[A clinical analysis of 22 patients with drug-induced liver injury caused by traditional Chinese medicine Periploca forrestii Schltr].

Objective: To investigate the clinical features, diagnosis, treatment, and prognosis of patients with liver injury caused by Periploca forrestii Schltr. Methods: A retrospective analysis was performed for the general data, clinical manifestations, and laboratory examinations of 22 patients who were diagnosed with liver injury caused by Periploca forrestii Schltr. from November 2014 to December 2015, and their clinical type was determined according to the classification criteria of drug-induced liver injury recommended by the Council for International Organizations of Medical Sciences. Results: There were 12 female and 10 male patients. The mean medication time ranged from 1 week to 2 months, and as for biochemical markers, there were mainly abnormalities in alanine aminotransferase(ALT), aspartate aminotransferase(AST), total bilirubin(TBil), alkaline phosphatase(ALP), and gamma-glutamyl transpeptidase(GGT). ALT and AST increased in all the patients, with mean levels of 676.68±481.11 U/L and 527.36±361.14 U/L, respectively; TBil increased to a mean level of 170.26±147.30 µmol/L in 19 patients; ALP increased to a mean level of 135.61±59.26 U/L in 13 patients; GGT increased to a mean level of 195.65±138.48 U/L in 20 patients. As for clinical typing, 18 patients had liver cell injury, none had cholestasis, 3 had a mixed type, and 1 had an unclassified type. One patient died and all the other patients fully recovered. Conclusion: Periploca forrestii Schltr. had complex constituents, and liver injury caused by this drug is mainly liver cell injury. The pathogenesis of liver injury caused by Periploca forrestii Schltr. is presumed to be related to patients' idiosyncratic reaction to its constituents.

Awareness and knowledge of Human papillomavirus (HPV) among ethnically diverse women varying in generation status.

Although Human papillomavirus (HPV) is a common sexually transmitted infection, there is limited knowledge of HPV with ethnic/racial minorities experiencing the greatest disparities. This cross-sectional study used the most recent available data from the California Health Interview Survey to assess disparities in awareness and knowledge of HPV among ethnically/racially diverse women varying in generation status (N = 19,928). Generation status emerged as a significant predictor of HPV awareness across ethnic/racial groups, with 1st generation Asian-Americans and 1st and 2nd generation Latinas reporting the least awareness when compared to same-generation White counterparts. Also, generation status was a significant predictor of HPV knowledge, but only for Asian-Americans. Regardless of ethnicity/race, 1st generation women reported lowest HPV knowledge when compared to 2nd and 3rd generation women. These findings underscore the importance of looking at differences within and across ethnic/racial groups to identify sub-groups at greatest risk for poor health outcomes. In particular, we found generation status to be an important yet often overlooked factor in the identification of health disparities.

Percutaneous closure of perimembranous ventricular septal defects with the eccentric Amplatzer device: multicenter follow-up study.

Using an Amplatzer membranous eccentric occluder, 186 patients with an average weight of 43.5 kg (range 12.5-77) underwent attempted catheter closure of a perimembranous venricular septal defect (PMVSD). Their age ranged from 3 to 51 years, with the an average age being 15.9 years. The patients were divided into three groups according to morphology of PMVSD: 106 patients with single PMVSD, 63 patients with single PMVSD with aneurysmatic formation, and 17 patients with multiple VSD with aneurysmatic formation. Using angiography, PMVSDs were measured to be between 2.5 and 12 mm, with an average of 5.1 mm. In the third group of patients, we did not measure the size of PMVSD and a device was selected according to the size of entry to the aneurysm. The device was successfully implanted in all patients. The immediate closure rate was 90% in the first group, increasing to 100% at 1 month and remained at that level during follow-up. The immediate closure rate in the second group was 98% and remained the same during follow-up. The immediate closure rate in the third group was 89% and during 1 year of follow-up remained the same. There was no clinical evidence of hemolysis and no incidence of device embolization or bacterial endocarditis after implantation. Before the procedure, all patients showed normal electrocardiogram (ECG) or left ventricle enlargement. After the procedure (at least 3 months later) ECG showed left anterior hemiblock (LAH) in nine patients, complete right bundle branch block in eight patients, and incomplete right bundle branch block in seven patients. A complete heart block (CHB) developed in 2 patients after the procedure (1.07%). The first patient developed LAH immediately after closure and CHB within 24 hours, The heart rate was 28 beats per minute. After treatment with steroids and atropine, CHB changed to sinus rhythm with LAH within 2 months. One year later, the ECG revealed the same findings. The second patient developed CHB immediately after the procedure and was on temporary pacing for 1 week. After 1 month, the patient recovered to sinus rhythm and ECG showed LAH.

