[The short-term and long-term prognostic analysis in patients with chronic total occlusion acute non-ST segment elevation myocardial infarction].

Objectives: To investigate the clinical impacts of chronic total occlusion (CTO) in acute non-ST segment elevation myocardial infarction (NSTEMI) patients underwent primary percutaneous coronary intervention (PCI). Methods: A total of 2 271 acute NSTEMI patients underwent primary PCI from China Acute Myocardial Infarction Registry were enrolled in this study and divided into the CTO group and the non-CTO group according to the angiography. The primary endpoint was in-hospital mortality and mortality during a 2-year follow-up. The secondary endpoint was major adverse cardiovascular events (MACE) including revascularization, death, re-myocardial infarction, heart failure readmission, stroke and major bleeding. Results: Thirteen-point four percent of the total acute NSTEMI patients had concurrent CTO. In-hospital mortality (3.6% vs. 1.4%, P<0.01) and 2-year mortality (9.0% vs. 5.1%, P<0.01) were significantly higher in the CTO group than those in the non-CTO group, respectively. Multiple regression analyses showed that chronic obstructive pulmonary disease (HR 7.28, 95%CI 1.50-35.35, P=0.01) was an independent risk factor of in-hospital mortality, and advanced age (HR 1.04, 95%CI 1.01-1.07, P<0.01), and low levels of ejection fraction (HR 0.95, 95%CI 0.93-0.98, P<0.01) were independent risk factors of 2-year mortality. CTO (HR1.67, 95%CI 1.10-2.54, P=0.02) was an independent risk factor of revascularization, but not a risk factor of mortality. Conclusions: Although acute NSTEMI patients concurrent with CTO had higher mortality, CTO was only an independent risk factor of revascularization, but not of mortality. Advanced age and low levels of ejection fraction were independent risk factors of long-term death among acute NSTEMI patients.

[The acute and long-term outcome of patients with ST segment elevation myocardial infarction concurrent with chronic total occlusion].

Objective: To evaluate the acute and long-term outcome of patients with ST segment elevation myocardial infarction (STEMI) concurrent with chronic total occlusion (CTO) undergoing primary percutaneous coronary intervention (PCI). Methods: 11 905 STEMI patients from the China Acute Myocardial Infarction Registry were enrolled in this study and divided into CTO group and non-CTO group according to the angiography results of primary PCI. 1∶3 propensity score matching was used to match the patients between the two groups. The primary endpoint was in-hospital mortality and mortality at 1-year post PCI. The secondary endpoint was major adverse cardiovascular events (MACE) including death, re-myocardial infarction, revascularization, heart failure associated readmission, stroke and major bleeding at 1-year post PCI. Results: There were 931 CTO patients (7.8%) in this cohort (male=755 (81.1%), mean age (62.2±11.4 years)). The rest 10 974 patients were STEMI without CTO (male=8 829 (80.5%),mean age (60.0±11.8) years). After propensity score matching, 896 patients were enrolled in CTO group and 2 688 in non-CTO group. In-hospital mortality was significantly higher in the CTO group than in non-CTO group (4.2% vs. 2.4%, P=0.006). The ratio of all cause death, cardiac death, and MACE at 1-year follow up was also significantly higher in the CTO group than in non-CTO group (8.5% vs. 4.4%, P<0.001, 5.3% vs. 2.6%, P=0.001, 35.1% vs. 23.3%, P<0.001, respectively). Multiple regression analysis showed that CTO (HR=1.54, 95%CI 1.06-2.22, P=0.022), advanced age (HR=1.06, 95%CI 1.04-1.08, P<0.001), and previous heart failure history (HR=4.10, 95%CI 1.90-8.83, P<0.001) were independent risk factors of 1-year mortality. Conclusions: The in-hospital and 1-year mortality increased significantly in STEMI patients concurrent with CTO. CTO, advanced age and history of heart failure are independent risk factors of 1-year death among STEMI patients.

Association of Padua prediction score with in-hospital prognosis in COVID-19 patients.

