Regulation of interleukin-12 expression in human monocytes: selective priming by interferon-gamma of lipopolysaccharide-inducible p35 and p40 genes

Interleukin-12 (IL-12) is a monocyte/macrophage-derived cytokine that is critical for T lymphocyte and natural killer cell activities and functions. In this study, we examined the regulation of IL-12 expression by human monocytes in response to bacterial lipopolysaccharide (LPS). Several novel aspects of IL-12 induction from monocytes were shown. Optimal expression of IL-12 mRNA and bioactivity required specific priming of monocytes by interferon-gamma (IFN-gamma) before LPS stimulation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) provided an equivalent priming stimulus for LPS-induced tumor necrosis factor (TNF) and IL-12 p40 mRNA, but primed poorly for LPS-inducible p35 message and secreted IL-12 activity. Macrophage colony-stimulating factor (M-CSF), although a potent survival factor for monocytes, showed no priming activity for IL-12 production. Time course experiments demonstrated independent regulation of p40 and p35 by IFN-gamma and LPS. LPS inducibility of p40 expression required only a brief exposure to IFN-gamma (2 hours), while prolonged exposure (+/- 24 hours) to IFN-gamma resulted in diminishing levels of p40 mRNA. p35 inducibility (by LPS) required a longer exposure to IFN-gamma (8 to 16 hours), and continued to be inducible up to 40 hours following IFN- gamma priming. Both mRNAs were rapidly induced (1 to 2 hours) in IFN- gamma-primed monocytes; p35 message reached a plateau by 2 hours, while p40 continued to accumulate. Finally, both p40 and p35 were directly induced by LPS in the presence of cycloheximide. These results indicated that both p40 and p35 are LPS-inducible in monocytes following IFN-gamma pretreatment, and that the regulated expression of p35 controls the level of active IL-12 protein in purified human monocytes. The selectivity of priming by IFN-gamma is in accord with a putative role for IL-12 in the initiation and amplification of TH1-type responses.     

Pre-clinical development of the anti-tumour agent CB 7646, BIS N-(hydroxymethyl) trimethylmelamine,a stable analogue of trimelamol

Formulation difficulties prevented the otherwise promising clinical development of the anti-tumour agent trimelamol (TM; tris-[hydroxymethyl]trimethylmelamine). A synthetic analogue programme resulted in the identification of CB 7646 (bis N-[hydroxymethyl]trimethylmelamine) as a compound with improved stability and favourable formulation characteristics. The in vitro and in vivo activity of CB 7646 was shown to be very similar to that of TM. In addition, curative activities were shown in the PXN/65 human ovarian cancer xenograft and the MX-1 and T-61 human breast cancer xenograft models. The effectiveness of the N-(hydroxymethyl)melamines against platinum-refractory disease was noted in the phase I clinical trial of TM. In line with this finding, the present study confirmed the effective activity of both TM and CB 7646 against various forms of platinum resistance in in vitro models. Curative activity for TM and CB 7646 was seen in the HX110P human ovarian cancer xenograft with acquired carboplatin resistance. Animal studies indicated less neurotoxicity for CB 7646 than for TM. The pharmacokinetic profile of CB 7646 indicated a decreased plasma elimination, indicative of slower in vivo degradation than for TM. CB 7646, therefore, represents a promising candidate for clinical development, designed to supersede TM. © 1996 Wiley-Liss, Inc.     

Therapy of patients with human T-cell lymphotrophic virus I-induced adult T-cell leukemia with anti-Tac, a monoclonal antibody to the receptor for interleukin-2

Human T-cell lymphotropic virus I (HTLV-I)-induced adult T-cell leukemia (ATL) cells constitutively express interleukin-2 (IL-2) receptors identified by the anti-Tac monoclonal antibody (MoAb), whereas normal resting cells do not. This observation provided the scientific basis for a trial of intravenous anti-Tac in the treatment of nine patients with ATL. The patients did not suffer untoward reactions and did not have a reduction in the normal formed elements of the blood, and only one of the nine produced antibodies to the anti-Tac MoAb. Three patients had transient mixed, partial, or complete remissions lasting from 1 to more than 8 months after anti-Tac therapy, as assessed by routine hematologic tests, immunofluorescence analysis of circulating cells, and molecular genetic analysis of HTLV-I provirus integration and of the T-cell receptor gene rearrangement. The precise mechanism of the antitumor effects is unclear; however, the use of a MoAb that prevents the interaction of IL-2 with its receptor on ATL cells provides a rational approach for the treatment of this malignancy.     

