Impedance rheopneumogram (IRP) and right heart Swan-Ganz catheter examinations were simultaneously carried out in 63 patients. Two equations for calculating after-exercise-pulmonary-pressure (PAPm) were obtained by stepwise regression analysis: 1) PAPm (kPa) = -1.40-0.88.InHs+8.30.(B-F)+5.78.Q-B/B-Y (r = 0.730, IRP is measured at rest); 2) PAPm(kPa) = 6.46-5.04.Hs/square root of R-R +4.35.Q-B/B-Y-19.34.(Q-C) (r = 0.648, IRP is measured after exercise). This is a new method for diagnosing latent pulmonary hypertension noninvasively.

Bordetella pertussis is a Gram-negative bacterium and the causative agent of whooping cough. Whooping cough is currently re-emerging worldwide and, therefore, still poses a continuous global health threat. B. pertussis expresses several virulence factors that play a role in evading the human immune response. One of these virulence factors is virulence associated gene 8 (Vag8). Vag8 is a complement evasion molecule that mediates its effects by binding to the complement regulator C1 inhibitor (C1-INH). This regulatory protein is a fluid phase serine protease that controls proenzyme activation and enzyme activity of not only the complement system but also the contact system. Activation of the contact system results in the generation of bradykinin, a pro-inflammatory peptide. Here, the activation of the contact system by B. pertussis was explored. We demonstrate that recombinant as well as endogenous Vag8 enhanced contact system activity by binding C1-INH and attenuating its inhibitory function. Moreover, we show that B. pertussis itself is able to activate the contact system. This activation was dependent on Vag8 production as a Vag8 knockout B. pertussis strain was unable to activate the contact system. These findings show a previously overlooked interaction between the contact system and the respiratory pathogen B. pertussis. Activation of the contact system by B. pertussis may contribute to its pathogenicity and virulence.

A novel synthesis of 2,3-dihydrobenzo[b]thiophene-5-ol based on intramolecular homolytic substitution on sulfur was reported. The "antioxidant profile" of the series of 2,3-dihydrobenzo[b]furan-5-ol (2a) its 1-thio (2b), 1-seleno (2c) and 1-telluro (2d) analogues was determined by studies of redox properties, the capacity to inhibit stimulated lipid peroxidation, the reactivity toward tert-butoxyl radicals, the ability to catalyze decomposition of hydrogen peroxide in the presence of glutathione, and the inhibiting effect on stimulated peroxidation in liver microsomes. The one-electron reduction potentials of the aroxyl radicals corresponding to compounds 2a-2d, E degrees (ArO(*)/ArO(-)) were 0.49, 0.49, 0.49, and 0.52 V vs NHE, respectively, as determined by pulse radiolysis. With increasing chalcogen substitution the compounds become slightly more acidic (pK(a) = 10.6, 10.0, 9.9, and 9.5, respectively, for compounds 2a-2d). By using Hess' law, the homolytic O-H bond dissociation enthalpies of compounds 2a-2d (340, 337, 336, and 337 kJ mol(-)(1), respectively) were calculated. The reduction potentials for the proton coupled oxidation of compounds 2a-2d (ArOH ->> ArO(*) + H(+)) as determined by cyclic voltammetry in acetonitrile were 1.35 (irreversible), 1.35 (quasireversible) 1.13 (reversible), and 0.74 (reversible) V vs NHE, respectively. As judged by the inhibited rates of peroxidation, R(inh), in a water/chlorobenzene two-phase lipid peroxidation system containing N-acetylcysteine as a thiol-reducing agent in the aqueous phase, the antioxidant capacity increases (2d>> 2c = 2b>> 2a) as one traverses the group of chalcogens. Whereas the times of inhibition, T(inh), were slightly reduced for the oxygen (2a) and sulfur (2b) derivatives in the absence of the thiol-reducing agent, they were drastically reduced for the selenium (2c) and tellurium (2d) derivatives. This seems to indicate that the organochalcogen compounds are continuously regenerated at the lipid aqueous interphase and that regeneration is much more efficient for the selenium and tellurium compounds. The absolute rate constants for the oxidation of compounds 2a-2b by the tert-butoxyl radical in acetonitrile/di-tert-butyl peroxide (10/1) were the same-2 x 10(8) M(-)(1) s(-)(1). Whereas the oxygen, sulfur, and selenium derivatives 2a-2c were essentially void of any glutathione peroxidase-like activity, the organotellurium compound 2d accelerated the initial reduction of hydrogen peroxide, tert-butyl hydroperoxide, and cumene hydroperoxide in the presence of glutathione 100, 333, and 213 times, respectively, as compared to the spontaneous reaction. Compounds 2a-2d were assessed for their capacity to inhibit lipid peroxidation in liver microsomes stimulated by Fe(II)/ADP/ascorbate. Whereas the oxygen, sulfur, and selenium compounds showed weak inhibiting activity (IC(50) values of approximately 250, 25, and 13 microM, respectively), the organotellurium compound 2d was a potent inhibitor with an IC(50) value of 0.13 microM.

