Endorphins may function in heat adaptation.

Administration of the opiate antagonist naloxone to rats after acute or chronic heat exposure precipitates an increase in colonic temperature, an increase in escape attempts, and a decrease in body weight. These changes are accompanied by signs associated with hyperthermia such as salivation, diarrhea, and an abnormal extended posture. Although brain endorphin involvement is possible, hypophysectomy diminishes the intensity and magnitude of these naloxone effects, indicating that the naloxone effect in intact animals may be due to a functional antagonism of pituitary endorphins. These observations suggest that endorphins attenuate physiological responses to thermal and noxious stimuli triggered in common neuroanatomical pathways by heat.     

Changes in lipoprotein(a) concentration after orthotopic heart transplantation

BACKGROUND: Elevated concentrations of lipoprotein(a) have been considered an important risk factor in the development of premature cardiovascular disease and have been proposed as a risk factor in the development of accelerated cardiac allograft vasculopathy after orthotopic heart transplantation. METHODS: We prospectively measured lipoprotein(a), fasting cholesterol, and triglyceride concentrations before (n = 38), 6 months (n = 38), and 1 year (n = 21) after orthotopic heart transplantation. The mean age of the patients was 52 +/- 2 years. Eighty-seven percent of the patients were men, 82% were white, and 61% had ischemic cardiomyopathy. RESULTS: Mean lipoprotein(a) concentration was lower 6 months after transplantation than it was before the operation (23 +/- 3 mg/dL vs 17 +/- 3 mg/dL; P =.014) and remained low 1 year after transplantation (23 +/- 3 mg/dL vs 18 +/- 4 mg/dL; P = not significant). In contrast, mean cholesterol concentration was higher 6 months after transplantation (171 +/- 8 mg/dL vs 221 +/- 8 mg/dL; P <.001) and 1 year (171 +/- 8 mg/dL vs 205 +/- 10 mg/dL; P <.01) than it was before transplantation. Triglyceride concentration was higher 1 year after transplantation than it was before the operation (146 +/- 13 mg/dL vs 184 +/- 20 mg/dL; P =.017). CONCLUSIONS: Lipoprotein(a) concentrations decrease during the 6 months after transplantation and stay low for at least 1 year after the operation. Additional studies are needed to ascertain the effect these changes in lipoprotein(a) concentration on the development of cardiac allograft vasculopathy.     

Fluorescence in situ hybridization mapping of translocations and deletions involving the short arm of human chromosome 12 in malignant hematologic diseases

Translocations and deletions of the short arm of chromosome 12 [t(12p) and del(12p)] are common recurring abnormalities in a broad spectrum of hematologic malignant diseases. We studied 20 patients and one cell line whose cells contained 12p13 translocations and/or 12p deletions using fluorescence in situ hybridization (FISH) with phage, plasmid, and cosmid probes that we previously mapped and ordered on 12p12-13. FISH analysis showed that the 12p13 translocation breakpoints were clustered between two cosmids, D12S133 and D12S142, in 11 of 12 patients and in one cell line. FISH analysis of 11 patients with deletions demonstrated that the deletions were interstitial rather than terminal and that the distal part of 12p12, including the GDI-D4 gene and D12S54 marker, was deleted in all 11 patients. Moreover, FISH analysis showed that cells from 3 of these patients contained both a del(12p) and a 12p13 translocation and that the affected regions of these rearrangements appeared to overlap. We identified three yeast artificial chromosome (YAC) clones that span all the 12p13 translocation breakpoints mapped between D12S133 and D12S142. They have inserts of human DNA between 1.39 and 1.67 Mb. Because the region between D12S133 and D12S142 also represents the telomeric border of the smallest commonly deleted region of 12p, we also studied patients with a del(12p) using these YACs. The smallest YAC, 964c10, was deleted in 8 of 9 patients studied. In the other patient, the YAC labeled the del(12p) chromosome more weakly than the normal chromosome 12, suggesting that a part of the YAC was deleted. Thus, most 12p13 translocation breakpoints were clustered within the sequences contained in the 1.39 Mb YAC and this YAC appears to include the telomeric border of the smallest commonly deleted region. Whether the same gene is involved in both the translocations and deletions is presently unknown.     

Organ injury associated with extrathymic induction of immune tolerance in doubly transgenic mice.

