Showing papers by "Rush University Medical Center published in 1999"
TL;DR: Because the validity and reliability of some of the existing data are uncertain, caution is needed in an assessment of the information on this type of pain.
2,983 citations
TL;DR: Recombinant humanized anti-HER2 monoclonal antibody, administered as a single agent, produces durable objective responses and is well tolerated by women with HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease.
Abstract: PURPOSE: Overexpression of the HER2 protein occurs in 25% to 30% of human breast cancers and leads to a particularly aggressive form of the disease. Efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody as a single agent was evaluated in women with HER2-overexpressing metastatic breast cancer that had progressed after chemotherapy for metastatic disease. PATIENTS AND METHODS: Two hundred twenty-two women, with HER2-overexpressing metastatic breast cancer that had progressed after one or two chemotherapy regimens, were enrolled. Patients received a loading dose of 4 mg/kg intravenously, followed by a 2-mg/kg maintenance dose at weekly intervals. RESULTS: Study patients had advanced metastatic disease and had received extensive prior therapy. A blinded, independent response evaluation committee identified eight complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat population (95% confidence interval, 11% to 21%). The median duration of response ...
2,839 citations
TL;DR: This study has shown that a small molecule isolated for its ability to reversibly block p53-dependent transcriptional activation and apoptosis protected mice from the lethal genotoxic stress associated with anticancer treatment without promoting the formation of tumors.
Abstract: Chemotherapy and radiation therapy for cancer often have severe side effects that limit their efficacy. Because these effects are in part determined by p53-mediated apoptosis, temporary suppression of p53 has been suggested as a therapeutic strategy to prevent damage of normal tissues during treatment of p53-deficient tumors. To test this possibility, a small molecule was isolated for its ability to reversibly block p53-dependent transcriptional activation and apoptosis. This compound, pifithrin-alpha, protected mice from the lethal genotoxic stress associated with anticancer treatment without promoting the formation of tumors. Thus, inhibitors of p53 may be useful drugs for reducing the side effects of cancer therapy and other types of stress associated with p53 induction.
1,253 citations
TL;DR: Social and productive activities that involve little or no enhancement of fitness lower the risk of all cause mortality as much as fitness activities do, suggesting that in addition to increased cardiopulmonary fitness, activity may confer survival benefits through psychosocial pathways.
Abstract: Objectives: To examine any association between social, productive, and physical activity and 13 year survival in older people. Design: Prospective cohort study with annual mortality follow up. Activity and other measures were assessed by structured interviews at baseline in the participants9 homes Proportional hazards models were used to model survival from time of initial interview. Setting: City of New Haven, Connecticut, United States. Participants: 2761 men and women from a random population sample of 2812 people aged 65 and older. Main outcome measure: Mortality from all causes during 13 years of follow up. Results: All three types of activity were independently associated with survival after age, sex, race/ethnicity, marital status, income, body mass index, smoking, functional disability, and history of cancer, diabetes, stroke, and myocardial infarction were controlled for. Conclusions: Social and productive activities that involve little or no enhancement of fitness lower the risk of all cause mortality as much as fitness activities do. This suggests that in addition to increased cardiopulmonary fitness, activity may confer survival benefits through psychosocial pathways. Social and productive activities that require less physical exertion may complement exercise programmes and may constitute alternative interventions for frail elderly people. Key messages Little is known about predictors of survival among elderly people Physical activity is clearly good for health, but the potential benefits of social activities have not been studied Social and productive activities are as effective as fitness activities in lowering the risk of death Enhanced social activities may help to increase the quality and length of life
924 citations
TL;DR: This study used a large and ethnically diverse sample to address three questions relevant to including spirituality in QOL measurement: Does spirituality demonstrate a positive association with QOL?
Abstract: Most of the commonly used quality of life (QOL) instruments in oncology do not include spirituality as a core domain. However, previous research suggests that spirituality might be an important aspect of QOL for cancer patients and that it may, in fact, be especially salient in the context of life-threatening illness. This study used a large (n=1610) and ethnically diverse sample to address three questions relevant to including spirituality in QOL measurement: (1) Does spirituality demonstrate a positive association with QOL?; (2) Is this association unique?; and (3) Is there clinical utility in including spirituality in QOL measurement? Spirituality, as measured by the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being (FACIT-Sp), was found to be associated with QOL to the same degree as physical well-being, a domain unquestioned in its importance to QOL. The significant association between spirituality and QOL was unique, remaining after controlling for core QOL domains as well as other possible confounding variables. Furthermore, spiritual well-being was found to be related to the ability to enjoy life even in the midst of symptoms, making this domain a potentially important clinical target. It is concluded that these results support the move to the biopsychosocialspiritual model for QOL measurement in oncology.
