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This study examined reactions of part-time MBA students (n = 199) and undergraduate business students (n = 220) to the affair involving U.S. President Bill Clinton and White House intern Monica Lewinsky prior to Clinton's impeachment by the House of Representatives. Consistent with research on attitudes toward workplace romance in the private sector, women believed that this affair occurring in the public sector represented a more serious problem for the nation and more than men were inclined to prefer that some type of action, e.g., resignation or impeachment, be taken. Implications of the results are discussed.
The study examined what factors led pastors to say something either negative or positive about former President Clinton's affair with Monica Lewinsky for a sample from "Middletown." There was no significant difference between three Protestant categories (Holiness/Pentecostal, white conservative Protestant, and mainline Protestant) in whether ministers said something or not. Analysis for those who said something indicated that the ministers who made the most critical statements in their sermons were from the most conservative/orthodox of our category of churches, i.e., Holiness/Pentecostal congregations, from the strictest churches and from churches with the greatest number of Republicans (betas were .30, .26, and .19, respectively). Also, members of Holiness/Pentecostal churches were more likely to be working class but not more Republican. Possible explanations are discussed.
Objective: The goal was to investigate the relationship between methodological adherence and clinical outcomes in Progressive Resistance Training (PRT) for Parkinson's Disease (PD), specifically identifying why findings of "superiority" over active controls remain inconsistent. Methods: This umbrella review utilized a multi-stage process to identify a sample of the primary literature for methodological analysis. An initial search identified 38 systematic reviews published within the specified timeframe. From the reference lists of these reviews, a subset of 34 primary clinical studies was purposefully selected. Inclusion was prioritized for studies providing comprehensive methodological data on PRT protocols and standardized clinical outcomes. Interventions were evaluated using a three-tiered framework: (1) training protocol with specifications of Frequency, Intensity, Time, Type, Volume, and Progression (FITT-VP) (General Exercise), (2) FITT-VP integrated with the American College of Sports Medicine (ACSM) Supplementary Guidelines (Integrated Guidelines), and (3) principles of progression (mechanistic growth). Studies were categorized by control type (active (e.g., aerobic or balance), n = 26; passive (e.g., standard care or no exercise), n = 8). Results: In trials that compared PRT with an active control group, PRT achieved clinical superiority in 57% (n = 15) of trials and 46% (n = 12) when focusing on trials with an effect on specific functional or balance outcomes. Among these successful interventions, 75% maintained high adherence (≥70%) to the Integrated Guidelines, and 58% maintained high adherence to the principles of progression. In the 53% (n = 14) of studies where PRT was found non-superior (equivalent or inferior in functional or balance outcomes) to an active control, 0% met the high adherence threshold for progression. While general FITT-VP compliance remained high (78%), the failure to implement systematic load, specificity, and variation served as a definitive barrier to competitive superiority. In the 100% of studies where PRT outperformed passive controls, high progression was present in 57% of cases. This may suggest that while a baseline resistance stimulus outperforms inactivity, it is fundamentally insufficient to outperform other active clinical therapies. Conclusions: This umbrella review indicates that adherence to the principles of progression may be an important factor influencing the clinical outcomes of PRT in individuals with PD. The variability observed in the current literature suggests that inconsistent application of established exercise frameworks-rather than the failure of the modality itself-could be a contributing element to the reported "inconclusiveness." To potentially enhance functional outcomes and the comparative effectiveness of PRT, future research should consider prioritizing structured adherence to FITT-VP, Integrated Guidelines, and progression-based frameworks. Establishing a 70% adherence threshold is proposed as a potential benchmark to improve protocol consistency and support rehabilitation efficacy in this population.
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We examine links between factual recall, emotion and constructions of normativity in narrative accounts, using as an empirical case President Clinton's descriptions of his relationship with Monica Lewinsky. We analyse those accounts in the sequences of talk in which they occurred, under Grand Jury cross-examination. Clinton's accounts of Lewinsky were part of how he attended to issues alive in court concerning himself, including his possible exploitation and abuse of power in an asymmetrical relationship; his motives, sincerity, credibility and intentions; and, indirectly, his fitness for office as President. Analysis focuses on how Clinton's portrayal of Lewinsky accomplished a reflexive portrayal of himself, not as mendacious and exploitative, but as caring, responsible, sincere, rational and consistent, while reducing the scope and implications of their admitted sexual relationship. This study is linked to a broader discursive psychology of factual description, memory, mental and emotional states, and their relevance to the larger business of institutional settings.
