Chemokines are important inflammatory mediators, and regulate disease due to viral infection. This article will discuss scientific papers published primarily since June 2002 that have introduced new ...concepts in how chemokines regulate the inflammatory response to specific viruses.
Acute respiratory viruses commonly induce inflammatory chemokines such as CCL3 (also known as macrophage inflammatory protein-1alpha) and CCL5 (RANTES), which can amplify inflammatory responses leading to immunopathology. Where single agent therapy fails, combination antiviral and anti-CCL3 treatment is synergistic and able to prevent mortality in mice infected with the highly lethal pneumonia virus of mice. Human herpesvirus-6 also induces production of CCL3 and CCL5, which are able to block HIV-1 replication in coinfected human lymphoid tissue. On this basis, Margolis has proposed a new and general approach to the treatment and prevention of infection by viral pathogens.
Inflammatory chemokines play both beneficial and harmful roles in infectious diseases caused by viruses. Blocking them or using them as immunomodulators, depending on the virus, may be rational approaches to treatment or prevention of disease. With regard to blockade, combination antiviral/antichemokine therapy is a new strategy worth considering as a general therapeutic approach to viral infections, including severe acute respiratory syndrome (SARS). With regard to immunomodulation, use of weak or attenuated viruses to skew the local cytokine network to a configuration able to inhibit a pathogen is a new and interesting concept, but is fraught with important safety issues. Identifying master chemokines to target or exploit in human viral infection is a major opportunity and challenge for clinical immunologists.
Vascular causes of dementia are increasing in importance because of the aging of the population. Biological markers to distinguish patients with vascular dementia (VaD) from Alzheimer disease (AD) ...would be very useful. Because cerebrovascular disease increases expression of brain matrix metalloproteinases (MMPs) and tissue inhibitors to metalloproteinases (TIMPs), we hypothesized that MMPs would be elevated in the cerebrospinal fluid (CSF) of patients with VaD, but not in patients with AD.
Fifteen patients with VaD were identified, including dementia caused by multiple infarcts and progressive dementia caused by disease of the small cerebral blood vessels. Patients were followed-up for 4 to 10 years to confirm the diagnosis. Thirty patients with AD were also studied. Patients had CSF collected at their initial evaluation. Gelatinase A (MMP-2) and gelatinase B (MMP-9) were quantified by gelatin-substrate zymography, and TIMPs were measured by reverse zymography. Control CSF was obtained from neurologically normal subjects.
MMP-9 levels were significantly elevated in the CSF of VaD patients compared either to those with AD (P<0.0001) or to controls. MMP-2, TIMP-1, and TIMP-2 were similar in patient groups and controls.
Patients with multiinfarct and small vessel VaD have elevated levels of MMP-9 in the CSF compared with AD and controls. Although CSF MMP-9 increases in other neurological conditions and is not specific for VaD, it could provide an additional biological marker for the separation of patients with VaD and AD.
Purpose: To assess the outcome of a multi-institutional, national cooperative group study attempting functional preservation of the anorectum for patients with limited, distal rectal cancer.
Methods ...and Materials: Between September 21, 1989 and November 1, 1992, a Phase II trial of sphincter-sparing therapy was conducted for patients with clinically mobile rectal cancers located below the pelvic peritoneal reflection. Protocol treatment was designed for patients who were, in the judgement of their attending surgeon, unsuitable for anal sphincter conservation in the context of anterior resection, and would have required abdominoperineal resection (APR) as conventional surgical therapy. Primary cancers were estimated to be 4 cm or less in largest clinical diameter, and occupied 40% or less of the rectal circumference. Chest radiography and computerized axial tomography (CT) of the abdomen and pelvis excluded patients with overt lymphatic or hematogenous metastases. Protocol surgery was intended to remove the primary cancer by en-bloc, transmural excision of an ellipse of rectal wall by transanal, transcoccygeal, or trans-sacral technique, while conserving the anal sphincter. Based on tumor size, T classification, grade, and adequacy of surgical margins, patients were allocated to one of three treatment assignments: observation, or adjuvant treatment with 5-fluorouracil (5-FU) and one of two different dose levels of local-regional radiation. After completion of protocol therapy, patients were observed with follow-up that included periodic general physical and rectal examination, determinations of CEA, abdominopelvic CT, chest radiography, and surveillance endoscopy. Sixty-five eligible and analyzable patients were registered.
