Showing papers by "Johns Hopkins University School of Medicine published in 2004"
TL;DR: It is demonstrated that cell shape regulates commitment of human mesenchymal stem cells to adipocyte or osteoblast fate and mechanical cues experienced in developmental and adult contexts, embodied by cell shape, cytoskeletal tension, and RhoA signaling, are integral to the commitment of stem cell fate.
3,995 citations
TL;DR: A narrative review of current understanding of the definitions and distinguishing characteristics of each of these conditions, including their clinical relevance and distinct prevention and therapeutic issues, and how they are related is provided.
Abstract: Three terms are commonly used interchangeably to identify vulnerable older adults: comorbidity, or multiple chronicconditions,frailty, anddisability. However, in geriatricmedicine,there isagrowingconsensusthatthese are distinct clinical entities that are causally related. Each, individually, occurs frequently and has high import clinically. This article provides a narrative review of current understanding of the definitions and distinguishing characteristics of each of these conditions,including theirclinical relevance and distinct prevention and therapeutic issues, and how they are related. Review of the current state of published knowledge is supplemented by targeted analysesin selectedareas where no current publisheddataexists. Overall,the goalof this articleis to providea basis fordistinguishingbetweenthesethreeimportantclinicalconditionsinolderadultsandshowinghowuseofseparate, distinct definitions of each can improve our understanding of the problems affecting older patients and lead to development of improved strategies for diagnosis, care, research, and medical education in this area.
3,394 citations
TL;DR: There is increased understanding of the pathways involved in protein aggregation, and some recent clues have emerged as to the molecular mechanisms of cellular toxicity, leading to approaches toward rational therapeutics.
Abstract: Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and prion diseases are increasingly being realized to have common cellular and molecular mechanisms including protein aggregation and inclusion body formation. The aggregates usually consist of fibers containing misfolded protein with a beta-sheet conformation, termed amyloid. There is partial but not perfect overlap among the cells in which abnormal proteins are deposited and the cells that degenerate. The most likely explanation is that inclusions and other visible protein aggregates represent an end stage of a molecular cascade of several steps, and that earlier steps in the cascade may be more directly tied to pathogenesis than the inclusions themselves. For several diseases, genetic variants assist in explaining the pathogenesis of the more common sporadic forms and developing mouse and other models. There is now increased understanding of the pathways involved in protein aggregation, and some recent clues have emerged as to the molecular mechanisms of cellular toxicity. These are leading to approaches toward rational therapeutics.
2,926 citations
TL;DR: It is reported that, unlike other brain cancers, the lethal glioblastoma multiforme contains neural precursors endowed with all of the critical features expected from neural stem cells.
Abstract: Transformed stem cells have been isolated from some human cancers. We report that, unlike other brain cancers, the lethal glioblastoma multiforme contains neural precursors endowed with all of the critical features expected from neural stem cells. Similar, yet not identical, to their normal neural stem cell counterpart, these precursors emerge as unipotent (astroglial) in vivo and multipotent (neuronal-astroglial-oligodendroglial) in culture. More importantly, these cells can act as tumor-founding cells down to the clonal level and can establish tumors that closely resemble the main histologic, cytologic, and architectural features of the human disease, even when challenged through serial transplantation. Thus, cells possessing all of the characteristics expected from tumor neural stem cells seem to be involved in the growth and recurrence of adult human glioblastomas multiforme.
2,489 citations
TL;DR: This timeline traces the field from its conception to the present day and addresses the genetic basis of epigenetic changes — an emerging area that promises to unite cancer genetics and epigenetics, and might serve as a model for understanding the epigenetic basis of human disease more generally.
Abstract: Since its discovery in 1983, the epigenetics of human cancer has been in the shadows of human cancer genetics. But this area has become increasingly visible with a growing understanding of specific epigenetic mechanisms and their role in cancer, including hypomethylation, hypermethylation, loss of imprinting and chromatin modification. This timeline traces the field from its conception to the present day. It also addresses the genetic basis of epigenetic changes — an emerging area that promises to unite cancer genetics and epigenetics, and might serve as a model for understanding the epigenetic basis of human disease more generally.