Rapid emergence of drug resistance in Mycobacterium tuberculosis (MTB) is a major health concern and demands the development of novel adjunct immunotherapeutic agents capable of modulating the host immune responses in order to control the pathogen. In the present study, we sought to investigate the immunomodulatory effects of G1-4A, a polysaccharide derived from the Indian medicinal plant Tinospora cordifolia, in in-vitro and aerosol mouse models of MTB infection. G1-4A treatment of MTB infected RAW264.7 macrophages significantly induced the surface expression of MHC-II and CD-86 molecules, secretion of proinflammatory cytokines (TNF-α, IL-β, IL-6, IL-12, IFN-γ) and nitric oxide leading to reduced intracellular survival of both drug sensitive (H37Rv) as well as multi drug resistant strains (Beijing and LAM) of MTB, which was partially attributed to G1-4A induced NO production in TLR4-MyD88 dependent manner. Similarly, bacillary burden was significantly reduced in the lungs of MTB infected BALB/c mice treated with G1-4A, with simultaneous up-regulation of the expression of TNF-α, INF-γ and NOS2 in the mouse lung along with increased levels of Th1 cytokines like IFN-γ, IL-12 and decreased levels of Th2 cytokine like IL-4 in the serum. Furthermore, combination of G1-4A with Isoniazid (INH) exhibited better protection against MTB compared to that due to INH or G1-4A alone, suggesting its potential as adjunct therapy. Our results demonstrate that modulation of host immune responses by G1-4A might improve the therapeutic efficacy of existing anti-tubercular drugs and provide an attractive strategy for the development of alternative therapies to control tuberculosis.

The neurotoxin vipoxin is the major lethal component of the venom of Vipera ammodites meridionalis, the most toxic snake in Europe. It is a complex between a toxic phospholipase A2 (PLA2) and a non-toxic protein inhibitor (Inh). Tyrosyl residues are involved in the catalytic site (Tyr 52 and 73) and in the substrate binding (Tyr 22). Spectroscopic studies demonstrated differences in the ionization behavior of the various phenolic hydroxyl groups in the toxic PLA2. The tyrosyl side chains of the enzyme can be classified into three groups: (a) three phenolic hydroxyls are accessible to the solvent and titrate normally, with a pKeff = 10.45; (b) three residues are partially 'buried' and participate in hydrogen bonds with neighboring functional groups. They titrate anomalously with a pKeff = 12.17; (c) two tyrosines with a pKeff = 13.23 are deeply 'buried' in the hydrophobic interior of PLA2. They became accessible to the titrating agent only after alkaline denaturation of the protein molecule. The spectroscopic data are related to the X-ray structure of the vipoxin PLA2. The refined model was investigated in the region of the tyrosyl side chains. The accessible surface area of each tyrosyl residue and each phenolic hydroxyl group was calculated. A good correlation between the spectrophotometric and the crystallographic data was observed. The ionization behavior of the phenolic groups is explained by peculiarities of the protein three-dimensional structure and the participation of tyrosines in the catalytic site hydrogen bond network. Attempts are made to assign the calculated pKeff values to individual residues. The high degree of 'exposure' on the protein surface of Tyr 22 and 75 is probably important for their function as parts of the substrate binding and pharmacological sites.