BACKGROUND: Nearly 20% novel coronavirus disease 2019 (COVID-19) patients have abnormal coagulation function. Padua prediction score (PPS) is a validated tools for venous thromboembolism (VTE) risk assessment. However, its clinical value in COVID-19 patients' evaluation was unclear. METHODS: We prospectively evaluated the VTE risk of COVID-19 patients using PPS. Demographic and clinical data were collected. Association of PPS with 28-day mortality was analyzed by multivariate logistic regression and Kaplan-Meier analysis. RESULTS: Two hundred and seventy-four continuous patients were enrolled, with total mortality of 17.2%. Patients in high PPS group, with significantly abnormal coagulation, have a higher levels of interleukin 6 (25.27 vs. 2.55 pg/ml, P < 0.001), prophylactic anticoagulation rate (60.7% vs. 6.5%, P < 0.001) and mortality (40.5% vs. 5.9%, P < 0.001) when compared with that in low PPS group. Critical patients showed higher PPS (6 vs. 2 score, P < 0.001) than that in severe patients. Multivariate logistic regression revealed the independent risk factors of in-hospital mortality included high PPS [odds ratio (OR): 7.35, 95% confidence interval (CI): 3.08-16.01], increased interleukin-6 (OR: 11.79, 95% CI: 5.45-26.20) and elevated d-dimer (OR: 4.65, 95% CI: 1.15-12.15). Kaplan-Meier analysis indicated patients with higher PPS had a significant survival disadvantage. Prophylactic anticoagulation in higher PPS patients shows a mild advantage of mortality but without statistical significance (37.1% vs. 45.7%, P = 0.42). CONCLUSION: Higher PPS associated with in-hospital poor prognosis in COVID-19 patients. Prophylactic anticoagulation showed a mild advantage of mortality in COVID-19 patients with higher PPS, but it remain to need further investigation.

[Clinical features of atrial fibrillation complicated with occult pulmonary embolism].

Objective: To investigate the clinical features of patients with atrial fibrillation (AF) and occult pulmonary embolism (PE). Methods: Clinical data of 67 AF patients complicated with PE (AP group) admitted to the Tianjin Chest hospital from January 2014 to July 2018 were analyzed. A total of 70 AF patients without PE served as the control group (AF group). The AP group was divided into 2 subgroups: AF with occult PE (OPE subgroup) and symptomatic PE (SPE subgroup). The clinical features of OPE subgroup were analyzed. Results: The levels of leukocyte counts, C-reactive protein, D-dimer and N-terminal pro-brain natriuretic peptide in the AP group were (7.4±2.7)×10(9)/L, 18.0 (5.9, 65.7) mg/L, 2.61 (1.63, 3.72) mg/L and 1 657 (600, 3 172)ng/L, which were higher than those in the AF group (P=0.008, P<0.001, P<0.001 and P=0.002, respectively); Arterial oxygen pressure in the AP group was (74±13) mmHg (1 mmHg=0.133 kPa), lower than the AF group (P<0.001); and pulmonary artery systolic pressure was (46±16) mmHg, higher than the AF group (P<0.001). In the OPE subgroup, 12 cases (66.7%) were complicated with localized pulmonary embolism, more than those in the SPE subgroup (P=0.008), and pulmonary artery systolic pressure was (39±11) mmHg, which was lower than the SPE subgroup (P<0.001); the levels of leukocyte counts, C-reactive protein and D-dimer in the OPE subgroup were (7.6±2.3)×10(9)/L, 18.3 (3.7, 67.3) mg/L and 2.31 (1.27, 3.61) mg/L, higher than the AF group (all P<0.05); arterial oxygen pressure in the OPE subgroup was (75±12) mmHg, lower than the AF group (P<0.05). Conclusions: Occult pulmonary embolism is not uncommon in patients with atrial fibrillation. Comparing with AF group, the OPE subgroup was associated with increased levels of inflammatory markers and D-dimer and hypoxemia.

Handgrip strength is associated with dyspnoea and functional exercise capacity in male patients with stable COPD.