CD74 is receptor for the cytokine macrophage migration inhibitory factor (MIF). MIF binding to CD74 induces a signaling cascade resulting in the release of its cytosolic intracellular domain (CD74-ICD) that serves as a transcriptional regulator in chronic lymphocytic leukemia (CLL) cells. In the current study, we investigated the transcriptional and regulatory function of CD74-ICD in normal B cells. We show that following activation, CD74-ICD forms a complex in the cytosol with transcription factors, like PAX5, and binds the chromatin at a significantly higher number of sites compared with its binding in CLL cells. The expression of a major portion of these bound genes is shut down in the malignant cells. The CD74-ICD:PAX5 complex binds the promoter areas of a tumor-suppressor gene, DMTF1, and downregulates its expression through inhibition of transcription. These findings can help identify novel therapeutic pathways that are regulated during oncogenic transformation and are targets for future treatments.
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of small, mature CD5+ B lymphocytes in the blood, marrow, and lymphoid organs. Cell survival depends on interaction with the leukemic microenvironment. However, the mechanisms controlling CLL cell survival are still incompletely understood. Macrophage migration-inhibitory factor (MIF), a pro-inflammatory and immunoregulatory chemokine-like cytokine, interacts with CXCR4, a major chemokine receptor, as well as with CD74/invariant chain, a single-pass type II receptor. In this study, we analyzed the roles of CXCR4, CD74, and MIF in CLL. Mononuclear cells from patients with hematological malignancies were analyzed for coexpression of CXCR4 and CD74 by flow cytometry. Strong co- and overexpression of CXCR4 and CD74 were observed on B cells of CLL patients (n = 10). Survival and chemotaxis assays indicated that CXCR4 and CD74 work together to enhance the survival and migration of malignant cells in CLL. Blockade of the receptors, either individually or in combination, promoted cell death and led to an abrogation of MIF-driven migration responses in murine and human CLL cells, suggesting that joint activation of both receptors is crucial for CLL cell survival and mobility. These findings indicate that the MIF/CXCR4/CD74 axis represents a novel therapeutic target in CLL.
Ten excerpts of both President Clinton's Grand Jury Testimony of August 17, 1998 and of each of two interviews with Hillary Rodham Clinton (Today Show, January 27, 1998; Good Morning America, January 28, 1998) were analyzed. In all of them, the topic under discussion was the President's insistence on his innocence in the Lewinsky case. Comparisons between the President and First Lady revealed long and short within-speaker pauses, respectively. His replies to questions average more than twice the length of hers. Comparisons were also made with other speech genres, including modern presidential inaugural rhetoric. In particular, President Clinton's statement of his innocence at the conclusion of an educational press conference on January 26, 1998 and his prepared statement at the beginning of his Grand Jury Testimony were found to vary notably from all the other corpora. Both are characterized by several of Ekman's (1985, p. 286) behavioral cues for the detection of deception.
Four studies examined status conferral (decisions about who should be granted status). The studies show that people confer more status to targets who express anger than to targets who express sadness. In the 1st study, participants supported President Clinton more when they viewed him expressing anger about the Monica Lewinsky scandal than when they saw him expressing sadness about the scandal. This effect was replicated with an unknown politician in Study 2. The 3rd study showed that status conferral in a company was correlated with peers' ratings of the workers' anger. In the final study, participants assigned a higher status position and a higher salary to a job candidate who described himself as angry as opposed to sad. Furthermore, Studies 2-4 showed that anger expressions created the impression that the expresser was competent and that these perceptions mediated the relationship between emotional expressions and status conferral.
Multiple long-term studies have demonstrated a propensity for breast cancer recurrences to develop near the site of the original breast cancer. Recognition of this local recurrence pattern laid the foundation for the development of accelerated partial breast irradiation (APBI) approaches designed to limit the radiation treatment field to the site of the malignancy. However, there is a paucity of data regarding the efficacy of APBI in general, and intraoperative radiotherapy (IORT), in particular, for the management of ductal carcinoma in situ (DCIS). As a result, use of APBI, remains controversial. A prospective nonrandomized trial was designed to determine if patients with pure DCIS considered eligible for concurrent IORT based on preoperative mammography and contrast-enhanced magnetic resonance imaging (CE-MRI) could be successfully treated using IORT with minimal need for additional therapy due to inadequate surgical margins or excessive tumor size. Between November 2007 and June 2014, 35 women underwent bilateral digital mammography and bilateral breast CE-MRI prior to selection for IORT. Patients were deemed eligible for IORT if their lesion was ≤4 cm in maximal diameter on both digital mammography and CE-MRI, pure DCIS on minimally invasive breast biopsy or wide local excision, and considered resectable with clear surgical margins using breast-conserving surgery (BCS). Postoperatively, the DCIS lesion size determined by imaging was compared with lesion size and surgical margin status obtained from the surgical pathology specimen. Thirty-five patients completed IORT. Median patient age was 57 years (range 42-79 years) and median histologic lesion size was 15.6 mm (2-40 mm). No invasive cancer was identified. In more than half of the patients in our study (57.1%), MRI failed to detect a corresponding lesion. Nonetheless, 30 patients met criteria for negative margins (i.e., margins ≥2 mm) whereas five patients had positive margins (<2 mm). Two of the five patients with positive margins underwent mastectomy due to extensive imaging-occult DCIS. Three of the five patients with positive margins underwent successful re-excision at a subsequent operation prior to subsequent whole breast irradiation. A total of 14.3% (5/35) of patients required some form of additional therapy. At 36 months median follow-up (range of 2-83 months, average 42 months), only two patients experienced local recurrences of cancer (DCIS only), yielding a 5.7% local recurrence rate. No deaths or distant recurrences were observed. Imaging-occult DCIS is a challenge for IORT, as it is for all forms of breast-conserving therapy. Nonetheless, 91.4% of patients with DCIS were successfully managed with BCS and IORT alone, with relatively few patients requiring additional therapy.
