Pharmacokinetics of doxycycline in laying hens after intravenous and oral administration.

The pharmacokinetics of doxycycline in laying hens was investigated after a single intravenous (IV) or an oral (PO) dose at 20 mg/kg body weight. The concentrations of doxycycline in plasma samples were determined by high-performance liquid chromatography with an ultraviolet detector, and pharmacokinetic parameters were calculated using a compartmental model method. The disposition of doxycycline after one single IV injection was best described by a two-compartment open model and the main pharmacokinetic parameters were as follows: volume of distribution (Vd) was 865.15 ± 127.64 ml/kg, distribution rate constant (α) was (2.28 ± 0.38) 1/h, elimination rate constant (ß) was 0.08 ± 0.02 1/h and total body clearance (Cl) was104.11 ± 18.32 ml/h/kg, while after PO administration, the concentration versus time curve was best described by a one-compartment open model and absorption rate constant (Ka), peak concentration (Cmax), time to reach Cmax (tmax) and absolute bioavailability (F) were 2.55 ± 1.40 1/h, 5.88 ± 0.70 µg/ml, 1.73 ± 0.75 h and 52.33%, respectively. The profile of doxycycline exhibited favourable pharmacokinetic characteristics in laying hens, such as quick absorption and slow distribution and elimination, though oral bioavailability was relatively low. A multiple-dosing regimen (a dose of 20 mg/kg/d for 3 consecutive days) of doxycycline was recommended to treat infections in laying hens. But a further study should be conducted to determine the withdrawal time of doxycycline in eggs.

[Association between the C46T polymorphism of coagulation factor â « gene and the involvement of factor â « activity in patients with unexplained recurrent spontaneous abortion].

OBJECTIVE: To explore the association between the C46T polymorphism of coagulation factor Ⅻ (FⅫ) gene and the involvement of FⅫ activity (FⅫ:C) in patients with unexplained recurrent spontaneous abortion (URSA), and to elucidate its role in the pathogenesis of URSA. METHODS: This study included 203 patients with URSA (URSA group) and 171 healthy women with at least one child and no history of infertility or miscarriage (control group) in the southern area of Zhejiang Province. The C46T polymorphism of the FⅫ gene was analyzed with matrix-assisted laser desorption/ionization time of flight-mass spectrometry (MALDI-TOF-MS) in all subjects. The values of prothrombin time, activated partial thromboplastin time (APTT), fibrinogen, FⅫ:C and other coagulant parameters were determined. The frequency distribution of the wild-type (CC), heterozygote (CT), homozygote (TT) genotypes and C and T alleles were compared between the patients and controls. A comprehensive analysis of association was conducted between C46T genotypes and the FⅫ:C levels in URSA patients. RESULTS: The CC, CT, TT genotypes of the FⅫ gene were observed in 7 (3.4%, 7/203), 83 (40.9%, 83/203) and 113 (55.7%, 113/203) patients with URSA versus 7 (4.1%, 7/171), 46 (26.9%, 46/171) and 118 (69.0%, 118/171) controls. The frequency of CT in the patients with URSA was significantly higher than that in controls, but the frequency of TT in the patients was lower than that in controls (χ(2)=7.939, OR=1.884, 95%CI: 1.210-2.935, P<0.05). The frequencies of allele C and allele T were observed in 97 (23.9%, 97/406) and 309 (76.1%, 309/406) patients with URSA versus 60 (17.5%, 60/342) and 282 (82.5%, 282/342) controls. The distribution frequency of allele T in URSA group was lower than that in control group (χ(2)=4.510, OR=1.475, 95%CI: 1.029-2.115, P<0.05). The FⅫ: C levels in the patients were (102±13)% in CC genotype, (78±11)% in CT genotype and (59±9)% in TT genotype, respectively. The differences of the FⅫ: C levels between the CC and CT, CT and TT, CC and TT genotypes in the patients were significant (all P<0.05). CONCLUSIONS: The low level of FⅫ:C maybe result from the T allele of the FⅫ gene in URSA patients. The CT genotype might be relative to the pathogenesis of URSA in a Chinese Han female population from the southern area of Zhejiang province.