Handgrip strength (HGS) is widely used to evaluate nutrition and adverse outcomes in several diseases. However, the relationship between HGS and the parameters of chronic obstructive pulmonary disease (COPD) are not known. To evaluate HGS in male patients with stable COPD, and to assess its correlation with dyspnoea and functional exercise capacity. We recruited 116 male out-patients with stable COPD from a general hospital in China between February and December 2017. For each patient, we recorded demographic characteristics and measured pulmonary function, dyspnoea, exercise capacity, body composition and HGS. HGS had a significantly positive correlation with muscle mass, lung function, and 6-min walking distance (6MWD) and a negative correlation with the modified Medical Research Council dyspnoea score. Multiple linear regression analysis showed that combining age, fat-free mass (FFM), 6MWD and duration of COPD accounted for 43.1% of the total variance in HGS. HGS was correlated with dyspnoea and exercise capacity. Aging and disease could alter upper limb muscle strength in COPD patients. Hence, HGS might be a simple method for assessing muscle function and for identifying patients with a noticeable reduction in HGS, who will need early, multidisciplinary intervention. .

GLI2 induces PDGFRB expression and modulates cancer stem cell properties of gastric cancer.

OBJECTIVE: In this study, we aimed to investigate the downstream effector of GLI2 in gastric cancer (GC) and their regulative effect on cancer stem cell (CSC) properties of GC. MATERIALS AND METHODS: Bioinformatic data mining was performed in TCGA-Stomach Adenocarcinoma (STAD), as well as in Kaplan-Meier plotter. Moderate-differentiated GC cell line SGC-7901 and poor-differentiated GC cell line MKN-45 were used as in-vitro model to investigate the regulative effect of GLI2 on PDGFRB expression. MKN-45 cells were further used to explore the effect of GLI2 shRNA or PDGFRB shRNA on CSC properties of the cells. RESULTS: Bioinformatic results showed that GLI2 is usually upregulated in GC tissues than in normal tissues, and high GLI2 expression is associated with unfavorable first progression free survival (PFS) and also worse overall survival (OS) in patients with GC. PDGFRB is co-upregulated with GLI2 in GC and its promoter region contains a putative GLI2 binding site. The results of dual luciferase assay confirmed this binding site. Enforced GLI2 expression elevated PDGFRB expression at both mRNA and protein level. GLI2 or PDGFRB knockdown showed similar effect on reducing spheroid colony formation and on reducing the expression of CSC related genes, including CD44, Nanog, and Oct4 in MKN-45 cells. CONCLUSIONS: High GLI2 or PDGFRB expression is associated with unfavorable survival in GC patients. GLI2 can induce PDGFRB expression in GC cells via directly binding to its promoter. In addition, the GLI2-PDGFRB axis might be an important signaling pathway modulating CSC properties of GC cells.

Late gestational liver dysfunction and its impact on pregnancy outcomes.

OBJECTIVE: The aim of this study was to investigate the impacts of late gestational liver dysfunction and its impact on pregnancy outcomes. MATERIALS AND METHODS: The patients hospitalized for liver dysfunction in their late pregnancy between 2010-2012 were set as the observation group, and the pregnant women with normal liver function at the same period were randomly selected and set as the control group. The impacts towards the pregnancy outcomes were compared between these two groups and the impacts of different-degree transaminase increasing towards the pregnancy outcome were analyzed. RESULTS: The incidence rates of cesarean section, post-partum hemorrhage, fetal distress, premature birth, premature rupture of membranes (PROM) of the observation group and the transaminase-severely-increased group (the severe group) were higher, and the differences were statistically significant (p < 0.01 or < 0.05); while only the cesarean rate of the mild and moderate group was significantly different from the control group (p < 0.01 or < 0.05). The ratios of intrahepatic cholestasis in pregnancy (ICP), gestational hypertension + HELLP syndrome, acute fatty liver in pregnancy (AFLP) of the severe group were higher than the mild and moderate group, and the differences were statistically significant; the non-alcoholic fatty liver disease (NAFLD) group and the unknown cause group mainly showed a mildly increased transaminase; the distributions of viral hepatitis in pregnancy (VHP), post-viral-hepatitis-B cirrhosis, biliary tract disease, and infected toxic liver dysfunction in different-degree increased transaminase groups had no significant difference. CONCLUSIONS: Liver dysfunction in later pregnancy, especially with severe transaminase increase, might significantly increase the risk of adverse maternal events. The major causes of severe liver dysfunction in late pregnancy were ICP, gestational hypertensive disorders, and AFLP.