794 citations
TL;DR: Current understanding of ICAM‐1 gene regulation is summarized with a particular emphasis on the transcription factors and signal transduction pathways critical for the cell type‐ and stimulus‐specific activation of IC AM‐1 Gene transcription.
Abstract: Intercellular adhesion molecule-1 (ICAM-1, CD54) is an inducible cell adhesion glycoprotein of the immunoglobulin supergene family expressed on the surface of a wide variety of cell types. ICAM-1 interactions with the beta2 integrins CD11a/CD18 (LFA-1) and CD11b/CD18 (MAC-1) on the surface of leukocytes are important for their transendothelial migration to sites of inflammation and their function as costimulatory molecules for T cell activation. ICAM-1 is constitutively expressed on the cell surface and is up-regulated in response to a variety of inflammatory mediators, including proinflammatory cytokines, hormones, cellular stresses, and virus infection. These stimuli increase ICAM-1 expression primarily through activation of ICAM-1 gene transcription. During the past decade much has been learned about the cell type- and stimulus-specific transcription of ICAM-1. The architecture of the ICAM-1 promoter is complex, containing a large number of binding sites for inducible transcription factors, the most important of which is nuclear factor-kappa B (NF-kappaB). NF-kappaB acts in concert with other transcription factors and co-activators via specific protein-protein interactions, which facilitate the assembly of distinct stereospecific transcription complexes on the ICAM-1 promoter. These transcription complexes presumably mediate the induction of ICAM-1 expression in different cell types and in response to different stimuli. In this review, we summarize our current understanding of ICAM-1 gene regulation with a particular emphasis on the transcription factors and signal transduction pathways critical for the cell type- and stimulus-specific activation of ICAM-1 gene transcription.
540 citations
TL;DR: It is concluded that c-KIT somatic mutations substituting valine in position 816 of KIT are characteristic of sporadic adult mastocytosis and may cause this disease.
Abstract: Human mastocytosis is characterized by increased mast cells. It usually occurs as a sporadic disease that is often transient and limited in children and persistent or progressive in adults. The c-KIT protooncogene encodes KIT, a tyrosine kinase that is the receptor for mast cell growth factor. Because mutated KIT can transform cells, we examined c-KIT in skin lesions of 22 patients with sporadic mastocytosis and 3 patients with familial mastocytosis. All patients with adult sporadic mastocytosis had somatic c-KIT mutations in codon 816 causing substitution of valine for aspartate and spontaneous activation of mast cell growth factor receptor (P = 0.0001). A subset of four pediatric onset cases with clinically unusual disease also had codon 816 activating mutations substituting valine, tyrosine, or phenylalanine for aspartate. Typical pediatric patients lacked 816 mutations, but limited sequencing showed three of six had a novel dominant inactivating mutation substituting lysine for glutamic acid in position 839, the site of a potential salt bridge that is highly conserved in receptor tyrosine kinases. No c-KIT mutations were found in the entire coding region of three patients with familial mastocytosis. We conclude that c-KIT somatic mutations substituting valine in position 816 of KIT are characteristic of sporadic adult mastocytosis and may cause this disease. Similar mutations causing activation of the mast cell growth factor receptor are found in children apparently at risk for extensive or persistent disease. In contrast, typical pediatric mastocytosis patients lack these mutations and may express inactivating c-KIT mutations. Familial mastocytosis, however, may occur in the absence of c-KIT coding mutations.
533 citations
Rush University Medical Center1, Columbia University2, Duke University3, George Washington University4, University of Pennsylvania5, Georgetown University6, Yale University7, Jefferson Community and Technical College8, Anschutz Medical Campus9, United States Department of Veterans Affairs10, Johns Hopkins University11, Wake Forest University12, University of California, Los Angeles13
TL;DR: A literature review was carried out by the Department of Healthcare Services Research, Cedars-Sinai Health System, Los Angeles, California, using the MEDLINE database search for 1990 through April 1998 and updated in November 1998 as discussed by the authors.
