Functional differences between two Fc receptor ITAM signaling motifs

Most Ig receptors exist as multi-subunit complexes with a unique ligand binding alpha chain and a common signaling FcR gamma-chain. The myeloid Fc gamma RIIa (CD32) appears unique among FcR because both ligand- binding and signaling capacity are found in the alpha chain. Within the cytoplasmic tails of Fc gamma RIIa and FcR gamma-chain similar, but not identical, activatory motifs (ITAMs) have been defined, in which tyrosines play an important role. Previously, Fc gamma RIIa-ITAM was shown to be critical for both proximal and distal activatory functions in IIA1.6 B-cell transfectants. Triggering of interleukin-2 (IL-2) release and antigen presentation was absent in Fc gamma RIIa, but not in FcR gamma-chain receptor complexes. We now assessed the capacity of Fc gamma RIIa wild-type and Fc gamma RIIa/gamma chimeric molecules to trigger IL-2 production and antigen presentation by B cells. Both of these functions could solely be triggered by receptors containing the FcRIIa was capable of functional interaction with FcR gamma-chain, thus reconstituting the capacity to trigger IL-2 release and antigen presentation. These data document qualitative differences between Fc receptor ITAMs.     

Cumulative conception and live birth rates after oocyte donation: implications regarding endometrial receptivity

The purpose of the present study was to determine the cumulative likelihood of pregnancy success after repetitive cycles of oocyte donation and specifically to examine the influence of recipient age and diagnosis upon the cumulative likelihood of pregnancy in an effort to identify any potential subgroup of recipients who might have diminished endometrial receptivity. We retrospectively analysed the outcome of 418 consecutive embryo transfer cycles among 276 recipients of oocyte donation in our institution. We analysed clinical pregnancy and delivery rates in the recipients divided by age groups and diagnostic groups. For the purpose of life-table analysis, only cycles prior to and including the first cycle producing a successful pregnancy were included. Frozen-thawed embryo transfers were not included in the analysis. The overall clinical pregnancy rate was 36.2% (95% CI 31-41%) and the cumulative pregnancy rate after four cycles was 87.9%. The overall delivery rate was 29.3% (95% CI 25-33%) and the cumulative delivery rate after four cycles was 86.1%. There were no statistically significant differences in any of the rates attributable to recipient age or diagnosis. No decline in per cycle success was noted over consecutive cycles. We conclude that neither recipient age nor diagnosis plays a substantial role in the success of oocyte donation, implying that endometrial receptivity is unaltered by age or diagnosis. Furthermore, up to four successive cycles of oocyte donation are associated with the same probability of success.      

Luteinizing hormone response to gonadotrophin-releasing hormone in normal women undergoing ovulation induction with urinary or recombinant follicle stimulating hormone

Oestradiol enhances pituitary sensitivity to gonadotrophin-releasing hormone (GnRH) in normal women, while in women undergoing ovulation induction the putative factor gonadotrophin surge attenuating factor (GnSAF) attenuates the response of luteinizing hormone (LH) to GnRH. To study the relationships between oestradiol and GnSAF during ovulation induction, 15 normally ovulating women were investigated in an untreated spontaneous cycle (control, first cycle), in a cycle treated with daily i.m. injections of 225 IU urinary follicle-stimulating hormone (FSH) (Metrodin HP, uFSH cycle) and in a cycle treated with daily s.c. injections of 225 IU recombinant FSH (Gonal-F, rFSH cycle). Treatment with FSH started on cycle day 2. The women during the second and third cycle were allocated to the two treatments in an alternate way. One woman who became pregnant during the first treatment cycle (rFSH) was excluded from the study. In all cycles, an i.v. injection of 10 microg GnRH was given to the women (n = 14) daily from days 2-7 as well as from the day on which the leading follicle was 14 mm in diameter (day V) until mid-cycle (n = 7). The response of LH to GnRH at 30 min (deltaLH), representing pituitary sensitivity, was calculated. In the spontaneous (control) cycles, deltaLH values increased significantly only during the late follicular phase, i.e. from day V to mid-cycle, at which time they were correlated significantly with serum oestradiol values (r = 0.554, P < 0.01). Initially during the early follicular phase in the uFSH and the rFSH cycles, deltaLH values showed a significant decline which was not related to oestradiol (increased GnSAF bioactivity). Then, deltaLH values increased significantly on cycle day 7 and further on day v with no change thereafter up to mid- cycle. On these two days, deltaLH values were correlated significantly with serum oestradiol values (r = 0.587 and r = 0.652 respectively, P < 0.05). During the pre-ovulatory period, deltaLH values in the FSH cycles were significantly lower than in the spontaneous cycles. Significantly higher serum FSH values were achieved during treatment with uFSH than rFSH. However, serum values of oestradiol, immunoreactive inhibin, and deltaLH as well as the number of follicles > or = 12 mm in diameter did not differ significantly between the two FSH preparations. These results suggest that in women undergoing ovulation induction with FSH, oestradiol enhances pituitary sensitivity to GnRH, while GnSAF exerts antagonistic effects. The rFSH used in this study (Gonal-F) was at least as effective as the uFSH preparation (Metrodin-HP) in inducing multiple follicular maturation in normally cycling women.      

