急性和慢性呼吸道炎症疾病激肽形成机制探讨

目的探讨急性和慢性呼吸道炎症过程中激肽的生成途径和机制。方法测定支气管肺癌伴阻塞性肺炎,慢性支气管炎和健康对照组支气管肺泡灌洗液（ＢＡＬＦ）凝胶过滤前后激肽、激肽形成酶活性（ＴＡＭＥｅａ）,血浆血管舒缓素（ＰＫ）和α２巨球蛋白（α２Ｍ）,并进一步鉴定ＴＡＭＥｅａ性质。结果急、慢性组ＴＡＭＥｅａ和激肽水平与健康对照组比较差异有显著性（Ｐ＜０００１,Ｐ＜０．０１）,但两组间差异无显著性（Ｐ＞００５）;急性组ＰＫ和α２Ｍ与慢性组比较差异有显著性（Ｐ＜０００１）。凝胶过滤结果显示：急性组ＢＡＬＦ的ＴＡＭＥｅａ最高峰位于分子量约８０００００处,与第一个α２Ｍ峰重叠,而慢性组的最高峰位于４００００处。ＴＡＭＥｅａ抑制试验证实８０００００处的ＴＡＭＥｅａ来自于ＰＫ;而４００００处的ＴＡＭＥｅａ主要来源于组织血管舒缓素（ＴＫ）。结论急性呼吸道炎症的ＴＡＭＥｅａ主要来自血浆的ＰＫ;而慢性呼吸道炎症则以局部组织腺体分泌的ＴＫ为主。     

Loss to follow-up among youth accessing outpatient HIV care and treatment services in Kisumu,Kenya

Youth are particularly vulnerable to acquiring HIV, yet reaching them with HIV prevention interventions and engaging and retaining those infected in care and treatment remains a challenge. We sought to determine the incidence rate of loss to follow-up (LTFU) and explore socio-demographic and clinical characteristics associated with LTFU among HIV-positive youth aged 15–21 years accessing outpatient care and treatment clinics in Kisumu, Kenya. Between July 2007 and September 2010, youth were enrolled into two different HIV care and treatment clinics, one youth specific and the other family oriented. An individual was defined as LTFU when absent from the HIV treatment clinic for ≥?4 months regardless of their antiretroviral treatment status. The incidence rate of LTFU was calculated and Cox regression analysis used to identify factors associated with LTFU. A total of 924 youth (79% female) were enrolled, with a median age of 20 years (IQR 18–21). Over half, (529 (57%)), were documented as LTFU, of whom 139 (26%) were LTFU immediately after enrolment. The overall incidence rate of LTFU was 52.9 per 100 person-years (p-y). Factors associated with LTFU were pregnancy during the study period (crude HR 0.68, 95% CI 0.53–0.89); CD4 cell count >350 (adjusted hazard ratios (AHR) 0.59, 95% CI 0.39–0.90); not being on antiretroviral therapy (AHR 4.0, 95% CI 2.70–5.88); and non-disclosure of HIV infection status (AHR 1.43, 95% CI 1.10–1.89). The clinic of enrolment, age, marital status, employment status, WHO clinical disease stage and education level were not associated with LTFU. Interventions to identify and enrol youth into care earlier, support disclosure, and initiate ART earlier may improve retention of youth and need further investigation. Further research is also needed to explore the reasons for LTFU from care among HIV-infected youth and the true outcomes of these patients.     

Sleep in Type 1 Diabetes: Implications for Glycemic Control and Diabetes Management

Purpose of Review

To highlight recent findings from studies of sleep in type 1 diabetes (T1D), with a focus on the role of sleep in self-management, the cognitive and psychosocial outcomes related to sleep disturbances, and factors associated with sleep disturbances specific to T1D.

Recent Findings

People with T1D experience higher rates of sleep disturbances than people without diabetes, and these disturbances have negative implications for glycemic control and diabetes management, as well as psychosocial and cognitive outcomes. Inconsistent sleep timing (bedtime and wake time) has emerged as a potential target for interventions, as variability in sleep timing has been linked with poorer glycemic control and adherence to treatment. Sleep-promoting interventions and new diabetes technology have the potential to improve sleep in people with T1D.