The mycobacterial FASII multi-enzyme complex has been identified to be a target of Ser/Thr protein kinases (STPKs) of Mycobacterium tuberculosis (MTB), with substrates, including the malonyl-CoA:ACP transacylase (FabD) and the β-ketoacyl-ACP synthases KasA and KasB. These proteins are phosphorylated by various kinases in vitro. The present study links the correlation of FASII pathway with serine threonine protein kinase of MTB. In the preliminary finding, we have shown that mycobacterial protein Rv3080c (PknK) phosphorylates FabD and the knockdown of PknK protein in mycobacteria down regulates FabD expression. This event leads to the differential inhibition of mycobacteria in the presence of isoniazid (INH), as the inhibition of growth of mycobacteria in the presence of INH is enhanced in PknK deficient mycobacteria.

The infectious disease is one of the most important complications related to the organ transplantation. Patients using immunosuppressive agents often present atypical tuberculosis and the treatment of such case is far more difficult in some cases due to the liver damage and/or the drug interaction. We report a case of pulmonary tuberculosis in a patient of 60-year-old man using tacrolimus after an orthotopic liver transplantation. He had liver transplanted orthotopically for the long-term history of chronic hepatitis B and subsequent liver failure on January 28, 2004. An abnormal shadow was first detected on his chest X-ray film on October, 2004. He was admitted to our hospital after the smear of the gastric juice showed some acid-fast bacilli and tubercle bacilli were confirmed by polymerase chain reaction (PCR). Tuberculin skin test was positive (erythema 10 x 10) and the computed tomography (CT) scan of his chest revealed a nodular opacity with some smaller nodules scattered around in the right upper lobe. We started four anti-tuberculous drugs other than pyrazinamide (PZA) and rifampicin (RFP), which included isoniazid (INH), ethambutol (EB), streptomycin (SM), levofloxacin (LVFX). The liver enzyme was transiently elevated (AST 123 IU/I, ALT 103 IU/I) but improved after desensitization against INH. The blood concentration of tacrolimus preserved between 5 and 7 ng/ml and there was no need to change the dosage.

BACKGROUND

Isoniazid (INH) is the drug of choice for treatment of tuberculosis (TB) and it is a well-known-cause of acute clinical liver injury which can be severe and sometimes fatal. The study was designed to investigate the effects of Saccharum officinarum L. juice on oxidative liver injury due to INH in mice.

METHODS

This was a laboratory based experimental study. Thirty mice were divided into three groups, containing 10 mice each. Group A being the control, group B and C were experimental and were treated orally with INH 100 mg/kg per day and INH 100 mg/kg per day plus Saccharum officinarum L. juice 15 ml/ kg per day respectively for a period of 30 days. Blood samples were taken at 30th day by cardiac puncture under anaesthesia and liver in each was taken out for microscopic examination.

RESULTS

INH treated mice showed; rise in serum ALT, AST, ALP and total bilirubin levels (Mean?SEM), while group C mice treated with Saccharum officinarum L. juice significantly decreased the levels of these biochemical parameters. The histopathological examination of groups A showed normal liver structure which was deranged in (INH) group B, whereas group C showed significant recovery in histological structure. Saccharum officinarum L. constituents, especially flavanoids and anthocyanins have strong antioxidant properties which provides hepatoprotection against oxidative liver injury produced by INH.

CONCLUSIONS

INH-induced liver injury is associated with oxidative stress, and co-administration of Saccharum officinarum L. juice (15 ml/Kg bw) may reduce this damage effectively in mice.

Fourteen autopsy cases of neonatal hepatitis have been studied. Of these seven cases were due to infections viz.: cytomegalovirus infection (four cases), probable cases of congenital syphilis (two cases) and neonatal herpes (one case). The remaining seven cases were of Idiopathic Neonatal Hepatitis (INH) with giant cell change in six cases. Even in these cases (INH) there was a high index of suspicion of intrauterine or acquired infection in view of severe mononuclear inflammation in the pancreas, alimentary tract and lungs. Most of these neonates with INH had low birth weight and two were preterm pointing towards a prenatal insult. The orcein stain and Periodic Acid Schiff (PAS) with diastase in all the cases were negative making hepatitis B virus infection and infinity 1 antitrypsin deficiency less likely. These autopsies represent the tip of the iceberg and only the severe cases of infection. The fatal outcome could have been prevented by maternal screening for infections and earlier clinical diagnosis.