[Impact of long-term continuous positive airway pressure treatment for patients with obstructive sleep apnea syndrome].

OBJECTIVE: To investigate the long-term efficacy of continuous positive airway pressure (CPAP) treatment for patients with obstructive sleep apnea syndrome (OSAS). METHODS: This case control study was performed among 154 patients with moderate or severe OSAS between September 2009 and September 2014. Patients were divided into treatment group (n=66, 53 patients with hypertension) and control group (n=88, 67 patients with hypertension). The long-term efficacy of CPAP treatment on clinical events and blood pressure was evaluated. RESULTS: The combined incidence of death, myocardial infarction, coronary revascularization and stroke events was 1.5% (1/66) in treatment group and 11.4% (10/88) in control group (P<0.05). CPAP treatment also led to more significant reduction in systolic blood pressure ((12.24±18.06) mmHg(1 mmHg=0.133 kPa) to (4.24±16.63) mmHg, P<0.05) in the patients with hypertension in these two groups. CONCLUSIONS: CPAP treatment could reduce the risk of cardiovascular and neurovascular events for patients with moderate or severe OSAS.

Expression of neurotrophin-4/5 in Streptococcus pneumoniae meningitis.

This study aims to investigate the expression of neurotrophin-4/5 (NT-4/5) in the pallium and hippocampus in juvenile rats with intraventricular injection of Streptococcus pneumoniae. We used 40 SPF SD rats (3 weeks old, regardless of gender) in this study. We drew 50 µL cerebrospinal fluid, and then, we injected 50 µL normal saline and S. pneumoniae suspension (10(8) CFU/mL) in the brain pool (normal control group and infection group, respectively). After 24 h, the cerebrospinal fluid was collected for bacterial culture and white blood cell count. The immunohistochemical staining was conducted at the day 1, 2, and 5, and the expression of NT-4/5 in rat brain tissue was observed. Compared with the normal control group, NT-4/5 expression in the pallium and hippocampus of rats in the 24-h infection group was significantly increased (both P < 0.05). NT-4/5 expression in the pallium and hippocampus in the 5-day infection group was significantly lower than that in the 24-h infection group (P < 0.05), and they were significantly higher than the normal control group (P < 0.05). After intraventricular injection of S. pneumoniae, the expression of NT-4/5 in the pallium and hippocampus in juvenile rats was increased, especially during early disease course.

Statin administration does not improve the mobilization of very small embryonic-like stem cells (VSELs) in contrast to resveratrol treatment in a murine model of acute myocardial infarction.

We have found that short-term statin treatment plus stem cell transplantation in acutely infarcted hearts improves cardiac function because statins promote the efficacy of cellular cardiomyoplasty. Autologous Sca-1(+)Lin(-)CD45(-)(CXCR(+)) very small embryonic-like stem cell (VSEL) mobilization in acute myocardial infarction (AMI) correlates with the preservation of cardiac function. Whether short-term atorvastatin (Ator) can enhance the mobilization or recruitment of VSELs in AMI is still unclear. We divided mice into 4 groups: 1) sham; 2) AMI; 3) AMI+resveratrol (RSV) as a positive control; and 4) AMI+Ator. There was an increase in the circulating VSEL/full population of leukocytes (FPL) ratio 48 hours after AMI, and AMI+RSV increased it further. Ator administration did not increase the VSEL/FPL ratio. The cardiac stromal cell-derived factor-1 (SDF-1) and SDF-1alpha levels were in agreement with the results of VSEL mobilization. One week after AMI, more Sca-1(+)CXCR(+) cells were recruited to the myocardium of AMI+RSV mice but not AMI+Ator mice. Short-term Ator administration failed to upregulate cardiac SDF-1 and could not enhance the recruitment of VSELs early after AMI.