Pharmacokinetics of doxycycline after a single intravenous, oral or intramuscular dose in Muscovy ducks (Cairina moschata).

1. The pharmacokinetics of doxycycline in ducks were investigated after a single intravenous (IV), intramuscular (IM) or oral (PO) dose at 20 mg/kg body weight. 2. The concentrations of doxycycline in plasma samples were assayed using a high performance liquid chromatography method, and pharmacokinetic parameters were calculated using a non-compartmental model. 3. After IV administration, doxycycline had a mean (±SD) distribution volume (Vz) of 1761.9 ± 328.5 ml/kg and was slowly eliminated with a terminal half-life (t1/2λz) of 21.21±1.47 h and a total body clearance (Cl) of 57.51 ± 9.50 ml/h/kg. Following PO and IM administration, doxycycline was relatively slowly absorbed - the peak concentrations (Cmax) were 17.57 ± 4.66 µg/ml at 2 h and 25.01 ± 4.18 µg/ml at 1.5 h, respectively. The absolute bioavailabilities (F) of doxycycline after PO and IM administration were 39.13% and 70.71%, respectively. 4. The plasma profile of doxycycline exhibited favourable pharmacokinetics characteristics in Muscovy ducks, such as wide distribution, relatively slow absorption and slow elimination, though oral bioavailability was low.

Differential clinical and pathological characteristics of esophageal stromal tumors and leiomyomata.

The objective of the study was to assess the differences in clinical and pathological characteristics between esophageal stromal tumor and leiomyoma. Data from 93 esophageal stromal tumors and leiomyomata cases were retrospectively analyzed, including clinical symptoms, endoscopic features, pathological characteristics, immunohistochemistry (IHC), and treatment. All cases underwent endoscopic ultrasonography examination before treatment. Lesions arising from the muscularis mucosa were resected by endoscopic mucosal resection or endoscopic submucosal dissection. Lesions arising from the muscularis propria were resected by surgery. All specimens were examined by IHC. Patients were followed up after endoscopic mucosal resection or endoscopic submucosal dissection. No difference was observed in clinical symptoms and endoscopic features between the two groups. Endoscopic ultrasonography demonstrated all lesions to be hypoechoic and well circumscribed. Most lesions >2 cm had heterogeneous internal ultrasound signal. In esophageal stromal tumor, 100% (29/29) were CD117-positive and DOG-1-positive; 72.4% (21/29) and 51.7% (15/29) were CD34-positive and smooth muscle actin-positive, respectively. In esophageal leiomyomata, 100% (64/64) were smooth muscle actin-positive and desmin-positive; 100% were CD117-negative and DOG-1-negative. No local recurrence was detected in followed up patients (n = 49) after an average of 1.8 years (1.0-3.0 years). IHC analyses are important for distinguishing esophageal stromal tumor from leiomyoma. Early endoscopic resection is an effective treatment option for esophageal stromal tumors >1 cm.

Preoperative BMI and Hb levels are important predictors of massive bleeding in liver transplant patients.

OBJECTIVE: This study aims to compare intraoperative bleeding during liver transplant procedures and analyze the predictive role of preoperative laboratory indicators in significant intraoperative bleeding. PATIENTS AND METHODS: A retrospective analysis was conducted on 271 cases of allogeneic liver transplant patients from January 2018 to June 2023. Patients were categorized into the massive bleeding (MB) group and the non-massive bleeding (non-MB) group based on the occurrence of significant intraoperative bleeding. Preoperative laboratory parameters between the MB and non-MB groups were compared, and univariate and multivariate regression analyses were performed. ROC curves were performed to analyze the value of these parameters in distinguishing the MB and non-MB groups. RESULTS: In the MB group, body mass index (BMI), hemoglobin (Hb), platelet count (PLT), fibrinogen (Fib), and total protein (TP) levels were significantly lower than those in the non-MB group (p < 0.05). Conversely, prothrombin time (PT), international normalized ratio (INR), total bilirubin (TBIL), creatinine (CRE), blood urea nitrogen (BUN), the model for end-stage liver disease (MELD) score, length of stay, and hospital stay were significantly higher in the MB group compared to the non-MB group (p < 0.05). Univariate and multivariate logistic regression analyses revealed that preoperative BMI and Hb were independent risk factors for massive bleeding during liver transplantation. ROC curve analysis for predicting massive intraoperative bleeding showed that the area under the curve (AUC) of Hb was considerable (AUC: 0.83). CONCLUSIONS: Preoperative BMI and Hb levels are critical predictors of massive bleeding during liver transplantation, emphasizing the importance of proactive management based on these indicators for improved patient outcomes.