B cells have essential functions in multiple sclerosis and in its mouse model, experimental autoimmune encephalomyelitis, both as drivers and suppressors of the disease. The suppressive effects are driven by a regulatory B cell (Breg) population that functions, primarily but not exclusively, via the production of IL-10. However, the mechanisms modulating IL-10-producing Breg abundance are poorly understood. Here we identify SLAMF5 for controlling IL-10+ Breg maintenance and function. In EAE, the deficiency of SLAMF5 in B cells causes accumulation of IL10+ Bregs in the central nervous system and periphery. Blocking SLAMF5 in vitro induces both human and mouse IL-10-producing Breg cells and increases their survival with a concomitant increase of a transcription factor, c-Maf. Finally, in vivo SLAMF5 blocking in EAE elevates IL-10+ Breg levels and ameliorates disease severity. Our results suggest that SLAMF5 is a negative moderator of IL-10+ Breg cells, and may serve as a therapeutic target in MS and other autoimmune diseases.
Breast conservation therapy is a practical alternative to mastectomy for the treatment of ductal carcinoma in situ (DCIS). The role of radiation therapy after excision for DCIS has been debated, however, its value in reducing recurrence has been proven by multiple prospective randomized trials and is well accepted. We examined a prospective database of 260 patients treated for DCIS with excision and radiation from 1979 to 2002. Two different treatment regimens were examined for local recurrence-free survival. Patients treated with radiation therapy 4 days per week were compared with patients treated 5 days per week. The total doses were similar for both groups; boost types differed. Local recurrence as a function of other factors, including nuclear grade, comedonecrosis, and margin width was evaluated. The median time to local recurrence was 61 months for patients treated 4 days per week compared with 52 months for patients treated 5 days per week (P = not significant). There was no statistical difference in the Kaplan-Meier detailing the probability of local recurrence-free survival for patients treated 4 days per week versus patients treated 5 days per week. Overall, cosmetic results between the two groups were equivalent. The comparison of two different radiation treatment regimens shows no difference in local disease-free survival or cosmetic result.
A case of fetal ovarian cyst associated with transient ascites is presented. The cyst showed serial changes from a fluid-debris interface to an anechoic structure. The changing ultrasonographic appearance of the cyst, disappearance of ascites and postnatal spontaneous resolution, suggests in utero torsion of the cyst.
Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known. We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding. The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P<0.001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P<0.001) and 1.61% with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P<0.001). The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), and 2.71% (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.008), and the corresponding rates of the key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% versus 3.85% (hazard ratio, 0.87; 95% CI, 0.78 to 0.96; P=0.005), and 4.23% (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.32). Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. (Funded by Daiichi Sankyo Pharma Development; ENGAGE AF-TIMI 48 ClinicalTrials.gov number, NCT00781391.).
In most people worldwide intestinal lactase expression declines in childhood. In many others, particularly in Europeans, lactase expression persists into adult life. The lactase persistence phenotype is in Europe associated with the -13910*T single nucleotide variant located 13,910 bp upstream the lactase gene in an enhancer region that affects lactase promoter activity. This variant falls in an Oct-1 binding site and shows greater Oct-1 binding than the ancestral variant and increases enhancer activity. Several other variants have been identified very close to the -13910 position, which are associated with lactase persistence in the Middle East and Africa. One of them, the -14010*C, is associated with lactase persistence in Africa. Here we show by deletion analysis that the -14010 position is located in a 144 bp region that reduces the enhancer activity. In transfections the -14010*C allele shows a stronger enhancer effect than the ancestral -4010*G allele. Binding sites for Oct-1 and HNF1α surrounding the -14010 position were identified by gel shift assays, which indicated that -14010*C has greater binding affinity to Oct-1 than -14010*G.