Results: With minimum follow-up of 5 years and median follow-up of 6.1 years, 11 patients have failed: 3 patients recurred local-regionally only, 3 patients had distant failure alone, and 5 patients manifested local-regional and distant failure. Eight patients died of intercurrent illness. Local-regional failure correlated with T-category revealed: T
1 1/27 (4%), T
2 4/25 (16%), and T
3 3/13 (23%). Local-regional failure escalated with percentage involvement of the rectal circumference: 2/31 (6%) among patients with cancers involving 20% or less of the rectal circumference, and 6/34 (18%) among patients with cancers involving 21–40% of the circumference. Distant dissemination rose with T-category with 1/27 (4%) T
1, 3/25 (12%) T
2, and 4/13 (31%) T
3 patients manifesting hematogenous spread. Eight patients (12%) required temporary or permanent colostomy. Five of 8 patients with local-regional recurrence achieved local-regional control with management including surgery, although 4 of these patients subsequently developed distant dissemination. Three patients (5%) had persistent, uncontrolled, local disease. Actuarial freedom from pelvic relapse at 5 years is 88% based on the entire study population, and 86% for the less favorable patients treated with adjuvant radiation and 5-FU.
Conclusion: Conservative, sphincter-sparing therapy is a feasible alternative treatment for selected patients with limited cancer involving the middle and lower rectum. Risk of both local and distant failure appears to escalate with increasing T-category (depth of invasion). Results achieved in the multi-institutional, cooperative group setting approximate results reported from single institutions.
As sites of documentary preservation rooted in various national and social contexts, artifacts of culture, and places of uncovering, archives provide tangible evidence of memory for individuals, ...communities, and states. Archives also define memory institutionally within prevailing political systems and cultural norms. By assigning the prerogatives of record keeper to the archivist, whose acquisition policies, finding aids, and various institutionalized predilections mediate between scholarship and information, archives produce knowledge, legitimize political systems, and construct identities. Far from being mere repositories of data, archives actually embody the fragments of culture that endure as signifiers of who we are, and why. The essays in Archives, Documentation, and Institutions of Social Memory conceive of archives not simply as historical repositories but as a complex of structures, processes, and epistemologies situated at a critical point of the intersection between scholarship, cultural practices, politics, and technologies.
More than seventy years since the Bolsheviks came to power, there is still no comprehensive study of workers' activism in history's first successful workers' revolution. Strikes and Revolution in ...Russia, 1917 is the first effort in any language to explore this issue in both quantitative and qualitative terms and to relate strikes to the broader processes of Russia's revolutionary transformation. Diane Koenker and William Rosenberg not only provide a new basis for understanding essential elements of Russia's social and political history in this critical period but also make a strong contribution to the literature on European labor movements. Using statistical techniques, but without letting methodology dominate their discussion, the authors examine such major problems as the mobilization of labor and management, factory relations, perceptions, the formation of social identities, and the relationship between labor protest and politics in 1917. They challenge common assumptions by showing that much strike activity in 1917 can be understood as routine, but they are also able to demonstrate how the character of strikes began to change and why.
Originally published in 1990.
ThePrinceton Legacy Libraryuses the latest print-on-demand technology to again make available previously out-of-print books from the distinguished backlist of Princeton University Press. These paperback editions preserve the original texts of these important books while presenting them in durable paperback editions. The goal of the Princeton Legacy Library is to vastly increase access to the rich scholarly heritage found in the thousands of books published by Princeton University Press since its founding in 1905.
•A risk-adapted clinical trial for IDH2-mutant AML demonstrates feasibility of achieving responses with upfront enasidenib monotherapy.•Mechanisms of therapeutic resistance include clonal evolution ...and inform future directions of investigation with enasidenib.
