secretion rule of <em>INH</em> <em>B</em>, ACT A, and FSH during an estrus cycle of two goat breeds. The results indicated that the secretion of FSH showed a positive correlation with ACT A and a negative correlation with <em>INH</em> <em>B</em>. The mean concentration of FSH in Dazu black goat was higher than that in Sanen dairy goat during a estrous cycle. However, during the time from obviously estrus to ovulation, the mean concentration of FSH in Dazu black goat was significantly higher than that in Sannen dairy goat (0.01<P<0.05). These results showed that during an estrus cycle, the differences in <em>INH</em> <em>B</em>, ACT A, and FSH might be the reason for fecundity differences. Activin A might not be responsible for the number of eggs ovulated of goats. The main effect of ACT A may be extention of follicular stage. Inhibin <em>B</em> indirectly influences ovulation by regulation of FSH level.

In addition to its role in hemolysis and host defense against Neisseria infection, the eighth component of human complement (C8) is one of several plasma proteins that are C5b67-inhibitors (C5b67-INH). The recent identification in our laboratory of two new families with hereditary deficiency of C8 provided an opportunity to study further the role of C8 as a C5b67-INH. Based on mixing and reconstitution experiments, the deficiency of C8 seemed to be due to a selective lack of the C8 beta-chain in one family and the C8 alpha-gamma subunit in the other family. Sera from individuals homozygous for the C8 abnormality were substantially deficient in C5b67-INH activity as well as totally deficient in hemolytic activity. Sera from control individuals possessed approximately 2500 C5b67-INH U/ml, whereas sera from the C8-deficient individuals had markedly depressed C5b67-INH activity, with a mean of only 428 U/ml. C5b67-INH activity was completely reconstituted in C8-deficient serum by the addition of purified human C8. We conclude that C8 constitutes the substantial majority of the C5b67-INH activity of normal human serum.

The coronavirus disease 2019 (COVID-19) pandemic has spread rapidly worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, enters host cells via angiotensin-converting enzyme 2 (ACE2) and depletes ACE2, which is necessary for bradykinin metabolism. The depletion of ACE2 results in the accumulation of des-Arg (9)-bradykinin and possible bradykinin, both of which bind to bradykinin receptors and induce vasodilation, lung injury, and inflammation. It is well known that an overactivated contact system and excessive production of bradykinin comprise the key mechanisms that drive the pathogenesis of hereditary angioedema (HAE). It is reasonable to speculate that COVID-19 may increase disease activity in patients with HAE and vice versa. In this review, we explore the potential interactions between COVID-19 and HAE in terms of the contact system, the complement system, cytokine release, increased T helper 17 cells, and hematologic abnormalities. We conclude with the hypothesis that comorbidity with HAE might favor COVID-19 progression and may worsen its outcomes, while COVID-19 might in turn aggravate pre-existing HAE and prompt the onset of HAE in asymptomatic carriers of HAE-related mutations. Based on the pathophysiologic links, we suggest that long-term prophylaxis should be considered in patients with HAE at risk of SARS-CoV-2 infection, especially the prophylactic use of C1 inhibitor and lanadelumab and that HAE patients must have medications for acute attacks of angioedema. Additionally, therapeutic strategies employed in HAE should be considered for the treatment of COVID-19, and clinical trials should be performed.

Keywords: ACE2; ADAM metallopeptidase domain 17, ADAM17; C1 inhibitor, C1–INH; COVID-19; Complement system; Contact system; Coronavirus disease 2019, COVID-19; Hereditary angioedema; Middle East respiratory syndrome coronavirus, MERS-CoV; acute respiratory distress syndrome, ARDS; angiotensin-converting enzyme, ACE; bradykinin receptor B1, B1R; bradykinin receptor B2, B2R; bradykinin, BK; des-Arg(9)-bradykinin, DABK; granulocyte-colony stimulating factor, GCSF; granulocyte-macrophage colony stimulating factor, GM-CSF; hereditary angioedema, HAE; high-molecular-weight kininogen, HMWK; interleukin-1, IL-1; macrophage inflammatory protein, MIP; mannose-binding lectin associated serine protease, MASP; mannose-binding lectin, MBL; severe acute respiratory syndrome coronavirus 2, SARS-CoV-2; transforming growth factor-β, TGF-β; transmembrane serine protease, TMPRSS2; tumor necrosis factor γ, TNF-γ.

Semantic processing errors are symptoms of an up-regulation (schizophrenia) or degradation (Parkinsonism) of dopaminergic pathways. A recent connectionist model attributed errors in the schizophrenic processing of context to increased gain in competitive neural processes. This study extends this "gain hypothesis" by comparing the sensitivity to reduced gain of a simulation of semantic route activation to characteristic semantic judgment errors made by Parkinson's patients in an open search task. Under normal gain conditions, the dominant sense of polysemous words "wins" through competition and lateral inhibition at the word sense level (beta(inh)). For words with very different sense frequencies, decreasing gain by increasing beta(inh) resulted in the dominant word sense winning; however, for words with similar sense frequencies, increasing beta(inh) resulted in the dominant word sense winning only for low to moderate values. At high levels, no clear winner emerged after 200 epochs, with the least dominant sense reaching the maximum activation value. These results are discussed in the context of the Yerkes-Dodson Law, which may provide a theoretical basis for understanding normal and impaired semantic performance in catecholaminergic disorders.