Abstract: ObjectiveTo establish, in a single resource, up-to-date
recommendations for primary care physicians regarding prevention
strategies for a first strokeParticipantsMembers of the National Stroke Association's
(NSA's) Stroke Prevention Advisory Board and Cedars-Sinai Health
System Department of Health Services Research convened on April 9,
1998, in an open meeting The conference attendees, selected to
participate by the NSA, were recognized experts in neurology (9),
cardiology (2), family practice (1), nursing (1), physician assistant
practices (1), and health services research (2)EvidenceA literature review was carried out by the Department of
Health Services Research, Cedars-Sinai Health System, Los Angeles,
Calif, using the MEDLINE database search for 1990 through April 1998
and updated in November 1998 English-language guidelines, statements,
meta-analyses, and overviews on prevention of a first stroke were
reviewedConsensus ProcessAt the meeting, members of the advisory board
identified 6 important stroke risk factors (hypertension, myocardial
infarction [MI], atrial fibrillation, diabetes mellitus, blood
lipids, asymptomatic carotid artery stenosis), and 4 lifestyle factors
(cigarette smoking, alcohol use, physical activity, diet)ConclusionsSeveral interventions that modify well-documented and
treatable cardiovascular and cerebrovascular risk factors can reduce
the risk of a first stroke Good evidence for direct stroke reduction
exists for hypertension treatment; using warfarin for patients after MI
who have atrial fibrillation, decreased left ventricular ejection
fraction, or left ventricular thrombus; using 3-hydroxy-3
methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors for patients
after MI; using warfarin for patients with atrial fibrillation and
specific risk factors; and performing carotid endarterectomy for
patients with stenosis of at least 60% Observational studies support
the role of modifying lifestyle-related risk factors (eg, smoking,
alcohol use, physical activity, diet) in stroke prevention Measures to
help patients improve adherence are an important component of a stroke
prevention plan
479 citations
Journal Article•
University of Massachusetts Boston1, Brown University2, University of Texas MD Anderson Cancer Center3, University of California, San Diego4, University of South Florida5, University of Massachusetts Medical School6, Loyola University Chicago7, University of Florida8, Rush University Medical Center9, Dartmouth College10
TL;DR: In patients with solid tumor neoplastic meningitis, DepoCyt produced a response rate comparable to that of methotrexate and significantly increased the time to neurological progression while offering the benefit of a less demanding dose schedule.
Abstract: Standard treatment for neoplastic meningitis requires frequent intrathecal (IT) injections of chemotherapy and is only modestly effective. DepoCyt is a sustained-release formulation of cytarabine that maintains cytotoxic concentrations of the drug in the cerebrospinal fluid (CSF) for more than 14 days after a single 50-mg injection. We conducted a randomized, controlled trial of DepoCyt versus methotrexate in patients with solid tumor neoplastic meningitis. Sixty-one patients with histologically proven cancer and positive CSF cytologies were randomized to receive IT DepoCyt (31 patients) or IT methotrexate (30 patients). Patients received up to six 50-mg doses of DepoCyt or up to sixteen 10-mg doses of methotrexate over 3 months. Treatment arms were well balanced with respect to demographic and disease-related characteristics. Responses occurred in 26% of DepoCyt-treated and 20% of methotrexate-treated patients (P = 0.76). Median survival was 105 days in the DepoCyt arm and 78 days in the methotrexate arm (log-rank P = 0.15). The DepoCyt group experienced a greater median time to neurological progression (58 versus 30 days; log-rank P = 0.007) and longer neoplastic meningitis-specific survival (log-rank P = 0.074; median meningitis-specific survival, 343 versus 98 days). Factors predictive of longer progression-free survival included absence of visible central nervous system disease on neuroimaging studies (P<0.001), longer pretreatment duration of CSF disease (P<0.001), history of intraparenchymal tumor (P<0.001), and treatment with DepoCyt (P = 0.002). The frequency and grade of adverse events were comparable between treatment arms. In patients with solid tumor neoplastic meningitis, DepoCyt produced a response rate comparable to that of methotrexate and significantly increased the time to neurological progression while offering the benefit of a less demanding dose schedule.
465 citations
TL;DR: IL-8 transcription appears to be activated by a promoter recruitment mechanism where inducible transcription factor binding to the IL-8 promoter is required for binding of constitutively active TATA box-binding proteins and formation of a stable preinitiation complex.
Abstract: Interleukin-8 (IL-8), a member of the CXC chemokine family, is an important activator and chemoattractant for neutrophils and has been implicated in a variety of inflammatory diseases. IL-8 is secreted in a stimulusspecific manner by a wide variety of cell types and is regulated primarily at the level of gene transcription. Functional studies indicate that IL-8 transcriptional responses to proinflammatory mediators are rapid and require only 100 nucleotides of 5'-flanking DNA upstream of the TATA box. Within the IL-8 promoter sequence are DNA binding sites for the inducible transcription factors AP-1, NF-IL-6, and NF-kappa B. Transcription factors in these families bind the IL-8 promoter as dimers, and several distinct subunit combinations have been identified as important for IL-8 transcription. In addition, these factors can act in concert to synergistically activate the IL-8 promoter. AP-1 and NF-IL-6 physically interact with NF- kappa B, and functional cooperativity among the factors appears to be cri...