Herein we describe the discovery of ACP-105 (1), a novel and potent nonsteroidal selective androgen receptor modulator (SARM) with partial agonist activity relative to the natural androgen testosterone. Compound 1 was developed from a series of compounds found in a HTS screen using the receptor selection and amplification technology (R-SAT). In vivo, 1 improved anabolic parameters in a 2-week chronic study in castrated male rats. In addition to compound 1, a number of potent antiandrogens were discovered from the same series of compounds whereof one compound, 13, had antagonist activity at the AR T877A mutant involved in prostate cancer.
> Objective: The aim of our study was to evaluate sonographic and Doppler detectable differences in umbilical coiling index and fetoplacental circulation of discordant twins. Study Design: Doppler blood flow studies in 13 pairs of concordant and 20 pairs of discordant twins were performed from umbilical artery, middle cerebral artery, inferior vena cava, and ductus venosus. Flow studies were compared and correlated with the antenatal sonographic coiling index and the actual umbilical cord length, number of vascular helices, and birth weight. All studies were performed within 72 h before delivery. Pulsatility index (PI) values were calculated for the arteries and preload index (PLI) values for the veins. The umbilical coiling index (CI) was calculated using sonographic longitudinal views of cord vessels from several segments antenatally and by dividing the total number of helices by cord length (cm) postnatally. Discordancy was defined as a more than 20% intrapair actual birth weight difference. For all these index values the intertwin differences (Delta values) were calculated by subtracting the values obtained in the larger twin with those of the smaller twin. Results: The mean +/- SD intertwin difference in umbilical coiling index was 27.4 +/- 10.5% in the antepartum period and 28.9 +/- 10.0% after birth. Regression analysis showed a significant linear trend (r = 0.77, P < 0.001) between intertwin birth weight difference (DeltaBW) and intertwin coiling index difference (DeltaCI). A good correlation was found between DeltaCI and DeltaPLI in the ductus venosus (r = 0.63, P < 0.05), DeltaPLI in the inferior vena cava (r = 0.51, P < 0.005), and DeltaPI in the middle cerebral artery (r = 0.44, P < 0.05). Conclusions: Intertwin difference in antepartum umbilical coiling index can be determined by ultrasound and correlates well with: 1) the actual difference in coiling indices at birth, 2) the intertwin birth weight difference and 3) the intertwin Doppler flow characteristics in the fetal cerebral and venous circulation.
It has recently been shown that NDRG2 mRNA is down-regulated or undetectable in several human cancers and cancer cell-lines. Although the function of NDRG2 is unknown, high NDRG2 expression correlates with improved prognosis in high-grade gliomas. The aim of this study has been to examine NDRG2 mRNA expression in colon cancer. By examining affected and normal tissue from individuals with colorectal adenomas and carcinomas, as well as in healthy individuals, we aim to determine whether and at which stages NDRG2 down-regulation occurs during colonic carcinogenesis. Using quantitative RT-PCR, we have determined the mRNA levels for NDRG2 in low-risk (n = 15) and high-risk adenomas (n = 57), colorectal carcinomas (n = 50) and corresponding normal tissue, as well as control tissue from healthy individuals (n = 15). NDRG2 levels were normalised to beta-actin. NDRG2 mRNA levels were lower in colorectal carcinomas compared to normal tissue from the control group (p < 0.001). When comparing adenomas/carcinomas with adjacent normal tissue from the same individual, NDRG2 expression levels were significantly reduced in both high-risk adenoma (p < 0.001) and in colorectal carcinoma (p < 0.001). There was a trend for NDRG2 levels to decrease with increasing Dukes' stage (p < 0.05). Our results demonstrate that expression of NDRG2 is down-regulated at a late stage during colorectal carcinogenesis. Future studies are needed to address whether NDRG2 down-regulation is a cause or consequence of the progression of colorectal adenomas to carcinoma.
We present a new prognostic classification designated the Van Nuys classification for ductal carcinoma-in-situ (DCIS). The classification combines high nuclear grade and comedo-type necrosis to predict clinical recurrence. Three groups of DCIS patients were defined by the presence or absence of high nuclear grade and comedo-type necrosis: 1--non-high-grade DCIS without comedo-type necrosis, 2--non-high-grade DCIS with comedo-type necrosis, 3--high-grade DCIS with or without comedo-type necrosis. There were 31 local recurrences in 238 patients after breast-conservation surgery 3.8% (3/80) in group 1, 11.1% (10/90) in group 2, and 26.5% (18/68) in group 3. The 8-year actuarial disease-free survivals were 93%, 84%, and 61%, respectively (all p < or = 0.05). The Van Nuys classification defines three distinct and easily recognisable groups, each of which has a different likelihood of local recurrence if treated with breast conservation.