Kinetics of the biosynthesis of complement subcomponent C1q by murine macrophages: LPS, immune complexes, and zymosan alone and in combination with interferon-gamma.

We investigated the effects of bacterial lipopolysaccharide (LPS), immune complexes (IC), and C3b opsonized zymosan (AZ) alone and in combination with interferon-gamma (IFN-gamma) priming on macrophage synthesis and secretion of C1q. Our results indicated that LPS, IC, and AZ alone stimulated C1q mRNA and secretion in the absence of IFN-gamma. The increase in mRNA accumulation was detectable after 3 h, peaked at 6 h and was maintained at constitutive levels for 24 h. There was a corresponding early burst of increased secretion of functional C1q after 3 to 6 h which declined rapidly after 9 to 24 h culture of LPS-stimulated macrophages. Priming of macrophages with IFN-gamma and simultaneous triggering with LPS, IC, or AZ produced additive rather than synergistic increases in C1q mRNA accumulation. These same agents inhibited constitutive secretion of C1q in the absence of IFN-gamma priming as determined by autoradiographic analysis of metabolically radiolabeled secretory C1q. Triggering of IFN-gamma primed macrophages with LPS, IC, or AZ also markedly suppressed the increased rate of C1q secretion induced by IFN-gamma in a dose-related fashion. A corresponding dose-dependent increased accumulation of endogenous C1q in cell lysates was detected by Western blot analysis of macrophages which had been stimulated by LPS, IC, or AZ alone or in combination with IFN-gamma. Our findings indicate that LPS as well as FcR and C3bR triggering agents stimulate early and sustained C1q synthesis accompanied by an early and short-lived burst of C1q secretion which rapidly diminished and results in an increased intracellular accumulation of C1q due to ongoing synthesis. IFN-gamma appeared to further amplify the same kinetics of increased C1q mRNA accumulation and decreased extracellular accumulation mediated by LPS, IC, and ZM. Our results suggest that LPS, IC, and AZ alone or in combination with IFN-gamma stimulate early C1q production to modulate macrophage effector functions followed by an inhibition of C1q secretion when the activation process has been culminated.

Reconstitution of a deficiency of AKR mouse macrophages for their response to lipid A activation for tumor cytotoxicity by complement subcomponent C1q: role of IFN-gamma.

C5-deficient AKR mouse macrophages were initially found to be refractory to activation by lipid A to mediate tumor cytotoxicity for P815 mastocytoma or L1210 mouse leukemia targets as compared with responsive C3H mouse macrophages. The lower level of tumor cytotoxicity by lipid A-activated AKR macrophages correlated with lower levels of cytotoxic nitric oxide generation as measured by nitrite end product accumulation. The refractory state of AKR macrophages was unexpectedly found to be independent of their C5 deficiency in that IFN-gamma reconstituted their response to activation by lipid A coincident with an increase in C1q mRNA synthesis. AKR macrophages were augmented in their lipid A activation by exogenous soluble C1q in the absence of IFN-gamma, which corresponded with an increased production of nitric oxide by C1q-reconstituted macrophages. In contrast, responsive C3H mouse macrophages with sufficient levels of C1q synthesis were inhibited by exogenous soluble monomeric C1q in their lipid A activation. Both AKR and C3H macrophages plated over immobilized C1q were inhibited in their lipid A activation for tumor cytotoxicity and nitric oxide generation. Our results provide evidence that C1q modulates macrophage activation by lipid A for nitric oxide-mediated tumor cytotoxicity under the influence of IFN-gamma, which stimulates C1q synthesis and secretion. These findings strongly suggest that macrophage synthesis of C1q, but not C5, is a prerequisite for their activation by lipid A.