428 citations
TL;DR: Improvements associated with BoNT/B treatment were greatest for patients who received the 10,000-U dose, and Botulinum toxin type B (NeuroBloc) is safe and efficacious at 5,000 U and 10, thousand U for the management of patients with cervical dystonia.
Abstract: Objective: To determine the safety and efficacy of botulinum toxin type B (BoNT/B) in patients with cervical dystonia (CD). Background: BoNT/B is a form of chemodenervation therapy for the treatment of patients with CD. Methods: The authors performed a 16-week, randomized, multicenter, double-blind, placebo-controlled trial of BoNT/B in patients with CD who continue to respond to botulinum toxin type A. Placebo, or 5,000 U or 10,000 U of BoNT/B was administered in two to four muscles involved clinically in CD. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at week 4 was the primary efficacy measure. Clinical assessments and adverse events were recorded for treatment day 1 and at weeks 2, 4, 8, 12, and 16. Results: A total of 109 patients were enrolled randomly across all three treatment groups. The mean improvement in the TWSTRS-Total scores in each group at week 4 was 4.3 (placebo), 9.3 (5,000 U), and 11.7 (10,000 U). For the prospectively defined primary contrast (10,000 U versus placebo), highly significant differences were noted for the primary (TWSTRS-Total, baseline to week 4, p = 0.0004) and supportive secondary (Patient Global Assessment, baseline to week 4, p = 0.0001) outcome measures. Improvement in pain, disability, and severity of CD occurred for patients who were treated with BoNT/B when compared with placebo-treated patients. Overall, improvements associated with BoNT/B treatment were greatest for patients who received the 10,000-U dose. The duration of treatment effect for BoNT/B was 12 to 16 weeks for both doses. Conclusion: Botulinum toxin type B (NeuroBloc) is safe and efficacious at 5,000 U and 10,000 U for the management of patients with cervical dystonia.
TL;DR: The present study supports the hypothesis that “disc degeneration precedes facet joint osteoarthritis”, and also supports the concept that it may take 20 or more years to develop facet joint fractures following the onset of disc degeneration.
Abstract: The role of MRI in assessing facet joint osteoarthritis is unclear. By developing a grading system for severity of facet joint osteoarthritis on MRI, the relationship between disc degeneration and facet joint osteoarthritis was determined. The accuracy of MRI in assessing facet joint osteoarthritis against CT was 94%. Under 40 years of age, the degree of disc degeneration varied among individuals. Over the age of 60, most of the discs were markedly degenerated. Under 40 years of age osteoarthritic changes in facet joints were minimal. Over the age of 60, variable degrees of facet joint osteoarthritis were observed but some facets did not show osteoarthritis. No facet joint osteoarthritis was found in the absence of disc degeneration and most facet joint osteoarthritis appeared at the intervertebral levels with advanced disc degeneration. Disc degeneration is more closely associated with aging than with facet joint osteoarthritis. The present study supports the hypothesis that “disc degeneration precedes facet joint osteoarthritis”, and also supports the concept that it may take 20 or more years to develop facet joint osteoarthritis following the onset of disc degeneration.
TL;DR: There was no evidence of significant regeneration of nigrostriatal neurons or intraparenchymal diffusion of the intracerebroventricular GDNF to relevant brain regions in a 65-year-old man with Parkinson's disease.
Abstract: As part of a safety and tolerability study, a 65-year-old man with Parkinson's disease (PD) received monthly intracerebroventricular injections of glial-derived neurotrophic factor (GDNF). His parkinsonism continued to worsen following intracerebroventricular GDNF treatment. Side effects included nausea, loss of appetite, tingling, L'hermitte's sign, intermittent hallucinations, depression, and inappropriate sexual conduct. There was no evidence of significant regeneration of nigrostriatal neurons or intraparenchymal diffusion of the intracerebroventricular GDNF to relevant brain regions. Alternative GDNF delivery systems should be explored.
TL;DR: In patients with angina refractory to medical treatment and coronary artery disease that precluded coronary-artery bypass surgery or percutaneous transluminal coronary angioplasty, transmyocardial revascularization improved cardiac perfusion and clinical status over a 12-month period.