Novel splice variants of the bovine PCK1 gene.

Phosphoenolpyruvate carboxykinase 1 (PCK1), also named PEPCK-C, is a multiple-function gene that is involved in gluconeogenesis, glyceroneogenesis, reproduction, female fertility, and development of obesity and diabetes. How its many functions are regulated was largely unknown. Therefore, we investigated mRNA expression and possible splice variants of PCK1 by screening cDNA in nine tissues from Holstein bulls and cows. PCK1 mRNA was highly expressed in the liver, kidney, ovary and testis; expression levels were low in the heart, spleen, and lung tissues. Expression of this gene was not detected in skeletal muscle. This led to the discovery of five novel bovine splice variants, named PCK1-AS1-PCK1-AS5. In PCK1-AS1, 51 nucleotides in the interior of exon 2 were spliced out. In PCK1-AS2, exons 2 and 3 were altered by the alternative 3' and 5' splice sites, respectively. PCK1-AS3 was truncated from the 3' end of exon 2 to the 5' end of exon 4. In PCK1-AS4, exon 5 was completely spliced out. In PCK1-AS5, exons 5 and 6 and the 5' end of exon 7 were spliced out. These splice variants (PCK1-AS1-PCK1-AS5) potentially encoded shorter proteins (605, 546, 373, 246 and 274 amino acids, respectively), when compared to the complete protein (622 amino acids). Considering the functional domains of the PCK1 protein, it is likely that these splice variants considerably affect the function of this protein; alternative splicing could be one of the mechanisms by which the diverse functions of PCK1 are regulated.

The relationship between MHC-DRB1 gene second exon polymorphism and hydatidosis resistance of Chinese Merino (Sinkiang Junken type), Kazakh and Duolang sheep.

The present study aimed at detecting the association of ovine major histocompatibility complex class II (Ovar II) DRB1 gene second exon and susceptibility or resistance to hydatidosis in three sheep breeds of Sinkiang. The MHC-DRB1 second exon was amplified by polymerase chain reaction (PCR) from DNA samples of healthy sheep and sheep with hydatidosis. PCR products were characterized by the restriction fragment length polymorphism (RFLP) technique. Five restriction enzymes, Mval, Haelll, Sacl, Sacll, Hin1l, were used, yielding 14 alleles and 31 restriction patterns. Frequencies of patterns Mvalbc, Hin1lab, Sacllab, Haelllde, Haellldf, Haellldd (P < 0.01) in Kazakh sheep, Saclab (P < 0.05) in Duolang sheep, and Haelllab, Haelllce, Haelllde, Haelllee (P < 0.01) in Chinese Merino (Sinkiang Junken type) sheep, were significantly higher in healthy sheep compared with infected sheep. These results indicated a strong association between these patterns and hydatidosis resistance. In contrast, the frequencies of Mvalbb, Saclaa, Hinl lbb, Haelllef (P < 0.01) and Haelllab (P < 0.05) in Kazakh sheep, Saclbb, Haelllae, Hin1lab (P < 0.05), Haelllaa, Haelllbe, Haelllef (P < 0.01) in Duolang sheep, Sacllaa (P < 0.05) and Haelllbd, Hin1lbb, Haelllcf, Haelllef (P < 0.01) in Chinese Merino sheep (Sinkiang Junken type) were significantly lower in healthy sheep compared with infected sheep. This indicated a strong association between these patterns and hydatidosis susceptibility. In addition, sheep with the pattern of Haelllef demonstrated a high hydatidosis susceptibility (P < 0.01) in all three breeds, while sheep with the pattern Haelllde demonstrated significant hydatidosis resistance (P < 0.01) in Kazakh and Chinese Merino sheep (Sinkiang Junken type). These results suggest that the Ovar-DRB1 gene plays a role in resistance to hydatidosis infection in the three sheep breeds.