<A<em>b</em>stractText>Hereditary angioedema due to C1-<em>INH</em> deficiency (C1-<em>INH</em>-HAE) or with normal C1-<em>INH</em> is characterized <em>b</em>y recurrent swellings due to uncontrolled production of vasoactive mediators, among which <em>b</em>radykinin (BK) is crucial. Through the <em>b</em>inding and activation of the two human BK-receptors, kinins may have dual <em>b</em>eneficial and deleterious effects in vascular and inflammation physiopathology <em>b</em>y inducing oxidative stress. We aimed to assess the serum concentrations of advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs) in patients affected <em>b</em>y HAE.</A<em>b</em>stractText><A<em>b</em>stractText>Blood samples were collected to measure the serum concentrations of AGEs and AOPPs <em>b</em>y spectrofluorimetric and spectrophotometric methods in patients affected <em>b</em>y C1-<em>INH</em>-HAE and FXII-HAE during the remission state.</A<em>b</em>stractText><p><div>(<em>b</em>)Results</<em>b</em>)</div>We showed that the circulating levels of AOPPs o<em>b</em>served on control group (0.94 (0.36) nmol/mg) were significantly lower than those o<em>b</em>served on the C1-<em>INH</em>-HAE group (1.68 (0.47) nmol/mg; <i>p</i> = 0.002) and FXII-HAE (1.50 (0.27) nmol/mg; <i>p</i> = 0.001). Moreover, the circulating levels of AGEs were significantly higher in C1-<em>INH</em>-HAE group (211.58 (151.05) AU/g; <i>p</i> = 0.02) than the FXII group (141.48 (89.59) AU/g), thus demonstrating a state of heightened oxidative stress.</p><A<em>b</em>stractText>Our o<em>b</em>servations show additional underlying events involved in HAE and are of central importance for further investigations of differences in <em>b</em>radykinin receptors signaling among the two disease su<em>b</em>groups.</A<em>b</em>stractText>

OBJECTIVE

To determine whether granulosa cells contribute to excess androgen production, by assessing inhibin B (Inh B) responses to hCG in women with polycystic ovary syndrome (PCOS) and in normal women.

METHODS

Prospective study.

METHODS

Academic medical center.

METHODS

Twenty women with PCOS and 16 normal women.

METHODS

Blood samples obtained before and 24 hours after injection of 25 μg recombinant hCG (r-hCG).

METHODS

Basal and stimulated Inh B, E2, androstenedione (A), and T responses after r-hCG administration.

RESULTS

In normal and PCOS women, r-hCG induced a significant reduction of Inh B levels. Lowered Inh B responses were not related to body mass index, PCOS status, or age by multivariate regression. Recombinant hCG significantly increased serum A and E2 in both normal and PCOS women.

CONCLUSIONS

In normal and PCOS women, Inh B production was decreased following r-hCG administration. These findings strongly suggest that in PCOS women androgen excess is not enhanced by LH-stimulated Inh B production.

BACKGROUND

NCT00747617.

After oral administration of isoniazid (INH) to volunteers, a significant reduction in circulating T lymphocytes and a significant increase in B lymphocytes was found. These findings suggest that INH may be useful as an immunosuppressive agent.

Tuberculostatic drugs are the most common drug groups with global hepatotoxicity. Awareness of potentially severe hepatotoxic reactions is vital, as hepatic impairment can be a devastating and often fatal condition. The treatment problems that may arise, within this class of medicines, are mainly of two types: adverse reactions (collateral, toxic or hypersensitive reactions) and the initial or acquired resistance of Mycobacterium tuberculosis to one or more antituberculosis drugs. Prevention of adverse reactions, increase treatment adherence and success rates, providing better control of tuberculosis (TB). In this regard, obtaining new drugs with low toxicity and high tuberculostatic potential is essential. Thus, in this work, we have designed or synthesized new derivatives of isoniazid (INH), such as new Isonicotinoylhydrazone (INH-a, INH-b and INH-c). These derivatives demonstrated good biocompatibility, antimicrobial property similar to that of parent isoniazid and last but not least, a significantly improved Pharmacotoxicological profile compared to that of isoniazid.

OBJECTIVE

The aim of our study was to assess the association between reproductive hormones (inhibin B [inh B], follicle-stimulating hormone [FSH]) with testicular volume, echogenicity, and blood flow (resistive index [RI]) in children with undescended testis (UDT).

METHODS

This was a prospective study of 1-year study duration.