Abstract: Background The construction of subendocardial channels to perfuse ischemic areas of the myocardium has been investigated since the 1950s. We assessed the safety and efficacy of transmyocardial revascularization with a carbon dioxide laser in patients with refractory angina and left ventricular free-wall ischemia that was not amenable to direct coronary revascularization. Methods In a prospective, controlled, multicenter trial, we randomly assigned 91 patients to undergo transmyocardial revascularization and 101 patients to receive continued medical treatment. The severity of angina (according to the Canadian Cardiovascular Society [CCS] classification), quality of life, and cardiac perfusion (as assessed by thallium-201 scanning) were evaluated at base line and 3, 6, and 12 months after randomization. Results At 12 months, angina had improved by at least two CCS classes in 72 percent of the patients assigned to transmyocardial revascularization, as compared with 13 percent of the patients assigned to medi...
TL;DR: Results indicated that lower ego integrity, more physical problems, and more psychological problems are predictive of higher levels of death anxiety in elderly people, and a suggestive but equivocal relationship was found for the predictor institutionalization.
Abstract: This literature review quantitatively summarized 49 published and unpublished research studies concerning the relationship between death anxiety and age, ego integrity, gender, institutionalization, physical and psychological problems, and religiosity in older adults. Results indicated that lower ego integrity, more physical problems, and more psychological problems are predictive of higher levels of death anxiety in elderly people. A suggestive but equivocal relationship was found for the predictor institutionalization. Furthermore, the review statistically demonstrated the importance of using sound methods for measuring death anxiety and sampling from the elderly population. It has been said that we may learn looking backward - we live looking forward. A person's thinking and behavior may be influenced more than we recognize by his views, hopes and fears concerning the nature and meaning of death. (Feifel,1959,p.116)
TL;DR: The Profile of Mood States (POMS; McNair, Lorr, & Droppleman) is widely used to assess mood states, but the utility of the POMS has been restricted by the lack of normative data from the general population.
Abstract: The Profile of Mood States (POMS; McNair, Lorr, & Droppleman) is widely used to assess mood states However, the utility of the POMS has been restricted by the lack of normative data from the general population We report on our adult (N = 400) and geriatric (N = 170) POMS standardization samples Both groups were age-, gender-, and race-stratified according to 1990 census data We also report on convergent and discriminant validity of POMS scales, using a multitrait, multimethod paradigm
TL;DR: The differential induction of IL-8 and ICAM-1 by H2O2 and TNFalpha suggest that the two inflammatory stimuli target distinct redox responsive signaling pathways to activate cell type-specific gene expression.
Abstract: Reactive oxygen species (ROS), generated either extracellularly or intracellularly through ligand-receptor interactions, can function as signal transduction molecules to activate the chemotactic cytokine interleukin-8 (IL-8) and the cell surface adhesion protein, intercellular adhesion molecule-1 (ICAM-1; CD54). Together, IL-8 and ICAM-1 orchestrate the transendothelial migration of neutrophils to sites of inflammation and injury. Recent results demonstrate that oxidant stress generated directly by exogenous H2O2 differentially induce IL-8 and ICAM-1 transcription in epithelial and endothelial cells. H2O2 induces IL-8 but not ICAM-1 in the A549 type-II-like epithelial cell line, whereas in a microvessel endothelial cell line (HMEC-1) as well as in primary endothelial cells, H2O2 induces ICAM-1 but not IL-8, which is spontaneously expressed. In contrast, the pro-inflammatory cytokine TNFalpha, whose activity is dependent on the generation of intracellular ROS, induces IL-8 and ICAM-1 in both cell types. The differential induction of IL-8 and ICAM-1 by H2O2 and TNFalpha suggest that the two inflammatory stimuli target distinct redox responsive signaling pathways to activate cell type-specific gene expression. In this regard, we found that the cell type-specific pattern of IL-8 and ICAM-1 gene expression was associated with the differential activation and promoter binding of the redox regulated transcription factors AP-1 and NF-kappaB. In this review, our current understanding of the redox regulation of the IL-8 and ICAM-1 genes is summarized, and the differential roles AP-1 and NF-kappaB play in their cell type-specific expression, with particular emphasis on the differential effects induced by TNFalpha and H2O2 is discussed.
TL;DR: Osteopathic manual care and standard medical care had similar clinical results in patients with subacute low back pain, however, the use of medication was greater with standard care.
Abstract: Background The effect of osteopathic manual therapy (i.e., spinal manipulation) in patients with chronic and subchronic back pain is largely unknown, and its use in such patients is controversial. Nevertheless, manual therapy is a frequently used method of treatment in this group of patients. Methods We performed a randomized, controlled trial that involved patients who had had back pain for at least three weeks but less than six months. We screened 1193 patients; 178 were found to be eligible and were randomly assigned to treatment groups; 23 of these patients subsequently dropped out of the study. The patients were treated either with one or more standard medical therapies (72 patients) or with osteopathic manual therapy (83 patients). We used a variety of outcome measures, including scores on the Roland–Morris and Oswestry questionnaires, a visual-analogue pain scale, and measurements of range of motion and straight-leg raising, to assess the results of treatment over a 12-week period. Results Patients...