Enasidenib is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML sub-study, we applied a risk-adapted approach to assess the efficacy of enasidenib monotherapy for patients 60 years and older with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated mutant IDH2 was in the dominant leukemic clone. Patients for whom enasidenib monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled on a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to enasidenib alone demonstrated efficacy, with a composite complete response(cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and one dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of enasidenib monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as NCT03013998.
Kidney failure is an important outcome for patients, clinicians, researchers, healthcare systems, payers, and regulators. However, no harmonized international consensus definitions of kidney failure ...and key surrogates of progression to kidney failure exist specifically for clinical trials. The International Society of Nephrology convened an international multi-stakeholder meeting to develop consensus on this topic. A core group, experienced in design, conduct, and outcome adjudication of clinical trials, developed a database of 64 randomized trials and the 163 included definitions relevant to kidney failure. Using an iterative process, a set of proposed consensus definitions were developed and subsequently vetted by the larger multi-stakeholder group of 83 participants representing 18 different countries. The consensus of the meeting participants was that clinical trial kidney failure outcomes should be comprised of a composite that includes receipt of a kidney transplant, initiation of maintenance dialysis, and death from kidney failure; it may also include outcomes based solely on laboratory measurements of glomerular filtration rate: a sustained low glomerular filtration rate and a sustained percent decline in glomerular filtration rate. Discussion included important considerations, such as (i) recognition of existing nomenclature for kidney failure; (ii) applicability across resource settings; (iii) ease of understanding for all stakeholders; and (iv) avoidance of inappropriate complexity so that the definitions can be used across ranges of populations and trial methodologies. The final definitions reflect the consensus for use in clinical trials.
Identify the Endodontic Treatment Modalities Rosenberg, Paul A., DDS; Schindler, William G., DDS, MS; Krell, Keith V., DDS, MS, MA ...
Journal of endodontics,
12/2009, Letnik:
35, Številka:
12
Journal Article, Conference Proceeding
Recenzirano
Abstract Introduction This paper sought to determine the levels of evidence associated with treatment for specific diagnostic categories and the prognosis of treatment. Materials and Methods A review ...of the literature was conducted using MEDLINE, PubMed, Google Scholar and the Cochrane Database. The Journal of Endodontics, International Journal of Endodontics, Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology, Endodontic Topics, and Dental Traumatology were also searched. The bibliographies of relevant articles were manually searched. Conclusion The review found a low level of evidence to assess clinical treatment modalities. The development of higher levels of evidence to facilitate the selection of appropriate treatment modalities for each diagnostic category is recommended.
The purpose of this study was to assess the cross-sectional prevalence and characteristics of anxiety among patients with Alzheimer's disease (AD), as compared with patients with frontotemporal ...dementia (FTD), patients with vascular dementia (VaD), and normal control subjects. The authors used the anxiety subscale of the Neuropsychiatric Inventory (NPI), an instrument with established reliability and validity, to compare patients. Patients were identified in a query of the UCLA Alzheimer's Disease Center database and included 115 patients with probable AD, 43 patients with VaD, 33 patients with FTD, and 40 normal, elderly control subjects. Descriptive statistics were generated, and partial correlations, controlling for Mini-Mental State Examination (MMSE) score, were performed between the anxiety subscale and other behavioral features as measured by the NPI and the Functional Activities Questionnaire (FAQ). Relationships between cognitive status (as indicated by MMSE score) and anxiety were explored. Anxiety was reported more commonly in patients with VaD and FTD than in patients with AD. These differences remained significant (P<0.01) in an analysis of variance (ANOVA) after adjusting for age, age at onset, educational level, and MMSE score. In AD, anxiety was inversely related to MMSE score (i.e., worse with more severe dementia), was more prevalent among patients with a younger age at onset (under age 65), and correlated with disability as measured by the FAQ score. These data suggest that anxiety is common among patients with diverse forms of dementia. In AD, anxiety is most common in those with more severe cognitive deterioration and an earlier age at onset.
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