Monoclonal Antibody Specific for TIRC7 Induces Donor-specific Anergy and Prevents Rejection of Cardiac Allografts in Mice

T cell immune response c-DNA (TIRC7) is up-regulated during the early stages of T-cell activation in response to alloantigens. In this study, we analyzed the effects of newly developed monoclonal antibodies (mAb) against TIRC7 in acute cardiac allograft rejection. Fully vascularized heterotopic allogeneic heart transplantation was performed in mice across a full-mismatch barrier (C57Bl/10 into CBA). Recipients received seven injections (day 0-7) of a novel anti-TIRC7 mAb or remained untreated. Graft survival, histology and ex vivo lymphocyte functions were tested. Targeting of TIRC7 with an anti-TIRC7 mAb diminishes lymphocyte infiltration into grafts resulting in delay of morphological graft damage and prolongation of allograft survival. The lymphocytes from anti-TIRC7 mAb-treated animals exhibit hypo-responsiveness without evidence of lymphocyte depletion against the donor allo-antigens. Proliferation and expression of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) were down-regulated while interleukin-4 (IL-4) and IL-10 expression were spared. Moreover, anti-TIRC7 mAb enhanced up-regulation of CTLA-4 expression but suppressed up-regulation of CD25 on stimulated lymphocytes in vitro and in vivo. Ligation of TIRC7 has important effects on the regulation of co-stimulatory signaling pathways associated with suppressing of T-cell activation. Targeting of TIRC7 may therefore provide a novel therapeutic approach for modulating T cell immune responses during organ transplantation.     

Modeling of relationships between pharmacokinetics and blockade of agonist-induced elevation of intraurethral pressure and mean arterial pressure in conscious dogs treated with alpha(1)-adrenoceptor antagonists.

Fiduxosin is a new alpha(1)-adrenoceptor antagonist targeted for the treatment of symptomatic benign prostatic hyperplasia. The purpose of this study was to determine and compare the potencies of the alpha(1)-adrenoceptor antagonists terazosin, doxazosin, tamsulosin, and fiduxosin, based on relationships between plasma drug concentrations and blockade of phenylephrine (PE)-induced intraurethral (IUP) and mean arterial pressure (MAP) responses after single oral dosing in conscious male beagle dogs. Magnitude of blockade and plasma concentrations were evaluated at selected time points over 24 h. All drugs produced dose-dependent antagonism of PE-induced IUP and MAP responses. When IUP and MAP blockade effects were plotted against drug plasma concentrations, direct relationships were observed that were well described by the sigmoidal maximal effect model. IUP IC(50) values for terazosin, doxazosin, tamsulosin, and fiduxosin were 48.6, 48.7, 0.42, and 261 ng/ml, respectively. MAP IC(50) values were 12.2, 13.8, 1.07, and 1904 ng/ml, respectively. Uroselectivity index values, defined as MAP IC(50)/IUP IC(50), were 0.25, 0.28, 2.6, and 7.3, respectively. These results extend previous observations with terazosin in this model, showing that doxazosin exhibits a uroselectivity index comparable to terazosin, consistent with the lack of alpha(1)-adrenoceptor subtype selectivity or uroselectivity of these drugs. Tamsulosin, an alpha(1a)-/alpha(1d)-subtype selective agent, had an index value approximately 10-fold greater than the nonselective drugs. Based on its pharmacokinetic profile and a relative uroselectivity 29-fold greater than the nonselective drugs, fiduxosin is expected to exhibit greater selectivity for urethral compared with vascular alpha(1)-adrenoceptors in human and should be a novel, long-acting, uroselective alpha(1)-adrenoceptor antagonist.     

对广东患者抑郁体验的定性研究——医学人类学对精神病学视角的丰富

目的目前,对中国人抑郁体验的现象学理解很大程度上依赖于西方教科书和国际诊断系统中的描述。而临床经验告诉我们,不同地区、不同文化对情绪痛苦的表达有着各自的特点;但中国在这方面还缺乏研究。为此,我们采用民俗学方法对广州地区就诊人群的抑郁体验进行了研究。方法在广州市精神卫生中心门诊,采用定额取样招募40例有抑郁情绪的患者;问及的合适的病人共43人,只有3人不同意参加。采用开放式深入民俗学访谈了解患者的抑郁体验,即让患者用他们自己的话来讲述患病经历。对访谈进行录音,转录为文字并译成英文。对中英文记录分别进行了内容分析。结果除了西方教科书和诊断系统中描述的抑郁症状外,还发现了六个情感体验的类别:本地情感语汇、具身的情绪体验、隐含的忧伤、难以言状的痛苦、情绪不良造成的人际不和谐,以及专注于失眠。结论精神病学教科书和诊断系统中的描述未能涵盖中国抑郁患者对抑郁症状的全部体验。需要进一步研究抑郁体验与生活事件的关联及其在不同文化下的表现方式,这样才能作出与文化相适应的有效诊断。     

A new antisense oligonucleotide delivery system based on self-assembled ODN-PEG hybrid conjugate micelles.