METHODS

A total of 33 patients (16 unilateral and 17 bilateral) UDTs aged 5-12 years with palpable UDT were included in the study. Morning fasting blood samples were taken for estimation of serum inh B and FSH as well as inh B/FSH ratio. Testicular ultrasound was done to compute testicular volume, testicular echogenicity, and testicular vascularity in terms of RI.

RESULTS

The mean age of patients enrolled in the study was 8.29 years for unilateral UDT and 7.97 years in bilateral UDT and it was comparable. The study groups were further subdivided into two age-wise subgroups school goers (5-8 years) and prepubertal (9-12 years). The values of inh B, FSH, and inh B/FSH ratios as well as mean testicular volume were comparable between both groups and subgroups. Overall mean testicular volume had a positive correlation with FSH, inh B, and inh B/FSH, but statistical significance was reached only for inh B (P < 0.001) in children with both unilateral and bilateral UDT. Apart from five patients with hypoechogenicity within the testis, all remaining testes were of homogenous echotexture with no instances of irregular echogenicity or tumor. Children with RI >0.6 were separately studied. The incidence of high RI (>0.6) was also comparable in unilateral or bilateral disease. These subjects had unfavorable biochemical parameters in terms of low inh B levels and high FSH levels.

CONCLUSIONS

Our findings hint to the fact that palpable UDT forms a homogenous group, whether unilateral or bilateral, whereas impalpable testes may form a separate category and need further studies to substantiate this hypothesis.

The objective of the present study was to evaluate the effects of novel DNA vaccines fusing inhibin (INH) α (1-32) and RFamide-related peptide-3 (RFRP-3) genes on the immune response, reproductive hormone levels, and fertility of Tan sheep. Thirty-two female Tan sheep were divided into four groups (groups A, B, C, and D with 8 sheep per group) and respectively immunized (thrice, 20 d apart) with 0.6mg of p-TPA-SINH/TPA-SRFRP (group A), p-SINH/SRFRP (group B), p-SINH (group C) or 0.4ml saline (group D). Twenty days after primary immunization, all vaccines elicited significant immune responses, and the antibody levels of anti-INH and anti-RFRP-3 in the vaccinated groups were significantly higher (p<0.05) than that of the control group. Immunization with p-TPA-SINH/TPA-SRFRP induced higher antibodies against INH and RFRP-3. Hormone levels of FSH and LH in group A immunized with p-TPA-SINH/TPA-SRFRP were significantly higher (p<0.05) than those in group C, which are immunized with p-SINH and the control group 20 d after the third immunization. Additionally, the p-TPA-SINH/TPA-SRFRP, p-SINH/SRFRP, p-SINH and saline vaccine induced different twinning rate of ewes (37.5%, 37.5%, 12.5%, and 0, respectively), but no significant differences were found in improving twinning rate of ewes among four groups. These results suggested that neutralization of endogenous INH and RFRP-3 with novel DNA vaccine fusing INH α (1-32) and RFRP-3 genes successfully elicited a humoral immune response, increased reproductive hormone levels, but it did not significantly improve litter sizes and twinning rate of ewes in the present study.

Interaction and binding of isonicotinic acid hydrazide (INH) and its two analogs; pyrazine carboxylic acid hydrazide (PCH) and 2,4-dihydroxy benzoic acid hydrazide (2,4-DHBAH) with DNA has been investigated by UV-spectroscopy and cyclic voltammetry (CV) at physiological conditions of pH and temperature. Experimental results from both techniques were in good agreement and indicated stronger binding and formation of hydrazides-DNA complexes via intercalation. Among three hydrazides, 2,4-DHBAH showed greater interaction toward DNA at stomach pH (4.7) as evident from its comparatively greater binding constant, {K(b); 2.02 × 10(4) M(-1) (UV), 3.13 × 10(4) M(-1) (CV)}. The greater binding site size (n = 3) for 2,4-DHBAH at stomach pH inferred 3:1 binding stoichiometry and possibility of electrostatic interactions or hydrogen bonding along with intercalative mode of interaction between 2,4-DHBAH and DNA. The free energies of hydrazides-DNA complexes indicated the spontaneity of their binding. 2,4-DHBAH has shown promising anti-bacterial activities while anti-oxidant and cytotoxic potentials were exhibited by all three hydrazides.