2,240 citations
TL;DR: Two- and three-dimensional white matter atlases were created on the basis of high-spatial-resolution diffusion tensor magnetic resonance (MR) imaging and 3D tract reconstruction and showed which anatomic structures can be identified on diffusion Tensor images and where these anatomic units are located at each section level and orientation.
Abstract: Two- and three-dimensional (3D) white matter atlases were created on the basis of high-spatial-resolution diffusion tensor magnetic resonance (MR) imaging and 3D tract reconstruction. The 3D trajectories of 17 prominent white matter tracts could be reconstructed and depicted. Tracts were superimposed on coregistered anatomic MR images to parcel the white matter. These parcellation maps were then compared with coregistered diffusion tensor imaging color maps to assign visible structures. The results showed (a) which anatomic structures can be identified on diffusion tensor images and (b) where these anatomic units are located at each section level and orientation. The atlas may prove useful for educational and clinical purposes. © RSNA, 2003
1,865 citations
TL;DR: Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case.
1,771 citations
TL;DR: A systematic review of prospective cohort studies of glycosylated hemoglobin and cardiovascular disease in persons with diabetes mellitus found a graded relationship between fasting and postprandial blood glucose levels and subsequent risk for a cardiovascular event.
Abstract: This meta-analysis of observational studies in patients with diabetes shows that increased serum hemoglobin A1c levels are associated with an increased risk for cardiovascular disease in both type ...
1,561 citations
TL;DR: SPIO‐based cellular imaging has now become an established technique to label and detect the cells of interest and is aimed at obtaining a deeper insight into the dynamics of in vivo cell biology, including lymphocyte trafficking, and at monitoring therapies that are based on the use of stem cells and progenitors.
Abstract: Molecular and cellular MR imaging is a rapidly growing field that aims to visualize targeted macromolecules or cells in living organisms. In order to provide a different signal intensity of the target, gadolinium-based MR contrast agents can be employed although they suffer from an inherent high threshold of detectability. Superparamagnetic iron oxide (SPIO) particles can be detected at micromolar concentrations of iron, and offer sufficient sensitivity for T2(*)-weighted imaging. Over the past two decades, biocompatible particles have been linked to specific ligands for molecular imaging. However, due to their relatively large size and clearance by the reticuloendothelial system (RES), widespread biomedical molecular applications have yet to be implemented and few studies have been reproduced between different laboratories. SPIO-based cellular imaging, on the other hand, has now become an established technique to label and detect the cells of interest. Imaging of macrophage activity was the initial and still is the most significant application, in particular for tumor staging of the liver and lymph nodes, with several products either approved or in clinical trials. The ability to now also label non-phagocytic cells in culture using derivatized particles, followed by transplantation or transfusion in living organisms, has led to an active research interest to monitor the cellular biodistribution in vivo including cell migration and trafficking. While most of these studies to date have been mere of the ‘proof-of-principle’ type, further exploitation of this technique will be aimed at obtaining a deeper insight into the dynamics of in vivo cell biology, including lymphocyte trafficking, and at monitoring therapies that are based on the use of stem cells and progenitors. Copyright © 2004 John Wiley & Sons, Ltd.
1,444 citations
TL;DR: This work has reported the involvement of a 'parallel' but distinct kinase cascade leading to the activation of p38 MAPK, which might control distinct forms of synaptic plasticity in the adult brain.
Abstract: The mitogen-activated protein kinase (MAPK) cascade that leads to the activation of extracellular signal-regulated kinases-1 and -2 (ERK1 and ERK2) has a key role in the differentiation of some cell types and the proliferation of others. However, several recent reports implicate this cascade in the control of synaptic plasticity in the adult brain. ERK signalling seems to be essential for characterized neuronal transcriptional events, and might also regulate synaptic targets to control plasticity. Another recently emerging story is the involvement of a 'parallel' but distinct kinase cascade leading to the activation of p38 MAPK, which might control distinct forms of synaptic plasticity.