Dynamics of Sept4 expression in fibrotic livers of mice infected with Schistosoma japonicum.

n order to investigate the dynamics of Septin4 (Sept4) expression and its function in the formation of fibrotic livers in mice infected with Schistosoma japonicum, we constructed the mouse model of S. japonicum egg-induced liver fibrosis for 24 weeks. Immunohistochemical staining, qRT-PCR and Western blot were used to detect the expression of Sept4 and α-smooth muscle actin (α-SMA). We found Sept4 localized in the perisinusoidal space where hepatic stellate cells (HSCs) distribute in the periphery of circumoval granulomas and the portal venule. The expression of Sept4 and α-SMA had a similar significant tendency of an up-regulation to a peak at 12 weeks post-infection (p.i.) followed by a down-regulation. At 24 weeks p.i. both were at a low level. These results suggest that Sept4 and α-SMA may interact together in HSCs. Based on this evidence, we hypothesize that Sept4 seems to be involved in the formation of inflammatory granulomata and subsequent liver fibrosis by regulating HSCs activation.

Effects of enzyme addition on the nutritive value of broiler diets containing hulled or dehulled Chinese double-low rapeseed meals.

An in vitro and a feeding trial was conducted to investigate the effect of fibre-degrading enzymes A (xylanase + ß-glucanase), B (xylanase) and C (xylanase + cellulase) on the nutritive value of broiler diets containing either hulled (22.5% and 23.5% for 4­21 days and 22­42 days of age, respectively) or dehulled (20% and 21.5%) Chinese double-low rapeseed meals (DLRM). Overall, in vitro digestibility of dry matter (DM) or neutral digestibility fibre (NDF) did not differ (p > 0.05) because of meal types; both crude protein (CP) and NDF digestibility was improved (p < 0.05) because of addition of enzymes B or C either to hulled or dehulled DLRM diets. Birds fed dehulled DLRM diets had a higher (p < 0.05) growth rate, feed efficiency and lower (p < 0.05) feed intake than those fed hulled DLRM diets during the overall phase. Enzyme C addition to dehulled DLRM diets resulted in improved (p < 0.05) growth rate and feed efficiency during 4­21 days of age. Enzymes A and B addition elicited a positive response in feed intake and weight gain (p < 0.05), respectively, but did not affect (p > 0.05) feed efficiency. It would appear that the nutritive value of broiler diets containing Chinese DLRM could be improved by appropriate xylanase-based enzymes. Responses of broilers to fibre-degrading enzymes could be highlighted by hull removal of fed DLRM.

Implantation of BM cells transfected with phVEGF165 enhances functional improvement of the infarcted heart.

BACKGROUND: Experimental data have suggested that BM-cell implantation can improve infarcted cardiac function. However, the number of implanted cells that survive is still unknown. The present study was performed to investigate whether implantation of autologous BM mononuclear cells (BM-MNCs) transfected with phVEGF165 can increase the number of surviving implanted cells, and enhance functional improvement of infarcted hearts in rabbits. METHODS: Acute myocardial infarction (AMI) in rabbits was replicated by ligating the left anterior descending coronary artery, and animals were randomly divided into the following three groups: I AMI control group (n=7); II BM-MNCs transfected with phVEGF165 implantation group (n=7); III BM-MNCs implantation group (n=7). In addition, sham-operated (n=5) rabbits were randomly selected to serve as a non-infarction control group (VI). Animals for cell implantation received intramyocardial injections of autologous BM-MNCs 14 days after AMI. Echocardiography and hemodynamic studies were performed to evaluate cardiac structure and function 28 days after implantation. The implanted sites were examined using immunofluorescence to identify the phenotypes and number of the labelled cells. Reverse transcriptase (RT)-PCR and Western blot analysis were performed to detect the expression of hVEGF165 gene and VEGF165 protein respectively. RESULTS: Failed cardiac function produced by AMI was significantly improved in Groups II and III 28 days after cell implantation. BM-MNCs transfected with phVEGF165 implantation conferred a further improvement of cardiac function, with significant changes of all assessed parameters when compared with BM-MNCs implantation alone (all P<0.05). The implanted cells demonstrated myogenic differentiation with the expression of Troponin T and organized contractile proteins. The positive staining for Factor VIII-related Ag indicated the induction of angiogenesis in the infarct area. The percentage of Brdu-positive myocyte, endothelial cells was 75+/-%, 34.1+/-4.6% in Group II, significantly higher than that in Group III(51+/-7%, 11.3+/-2.5% respectively, P<0.05). RT-PCR analysis demonstrated exclusive expression of hVEGF165 gene in Group II, and Western blot showed the expression of VEGF165 protein was significantly higher in Group II than in Group III (P<0.05). CONCLUSIONS: Implantation of BM-MNCs transfected with phVEGF165 can increase the number of implanted cells surviving, and enhance the impaired cardiac function after AMI.