Molecular mimicry by herpes simplex virus-type 1: autoimmune disease after viral infection.

Viral infection is sometimes associated with the initiation or exacerbation of autoimmune disease, although the underlying mechanisms remain unclear. One proposed mechanism is that viral determinants that mimic host antigens trigger self-reactive T cell clones to destroy host tissue. An epitope expressed by a coat protein of herpes simplex virus-type 1 (HSV-1) KOS strain has now been shown to be recognized by autoreactive T cells that target corneal antigens in a murine model of autoimmune herpes stromal keratitis. Mutant HSV-1 viruses that lacked this epitope did not induce autoimmune disease. Thus, expression of molecular mimics can influence the development of autoimmune disease after viral infection.

Long non-coding RNA ROR regulated ABCB1 to induce cisplatin resistance in osteosarcoma by sponging miR-153-3p.

OBJECTIVE: Osteosarcoma (OS) is a common cancer among adolescences worldwide. Cisplatin is widely used to treat cancer, but many patients acquire chemoresistance over time. LncRNA regulator of reprogramming (ROR) has been reported to be associated with many malignancies, including OS. However, the function of ROR in cisplatin resistance and the biological mechanism of ROR remain unclear in OS. PATIENTS AND METHODS: The levels of ROR, miR-153-3p, and ABCB1 in cisplatin-resistant OS tissues and cells were detected by qRT-PCR and/or Western blot assay. The interactions of miR-153-3p, ROR, and ABCB1 were predicted by miRcode Tools and StarBase v2.0 online database, respectively, and validated by Dual-Luciferase reporter assay. The cell viability in different concentrations of DDP, cell proliferative capacity, migrated cells, and invaded cells were detected by MTT assay and transwell assay, respectively. RESULTS: The levels of ROR and ABCB1 were both drastically increased, and miR-153-3p was apparently decreased in relapsed OS tissues, MG63/DDP, and U2OS/DDP cells. MiRcode Tools and StarBase v2.0 predicted that miR-153-3p had complementary sequences with ROR and ABCB1 3'UTR, and following Dual-Luciferase reporter assay validated that miR-153-3p was a direct target of ROR and ABCB1. Moreover, ABCB1 overexpression alleviated the inhibitory effects on cell viability in different concentrations of DDP, cell proliferative capacity, migrated cells, and invaded cells in MG63/DDP and U2OS/DDP cells transfected with sh-ROR. ROR regulated ABCB1 expression in MG63/DDP and U2OS/DDP cells by sponging miR-153-3p. CONCLUSIONS: We found that ROR or ABCB1 knockdown can increase the cisplatin sensitivity of MG63/DDP and U2OS/DDP cells. ROR contributed to cisplatin resistance in OS via miR-153-3p/ABCB1 axis, unraveling a new regulatory network of chemoresistance in cisplatin-resistant OS cells and may provide a therapeutic target for OS patients.

Endoscopic ultrasonography in esophageal tuberculosis.

Esophageal tuberculosis is so rarely seen that it is difficult to identify by conventional endoscopy and computed tomography (CT), and is frequently misdiagnosed and inappropriately treated. To date, endoscopic ultrasonography (EUS) in the context of esophageal tuberculosis has only been sketchily described in a few case reports. In the present report we summarize and analyze four cases with regard to the EUS features of the lesions of esophageal tuberculosis. These features included heterogeneous or homogeneous hypoechoic masses in the esophageal wall, incrassation, interruption of esophageal adventitia, and mediastinal lymphadenitis. Most of the masses in the esophageal wall had hyperechoic spots and strips in the parenchyma. The esophageal lesions usually involved or had conglutinated with the enlarged mediastinal lymph nodes.