The authors present a study on 167 cases of post-vaccinal adenitis after B.C.G. administration. These occured after the experimental application in 1,187 newborns of two vaccines produced by different laboratories. Manifest adenitis developed only after the application of the vaccine with a higher virulence and a significant concentration of live germs (A), while the vaccine with a low concentration of live germs only determined inflammatory adenitis (vaccine B). In the cases when vaccine A was applied, both after intra-dermal introduction of a 0,10 mg dose or of a 0,05 mg dose, it determined adenitis with a long evolution and in 7,79 percent, respectively in 6,95 percent of the vaccinated children fistulization occured. In most of the cases adenitis developed in the first 6 months following vaccination (86,77 percent) but in some cases it appeared even after 1-2 years. In 78,3 percent of the cases adenitis had a long course and in only 21,7 percent they regressed rapidly. Adenitis did not involve the general condition of the children but determined a concern of the parents. The duration of evolution of adenitis was, as a general rule, of several months, or 1-2 years and even longer and the treatment with tuberculostatics (INH) did not significantly alter their evolution. When there was a tendency to the formation of abscesses, especially in the case of gigantic adenitis, a reduction of the duration of the evolution was obtained by puncture, and especially by lymph-node curettage. The intensity of the post-vaccinal allergy is noted in cases complicated by adenitis (100 percent), as well as its long persistance, while in non-complicated cases the allergy diminished each year both in intensity and frequency. The authors recommend that before the mass use of a vaccine this should be tested, especially in young children, in view of making the correct choice of the efficient dose, with a maximal efficiency and the lowest number of complications.

Haemolytic activities of the classical and alternative complement pathways, and levels of C1, C4, C3, factor B and C1 inhibitor (C1-INH) were measured in 137 serum samples of 69 patients with chronic lymphocytic leukaemia (CLL). In most sera IgG, IgA and IgM concentrations were determined as well. Clinical correlations of these laboratory parameters have been studied. C1 and C4 activities were found to be depressed in almost 50% of the sera tested, and hypogammaglobulinaemia was observed with a similar frequency. Low C1 and C4 levels were found mainly in the early stages of the disease. A strong association between the occurrence of infections and hypogammaglobulinaemia was observed, although low immunoglobulin levels frequently occurred in patients without a history of infections. Low C1 and C4 levels were significantly correlated with the incidence of infections, too, and this correlation was observed mostly in the early stages of the disease. The reason for this is not known. The present results suggest that not only low immunoglobulin levels but low C1 and/or C4 levels may contribute to the increased susceptibility to infections in patients with chronic lymphocytic leukaemia.

OBJECTIVE

To evaluate the relationship between complement activation and vascular endothelial damage in pregnancy induced hypertension (PIH).

METHODS

We quantified C1q, B-factor (BF) and C1-inhibitor (C1-INH) in peripheral and retroplacental sera of 35 nulliparous PIH patients and 20 normotensive controls with double antibody sandwich ELISA. Circulating endothelial cell (CEC)of the two groups were isolated with the density gradient system of Percoll liquid and counted under microscope. The correlation between CEC and C1q was analysed.

RESULTS

(1) C1q concentrations in peripheral and retroplacental sera were significantly decreased in PIH patients than that in normotensive controls, however, the concentrations of BF and C1-INH were significantly elevated in PIH patients. The changes in retroplacental serum were much more profound than those in peripheral serum. (2) The count of CEC was significantly increased in PIH patients than that in controls. (3) The count of CEC was negatively correlated to C1q concentration.

CONCLUSIONS

Not only the classical complement activation pathway but also the alternative complement activation pathway and complement regulatory protein play important roles in the pathogenesis of PIH, and complement activation and vascular endothelial damage is correlated. Evaluation of C1q, BF, C1-INH and CEC may be of value in clinical monitoring and management of PIH.

Isoniazid (INH) is among the most important anti-tuberculosis agents widely prescribed. However, its clinical use is restricted due to its severe side effects associated with neurotoxicity. The aim of the present study was to investigate the neuroprotective effects of chrysin (CR), a natural antioxidant, against INH-induced neurotoxicity in rats. The rats were treated orally with INH (400 mg/kg body weight) alone or with CR (25 and 50 mg/kg body weight) for 7 consecutive days. INH administration significantly increased brain lipid peroxidation and resulted in a significant decrease in antioxidant biomarkers including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione (GSH). INH treatment also increased levels of nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), glial fibrillary acidic protein (GFAP) and activities of p38α mitogen-activated protein kinase (p38α MAPK) while decreasing levels of neural cell adhesion molecule (NCAM). Double immunofluorescence expressions of c-Jun N-terminal kinase (JNK) and Bcl-2 associated X protein (Bax) in brain tissues were increased after INH administration. Furthermore, INH increased mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase 1 (NQO1), glutamate-cysteine ligase modifier subunit (Gclm), glutamate cysteine ligase catalytic subunit (Gclc), NF-κB, TNF-α, interleukin-1β (IL-1β), interleukin-6 (IL-6) and GFAP in rat brain tissues. Co-treatment with CR increased anti-oxidant capacity as well as regulated inflammation and apoptosis in brain. Additionally, molecular docking results showed that CR had the potential to interact with the active sites of TNF-α and NFκ-B. In conclusion, CR improved INH-induced brain oxidative damage, inflammation and apoptosis, possibly through their antioxidant properties.

Keywords: Chrysin; Inflammation; Isoniazid; Molecular docking; Neurotoxicity; Oxidative stress.