Targeting signal 1 through CD45RB synergizes with CD40 ligand blockade and promotes long term engraftment and tolerance in stringent transplant models.

The induction and maintenance of allograft tolerance is a daunting challenge. Although combined blockade of CD28 and CD40 ligand (CD40L)-costimulatory pathways prevents allograft rejection in some murine models, this strategy is unable to sustain engraftment in the most immunogenic allograft and strain combinations. By targeting T cell activation signals 1 and 2 with the novel combination of anti-CD45RB and anti-CD40L, we now demonstrate potent enhancement of engraftment in C57BL/6 recipients that are relatively resistant to costimulatory blockade. This combination significantly augments the induction of tolerance to islet allografts and dramatically prolongs primary skin allograft survival. Compared with either agent alone, anti-CD45RB plus anti-CD40L inhibits periislet infiltration by CD8 cells, B cells, and monocytes; inhibits Th1 cytokines; and increases Th2 cytokine expression within the graft. These data indicate that interference with activation signals one and two may provide synergy essential for prolonged engraftment in situations where costimulatory blockade is only partially effective.

Human allogeneic vascular rejection after arterial transplantation and peripheral lymphoid reconstitution in severe combined immunodeficient mice.

BACKGROUND: Interspecies differences create important shortcomings in existing animal models used to describe in vivo events responsible for allograft rejection. Alloimmune destruction of human dermal microvessels, histologically consistent with rejection, has been demonstrated in human skin-grafted severe combined immunodeficient (SCID) mice receiving allogeneic human peripheral blood mononuclear cells (PBMC). We have now documented human alloimmune injury in a vascularized, SCID-human arterial transplantation model. METHODS: Fresh human artery was used to replace the CB.17 SCID/beige mouse infrarenal aorta. Seven days later, 3x10(8) human PBMC were administered intraperitoneally, and lymphocyte engraftment was considered successful when circulating human CD3+ cells were later identified in peripheral blood. RESULTS: Forty-six of 49 (94%) mice undergoing transplantation survived, including 14 controls with arterial grafts receiving no PBMC. Twenty-eight of 32 mice demonstrated circulating human CD3+ cells, 14 days after PBMC administration. Animals were killed at 14, 21, or 28 days after receiving allogeneic PBMC, and arteries were recovered for histology and immunohistology. All 14 control mice had patent transplanted grafts with normal vascular histology and no lymphoid infiltration. Damage to transplanted arteries among lymphocyte-engrafted mice was apparent by 14 and 21 days in some animals, whereas 16 of 22 exhibited moderate to severe intimal, medial, and/or adventitial lymphocytic infiltration with intimal expansion by day 28. The infiltrate consisted of HLA-A, -B, -C+, and -DR+, human CD3+ cells, approximately equally distributed as CD4+ and CD8+ subsets. Some infiltrating lymphocytes were cytolytic cells as demonstrated by perforin staining. The endothelium of transplanted human arteries exhibited endothelialitis, and the endothelial cells stained intensely with anti-HLA-A, -B, -C and anti-HLA-DR antibodies. The expanded intima was predominantly smooth muscle cells, staining positively for smooth muscle alpha-actin, HLA-A, -B, -C and HLA-DR. Medial necrosis was not observed. CONCLUSION: The results provide evidence of alloimmune-mediated vascular rejection in this human arterial transplantation model.