Interaction between PAK and nck: a template for Nck targets and role of PAK autophosphorylation.

The kinase PAK binds tightly to the SH3 domain of its partner PIX via a central proline-rich sequence. A different N-terminal sequence allows alphaPAK to bind an SH3 domain of the adaptor Nck. The Nck SH3[2] domain interacts equally with an 18-mer PAK-derived peptide and full-length alphaPAK. Detailed analysis of this binding by saturation substitution allows related Nck targets to be accurately identified from sequence characteristics alone. All Nck SH3[2] binding proteins, including PAK, NIK, synaptojanin, PRK2, and WIP, possess the motif PXXPXRXXS; in the case of PAK, serine phosphorylation at this site negatively regulates binding. We show that kinase autophosphorylation blocks binding by both Nck and PIX to alphaPAK, thus providing a mechanism to regulate PAK interactions with its SH3-containing partners. One cellular consequence of the regulatable binding of PAK is facilitation of its cycling between cytosolic and focal complex sites.

Pheromone signalling in Saccharomyces cerevisiae requires the small GTP-binding protein Cdc42p and its activator CDC24.

Pheromone signalling in Saccharomyces cerevisiae is mediated by the STE4-STE18 G-protein beta gamma subunits. A possible target for the subunits is Ste20p, whose structural homolog, the serine/threonine kinase PAK, is activated by GTP-binding p21s Cdc42 and Rac1. The putative Cdc42p-binding domain of Ste20p, expressed as a fusion protein, binds human and yeast GTP-binding Cdc42p. Cdc42p is required for alpha-factor-induced activation of FUS1.cdc24ts strains defective for Cdc42p GDP/GTP exchange show no pheromone induction at restrictive temperatures but are partially rescued by overexpression of Cdc42p, which is potentiated by Cdc42p12V mutants. Epistatic analysis indicates that CDC24 and CDC42 lie between STE4 and STE20 in the pathway. The two-hybrid system revealed that Ste4p interacts with Cdc24p. We propose that Cdc42p plays a pivotal role both in polarization of the cytoskeleton and in pheromone signalling.

Coupling of PAK-interacting exchange factor PIX to GIT1 promotes focal complex disassembly.

The p21-activated kinase PAK is targeted to focal complexes (FCs) through interactions with the SH3 domains of the PAK-interacting exchange factor PIX and Nck. PIX is a Rac GTP exchange factor that also binds the G-protein-coupled receptor kinase-interacting protein known as GIT1. Overexpression of GIT1 in fibroblasts or epithelial cells causes a loss of paxillin from FCs and stimulates cell motility. This is due to the direct interaction of a C-terminal 125-residue domain of GIT1 with paxillin, under the regulation of PIX. In its activated state, GIT1 can promote FC disassembly independent of actin-myosin contractile events. Additionally, GIT directly couples to a key component of FCs, focal adhesion kinase (FAK), via a conserved Spa2 homology domain. We propose that GIT1 and FAK cooperate to promote motility both by directly regulating focal complex dynamics and by the activation of Rac.

A conserved negative regulatory region in alphaPAK: inhibition of PAK kinases reveals their morphological roles downstream of Cdc42 and Rac1.