The interaction of cupric isonicotinohydrazide (CuIIINH), an antiviral compound, with calf thymus DNA was investigated by circular dichroism (CD) and nuclear magnetic resonance (NMR). Gel electrophoresis of DNA incubated with CuIIINH showed cleavage of DNA to various extents. This cleavage was found to be time and concentration dependent. In the presence of CuIIINH the positive CD band at 274 nm disappeared and the negative band at 246 nm showed a decrease in the mean residual ellipticity value, indicating binding of CuIIINH to DNA. 31P NMR studies indicated that the binding of copper in CuIIINH is to the phosphate oxygen of the DNA backbone. The binding of CuIIINH was also found to be reversible. Addition of ethylenediaminetetraacetic acid to the CuIIINH-DNA complex resulted in breaking of the complex and restoring the original structural features of the B family of DNA in the resulting fragments. At the concentration level of CuIIINH employed, both CuSO4 and INH independently did not show any interaction with DNA.

Previous studies have demonstrated that the anti-androgenic effects of cypermethrin (CYP) are associated with testosterone (T) - related signaling pathway. This study was to investigate the effects of CYP on mouse Sertoli cells (TM4) and clarify whether the mechanisms were mediated by non-classical T signaling pathway activating mitogen-activated protein kinase (MAPK) cascade. The Cell Counting Kit 8 (CCK8) and Real-Time Cell Analysis iCELLigence (RTCA-iCELLigence) system were performed to detect the effects of 10 μM, 20 μM, 40 μM and 80 μM CYP on the viability and proliferation of TM4. The mammalian two hybrid assay, quantitative Real-Time PCR (qRT-PCR) and western blot were conducted to analyze the key genes and proteins involved in T-mediated MAPK signaling pathway. CYP was found to inhibit the viability and proliferation of TM4. Additionally, CYP disturbed the functions of Sertoli cells by inhibiting inhibin B (INH B) expression and facilitating androgen binding protein (ABP) and transferrin (TF) expression. Moreover, CYP suppressed the interaction of AR and Src kinase and inhibited androgen-mediated phosphorylation of Src, epidermal growth factor receptor (EGFR), extracellular-regulated kinase1/2 (ERK1/2) and transcription factor cAMP response element binding protein (CREB). Furthermore, the androgen-induced mRNA and protein expression of CREB-regulated gene early growth response factor (Egr1) decreased after treated with CYP. It is indicated that CYP inhibits the viability and proliferation of Sertoli cells and non-classical T signaling pathway activation of MAPK cascade is involved in anti-androgenic effect of CYP. This study provides a novel insight into the CYP-induced reproductive toxicity.

Β-Bergamotenoic acid, a compound previously shown to stimulate oviposition inH. zea, was converted into a set of bicyclic analogs and tested with a set of acyclic side chain analogs to ascertain the molecular structure that maximizes insect behavioral response. While changes in the bicyclic ring elicited no variation in response, alteration in the side chain structure ofΒ-bergamotenoic acid resulted in significant changes in moth preference. Free rotation about the C-C bond proximal to the carboxylic acid group appears to be an important structural factor, since saturation of the side chain double bond significantly increased activity. The carboxylic acid group seems to be required for strong oviposition stimulation, since analogs lacking the carboxylic acid group exhibited no significant oviposition activity. Oviposition preference ofH. zea was also influenced by the length of the hydrocarbon chain to which the carboxylic acid is attached. While hexanoic acid was found inactive, the ovipositional preference for the heptanoic and octanoic acids was greatest for the one 8-carbon tested. This and other work suggest that carboxylic acids of specific chain lengths influence the oviposition behavior of bothHelicoverpa andHeliothis species and may be associated with host-plant selection. The potential use of this information in designing integrated pest management strategies for control ofH. zea is discussed.