The developmental fate of autoreactive T cells encountering extrathymically expressed self-antigen was studied in a doubly transgenic mouse model system where pancreatic acinar cells expressed H-2Ld and T cells expressed an antigen receptor (2C TCR) specific for H-2Ld. Thymocytes bearing 2C TCR differentiated normally. They were positively selected without evidence of intrathymic clonal deletion. Survival of H-2Ld-bearing skin allografts was significantly prolonged in pancreatic H-2Ld singly and doubly transgenic mice, consistent with an in vivo state of T-cell tolerance. The mechanism of tolerance induction was determined and found to have two components. First, up to 80% of peripheral CD8+2C TCR+ T cells were eliminated. Second, those T cells which escaped elimination had a significantly reduced proliferative response to H-2Ld. Thus, autoreactive T cells can be made self-tolerant through interaction with self-antigen located extrathymically. This is accomplished by a reduction in the percentage of autoreactive T cells as well as by a reduction in the functional capacity of residual T cells. Surprisingly, although pancreatic lymphocytic infiltration and organ injury were absent in exocrine tissue of singly transgenic mice, it was present in doubly transgenic mice. This suggests that when the percentage of autoreactive T cells is high, tolerance induction can be associated with an inflammatory infiltrate in extrathymic tissue where self-antigen is presented.     

Two pathways of exocytosis of cytoplasmic granule contents and target cell killing by cytokine-induced CD3+ CD56+ killer cells

Cytokine-induced killer (CIK) cells are non-major histocompatibility complex-restricted cytotoxic cells generated by incubation of peripheral blood lymphocytes with anti-CD3 monoclonal antibody (MoAb), interleukin-2 (IL-2), IL-1, and interferon-gamma. Cells with the greatest effector function in CIK cultures coexpress CD3 and CD56 surface molecules. CIK cell cytotoxicity can be blocked by MoAbs directed against the cell surface protein leukocyte function associated antigen-1 but not by anti-CD3 MoAbs. CIK cells undergo release of cytoplasmic cytotoxic granule contents to the extracellular space upon stimulation with anti-CD3 MoAbs or susceptible target cells. Maximal granule release was observed from the CD3+ CD56+ subset of effector cells. The cytoplasmic granule contents are lytic to target cells. Treatment of the effector cells with a cell-permeable analog of cyclic adenosine monophosphate (cAMP) inhibited anti-CD3 MoAb and target cell- induced degranulation and cytotoxicity of CIK cells. The immunosuppressive drugs cyclosporin (CsA) and FK506 inhibited anti-CD3- mediated degranulation, but did not affect cytotoxicity of CIK cells against tumor target cells. In addition, degranulation induced by target cells was unaffected by CsA and FK506. Our results indicate that two mechanisms of cytoplasmic granule release are operative in the CD3+ CD56+ killer cells; however, cytotoxicity proceeds through a cAMP- sensitive, CsA- and FK506-insensitive pathway triggered by yet-to-be- identified target cell surface molecules.     

The validity of self‐reported cancer in an Australian population study

Objective: The aim of this study is to determine the validity of self‐reported cancer data by comparing it to the Australian Cancer Database (ACD). Methods: Self‐reported data were obtained from the Australian Diabetes, Obesity and Lifestyle (AusDiab) study, which were then linked to the ACD up until 31 December 2010. Positive predictive value, negative predictive value, sensitivity and specificity were calculated. Cohen's kappa coefficient (?) was also calculated to assess the agreement between self‐reported cancer and the ACD. Logistic regression was used to examine the determinants associated with false negative and false positive reporting. Results: The overall sensitivity of self‐report cancer was 71.1%, and sensitivities showed great variation by cancer site. Higher sensitivities were observed for breast (90.7%), bowel (77.8%) and prostate (77.1%) cancers, whereas the lowest sensitivity was observed for melanoma of the skin (36.9%). Similarly, the kappa coefficient analysis showed substantial agreement for self‐reported breast cancer (?= 0.79) and moderate agreement for melanoma (?= 0.45) against the ACD. Years since cancer diagnosis and older age were associated with false negative reporting and older age was associated with false positive reporting. Conclusions and implications: The use of self‐reported cancer to collect cancer outcomes has varying reliability, depending on cancer type and population. The findings presented here may assist medical researchers in making informed decisions when conducting research using self‐reported cancer data in Australia where the acquisition of registry data is not feasible.     