AlphaPAK in a constitutively active form can exert morphological effects (E. Manser, H.-Y. Huang, T.-H. Loo, X.-Q. Chen, J.-M. Dong, T. Leung, and L. Lim, Mol. Cell. Biol. 17:1129-1143, 1997) resembling those of Cdc42G12V. PAK family kinases, conserved from yeasts to humans, are directly activated by Cdc42 or Rac1 through interaction with a conserved N-terminal motif (corresponding to residues 71 to 137 in alphaPAK). alphaPAK mutants with substitutions in this motif that resulted in severely reduced Cdc42 binding can be recruited normally to Cdc42G12V-driven focal complexes. Mutation of residues in the C-terminal portion of the motif (residues 101 to 137), though not affecting Cdc42 binding, produced a constitutively active kinase, suggesting this to be a negative regulatory region. Indeed, a 67-residue polypeptide encoding alphaPAK83-149 potently inhibited GTPgammaS-bound Cdc42-mediated kinase activation of both alphaPAK and betaPAK. Coexpression of this PAK inhibitor with Cdc42G12V prevented the formation of peripheral actin microspikes and associated loss of stress fibers normally induced by the p21. Coexpression of PAK inhibitor with Rac1G12V also prevented loss of stress fibers but not ruffling induced by the p21. Coexpression of alphaPAK83-149 completely blocked the phenotypic effects of hyperactive alphaPAKL107F in promoting dissolution of focal adhesions and actin stress fibers. These results, coupled with previous observations with constitutively active PAK, demonstrate that these kinases play an important role downstream of Cdc42 and Rac1 in cytoskeletal reorganization.

Investigation of the Booroola (FecB) and Inverdale (FecX(I)) mutations in 21 prolific breeds and strains of sheep sampled in 13 countries.

Twenty-one of the world's prolific sheep breeds and strains were tested for the presence of the FecB mutation of BMPR1B and the FecX(I) mutation of BMP15. The breeds studied were Romanov (2 strains), Finn (2 strains), East Friesian, Teeswater, Blueface Leicester, Hu, Han, D'Man, Chios, Mountain Sheep (three breeds), German Whiteheaded Mutton, Lleyn, Loa, Galician, Barbados Blackbelly (pure and crossbred) and St. Croix. The FecB mutation was found in two breeds, Hu and Han from China, but not in any of the other breeds. The 12 Hu sheep sampled were all homozygous carriers of FecB (FecB(B)/FecB(B)) whereas the sample of 12 Han sheep included all three genotypes (FecB(B)/FecB(B), FecB(B)/FecB+, FecB+/FecB+) at frequencies of 0.33, 0.58 and 0.08, respectively. There was no evidence of FecX(I) in any of the breeds sampled.

Effect of Fas and Fas ligand deficiency in resistance of C57BL/6 mice to HSV-1 keratitis and chorioretinitis.

PURPOSE: To investigate the effect of Fas and Fas ligand (FasL) deficiency on the development of herpes stromal keratitis and on the von Szily model of herpes retinitis in C57BL/6 mice, which are ordinarily resistant to development of both of these herpetic diseases. METHODS: Anterior chamber inoculation of the right eye of each mouse with various titers of HSV-1 (KOS strain) was performed. Both eyes of each mouse were enucleated on postinoculation day 15 and processed for histopathologic examination. HSV-1 was inoculated into one cornea of other mice, and the severity of stromal keratitis was scored. RESULTS: Contralateral destructive chorioretinitis developed in susceptible Balb/cByj mice (19/23); ipsilateral chorioretinitis did not occur (0/23). Stromal keratitis developed in susceptible C.AL-20 mice (15/16). None of the C57BL/6 (0/10 for keratitis or 0/20 for retinitis) developed inflammation. Neither did B6.SMN.C3H.gld (FasL deficient; 0/12 or 0/28) or B6.MRL.lpr (Fas deficient; 0/11 or 0/34) mice (keratitis or contralateral chorioretinitis). Minimal scattering of inflammatory cells in the contralateral retina but not destructive chorioretinitis was observed in two C57BL/6, three B6.SMN.C3H.gld, and five B6.MRL.lpr mice. Few inflammatory cells were also found in the ipsilateral vitreous and vitreoretinal interface (but not destructive chorioretinitis) of all C57BL/6, two gld, and three lpr mice. CONCLUSIONS: Immune dysregulation secondary to deficiency in Fas or FasL system does not influence the resistance of the C57BL/6 mice to develop herpes simplex keratitis or destructive herpes simplex chorioretinitis.