Kinetics of the biosynthesis of complement subcomponent C1q by murine macrophages: effects of stimulation by interferon-gamma.

The effects of interferon-gamma (IFN-gamma) on the kinetics of biosynthesis of complement subcomponent C1q by mouse inflammatory peritoneal macrophages were determined. Stimulation of macrophages with various concentrations of IFN-gamma produced a dose-dependent increase in C1q mRNA accumulation which was detected as early as 3 h and sustained through 24 h, as determined by Northern blot analysis. A corresponding early increase in the extracellular accumulation of functional C1q was detected in culture supernatants after 3-9 h stimulation of macrophages with IFN-gamma that was sustained for 24-48 h as determined by a complement hemolytic assay. Autoradiographic analysis of [35S]methionine-labeled secretory C1q confirmed the protracted dose-dependent secretion of C1q by IFN-gamma stimulated macrophages during 24-48 h of culture. Western blot analysis of macrophage lysates indicated no significant changes in endogenous C1q levels following stimulation with IFN-gamma either after 3-9 h or 24-48 h when both C1q mRNA and extracellular accumulation were at their peak. Our results indicate that IFN-gamma promotes early and protracted mRNA accumulation and secretion of C1q by macrophages without intracellular accumulation, presumably due to the rapid rate of secretion of newly synthesized C1q. It is apparent that priming of macrophages with IFN-gamma provides a rapid and abundant source of secretory C1q for potential interaction with various macrophage triggering agents which also bind C1q.

Exogenous C1q reconstitutes a secondary deficiency of C5-deficient AKR mouse macrophages for FcR-dependent cellular cytotoxicity and phagocytosis.

Studies originally designed to assess the putative role of endogenous C5 in macrophage activation for antibody-dependent cellular cytotoxicity (ADCC) yielded unanticipated results. Resident and inflammatory peritoneal macrophages from C5-deficient AKR mice were found to have significantly lower capacity for FcR-dependent ADCC activation and phagocytosis of IgG-opsonized SRBC targets than did C5-competent C3HeB/FeJ (C3H) mice. Reconstitution of the ADCC response of AKR macrophages was accomplished initially with C5-sufficient C3H mouse serum, which suggested that endogenous C5 may be required for ADCC activation. However, further investigation largely eliminated C5 involvement in that a heat-labile component of C5-deficient AKR serum was shown to be active in the reconstitution of ADCC activation of AKR macrophages. Macrophages from AKR mice were found to have significantly lower levels of C1q mRNA synthesis, endogenous C1q levels, and C1q secretion than did C3H mouse macrophages as determined by Northern blot, Western blot, and presynthetic radiolabeling analysis, respectively. The addition of purified exogenous C1q to IgG-opsonized SRBC targets fully reconstituted ADCC activation for AKR inflammatory peritoneal macrophages to levels of normally FcR-responsive C3H macrophages. Similarly, exogenous C1q augmented FcR-dependent phagocytosis of AKR macrophages but had no effect on macrophages from responsive C3H mice. Our results indicate that AKR mice have a deficiency for FcR-dependent cellular cytotoxicity and phagocytosis that is related to their low potential for C1q synthesis and secretion rather than to their established genetic deficiency for C5 synthesis. We tentatively conclude that endogenous C1q is required as an accessory molecule for macrophage FcR-dependent effector functions and that C5 is not a prerequisite for ADCC activation.