1,396 citations
TL;DR: Through 144 weeks, the combination of tenofovir DF, lamivudine, and efavirenz was highly effective and comparable with stavudine for antiretroviral-naive patients and appeared to be associated with better lipid profiles and less lipodystrophy.
Abstract: ContextTenofovir disoproxil fumarate (DF) is a once-daily nucleotide analogue
reverse transcriptase inhibitor.ObjectiveTo evaluate the efficacy and safety of tenofovir DF compared with stavudine
in antiretroviral-naive patients.Design, Setting, and ParticipantsA prospective, randomized, double-blind study conducted at 81 centers
in the United States, South America, and Europe from June 9, 2000, to January
30, 2004. A total of 753 patients infected with HIV who were antiretroviral
naive were screened and 602 patients entered the study.InterventionPatients were randomized to receive either tenofovir DF (n = 299) or
stavudine (n = 303), with placebo, in combination with lamivudine and efavirenz.Main Outcome MeasureProportion of patients with HIV RNA levels of less than 400 copies/mL
at week 48.ResultsIn the primary intent-to-treat analysis in which patients with missing
data or who added or switched antiretroviral medications before week 48 were
considered as failures, the proportion of patients with HIV RNA of less than
400 copies/mL at week 48 was 239 (80%) of 299 in patients receiving tenofovir
DF and 253 (84%) of 301 in patients receiving stavudine (95% confidence interval,
−10.4% to 1.5%), exceeding the predefined −10% limit for equivalence.
However, equivalence was demonstrated in the secondary analyses (HIV RNA <50
copies/mL) at week 48 and through 144 weeks. Virologic failure was associated
most frequently with efavirenz and lamivudine resistance. Through 144 weeks,
the K65R mutation emerged in 8 and 2 patients in the tenofovir DF and stavudine
groups, respectively (P = .06). A more favorable
mean change from baseline in fasting lipid profile was noted in the tenofovir
DF group at week 144: for triglyceride levels (+1 mg/dL for tenofovir DF [n
= 170] vs +134 mg/dL for stavudine [n = 162], P<.001),
total cholesterol (+30 mg/dL [n = 170] vs +58 mg/dL [n = 162], P<.001), direct low-density lipoprotein cholesterol (+14 mg/dL [n
= 169] vs +26 mg/dL [n = 161], P<.001), and high-density
lipoprotein cholesterol (+9 mg/dL [n = 168] vs +6 mg/dL [n = 154], P = .003). Investigator-reported lipodystrophy was less common in the
tenofovir DF group compared with the stavudine group (9 [3%] of 299 vs 58
[19%] of 301, P<.001). The number of bone fractures
and the renal safety profile were similar between the 2 groups.ConclusionsThrough 144 weeks, the combination of tenofovir DF, lamivudine, and
efavirenz was highly effective and comparable with stavudine, lamivudine,
and efavirenz in antiretroviral-naive patients. However, tenofovir DF appeared
to be associated with better lipid profiles and less lipodystrophy.
TL;DR: A direct correlation between the concentration of Aβ42 and the rate of amyloid deposition is demonstrated and suggests that PS1 variants do not simply alter the preferred cleavage site for γ-secretase, but rather that they have more complex effects on the regulation of ιsecretase and its access to substrates.
Abstract: Amyloid precursor protein (APP) is endoproteolytically processed by BACE1 and γ-secretase to release amyloid peptides (Aβ40 and 42) that aggregate to form senile plaques in the brains of patients with Alzheimer's disease (AD). The C-terminus of Aβ40/42 is generated by γ-secretase, whose activity is dependent upon presenilin (PS 1 or 2). Missense mutations in PS1 (and PS2) occur in patients with early-onset familial AD (FAD), and previous studies in transgenic mice and cultured cell models demonstrated that FAD-PS1 variants shift the ratio of Aβ40 : 42 to favor Aβ42. One hypothesis to explain this outcome is that mutant PS alters the specificity of γ-secretase to favor production of Aβ42 at the expense of Aβ40. To test this hypothesis in vivo, we studied Aβ40 and 42 levels in a series of transgenic mice that co-express the Swedish mutation of APP (APPswe) with two FAD-PS1 variants that differentially accelerate amyloid pathology in the brain. We demonstrate a direct correlation between the concentration of Aβ42 and the rate of amyloid deposition. We further show that the shift in Aβ42 : 40 ratios associated with the expression of FAD-PS1 variants is due to a specific elevation in the steady-state levels of Aβ42, while maintaining a constant level of Aβ40. These data suggest that PS1 variants do not simply alter the preferred cleavage site for γ-secretase, but rather that they have more complex effects on the regulation of γ-secretase and its access to substrates.