The developmental toxicity of cyclophosphamide, coumarin, 2-acetyl-aminofluorine (2-AAF), and trichloroethylene (TCE) was assessed with Frog Embryo Teratogenesis Assay: Xenopus (FETAX). Late Xenopus laevis blastulae were exposed to each test material for 96-h in two separate static-renewal tests with and without the presence of five differently induced exogenous metabolic activation systems (MAS). The MAS consisted of Aroclor 1254- (Aroclor 1254 MAS), isoniazid- (INH MAS), phenobarbital- (PB MAS), or beta-naphthoflavone- (beta-NF MAS), or a post-isolation mixture (mixed MAS) of INH-, PB-, and beta-NF-induced rat liver microsomes. Addition of the Aroclor 1254 MAS bioactivated cyclophosphamide, coumarin, 2-AAF, but not TCE. Addition of the PB MAS bioactivated cyclophosphamide, weakly bioactivated coumarin and 2-AAF, but had no effect on TCE developmental toxicity. The beta-NF MAS bioactivated coumarin and 2-AAF, weakly bioactivated cyclophosphamide, but did not alter the developmental toxicity of TCE. Addition of the INH-induced MAS only bioactivated TCE, whereas the post-isolation mixed MAS bioactivated each test material. Based on LC50 and EC50 (malformation) values, embryo growth, and types and severity of induced malformations, each test material was developmentally toxic. Use of post-microsome isolation mixtures from differentially induced rat livers increased the efficacy of the exogenous MAS routinely used by FETAX.

C1 inhibitor (C1 INH) is the major inhibitor of the proteolytically active subcomponents of C1, kallikrein, activated forms of factor XII, and factor XIa in plasma. We determined the mechanism(s) how interferon-gamma (IFN-gamma) regulates C1 INH mRNA expression in HepG2 cells. Cycloheximide or anisomycin treatment alone did not increase C1 INH mRNA nor did it potentiate C1 INH mRNA expression after IFN-gamma stimulation. C1 INH mRNA levels on Northern blot from untreated and IFN-gamma-treated cells did not change for more than 20 hours after actinomycin D treatment. Actinomycin D and 5,6-dichloro-1-beta-ribofuranosylbenzimidazole abolished IFN-gamma-induced C1 INH mRNA expression. Relatively more C1 INH mRNA precursor (heterogeneous nuclear RNA [hnRNA]) was detected in total RNA from IFN-gamma-treated HepG2 cells than unstimulated cells. Treatment of HepG2 cells with the phosphatase 1 and 2A inhibitors, okadaic acid >> or = 50 nmol/L) and calyculin >> or = 25 nmol/L), decreased IFN-gamma's ability to upregulated C1 INH mRNA. The phosphatase 2A inhibitor, cantharidin >> or = 10 micromol/L), also blocked the IFN-gamma induction of the C1 INH gene. In HepG2 cells total phosphatase 2A activity was significantly increased by C6 ceramide but not IFN-gamma. However, C6 ceramide itself did not increase C1 INH mRNA expression. These data indicate that phosphatase 2A is required to dephosphorylate a substrate in order for IFN-gamma to induce the transcriptional upregulation of C1 INH mRNA, but phosphatase 2A is not a direct stimulator of C1 INH gene expression.

<A<em>b</em>stractText>Car<em>b</em>ocisteine (CCis), a mucoactive agent, is used to improve the symptoms of sinonasal diseases. However, the effect of CCis on nasal ciliary <em>b</em>eating remains uncertain. We examined the effects of CCis on ciliary <em>b</em>eat distance (CBD, an index of amplitude), and ciliary <em>b</em>eat frequency (CBF) in ciliated human nasal epithelial cells (cHNECs) in primary culture.</A<em>b</em>stractText><A<em>b</em>stractText>The cHNECs were prepared from the nasal tissue resected from patients required surgery for chronic sinusitis (CS) or allergic rhinitis (AR). CBD and CBF were measured using videomicroscopy equipped with a high-speed camera.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>CCis increased CBD <em>b</em>y 30%, <em>b</em>ut not CBF, and decreased intracellular Cl^- concentration ([Cl^- ]<su<em>b</em>)i</su<em>b</em>) ) in cHNECs. The CCis' actions were mimicked <em>b</em>y the Cl^- -free NO<su<em>b</em>)3</su<em>b</em>)^- solution. In contrast, prior treatment of NPPB (20 μM) or CFTR(<em>inh</em>)-172 (1 μM), which increased [Cl^- ]<su<em>b</em>)i</su<em>b</em>) <em>b</em>y 20%, decreased CBF <em>b</em>y 10% and CBD <em>b</em>y 25% and <em>inh</em>i<em>b</em>ited the CCis' actions. However, prior treatment of T16A<em>inh</em>-A01 (10 μM) did not <em>inh</em>i<em>b</em>it the CCis' actions, although it decreased [Cl^- ]<su<em>b</em>)i</su<em>b</em>) <em>b</em>y 10% and CBD <em>b</em>y 15%. Thus, CCis stimulates Cl^- channels including cystic fi<em>b</em>rosis transmem<em>b</em>rane conductance regulator (CFTR). Moreover, CCis enhanced the transport of micro<em>b</em>eads driven <em>b</em>y the <em>b</em>eating cilia in cHNECs. The CCis actions were similar in cHNECs from <em>b</em>oth types of pateints.</p><p><div>(<em>b</em>)CONCLUSION</<em>b</em>)</div>CCis increased CBD <em>b</em>y 30% in cHNECs via an [Cl^- ]<su<em>b</em>)i</su<em>b</em>) decrease stimulated <em>b</em>y activation of Cl^- channels, including CFTR. CCis may stimulate nasal mucociliary clearance <em>b</em>y increasing CBD in patients contracting CS or AR.</p><A<em>b</em>stractText>NA. Laryngoscope, 2019.</A<em>b</em>stractText>