Inhibitors of C1q biosynthesis suppress activation of murine macrophages for both antibody-independent and antibody-dependent tumor cytotoxicity.

The inhibitors of C1q biosynthesis and secretion, 3,4-dehydro-DL-proline (DHP) and 2,2'-dipyridyl, were previously shown to suppress murine macrophage FcR-dependent phagocytosis and cytolysis of IgG-opsonized RBC targets. Inasmuch as non-antibody macrophage activators also bind C1q to initiate C1 activation, we determined the effects of these same inhibitors of C1q biosynthesis on activation of macrophages for antibody-independent, nonspecific tumor cytotoxicity by lipid A and a variety of other non-antibody activators. Preexposure of mouse inflammatory peritoneal macrophages to either DHP (0.5 to 2.5 mM) or 2,2'-dipyridyl (0.1 to 0.3 mM) for 24 h produced a dose-related suppression of their response to activation by lipid A to mediate tumor cytotoxicity of L1210 mouse leukemia targets. Inhibition of C1q secretion by DHP-treated macrophages was confirmed both by a complement hemolytic assay and by autoradiographic analysis of [35S]methionine-labeled culture supernatants. DHP-treated macrophages were inhibited in their response to direct activation and triggering of IFN-gamma-primed macrophages by lipid A, Poly I:C, and cobra venom factor for tumor cytotoxicity. DHP inhibited macrophage activation for antibody-dependent cellular cytotoxicity of L1210 tumor targets mediated by antitumor target IgG. The addition of exogenous purified C1q (2 micrograms/ml) to macrophages after DHP treatment, reconstituted their response to activation for both antibody-independent and antibody-dependent tumor cytotoxicity. Our results indicate that C1q synthesis and secretion by effector macrophages is a prerequisite for the initiation of their activation by both immune complex and by non-antibody agents that also bind C1q. It now appears that macrophage-derived C1q may act as an auxiliary amplification signal for autocrine-like modulation of the initiation of macrophage activation by both the antibody-dependent and independent pathways.

Exogenous C1q reconstitutes resident but not inflammatory mouse peritoneal macrophages for Fc receptor-dependent cellular cytotoxicity and phagocytosis. Relationship to endogenous C1q availability.

Murine resident peritoneal macrophages (PM) were refractory to activation for antibody-dependent cellular cytotoxicity (ADCC) of SRBC targets as compared with either oil or thioglycollate-elicited inflammatory macrophages. Western blot analysis of macrophage cellular lysates indicated a direct correlation between the endogenous C1q levels and their innate response to activation for ADCC. Inflammatory PM had 7- to 14-fold higher C1q levels (ca. 23 to 45 ng C1q/100 micrograms protein) than resident PM (ca. 3 ng C1q/100 micrograms protein) as determined by densitometric scanning of blots. Purified exogenous mouse or human C1q were found to reconstitute the response of resident PM for ADCC mediated by C-activating mouse IgG2a or IgG2b mAb, but not by non-C-activating IgG1. Thioglycollate-elicited PM with highest endogenous C1q levels were unaffected by exogenous C1q, whereas oil-elicited PM with intermediate C1q levels were slightly augmented in their ADCC response by exogenous C1q. Augmentation of the resident PM response for ADCC activation was accomplished by either coincubation of effector macrophages with physiologic concentrations of C1q (0.5 to 4.0 micrograms/ml), IgG, and SRBC targets or by IgG and C1q preopsonized targets. FcR-dependent phagocytosis by resident PM was similarly reconstituted by exogenous C1q. The results indicate that resident macrophages with low potential for C1q biosynthesis and secretion were reconstituted by exogenous C1q in their FcR-dependent phagocytosis and ADCC, whereas inflammatory macrophages with sufficient endogenous C1q levels were largely unaffected. Thus C1q appears to have a pivotal mechanistic role in the initiation of macrophage activation for FcR-dependent effector functions.