TL;DR: This model of carcinogenesis reconciles the relationship of borderline tumors to invasive carcinoma and provides a morphological and molecular framework for studies aimed at elucidating the pathogenesis of ovarian cancer.
Abstract: The pathogenesis of ovarian carcinoma, the most lethal gynecological malignancy, is unknown because of the lack of a tumor progression model. Based on a review of recent clinicopathological and molecular studies, we propose a model for their development. In this model, surface epithelial tumors are divided into two broad categories designated type I and type II tumors that correspond to two main pathways of tumorigenesis. Type I tumors tend to be low-grade neoplasms that arise in a stepwise manner from borderline tumors whereas type II tumors are high-grade neoplasms for which morphologically recognizable precursor lesions have not been identified, so-called de novo development. As serous tumors are the most common surface epithelial tumors, low-grade serous carcinoma is the prototypic type I tumor and high-grade serous carcinoma is the prototypic type II tumor. In addition to low-grade serous carcinomas, type I tumors are composed of mucinous carcinomas, endometrioid carcinomas, malignant Brenner tumors, and clear cell carcinomas. Type I tumors are associated with distinct molecular changes that are rarely found in type II tumors, such as BRAF and KRAS mutations for serous tumors, KRAS mutations for mucinous tumors, and β-catenin and PTEN mutations and microsatellite instability for endometrioid tumors. Type II tumors include high-grade serous carcinoma, malignant mixed mesodermal tumors (carcinosarcoma), and undifferentiated carcinoma. There are very limited data on the molecular alterations associated with type II tumors except frequent p53 mutations in high-grade serous carcinomas andmalignant mixed mesodermal tumors (carcinosarcomas). This model of carcinogenesis reconciles the relationship of borderline tumors to invasive carcinoma and provides a morphological and molecular framework for studies aimed at elucidating the pathogenesis of ovarian cancer.
TL;DR: Several newly described co-inhibitory pathways in the B7–CD28 family are focused on, which control the priming, growth, differentiation and functional maturation of a T-cell response.
Abstract: Co-signalling molecules are cell-surface glycoproteins that can direct, modulate and fine-tune T-cell receptor (TCR) signals. On the basis of their functional outcome, co-signalling molecules can be divided into co-stimulators and co-inhibitors, which promote or suppress T-cell activation, respectively. By expression at the appropriate time and location, co-signalling molecules positively and negatively control the priming, growth, differentiation and functional maturation of a T-cell response. We are now beginning to understand the power of co-inhibitors in the context of lymphocyte homeostasis and the pathogenesis of human diseases. In this article, I focus on several newly described co-inhibitory pathways in the B7–CD28 family.
TL;DR: The long-known association between cancer and chronic tissue injury, and the more recently appreciated roles of Hedgehog and Wnt signalling pathways in tissue regeneration, stem cell renewal and cancer growth together suggest that carcinogenesis proceeds by misappropriating homeostatic mechanisms that govern tissue repair and stem cell self-renewal.
Abstract: Cancer is increasingly being viewed as a stem cell disease, both in its propagation by a minority of cells with stem-cell-like properties and in its possible derivation from normal tissue stem cells. But stem cell activity is tightly controlled, raising the question of how normal regulation might be subverted in carcinogenesis. The long-known association between cancer and chronic tissue injury, and the more recently appreciated roles of Hedgehog and Wnt signalling pathways in tissue regeneration, stem cell renewal and cancer growth together suggest that carcinogenesis proceeds by misappropriating homeostatic mechanisms that govern tissue repair and stem cell self-renewal.
