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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.

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.

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.

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.

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.

The UDP glucuronosyltransferases (UGT) of the gastrointestinal (GI) tract have a crucial role in protection against the toxic effects of lipophilic chemicals in the environment. UGTs such as UGT1A7, UGT1A8, and UGT1A10 are exclusively expressed in gastrointestinal tissues, each with a unique tissue distribution pattern that is subject to interindividual variation. The factors regulating this tissue-specific expression and that contribute to variability are beginning to be elucidated. Studies on the UGT1A7, 1A8, 1A9, and 1A10 gene promoters in Caco-2 cells, an in vitro model of enterocytes of the gastrointestinal tract, have identified the caudal homeodomain transcription factor, Cdx2, as an important regulator of the UGT1A8 and 1A10 gene proximal promoters. This transcription factor is found exclusively in the small intestine and colon: it is absent in the gastric epithelium and the esophagus. Cdx2 regulates the UGT1A8 and 1A10 promoters in cooperation with hepatocyte nuclear factor 1alpha (HNF1alpha). It is noteworthy that UGT1A7 is not expressed in gastrointestinal tissue distal to the gastric mucosa and does not contain a Cdx2 binding site in its proximal promoter. Transcription factors, including Sp1, which differentially bind to the initiator regions of the UGT1A8, 1A9, and 1A10 promoters, also contribute to the differences in expression of these UGTs in Caco-2 cells. The identification of important regulatory regions of UGT genes expressed in the gastrointestinal tract, and the transcription factors that bind to these regions, will aid in the elucidation of factors that contribute to interindividual differences in gastrointestinal UGT expression. In turn, this will lead to further understanding of interindividual variation in the capacity of the GI tract to metabolize lipophilic chemicals and to act as a barrier to dietary toxins and orally administered drugs.

The human UDP-glucuronosyltransferases, UGT1A8, 1A9, and 1A10, are closely related in sequence and have a major role in the elimination of lipophilic chemicals by glucuronidation. UGT1A8 and 1A10 are expressed exclusively in the gastrointestinal tract, whereas UGT1A9 is expressed mainly in the liver and kidneys. To determine the factors contributing to the extrahepatic expression of these UDP-glucuronosyltransferases, we have cloned and characterized the promoters of the UGT1A8, 1A9, and 1A10 genes and studied their regulation in the colon cell line, Caco2. Their transcription start sites were mapped, and a functional overlapping Sp1/initiator-like site was identified which strongly contributed to UGT1A8 and 1A10 promoter activity. The high promoter activity of UGT1A8 and 1A10 correlated with the binding of nuclear proteins (complex B) to this region. Two-bp differences in the corresponding site in the UGT1A9 promoter prevented the binding of complex B and reduced promoter activity. Although Sp1 was able to bind to the Sp1/initiator-like site, its binding was dispensable for promoter activity. However, the binding of Sp1 to a second Sp1 site 30 bp 5' to the Sp1/initiator-like site greatly enhanced the activity of the UGT1A8 and 1A10 promoters. These results provide evidence that the UGT1A8, 1A9, and 1A10 genes are differentially regulated through an initiator element in their 5'-flanking regions.

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Hematopoietic stem and progenitor cells (HSPCs) are a small population of undifferentiated cells that have the capacity for self-renewal and differentiate into all blood cell lineages. These cells are the most useful cells for clinical transplantations and for regenerative medicine. So far, it has not been possible to expand adult hematopoietic stem cells (HSCs) without losing their self-renewal properties. CD74 is a cell surface receptor for the cytokine macrophage migration inhibitory factor (MIF), and its mRNA is known to be expressed in HSCs. Here, we demonstrate that mice lacking CD74 exhibit an accumulation of HSCs in the bone marrow (BM) due to their increased potential to repopulate and compete for BM niches. Our results suggest that CD74 regulates the maintenance of the HSCs and CD18 expression. Its absence leads to induced survival of these cells and accumulation of quiescent and proliferating cells. Furthermore, in in vitro experiments, blocking of CD74 elevated the numbers of HSPCs. Thus, we suggest that blocking CD74 could lead to improved clinical insight into BM transplant protocols, enabling improved engraftment.

Laparoscopic partial nephrectomy (LPN) is a challenging surgery that requires precise tissue cutting and meticulous hemostasis under warm ischemia conditions. In this study, we tested the feasibility of performing LPN using CO2 laser energy transmitted through a specialized flexible mirror optical fiber. General anesthesia and pneumoperitoneum were induced in 7 farm pigs. Various portions of a kidney, either a pole or a midportion of the kidney, were removed using a novel flexible fiber to transmit CO2 laser energy set at a power of 45W and energy per pulse of 100mJ. The collecting system was approximated with a suture or 2, but no hemostatic measures were taken besides applying a few pulses of the laser to bleeding points. The pigs were sacrificed 3 wk later. Average renal mass removed was 18% of the total kidney weight. All pigs tolerated surgery well. Sharp renal cutting was accomplished in a single continuous incision, with minimal tissue charring and minimal blood loss (<10cc) in all animals. Necropsy revealed no peritoneal or retroperitoneal abnormalities. Histologic examination of the cut surface showed a thin sector of up to 100 m of coagulation necrosis. We report on the first LPN done using a CO2 laser transmitted through a flexible fiber in an animal model. This novel application of the CO2 laser produced excellent parenchymal incision and hemostasis along with minimal damage to adjacent renal tissue, thus, potentially shortening ischemia time and kidney function loss. Further studies comparing this laser to standard technique are necessary to verify its usefulness for partial nephrectomy.

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.

CD74 is a cell-surface receptor for the cytokine macrophage migration inhibitory factor. Macrophage migration inhibitory factor binding to CD74 induces its intramembrane cleavage and the release of its cytosolic intracellular domain (CD74-ICD), which regulates cell survival. In the present study, we characterized the transcriptional activity of CD74-ICD in chronic lymphocytic B cells. We show that following CD74 activation, CD74-ICD interacts with the transcription factors RUNX (Runt related transcription factor) and NF-&#x3ba;B and binds to proximal and distal regulatory sites enriched for genes involved in apoptosis, immune response, and cell migration. This process leads to regulation of expression of these genes. Our results suggest that identifying targets of CD74 will help in understanding of essential pathways regulating B-cell survival in health and disease.

To examine the feasibility of antepartum fetal pulse oximetry by using a specially designed probe. Twenty multiparous patients at term planned for induction of labor. The probe was passed through the cervix and held against the fetal scalp. Two laser diodes provided light in the near-infrared spectral region. Only reflected signals of both wavelengths which were consistent in pulse frequency and phase and with an AC/DC ratio of > 0.02% were considered usable. Usable measurements were obtained in 16 out of 20 cases. Overall usable signal time was 45% (range 30.2-61.5%). There was no accidental rupture of membranes. Mean fetal oxygen saturation was 76.1 +/- 6.2%. This study has shown that antepartum fetal pulse oximetry is feasible once a specially designed probe and signal analysis system are used.