TL;DR: Using stringent selection criteria, unicompartmental knee replacement can yield excellent results and represents a superb alternative to total knee replacement.
Abstract: Sixty-two consecutive cemented modular unicompartmental knee arthroplasties in 51 patients were studied prospectively. At surgery, the other compartments had at most Grade 2 chondromalacia. The average age of the patients at arthroplasty was 68 years (range, 51-84 years). One patient was lost to followup and 10 died with less than 6 years followup. The average followup of the remaining 51 knees was 7.5 years (range, 6-10 years). The preoperative Hospital for Special Surgery knee score of 55 points (range, 30-79 points) improved to 92 points (range, 60-100 points) at followup; 78% (40 knees) had excellent and 20% (10 knees) had good results. The mean range of motion at followup was 120° with 26 knees (51%) having range of motion greater than 120°. One patient underwent revision surgery for retained cement, one patient underwent knee manipulation, and one patient underwent revision surgery at 7 years for opposite compartment degeneration and pain. Radiographically, 26 knees (51%) had at least one partial radiolucency. There were no complete femoral radiolucencies, but there were three complete tibial radiolucencies, all less than 2 mm. No component was loose as seen on radiographs. At final followup, five of the opposite compartments (10%) and three of the patellofemoral joints (6%) had some progressive radiographic joint space loss; this was less than a 25% loss in all but one knee component that was revised. At 6- to 10-years followup, cemented unicompartmental knee arthroplasty yielded excellent clinical and radiographic results. The 10-year survival using radiographic loosening or revision as the end point was 98%. Using stringent selection criteria, unicompartmental knee replacement can yield excellent results and represents a superb alternative to total knee replacement.
TL;DR: It was possible to restore stability to a model based on a bilayer-derived gating scheme, by introducing allosteric interactions between nearest-neighbor RyRs so as to stabilize the inactivated state and produce cooperativity among calcium binding sites on different RyRs.
Abstract: In cardiac muscle, release of activator calcium from the sarcoplasmic reticulum occurs by calcium- induced calcium release through ryanodine receptors (RyRs), which are clustered in a dense, regular, two-dimensional lattice array at the diad junction. We simulated numerically the stochastic dynamics of RyRs and L-type sarcolemmal calcium channels interacting via calcium nano-domains in the junctional cleft. Four putative RyR gating schemes based on single-channel measurements in lipid bilayers all failed to give stable excitation–contraction coupling, due either to insufficiently strong inactivation to terminate locally regenerative calcium-induced calcium release or insufficient cooperativity to discriminate against RyR activation by background calcium. If the ryanodine receptor was represented, instead, by a phenomenological four-state gating scheme, with channel opening resulting from simultaneous binding of two Ca2+ ions, and either calcium-dependent or activation-linked inactivation, the simulations gave a good semiquantitative accounting for the macroscopic features of excitation–contraction coupling. It was possible to restore stability to a model based on a bilayer-derived gating scheme, by introducing allosteric interactions between nearest-neighbor RyRs so as to stabilize the inactivated state and produce cooperativity among calcium binding sites on different RyRs. Such allosteric coupling between RyRs may be a function of the foot process and lattice array, explaining their conservation during evolution.
TL;DR: The majority of cost in providing hospital service is related to buildings, equipment, salaried labor, and overhead, which are fixed over the short term.
Abstract: ContextMost strategies proposed to control the rising cost of
health care are aimed at reducing medical resource consumption rates.
These approaches may be limited in effectiveness because of the
relatively low variable cost of medical care. Variable costs (for
medication and supplies) are saved if a facility does not provide a
service while fixed costs (for salaried labor, buildings, and
equipment) are not saved over the short term when a health care
facility reduces service.ObjectiveTo determine the relative variable and fixed costs of
inpatient and outpatient care for a large urban public teaching
hospital.DesignCost analysis.SettingA large urban public teaching hospital.Main Outcome MeasuresAll expenditures for the institution during
1993 and for each service were categorized as either variable or fixed.
Fixed costs included capital expenditures, employee salaries and
benefits, building maintenance, and utilities. Variable costs included
health care worker supplies, patient care supplies, diagnostic and
therapeutic supplies, and medications.ResultsIn 1993, the hospital had nearly 114,000 emergency
department visits, 40,000 hospital admissions, 240,000
inpatient days, and more than 500,000 outpatient clinic visits.