TL;DR: It is proposed that tumor Stat-3 activity can mediate immune evasion by blocking both the production and sensing of inflammatory signals by multiple components of the immune system.
Abstract: Although tumor progression involves processes such as tissue invasion that can activate inflammatory responses, the immune system largely ignores or tolerates disseminated cancers. The mechanisms that block initiation of immune responses during cancer development are poorly understood. We report here that constitutive activation of Stat-3, a common oncogenic signaling pathway, suppresses tumor expression of proinflammatory mediators. Blocking Stat-3 in tumor cells increases expression of proinflammatory cytokines and chemokines that activate innate immunity and dendritic cells, leading to tumor-specific T-cell responses. In addition, constitutive Stat-3 activity induces production of pleiotropic factors that inhibit dendritic cell functional maturation. Tumor-derived factors inhibit dendritic cell maturation through Stat-3 activation in progenitor cells. Thus, inhibition of antitumor immunity involves a cascade of Stat-3 activation propagating from tumor to dendritic cells. We propose that tumor Stat-3 activity can mediate immune evasion by blocking both the production and sensing of inflammatory signals by multiple components of the immune system.
TL;DR: The 3.2 A X-ray crystal structure of the extracellular domain of the human epidermal growth factor receptor 2 (ErbB2 or HER2) in a complex with the antigen binding fragment of pertuzumab, an anti-Erb B2 monoclonal antibody, is determined.
TL;DR: Multifaceted interventions that helped to ensure adherence with evidence-based infection control guidelines nearly eliminated CR-BSIs in the authors' surgical ICU.
Abstract: Objective To determine whether a multifaceted systems intervention would eliminate catheter-related bloodstream infections (CR-BSIs). Design Prospective cohort study in a surgical intensive care unit (ICU) with a concurrent control ICU. Setting The Johns Hopkins Hospital. Patients All patients with a central venous catheter in the ICU. Intervention To eliminate CR-BSIs, a quality improvement team implemented five interventions: educating the staff; creating a catheter insertion cart; asking providers daily whether catheters could be removed; implementing a checklist to ensure adherence to evidence-based guidelines for preventing CR-BSIs; and empowering nurses to stop the catheter insertion procedure if a violation of the guidelines was observed. Measurement The primary outcome variable was the rate of CR-BSIs per 1,000 catheter days from January 1, 1998, through December 31, 2002. Secondary outcome variables included adherence to evidence-based infection control guidelines during catheter insertion. Main results Before the intervention, we found that physicians followed infection control guidelines during 62% of the procedures. During the intervention time period, the CR-BSI rate in the study ICU decreased from 11.3/1,000 catheter days in the first quarter of 1998 to 0/1,000 catheter days in the fourth quarter of 2002. The CR-BSI rate in the control ICU was 5.7/1,000 catheter days in the first quarter of 1998 and 1.6/1,000 catheter days in the fourth quarter of 2002 (p = .56). We estimate that these interventions may have prevented 43 CR-BSIs, eight deaths, and 1,945,922 dollars in additional costs per year in the study ICU. Conclusions Multifaceted interventions that helped to ensure adherence with evidence-based infection control guidelines nearly eliminated CR-BSIs in our surgical ICU.
TL;DR: The discovery of the transcription factor HIF-1 has led to the identification of protein hydroxylation as a mechanism by which changes in PO2 are transduced to effect changes in gene expression.
Abstract: The ability to sense and respond to changes in oxygenation represents a fundamental property of all metazoan cells. The discovery of the transcription factor HIF-1 has led to the identification of protein hydroxylation as a mechanism by which changes in Po2 are transduced to effect changes in gene expression.
TL;DR: This work states that the discovery of aquaporins has stimulated a reconsideration of membrane water permeability by investigators across a wide range of disciplines and indicates diverse roles in the regulation of water homeostasis.