MMP-2和TIMP-2基因多态性与胃癌发病风险的研究

目的探讨西南汉族人群中基质金属蛋白酶-2(matrix metallopmteinase-2,MMP-2)和金属蛋白酶组织抑制剂-2(tissue inhibitor of metalloproteinase-2,TIMP-2)基因启动子区域单核苷酸多态性与胃癌发病风险的关系。方法在美国Sequenom MassARRAY系统上利用基质辅助激光解吸电离飞行时间质谱法(MALDI-TOF MS)针对308对胃癌病例和对照分析MMP-2-1306C/T和TIMP-2-418G/C基因多态特征。同时利用自行设计的问卷收集研究对象的人口学特征和日常生活习惯。结果 MMP-2-1306C/T的CC、CT和TT基因型在病例组和对照组中的频率分别为:79.5%、19.8%、0.6%和79.8%、19.2%、1%;TIMP-2-418G/C的GG、GC和CC基因型在病例组和对照组中的频率分别为:71.4%、26.6%、2.0%和70.5%、27.8%、1.7%;MMP-2-1306C/T(P=0.936和0.984)和TIMP-2-418G/C(P=0.817和0.898)的基因型和等位基因频率分布在胃癌组与对照组间均无统计学差异(P0.05)。同时未发现基因-基因联合作用(OR=1.004;95%CI:0.460~2.191)和基因-环境之间的交互作用。结论本研究未发现MMP-2-1306C/T和TIMP-2-418G/C多态性与胃癌发病风险有关,且两单核苷酸多态之间无基因-基因联合作用,也未发现基因与环境的交互作用。     

From the Cover: Preexisting CD8+ T-cell immunity to the H7N9 influenza A virus varies across ethnicities

The absence of preexisting neutralizing antibodies specific for the novel A (H7N9) influenza virus indicates a lack of prior human exposure. As influenza A virus–specific CD8⁺ T lymphocytes (CTLs) can be broadly cross-reactive, we tested whether immunogenic peptides derived from H7N9 might be recognized by memory CTLs established following infection with other influenza strains. Probing across multiple ethnicities, we identified 32 conserved epitopes derived from the nucleoprotein (NP) and matrix-1 (M1) proteins. These NP and M1 peptides are presented by HLAs prevalent in 16–57% of individuals. Remarkably, some HLA alleles (A*0201, A*0301, B*5701_, B*1801, and B*0801) elicit robust CTL responses against any human influenza A virus, including H7N9, whereas ethnicities where HLA-A*0101, A*6801, B*1501, and A*2402 are prominent, show limited CTL response profiles. By this criterion, some groups, especially the Alaskan and Australian Indigenous peoples, would be particularly vulnerable to H7N9 infection. This dissection of CTL-mediated immunity to H7N9 thus suggests strategies for both vaccine delivery and development.Emerging unexpectedly in February 2013, the H7N9 influenza A virus (IAV) has thus far caused 137 human infections with 45 deaths (1). Clinical manifestations include major respiratory compromise, multiorgan failure, and exceedingly high serum cytokine and chemokine levels (2). Although May through September saw only five such cases, two more were recorded in October (1), indicating that H7N9 may return during the northern winter. Furthermore, the presence of a natural avian reservoir and the severity of the disease emphasized the need to focus on protective immunity. Most patients had contact with poultry within a week before clinical onset (2), suggesting that domestic birds are the source (2, 3). Even so, the potential for person-to-person spread is highlighted by ferret experiments (4) and instances of infection via close family contact (3). A very real concern is that further mutations may facilitate human-to-human transmission (5).Evidence from animal (6) and human studies (7–9) suggests that, in the absence of neutralizing antibodies (NAbs), preexisting memory CD8⁺ T lymphocytes (CTLs) directed at conserved and/or cross-reactive IAV peptide + class I HLA (pHLA1) epitopes can diminish disease severity. The recall of IAV-specific CTLs promotes recovery manifested by milder symptoms, diminished virus shedding and transmission (6, 7). A comprehensive analysis of the 2009 pandemic H1N1 IAV (H1N1pdm-2009) indicated that CTL memory provided some protection for the antibody naïve (9). Thus, cross-reactive CTL memory generated after a prior encounter with seasonal or pandemic IAVs, or by a CTL-directed vaccine, could potentially limit the severity of an H7N9 pandemic.The present analysis probes the extent of preexisting CTL immunity in populations that have not been exposed to the H7N9 virus. This potential for CTL recall is defined for HLA1s that are differentially prominent in various ethnicities. Using an evolutionary and immunological approach, we show substantial levels of immunogenic peptide conservation for nucleoprotein (NP) and matrix-1 (M1), with estimated coverage according to known HLA1 presentation profiles ranging between 16% and 57% of the global population. Overall, the findings support the view that it is important to consider developing vaccines with a T cell–based component that has the potential to protect against severe novel IAV infections. Furthermore, given that some ethnicities, including Australia’s Indigenous and Alaskan people, show evidence of a diminished HLA1-related response capacity, it is essential that health policy development and planning gives such groups priority in IAV vaccination campaigns. The 2009 H1N1 pandemic caused higher attack rates and morbidity among Indigenous populations in the Americas, New Zealand, and Australia (10).