The total budget for 1993 was $429.2 million, of which $360.3 million
(84%) was fixed and $68.8 million (16%) was variable. Overall, 31.5%
of total costs were for support expenses such as utilities, employee
benefits, and housekeeping salaries, and 52.4% included direct costs
of salary for service center personnel who provide services to
individual patients.ConclusionsThe majority of cost in providing hospital service is
related to buildings, equipment, salaried labor, and overhead, which
are fixed over the short term. The high fixed costs emphasize the
importance of adjusting fixed costs to patient consumption to maintain
efficiency.
TL;DR: Patients had a 94% patient satisfaction rate with lasting relief of pain and improved function more than 4 years after open rotator cuff repair, and women with an associated biceps tendon rupture tended to have worse results.
Abstract: Seventy-two full thickness rotator cuff tears (72 patients) were treated with an open rotator cuff repair between 1986 and 1993. The average postoperative followup was 54 months (range, 24-102 months; standard deviation, 22 months). Fifty-three (74%) patients had no pain, 16 (22%) patients had slight pain without restriction of activities, and three (4%) patients had moderate pain with activity compromise. Women with an associated biceps tendon rupture tended to have worse results. Women had a negative, statistically significant relationship between age and shoulder scoring scales, but age at the time of surgery was not related to any outcome variables for men. A rotator cuff tear greater than or equal to 5 cm2 as determined at the time of surgery was associated with a poorer outcome. The average University of California at Los Angeles score was 32 points (range, 7-35 points; standard deviation, 5 points). The average Constant-Murley score was 78 of 100 points (range, 12-95 points; standard deviation, 15 points). A yes response was given for an average of 10 of 12 questions on the Simple Shoulder Test (range, 0-12 questions; standard deviation, 3 questions). More than 4 years after open rotator cuff repair, patients had a 94% patient satisfaction rate with lasting relief of pain and improved function.
TL;DR: The findings do not suggest a linear association of BP with cognitive decline, but they are consistent with a more complex relationship between BP and cognition than previously appreciated.
Abstract: ContextPrevious studies raise the possibility that blood
pressure (BP) in middle age predicts later cognitive decline.ObjectiveTo examine prospectively the relationship of BP with
level of and change in cognitive function in the elderly.DesignLongitudinal, population-based study comprising
subjects enrolled in the East Boston component of the Established
Populations for the Epidemiologic Study of the Elderly (EPESE)
(1982-1983) and the Hypertension Detection and Follow-Up Program (HDFP)
(1973-1974).SettingEast Boston, Mass.ParticipantsOf the 3657 participants in the EPESE
with baseline BP measurements, 2068 also participated in the HDFP.
Subjects were aged 65 to 102 years at baseline in the EPESE and had
mental status and memory assessed at baseline and 3 and 6 years.Main Outcome MeasuresNumbers of errors on the Short Portable
Mental Status Questionnaire and the East Boston Memory Test and rates
of change in these numbers of errors. Subjects had BP measured both at
baseline in the EPESE and 9 years before, as part of the HDFP.ResultsIn analyses adjusted for age, sex, and education, there
was no strong linear association between BP and cognition. The
associations found were fairly small in magnitude, and varied according
to which test was used to measure cognition. There was little evidence
for an effect of BP on change in cognitive function with either test,
or for an effect on level of function on the memory test. In analyses
of level of mental status questionnaire performance, however, elevated
systolic BP (≥160 mm Hg) 9 years before baseline was associated with a
14% (95% confidence interval [CI], 4%-25%) increase in error
rate, relative to the referent (130-139 mm Hg). Baseline systolic BP
had a U-shaped association with the number of errors; error rates were
9% higher compared with the referent group among those with systolic
BP lower than 130 mm Hg (95% CI, 1%-17%) and 7% greater (95% CI,
0%-15%) among those with elevated systolic BP. Diastolic BP 9 years
before baseline also had a U-shaped association with errors on the
mental status questionnaire.ConclusionThe findings do not suggest a linear association of BP
with cognitive decline, but they are consistent with a more complex
relationship between BP and cognition than previously
appreciated.
TL;DR: It is suggested that being "embedded" in a social network of relatives and friends reduces risk for ADL disability, and enhances recovery from ADL disabled people in old age.