Summary

Sleep is increasingly considered a critical factor in diabetes management, but more multi-method and longitudinal research is needed. We emphasize the importance of sufficient and consistent sleep for people with T1D, and the need for providers to routinely assess sleep among patients with T1D.

     

Analysis of p53 mutations in a large series of lymphoid hematologic malignancies of childhood

p53 mutations are found in a wide variety of cancers, including hematologic malignancies. These alterations apparently contribute to development of the malignant phenotype. We analyzed a large series of lymphoid (330 cases) and a smaller series of myeloid (29 cases) malignancies of childhood for p53 mutations by single-strand conformational polymorphism (SSCP) following polymerase chain reaction. Samples with abnormal SSCP were reamplified and analyzed by direct sequencing method. p53 mutations were detected within the known mutational hotspots (exons 5 to 8) in 8 of 330 lymphoid malignancies, and in none of 29 myeloid malignancies, showing that the frequency of p53 mutations in childhood lymphoid malignancies was very low (8 of 330 cases [2%]). Four of these patients had very aggressive, fatal acute lymphocytic leukemia (ALL). None of 13 infants and none of 48 patients with T-lineage leukemia had detectable p53 mutations in their ALL cells. Exceptionally, p53 mutations were comparatively frequent in a small sample of B-cell non-Hodgkin's lymphomas (2 of 8 cases). Mutations were detected in samples from two patients with ALL at relapse; these were not detected in samples at initial diagnosis from the same patients, suggesting that p53 mutations may be associated with progression to a more malignant phenotype. Seven of eight alterations of p53 were missense mutations, and seven of eight samples may be heterozygous for the mutant p53, indicating that p53 protein may act in a dominant negative fashion.     

Hypothalamic Syndrome and Central Sleep Apnoea Associated with Toluene Exposure

We describe a young man who developed extensive hypothalamicdysfunction including diabetes insipidus, adipsia, hyperprolactinaemia,and poikiliothermia together with central sleep apnoea followingexposure to toluene.     

Selective estrogen receptor modulators: discrimination of agonistic versus antagonistic activities by gene expression profiling in breast cancer cells

Selective estrogen receptor modulators (SERMs) such as tamoxifen are effective in the treatment of many estrogen receptor-positive breast cancers and have also proven to be effective in the prevention of breast cancer in women at high risk for the disease. The comparative abilities of tamoxifen versus raloxifene in breast cancer prevention are currently being compared in the Study of Tamoxifen and Raloxifene trial. To better understand the actions of these compounds in breast cancer, we have examined their effects on the expression of approximately 12,000 genes, using Affymetrix GeneChip microarrays, with quantitative PCR verification in many cases, categorizing their actions as agonist, antagonist, or partial agonist/antagonist. Analysis of gene stimulation and inhibition by the SERMs trans-hydroxytamoxifen (TOT) and raloxifene (Ral) or ICI 182,780 (ICI) and by estradiol (E2) in estrogen receptor-containing MCF-7 human breast cancer cells revealed that (a) TOT was the most E2-like of the three compounds, (b) all three compounds either partially or fully antagonized the action of E2 on most genes, with the order of antagonist activity being ICI > Ral > TOT, (c) TOT and Ral, but not ICI, displayed partial agonist/partial antagonist activity on a number of E2-regulated genes, (d) several stimulatory cell cycle-related genes were down-regulated exclusively by ICI, (e) the estrogen-like activity of Ral nearly always overlapped with that of TOT, indicating that Ral has little unique agonist activity different from that of TOT, and (f) some genes were specifically up-regulated by TOT but not Ral, ICI, or E2. Hence, gene expression profiling can discern fundamental differences among SERMs and provides insight into the distinct biologies of TOT, Ral, and ICI in breast cancer.     

A new antiestrogen, 2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol hydrochloride (ERA-923), inhibits the growth of tamoxifen-sensitive and -resistant tumors and is devoid of uterotropic effects in mice and rats.