Thy-1 antigen expression by cells in the osteoblast lineage.

Identification of surface markers involved in osteoblast differentiation provides a method to isolate osteoblasts at various stages of maturation. In this study, we examined expression of the T lymphocyte differentiation antigen, Thy-1, by osteoblastic cells from different species. Murine skeletal progenitor, neonatal calvarial, and adult bone cells (ABCs) were selected to represent osteoblasts at distinct stages of maturation. Flow cytometric analysis showed that Thy-1 expression was undetectable on the progenitor cells (mouse limb bud clones 14 and 17), appeared on calvarial cells (45%+), and was decreased on ABCs (< 10%+). Thy-1 was also detected in situ on osteoblastic cells in mouse calvariae. Thy-1 mRNA expression correlated with cell surface expression. Antigen expression was markedly increased during the cells' proliferative phase in culture. Furthermore, examination of primary rat and human osteoblast-like cells revealed that significant levels of Thy-1 were also expressed on those cells derived from subconfluent culture. This study indicates that osteoblasts express Thy-1 antigen and that its expression is maximal at their earliest stage of maturation, during the proliferative phase, and then declines as the cells mature. In a role similar to the one it plays in the hematopoietic system, Thy-1 antigen may be useful as a differentiation marker in following the development of the osteoblast.

The immune response: the efferent arm.

Once naive T cells encounter antigen, they become primed effector cells. The scope of effector functions mediated by these cells defines the efferent arm of the immune response. The change from naive to primed effector cell is known as adaptive immunity and takes 2 forms: cell mediated, in which T cells mediate effector function, and humoral, in which antibodies are the effector molecules. There are 3 types of effector T cells: inflammatory CD4 T cells, which activate macrophages; helper CD4 T cells, which help B lymphocytes produce antibody; and cytotoxic CD8 T cells, which kill their target cells. The interaction of primed effector cells with their targets results in phenotypic changes in the cells and the secretion of cytokines. These cytokines may be secreted by the primed effector T cell, the target cell, or both. Cytokines function in either autocrine (secreted and used by the same cell) or paracrine (secreted by 1 cell and used by a different cell) circuits and have marked regulatory effects on cells in both the immune and skeletal systems. Many of these cytokines, which were once thought to be products exclusively of immune cells, are now known to be produced by cells of the skeletal system. Both the specific and nonspecific components of the immune response have profound effects on remodeling of the musculoskeletal system during normal and pathologic states.

Identification of an inducible surface molecule specific to fusing macrophages.

Multinucleated giant cells and osteoclasts arise through the fusion of mononuclear phagocyte precursors. To elucidate the mechanism by which cells of monocytic lineage fuse and differentiate into giant cells and osteoclasts, we hypothesized that, as with other cell fusion events, specific surface molecules mediate the adhesion/fusion process. It has been observed that macrophages can be induced to fuse with one another in response to specific stimuli or when placed in a specific microenvironment. The formation of giant cells is primarily associated with chronic inflammatory reactions and tumors, while osteoclasts differentiate on bone which they resorb. The fact that, under normal conditions, macrophages and monocytes fail to fuse in regions and tissues where they are present in large numbers suggests the regulated and transient expression of potential fusion molecules. To identify such a fusion-associated molecule, we established a macrophage fusion assay and generated monoclonal antibodies (mAbs) that alter the fusion of macrophages in vitro. We selected four mAbs that each had the ability to block the fusion but not the aggregation of macrophages in vitro. All four antibodies recognize surface proteins of 150 kDa. The expression of the antigens recognized by all four mAbs is restricted to macrophages that have been induced to fuse in vitro and in vivo and is inducible, transient, and regulated, as neither nonfusing macrophages nor macrophages fused in vitro express these antigens. These results support the hypothesis that macrophage fusion is mediated by specific fusion/adhesion molecules and also provide a means to study the molecular mechanisms of macrophage fusion.