Abstract: Our understanding of the movement of water through cell membranes has been greatly advanced by the discovery of a family of water-specific, membrane-channel proteins — the aquaporins. These proteins are present in organisms at all levels of life, and their unique permeability characteristics and distribution in numerous tissues indicate diverse roles in the regulation of water homeostasis. The recognition of aquaporins has stimulated a reconsideration of membrane water permeability by investigators across a wide range of disciplines.
TL;DR: Behavioral and pharmacological manipulations that enhance 5-HT and BDNF signaling could help promote healthy brain aging and preserve brain function during aging.
TL;DR: The hypothesis of stimulation-induced modulation of pathological network activity as a therapeutic mechanism of DBS is supported after apparently contradictory results showing suppression of activity in the stimulated nucleus, but increased inputs to projection nuclei.
Abstract: Deep brain stimulation (DBS) is an effective therapy for medically refractory movement disorders. However, fundamental questions remain about the effects of DBS on neurons surrounding the electrode. Experimental studies have produced apparently contradictory results showing suppression of activity in the stimulated nucleus, but increased inputs to projection nuclei. We hypothesized that cell body firing does not accurately reflect the efferent output of neurons stimulated with high-frequency extracellular pulses, and that this decoupling of somatic and axonal activity explains the paradoxical experimental results. We studied stimulation using the combination of a finite-element model of the clinical DBS electrode and a multicompartment cable model of a thalamocortical (TC) relay neuron. Both the electric potentials generated by the electrode and a distribution of excitatory and inhibitory trans-synaptic inputs induced by stimulation of presynaptic terminals were applied to the TC relay neuron. The response of the neuron to DBS was primarily dependent on the position and orientation of the axon with respect to the electrode and the stimulation parameters. Stimulation subthreshold for direct activation of TC relay neurons caused suppression of intrinsic firing (tonic or burst) activity during the stimulus train mediated by activation of presynaptic terminals. Suprathreshold stimulation caused suppression of intrinsic firing in the soma, but generated efferent output at the stimulus frequency in the axon. This independence of firing in the cell body and axon resolves the apparently contradictory experimental results on the effects of DBS. In turn, the results of this study support the hypothesis of stimulation-induced modulation of pathological network activity as a therapeutic mechanism of DBS.
TL;DR: The most striking new finding is that signal transmission from membrane to cytoplasm proceeds through recruitment, by the seven-transmembrane protein Smoothened, of an atypical kinesin, which routes pathway activation by interaction with other components of a complex that includes the latent zinc finger transcription factor, Ci.
Abstract: The Hedgehog (Hh) signaling pathway is intimately linked to cell growth and differentiation, with normal roles in embryonic pattern formation and adult tissue homeostasis and pathological roles in tumor initiation and growth. Recent advances in our understanding of Hh response have resulted from the identification of new pathway components and new mechanisms of action for old pathway components. The most striking new finding is that signal transmission from membrane to cytoplasm proceeds through recruitment, by the seven-transmembrane protein Smoothened, of an atypical kinesin, which routes pathway activation by interaction with other components of a complex that includes the latent zinc finger transcription factor, Ci.
TL;DR: Comprehensive discharge planning plus postdischarge support for older patients with CHF significantly reduced readmission rates and may improve health outcomes such as survival and QOL without increasing costs.