PURPOSE: Tamoxifen is an antiestrogen used in women who have estrogen receptor (ER)-alpha-positive breast cancer. Unfortunately, resistance to tamoxifen is common in women with metastatic disease and side effects, including increased risk of endometrial cancer, exist. Here we describe the activity of a new selective ER modulator, ERA-923, in preclinical models focused on these limitations. EXPERIMENTAL DESIGN: The ability of ERA-923, 4-OH tamoxifen, or raloxifene to inhibit estrogen-stimulated growth was evaluated in cell-based and xenograft assays with tumor cells that are sensitive or resistant to tamoxifen. Uterine effects of selective ER modulators were compared in rodents. RESULTS: ERA-923 potently inhibits estrogen binding to ER-alpha (IC(50), 14 nM). In ER-alpha-positive human MCF-7 breast carcinoma cells, ERA-923 inhibits estrogen-stimulated growth (IC(50), 0.2 nM) associated with cytostasis. In vitro, a MCF-7 variant with inherent resistance to tamoxifen (10-fold) or 4-OH tamoxifen (>1000-fold) retains complete sensitivity to ERA-923. Partial sensitivity to ERA-923 exists in MCF-7 variants that have acquired profound tamoxifen resistance. In tumor-bearing animals, ERA-923 (10 mg/kg/day given p.o.) inhibits 17beta-estradiol-stimulated growth in human tumors derived from MCF-7, EnCa-101 endometrial, or BG-1 ovarian carcinoma cells, including a MCF-7-variant that is inherently resistant to tamoxifen. Raloxifene is inactive in the MCF-7 xenograft model. Unlike tamoxifen, droloxifene, or raloxifene, ERA-923 is not uterotropic in immature rats or ovariectomized mice. Consistent with this, tamoxifen, but not ERA-923, stimulates the growth of EnCa-101 tumors. CONCLUSIONS: In preclinical models, ERA-923 has an improved efficacy and safety compared with tamoxifen. Clinical trials with ERA-923 are in progress.     

Modulation of in vitro and in vivo T-cell responses by transferrin- gallium and gallium nitrate

Gallium is a group IIIa metal that has efficacy in the therapy of malignant disorders such as lymphoma and urothelial tract tumors. Preclinical studies also indicate a role for gallium in autoimmune disorders, suggesting that gallium is able to modulate T-cell immune reactivity. The purpose of this study was to examine the in vitro and in vivo immunomodulatory action of gallium on T-cell function. Since gallium binds to transferrin in vivo, in vitro studies evaluated the effect of transferrin-gallium (Tf-Ga) on human T cells. Tf-Ga inhibited the mitogen-induced proliferative response of peripheral blood mononuclear cells (PBMC) in a dose-dependent fashion. Alloantigen- induced proliferation was also potently suppressed when evaluated in a mixed lymphocyte culture assay. Tf-Ga affected a significant reduction in the density of IL-2 receptors on activated T cells and a slight reduction in the number of CD3+/CD25+ T cells in PHA-stimulated cultures. Neither secretion of interleukin-2 (IL-2) nor the induction of IL-2-stimulated lymphokine-activated killer activity, however, was inhibited by Tf-Ga. Tf-Ga produced significant upregulation of the transferrin receptor (CD71) in T cells as determined by flow cytometric analysis and northern blot assay, but did not affect the percentage of CD3+/ CD71+ T cells after mitogen stimulation. To assess the in vivo effects of gallium on alloreactive T cells, we evaluated the immunosuppressive effect of gallium in a murine model of graft-versus- host disease (GVHD). Administration of gallium significantly prolonged survival in mice undergoing severe GVHD, suggesting that gallium can ameliorate GVH reactivity. Collectively, these data demonstrate that, at clinically achievable concentrations, Tf-Ga potently inhibits T-cell activation and that this immunosuppressive property of gallium may be of adjunctive therapeutic value in the management of disorders characterized by the presence of autoreactive or alloreactive T-cell populations.