Effect of gonadotrophin-releasing hormone agonist treatment on growth hormone secretion in women with polycystic ovarian syndrome

The suppression of the pituitary-gonadal axis by the administration of gonadotrophin-releasing hormone agonists (GnRH-a) is used occasionally as an adjunct therapy with gonadotrophins for ovulation induction in women with polycystic ovarian syndrome (PCOS). A number of recent clinical studies have suggested that women with polycystic ovaries (PCO) may have disturbances of normal growth hormone (GH) kinetics and alterations in the GH/insulin-like growth factor (IGF)-I system. The purpose of this study was to determine the effect of GnRH-a administration on GH-releasing hormone (GHRH)-stimulated GH release in women with PCOS. Eight women with PCO and six control women were studied before and after 2 months of treatment with the long acting GnRH-a triptoreline (3.75 mg monthly injections). GHRH was given as a single i.v. injection and blood samples for GH measurements were obtained at -15, 0, 30, 60, 90 and 120 min. The GH responses were expressed as the area under the curve (AUC) or the differences from the basal value (delta(max)). The GH response to GHRH (mean +/- SEM) was lower in women with PCO (AUC 114.9 +/- 43.1 versus 206.2 +/- 28.7 ng/ml/120 min, P < 0.05 and delta(max) 31.6 +/- 8.2 versus 49.4 +/- 5.8 ng/ml, P < 0.05). After treatment with the GnRH-a, the GH response to GHRH was significantly smaller than before treatment in both groups (PCO AUC 34.6 +/- 9.0 ng/ml/120 min and delta(max) 12.4 +/- 3.1 ng/ml; controls AUC 148.8 +/- 28.4 ng/ml/120 min and delta(max) 31.2 +/- 6.1 ng/ml), but the PCO group had a significantly smaller response. These data demonstrate that women with PCO have a reduced GH response to GHRH compared with normal controls and that GnRH-a administration causes a further GH reduction in both groups. Women with PCO have a greater suppression of GH response to GHRH during treatment with GnRH-a. This suggests that a different level of sensitivity in the somatotrophic axis exists in PCOS.      

Differential chemokine response of murine macrophages stimulated with cytokines and infected with Listeria monocytogenes

During inflammatory processes the infected macrophage is a rich source of chemokines which induce infiltration of leukocytes to the site of infection. We investigated the regulation of chemokine production by murine macrophages in response to infection with the intracellular bacterial pathogen, Listeria monocytogenes. As a source of quiescent macrophages, murine bone marrow-derived macrophages (BMM) cultured under serum-free conditions were used. With RT-PCR, we detected induction of RNA message for the chemokines macrophage inflammatory protein (MIP)-2, KC, MIP-1alpha, MIP-1beta, IFN-gamma-inducible protein- 10 and RANTES in L. monocytogenes-infected macrophages. Accordingly, ELISA-detectable MIP-1alpha, MIP-2 and KC protein was induced by infection with L. monocytogenes. In contrast, L. monocytogenes infection of BMM alone failed to induce considerable expression of monocyte chemoattractant protein (MCP)-1 at the mRNA or protein level, but co-treatment with IFN-gamma was necessary. Release of infection- triggered MIP-2, MIP-1alpha and KC was negatively regulated by IFN- gamma. Similarly, IL-4 stimulated MCP-1 release by infected macrophages but reduced production of MIP-1alpha, MIP-2 and KC. IL-10 turned out to be a general deactivator in terms of macrophage chemokine production. IL-13 had no effect on MIP-1alpha, MIP-2 and KC production by infected BMM, but slightly reduced MCP-1 release. By using IFN-gamma and IL-4 gene deletion mutant mice, in vivo regulation of these chemokines by IL- 4 and IFN-gamma in listeriosis was studied. In summary, our results show that chemokines are produced by macrophages infected with L. monocytogenes, and that chemokine release is differentially regulated by the macrophage modulators IFN-gamma, IL-4, IL-10 and IL-13.      