Abstract: ContextComprehensive discharge planning plus postdischarge support may reduce
readmission rates for older patients with congestive heart failure (CHF).ObjectiveTo evaluate the effect of comprehensive discharge planning plus postdischarge
support on the rate of readmission in patients with CHF, all-cause mortality,
length of stay (LOS), quality of life (QOL), and medical costs.Data SourcesWe searched MEDLINE (1966 to October 2003), the Cochrane Clinical Trials
Register (all years), Social Science Citation Index (1992 to October 2003),
and other databases for studies that described such an intervention and evaluated
its effect in patients with CHF. Where possible we also contacted lead investigators
and experts in the field.Study SelectionWe selected English-language publications of randomized clinical trials
that described interventions to modify hospital discharge for older patients
with CHF (mean age ≥55 years), delineated clearly defined inpatient and
outpatient components, compared efficacy with usual care, and reported readmission
as the primary outcome.Data ExtractionTwo authors independently reviewed each report, assigned quality scores,
and extracted data for primary and secondary outcomes in an unblinded standardized
manner.Data SynthesisEighteen studies representing data from 8 countries randomized 3304
older inpatients with CHF to comprehensive discharge planning plus postdischarge
support or usual care. During a pooled mean observation period of 8 months
(range, 3-12 months), fewer intervention patients were readmitted compared
with controls (555/1590 vs 741/1714, number needed to treat = 12; relative
risk [RR], 0.75; 95% confidence interval [CI], 0.64-0.88). Analysis of studies
reporting secondary outcomes found a trend toward lower all-cause mortality
for patients assigned to an intervention compared with usual care (RR, 0.87;
95% CI, 0.73-1.03; n = 14 studies), similar initial LOS (mean [SE]: 8.4 [2.5]
vs 8.5 [2.2] days, P = .60; n = 10), greater percentage
improvement in QOL scores compared with baseline scores (25.7% [95% CI, 11.0%-40.4%]
vs 13.5% [95% CI, 5.1%-22.0%]; n = 6, P = .01), and
similar or lower charges for medical care per patient per month for the initial
hospital stay, administering the intervention, outpatient care, and readmission
(−$359 [95% CI, −$763 to $45]; n = 4, P =
.10 for non-US trials and −$536 [95% CI, −$956 to −$115];
n = 4, P = .03, for US trials).ConclusionComprehensive discharge planning plus postdischarge support for older
patients with CHF significantly reduced readmission rates and may improve
health outcomes such as survival and QOL without increasing costs.
TL;DR: The literature suggests that the relationship between clinical pain and insomnia is reciprocal and CBT treatments for pain or insomnia hold promise in reducing pain severity and improving sleep quality.
TL;DR: It is shown that Norrin and Fz4 function as a ligand-receptor pair that plays a central role in vascular development in the eye and ear, and it is indicated that ligands unrelated to Wnts can act through Fz receptors.
TL;DR: Novel results document that nonsense surveillance is a crucial post-transcriptional regulatory event that influences the expression of broad classes of physiologic transcripts, has been functionally incorporated into essential homeostatic mechanisms and suppresses expression of evolutionary remnants.
Abstract: Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise
TL;DR: The data suggest that MM "stem cells" are CD138- B cells with the ability to replicate and subsequently differentiate into malignant CD138+ plasma cells.
TL;DR: The existence of circulating tissue-specific growth inhibitors of this type was hypothesized over 40 years ago to explain how sizes of individual tissues are controlled and skeletal muscle appears to be the first example of a tissue whose size is controlled by this type of regulatory mechanism.
Abstract: Myostatin is a secreted protein that acts as a negative regulator of skeletal muscle mass. During embryogenesis, myostatin is expressed by cells in the myotome and in developing skeletal muscle and acts to regulate the final number of muscle fibers that are formed. During adult life, myostatin protein is produced by skeletal muscle, circulates in the blood, and acts to limit muscle fiber growth. The existence of circulating tissue-specific growth inhibitors of this type was hypothesized over 40 years ago to explain how sizes of individual tissues are controlled. Skeletal muscle appears to be the first example of a tissue whose size is controlled by this type of regulatory mechanism, and myostatin appears to be the first example of the long-sought chalone.
TL;DR: Observations of ALS4 suggest that mutations in SETX may cause neuronal degeneration through dysfunction of the helicase activity or other steps in RNA processing.
Abstract: Juvenile amyotrophic lateral sclerosis (ALS4) is a rare autosomal dominant form of juvenile amyotrophic lateral sclerosis (ALS) characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs. Individuals affected with ALS4 usually have an onset of symptoms at age Senataxin gene ( SETX ). The SETX gene encodes a novel 302.8-kD protein. Although its function remains unknown, SETX contains a DNA/RNA helicase domain with strong homology to human RENT1 and IGHMBP2, two genes encoding proteins known to have roles in RNA processing. These observations of ALS4 suggest that mutations in SETX may cause neuronal degeneration through dysfunction of the helicase activity or other steps in RNA processing.