Drug-induced liver injury is a major challenge in treating tuberculosis with isoniazid (INH) and rifampicin (RIF). This study was aimed at evaluating the protective effects of Bacopamonnieri (Brahmi) against INH and RIF-induced hepatotoxicity in a rat model and also to study the patterns of interaction between pregnane X receptor (PXR) and chosen active compounds of B. monnieri. Hepatotoxicity was induced in the experimental animals by the oral administration of INH and RIF (50 mg/kg b.w. each/day) for 28 days. The effects of co-administration of B. monnieri (500 mg/kg b.w./day) in INH- and RIF-induced rats were studied by the estimation of biochemical analyses. The standard hepatoprotective drug silymarin (25 mg/kg b.w./day) was used for the purpose of comparison. In silico docking experiments were carried out using the PatchDock server and the results were analysed on the PyMol molecular viewer. There was significant reduction in the antioxidant status of INH and RIF-induced rats. Also, there was significant elevation in the levels of serum liver function markers in the INH- and RIF-induced rats. B. monnieri was able to normalise the tested parameters. In silico studies reveal significant interaction between PXR and bacopaside I. B. monnieri exerts significant protective effects against INH and RIF-induced hepatotoxicity in rats.

OBJECTIVE

To study the clinical effects of one stage surgical treatment of thoracolumbar spinal tuberculosis by anterior radical debridement with bone graft fusion and posterior pedicle screw-rods system fixation.

METHODS

From February 2002 to March 2007, 21 patients who were 45.3 years old on average with thoracolumbar spinal tuberculosis, including 13 males and 8 females were underwent surgical treatment of posterior pedicle screw-rods system fixation, correction of deformities, anterior radical debridement, bone graft fusion. Among them, 3 patients had 2 involved vertebras, 17 patients had 3 involved vertebras, and 1 patient had 4 involved vertebras. The patients were all complicated with kyphosis deformity with an average Cobb angle of (28.0+/-9.7) degrees. According to the Frankel neurological function grade system, 3 cases in grade B, 5 in grade C, 1 in grade D, 12 in grade E. All the patients received antiphthisic treatment with isonicotinylhydrazide (INH), rifampicin (RFP), Ethambutol (EMB), pyrazinamide (PZA), and support therapy in preoperation. The chemotherapy was continued 9 to 12 months after operation. Neurological functions of all cases were investigated, and radiography was analyzed pre-operation and post-operation to determine the state of bony fusion and the correction of spinal kyphosis. Statistical analysis was made according to the preoperative and post-operative Cobb angle.

RESULTS

The follow-up period ranged from 1 to 6 years with 2.5 years on average. All the patients had primary healing of the incisions. The Cobb angle was (9.8+/3.3) degrees in post-operation. The kyphosis deformity was corrected 17.2 degrees in thoracolumbar on average (t=-13.48, P<0.01). According to the Frankel neurological functional grade system, 1 case was in grade C, 3 in grade D, and 17 in grade E.

CONCLUSIONS

It is effective for patients with thoracolumbar spinal tuberculosis in correction of spinal kyphosis, reconstruction of the spinal stability and bony fusion by anterior radical debridement with bone graft fusion and posterior pedicle screw-rods system fixation.