Catecholic iron complexes as cytoprotective superoxide scavengers against hypoxia:reoxygenation injury in isolated hepatocytes.

Reactive oxygen species including superoxide radicals (O2-.) have been implicated in the pathogenesis of radiotherapy, ischemia-reperfusion injury, aging, and inflammatory diseases. In the present work, 2:1 catecholic iron complexes were found to be more effective than uncomplexed catechols at protecting hepatocytes against hypoxia:reoxygenation cell injury. They also decreased markedly the level of reactive oxygen species formed before cytotoxicity ensued. Furthermore, these catecholic iron complexes were also more effective than uncomplexed catechols at scavenging superoxide radicals generated both enzymatically and nonenzymatically. The superoxide radical scavenging activity of catecholic iron complexes seemed to correlate with the redox potential of catechols. These results suggest that cytoprotection by catechols may involve an initial chelation with iron to form a complex that is a much more effective superoxide radical scavenger than the catechol itself.

The prevention of ferric nitrilotriacetate-induced nephro- and hepatotoxicity by methylenedioxybenzene antioxidants.

Previously it was shown that methylenedioxybenzenes (MDBs), particularly isosafrole, were highly effective at preventing CCl4-induced liver necrosis in vivo (Z.S. Zhao, P.J. O'Brien, The prevention of CCl4-induced liver necrosis in mice by naturally occurring methylenedioxybenzenes, Toxicol. Appl. Pharmacol., 140 (1996) 411-421), probably as a result of forming metabolic intermediate complexes with cytochrome P450. In the following it was shown that pretreatment of mice with isosafrole also completely prevented ferric nitrilotriacetate (FeNTA)-induced renal necrosis and lipid peroxidation, even though metabolic activation by cytochrome P450 is not involved. The naturally occurring or synthetic MDBs that prevented CCl4 hepatotoxicity also prevented hepatocyte lipid peroxidation. induced by FeNTA, but other cytochrome P450 inhibitors were ineffective. These compounds, in decreasing order of antioxidant effectiveness, were sesamol, 4-t-butyl-methylenedioxybenzene, isosafrole, piperonyl butoxide and 4-bromo-methylenedioxybenzene and safrole, whereas, benzodioxole, 3,4-(methylenedioxy)-toluene and 1,2-(methylenedioxy)-4-nitrobenzene were ineffective. Pre-incubating the hepatocytes with P450 inhibitors decreased the protective effects of isosafrole, suggesting that the catecholic metabolites of MDBs were responsible for the antioxidant activity. A greater inhibition of FeNTA-induced lipid peroxidation by catecholic metabolites was observed. Since cytochrome P450 did not participate in FeNTA-induced hepatocyte or microsomal lipid peroxidation, it is likely that the antioxidant properties of MDBs or their catecholic metabolites also contribute to their in vivo protection against CCl4 or FeNTA-induced hepato- or nephrotoxicity.

Functional status of pancreatic islet in acute leukemia.

Using enzymatic assay and radioimmunoassay, we studied the functional status of pancreatic islet in 50 patients with acute leukemia. Oral glucose tolerance test and insulin and C peptide release were made in 40 patients before and after treatment. 14 patients who revealed diabetic curve and delayed insulin and C peptide release before treatment showed normal values in 6 after therapy. Five patients with impaired glucose tolerance and decreased insulin and C peptide release before treatment showed normalization of these parameters following therapy. Five patients with normal pretreatment values disclosed abnormal post-treatment results. The remaining 16 patients displayed normal results both before and after therapy. Anti-insulin antibodies were negative, and glucagon level was normal in all the 50 patients. The red cell insulin receptor binding rate analysed in 47 patients was significantly higher than in controls (P < 0.001). We considered that the disturbed glucose metabolism in acute leukemia was not uncommon mainly due to the dysfunction of pancreatic islet beta cells as a result of islet damage by leukemic cells, the effect of corticosteroid and chemotherapy and the preexisting diabetes. Impaired glucose metabolism had no influence on therapeutic effect.