妊娠期妇女高危型人乳头瘤病毒感染与宫颈病变的相关性研究

目的探讨妊娠期妇女高危型人乳头瘤病毒(HR-HPV)感染与宫颈病变的相关性。方法选取重庆华西妇产医院就诊的18~43岁妊娠期妇女486例,行第二代分子杂交捕获技术(HC2-HPV-DNA)和超微病原体可视检测技术(TH)2种方法联合检测及电子阴道镜下病理活检,以病理活检结果为诊断宫颈病变的金标准。结果 486例妊娠期妇女HR-HPV检测阳性患者161例,阳性率33.12%(161/486);病理组织学诊断出宫颈癌(ICC)及癌前病变(CIN)24例;HPV阳性患者的宫颈癌及癌前病变22例,敏感性91.67%(22/24)。HR-HPV感染情况在不同年龄段分布,差异有统计学意义(P0.05),HR-HPV病毒载量及阳性表达率越高,宫颈病变的程度越高。结论妊娠期妇女不同年龄段的HR-HPV感染率不同;HR-HPV阳病毒载量与CIN及ICC发生有关,与宫颈病变的发生过程有关,但与宫颈病变的严重程度无关;妊娠期妇女HPV感染的宫颈病变阳性率和病毒载量与非妊娠期妇女相似;HC2-HPV-DNA法是目前筛查癌前病变及宫颈癌的最佳方法。     

医院医疗设备商业贿赂及其防治对策

商业贿赂是商品经济发展的一种负面经济现象,各行各业几乎都存在着商业贿赂,医疗界和医院也不例外。我国的医院等事业单位,因为具有某种公共权力、肩负着特殊的使命、具有公益性等特点,容易成为商业贿赂的目标单位。建设清正廉洁的医院既是深化医院体系改革的核心要求,也是防范医药购销领域商业贿赂行为发生的重要举措。     

Identification of signaling motifs within human Fc gamma RIIa and Fc gamma RIIb isoforms

To assess the functional capacity of the heterogeneous Fc gamma RII (CD32) family and to identify critical regions for functioning, we generated a panel of B-cell transfectants. The Fc gamma R-negative B- cell line IIA1.6 was transfected with wild-type or mutant human Fc gamma RIIa and IIb molecules. Solely Fc gamma RIIa-expressing IIA1.6 cells were capable of phagocytosing opsonized Staphylococcus aureus bacteria, and cross-linking of Fc gamma RIIa triggered a rapid induction of tyrosine phosphorylation after 20 seconds. Analysis of Fc gamma RIIa mutants identified the immunoreceptor tyrosine-based activation motif (ITAM; previously described as ARH-1 motif) within the IIa cytoplasmic tail to be critical for B-cell activation. In contrast, Fc gamma RIIb isoforms triggered tyrosine phosphorylation on cross- linking with much slower kinetics (> 3 minutes) than Fc gamma RIIa. Furthermore, solely Fc gamma RIIb molecules proved capable of downregulating [Ca2+]i and interleukin-2 production on co-cross-linking with sIgG in IIA1.6. The Fc gamma RIIb-mediated functions were absent in Fc gamma RIIb mutants in which the tyrosine or leucine within the YSLL motif in a conserved 13-aa region (now known as immunoreceptor tyrosine-based inhibitor motif [ITIM]) were changed into phenylalanines. In conclusion, these data show the presence of functionally critical motifs within Fc gamma RII cytoplasmic tails. Fc gamma RIIa contains an ITAM involved in B-cell activatory functions, whereas the downregulatory activity of Fc gamma RIIb isoforms is linked to an ITIM.     

HIV/AIDS related mortality among adult medical patients in a tertiary health institution in South–South,Nigeria

ObjectiveTo determine the causes of death among human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients as a step to planning strategies to improve mortality from this condition.MethodsThis study retrospectively analyzed the mortality pattern of adult HIV/AIDS patients in the University of Calabar Teaching Hospital from January 2005 to December 2007. The data were obtained from sexually transmitted infection/acquired immunodeficiency syndrome (STI/AIDS) clinic register, admissions and discharge/death registers as well as the patients' case records and the hospitals monthly mortality reviews. Information obtained included age, sex, diagnosis and cause(s) of death. The causes of death considered were the direct causes of death, since the originating antecedent cause of death is the same in all the patients, in this case, HIV/AIDS. Data was analysed using Epi Info 2002.ResultsThe total number of mortalities during the study period was 350,100 were HIV positive representing 28.6% of all deaths. While advanced HIV/AIDS disease was the leading cause of death in our study representing 27.0%, tuberculosis was the single leading cause of deaths in HIV/AIDS patients constituting about 24.0% of deaths. This was followed by sepsis and septicaemia (13.0%), meningitis and encephalitis, and anaemia accounting for 11.0%, while respiratory diseases constituted 5.0% of the mortality burden. The highest number of deaths occurred in those aged between 21–50 years (82.0%).ConclusionsThe study has shown that HIV/AIDS is a major cause of morbidity and mortality in our hospital. The causes of death reflect the varied spectrum of infection and other forms of organ involvement that affect HIV/AIDS patients. The present dismal situation of adult patients living with HIV/AIDS calls for enhanced strategies to decrease the mortality trend observed in Nigeria and sub-Saharan Africa.