Abstract: Objectives. There is considerable evidence that social networks are strongly related to survival and other health outcomes. However, findings regarding the effect of social networks on disability outcomes have been inconsistent. This study examines this relationship with respect to the risk of developing disability and recovering from disability. Methods. Data come from a community-based sample of the New Haven population aged 65 years and older, with nine annual interviews conducted between 1982 and 1991. Disability was measured by a 6-item index of activities of daily living (ADL), and a 3-item Rosow-Breslau index, with disability defined as impairment in one or more tasks on each measure. Social network variables were constructed for each of four domains of ties: children, relatives, friends, and a confidant, and a summary measure of total social networks. A Markov model was used to estimate one-year disability transitions averaged across all 8 intervals, after controlling for sociodemographic and health-related variables. Results. Total social networks was associated with a significantly reduced risk of developing ADL disability ((J = -0.009, p < .01), and a significantly increased likelihood of ADL recovery (f$ = 0.017,/; < .01). Emotional and instrumental support did not affect the protective effect of social networks against disability, but partially accounted for their effect on enhanced recovery. Network variables related to relatives and friends were significantly associated with disability and recovery risks, but those related to children or a confidant were not. The associations with disability transitions as measured by the Rosow-Breslau index were generally smaller and nonsignificant. Discussion. The findings lend further support for the role of social relationships in important health outcomes in old age. They suggest that being "embedded" in a social network of relatives and friends reduces risk for ADL disability, and enhances recovery from ADL disability.
TL;DR: The data suggest that cholinergic neurons, and the coexpression of ChAT and VAChT, are relatively preserved in early stages of AD.
Abstract: Immunocytochemistry for choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT) was used to examine the expression of these linked cholinergic markers in human basal forebrain, including cases with early stages of Alzheimer's disease (AD). Previous neurochemical studies have measured decreased ChAT activity in terminal fields, but little change or even increased levels of VAChT. To determine total cholinergic neuron numbers in the nucleus basalis of Meynert (nbM), stereologic methods were applied to tissue derived from three groups of individuals with varying levels of cognition: no cognitive impairment (NCI), mild cognitive impairment (MCI), and early-stage Alzheimer's disease (AD). Both markers were expressed robustly in nucleus basalis neurons and across all three groups. On average, there was no significant difference between the number of ChAT- (210,000) and VAChT- (174,000) immunopositive neurons in the nbM per hemisphere in NCI cases for which the biological variation was calculated to be 17%. There was approximately a 15% nonsignificant reduction in the number of cholinergic neurons in the nbM in the AD cases with no decline in MCI cases. The number of ChAT- and VAChT-immunopositive neurons was shown to correlate significantly with the severity of dementia determined by scores on the Mini-Mental State Examination, but showed no relationship to apolipoprotein E allele status, age, gender, education, or postmortem interval when all clinical groups were combined or evaluated separately. These data suggest that cholinergic neurons, and the coexpression of ChAT and VAChT, are relatively preserved in early stages of AD. J. Comp. Neurol. 411:693–704, 1999. © 1999 Wiley-Liss, Inc.
TL;DR: It is found that ER cholesterol in resting human fibroblasts comprised approximately 0.5% of the cell total, and brief exposure of cells to the oxysterol, 25-hydroxycholesterol, elevated and linearized the J-curve, increasing ER cholesterol at all values of cell cholesterol.
TL;DR: Children with LKSV and ASD have a greater frequency of serum antibodies to brain endothelial cells and to nuclei than children with NNIs or healthy children, which raises the possibility that autoimmunity plays a role in the pathogenesis of language and social developmental abnormalities in a subset of children with these disorders.
TL;DR: It is proposed that the differential activation and binding of inducible transcription factors to the promoter regions of chemokine genes provides a critical regulatory mechanism by which the CXC and CC chemokines can be selectively expressed in a cell type‐specific and stimulus‐specific manner.
Abstract: The promoters of the IL-8, MCP-1, and RANTES genes contain binding sites for the redox-responsive transcription factors AP-1 and NF-kappaB, which have been shown to be important for their expression. In this overview, we present evidence from our laboratories that the stimulus-specific regulation of these chemokines by the reactive oxidant H2O2, the proinflammatory cytokine TNF-alpha, and respiratory syncytial virus (RSV) is mediated in a cell type-specific manner involving different patterns of AP-1 and NF-kappaB binding activity. Our results demonstrate that H2O2 induction of IL-8 gene expression is linked with the selective binding of AP-1 to the IL-8 promoter, whereas TNF-alpha and RSV induction of IL-8 correlates with the activation of NF-kappaB binding. We propose that the differential activation and binding of inducible transcription factors to the promoter regions of chemokine genes provides a critical regulatory mechanism by which the CXC and CC chemokines can be selectively expressed in a cell type-specific and stimulus-specific manner. Such a regulatory mechanism of differential chemokine expression could critically influence the site-specific recruitment of distinct subsets of leukocytes to sites of inflammation and injury.
TL;DR: An automatic method for segmentation of images of skin cancer and other pigmented lesions is presented, which first reduces a color image into an intensity image and approximately segments the image by intensity thresholding and refines the segmentation using image edges.