The conjugate of antisense c-raf oligonucleotide (ODN) and poly(ethylene glycol) (PEG) was synthesized for intracellular ODN delivery. When combined with polyethylenimine (PEI), the ODN-PEG conjugate self-associated to form polyelectrolyte complex micelles in aqueous solution. The effective hydrodynamic diameter of the micelles was ca. 70 nm with a narrow size distribution. Flow cytometry analysis indicated that the cellular uptake of the micelles by A2780 cells was much higher than that of ODN alone. The micelles also showed a superior antiproliferative activity against ovarian cancer cells in vitro and in vivo.     

Features of pediatric head injury in Hong Kong

Head injury in children causes special concern in most communities. From 1989 to 1994, 2,785 children younger than 16 years old were admitted to our neurosurgical service because of head injury. Fall from a height was the major cause of head injury leading to admission in infants and children in preschool age groups, whereas traffic-related or bicycle-related accidents were more likely to be the cause of head injury for those aged 11–15 years. In all age groups there was a male preponderance. The overall mortality was 0.6%. Traffic-ralated accidents caused more severe injury and accounted for 67% of all fatalities. For patients under 6 years old, about 40% of head injuries occurred at home. Preventive measures for pediatric head injury in Hong Kong are suggested.     

Staphylococcus aureus nasal carriage in patients with rhinosinusitis

Toxic shock syndrome has been associated with rhinologic surgery and medical devices, and it has been linked to a circulating exotoxin of a toxogenic strain of Staphylococcus aureus. One hundred forty patients with rhinosinusitis were studied. Nasal cultures were obtained. The microbiological characteristics are described. The carrier rate for Staphylococcus aureus was 35%. Thirty percent of patients selected for surgery were Staphylococcus aureus carriers. Toxin-capable isolates were identified in 40% of those tested. Users of cocaine, topical decongestants, and steroid sprays had a statistically higher rate of Staphylococcus aureus carriage compared to non-users. It is hoped that by identifying the population at risk and defining the factors associated with the development of toxic shock syndrome, a cogent policy of prevention can be established.     

Mammalian response to subdermal implantation of textured microimplants

The development of small, textured implant particles suspended in a hydrogel has allowed for subdermal injection therapy to fill tissue defects. The microimplant particles were placed subdermally into the ears of white New Zealand rabbits in order to characterize the foreign body response and the permanence of the implant. Serial micrometer readings were performed on the implant sites to determine any change in thickness of the augmentation following baseline measurement. An initial increase in the thickness was noted approximately 20–30 days postimplantation, as expected. A stable thickness was noted for the remainder of the experiment. Serial histological sections were performed at irregular intervals from one week to one year. Histology demonstrated a mild foreign body response with collagen surrounding each individual microimplant particle. The response was stable after 30–40 days and has remained stable for over one year. It was determined that the histology demonstrated a Boros IA type, or nonimmunogenic, low-turnover foreign body reaction.     

Pretransplant Exposure to Donor HLA-DR Antigen in Random Transfusion Units and the Development of Donor Antigen-Specific Hyporeactivity

Our previous studies have shown that the in vitro assay of donor antigen-specific hyporeactivity is a useful marker for identifying solid organ transplant recipients (kidney, lung and heart) at low risk for immunologic complications (i.e., late acute rejection episodes and chronic rejection). Donor antigen-specific hyporeactivity is defined as a significantly decreased post- vs. pretransplant proliferative response to donor antigens while response to third-party controls remains unchanged. We analyzed whether exposure to the same HLA-DR antigen pretransplant via random blood transfusion and posttransplant via the transplanted organ influenced the development of hyporeactivity. Thirty previously nontransfused recipients, each receiving two 150 ml pretransplant random blood transfusions, were assessed for hyporeactivity at 1 year posttransplant. Of the 12 recipients with pretransplant exposure to kidney HLA-DR via transfusions, 6 (50%) developed hyporesponsiveness; in contrast, of the 18 recipients who were not preexposed, only 3 (15%) exhibited this form of immunomodulation. Of interest, 2 of the 3 hyporesponsive recipients who were not preexposed, received units containing HLA-DR antigens previously shown to share crossreactive epitopes with the kidney HLA-DR. In conclusion, these results suggest a increased incidence in the development of hyporeactivity in patients receiving pretransplant transfusions which share an HLA-DR antigen with the transplanted kidney.