Use of Clergy Services among Individuals Seeking Treatment for Alcohol Use Problems

This study examined the prevalence and characteristics of adults with an alcohol use‐related problem who receive clergy services. Data come from the National Epidemiologic Survey on Alcohol and Related Conditions. Among persons who sought any services for alcohol‐related problems (n = 1,910), 14.7% reported using clergy services. In a multivariable logistic regression model, factors associated with increased likelihood of service use included being Black, aged 35–54 years, a lifetime history of alcohol dependence, major depressive disorder, and personality disorder. Clergy may benefit from training to identify alcohol use problems and serve an important role in making treatment referrals. (Am J Addict 2010;00:1–7)     

Advanced Airway Type and Its Association with Chest Compression Interruptions During Out-of-Hospital Cardiac Arrest Resuscitation Attempts

Objective: To assess interruptions in chest compressions associated with advanced airway placement during cardiopulmonary resuscitation (CPR) of out-of-hospital cardiac arrest (OHCA) victims. Methods: The method used was observational analysis of prospectively collected clinical and defibrillator data from 339 adult OHCA victims, excluding victims with <5 minutes of CPR. Interruptions in CPR, summarized by chest compression fraction (CCF), longest pause, and the number of pauses greater than 10 seconds, were compared between patients receiving bag valve mask (BVM), supraglottic airway (SGA), endotracheal intubation (ETI) via direct laryngoscopy (DL), and ETI via video laryngoscopy (VL). Secondary outcomes included first pass success and the effect of multiple airway attempts on CPR interruptions. Results: During the study period, paramedics managed 23 cases with BVM, 43 cases with SGA, 148 with DL, and 125 with VL. There were no statistically significant differences between the airway groups with regard to longest compression pause (BVM 18 sec [IQR 11–33], SGA 29 sec [IQR 15–65], DL 26 sec [IQR 12–59], VL 22 sec [IQR 14–41]), median number of pauses greater than 10 seconds (BVM 2 [IQR 1–3], SGA 2 [IQR 1–3], DL 2 [IQR 1–4], VL 2 [IQR 1–3]), or CCF (0.92 for all groups). However, each additional attempt following failed initial DL was associated with an increase in the risk of additional chest compression pauses (relative risk 1.29, 95% confidence interval 1.02–1.64). Such an association was not observed with additional attempts using VL or SGA. First pass success was highest with SGA (77%), followed by between DL (68%) and VL (67%); these differences were not statistically significant. Conclusions: While summary measures of chest compression delivery did not differ significantly between airway classes in this observational study, repeated attempts following failed initial DL during cardiopulmonary resuscitation were associated with an increase in the number of pauses in chest compression delivery observed     

冠状动脉粥样硬化ADAMTS7新位点的发现和冠状动脉粥样硬化中ABO位点与心肌梗死的相关性:两项全基因组关联研究

<正>背景:该研究旨在评价在现有的冠状动脉粥样硬化的病变中,遗传因素对粥样硬化斑块进展及特异性心肌梗死是否存在显著作用。方法:对欧洲后裔参与者冠状动脉造影表型进行了两项全基因组关联研究(GWAS),为寻找冠状动脉疾病(CAD)易感性基因位点,研究比较了有异常(n=12393)和无异常的(对照组n=7383)个体;为寻找心肌梗死易感性基因位点,也同时比较了造影证实存在CAD并且有心肌梗死的个体(n=5783)与虽有CAD但无心肌梗死的个体(n=3644)。     

Immunophenotypic aspects of cylindroma and nodular hidradenoma

Background Some adnexal tumours have many controversies about their histogenesis. Objectives To evaluate the eccrine and/or apocrine differentiation phenotype in cases of cylindroma and clear cell hidradenoma with CD15 and p63 antibodies. Methodology Slides and blocks of six cases of cylindroma and seven cases of nodular hidradenoma (clear cells) were analyzed by the technique of immunohistochemistry with CD15 and p63 antibodies. Results In all cases of cylindroma we obtained negative results for CD15 antibody and positive for p63 antibody. In five of seven cases of nodular hidradenoma (clear cell), we could easily observe clear cells between 20% and 50% of tumour cells. In the two other cases, cystic lesions were present and occasional clear cells could be seen. The reaction with CD15 antibody was positive in granular and cytoplasmic pattern in six of seven cases, especially in cells with suggestive clear cytoplasm in lower proportion than this clear cells could be seen in haematoxylin and eosin. The positivity for p63 antibody, nuclear pattern, was observed in six of seven cases, in the major part of tumour cells. In only one case, the positivity was in 20% of cells. Limitation Samples are in small number because these are relatively rare tumours. Conclusions The present study suggests eccrine origin for both tumours: cylindroma and clear cell hidradenoma.