Showing papers by "University of Texas Medical Branch published in 2004"
TL;DR: fMRI experiments found that placebo analgesia was related to decreased brain activity in pain-sensitive brain regions, including the thalamus, insula, and anterior cingulate cortex, and was associated with increased activity during anticipation of pain in the prefrontal cortex, providing evidence that placebos alter the experience of pain.
Abstract: The experience of pain arises from both physiological and psychological factors, including one's beliefs and expectations Thus, placebo treatments that have no intrinsic pharmacological effects may produce analgesia by altering expectations However, controversy exists regarding whether placebos alter sensory pain transmission, pain affect, or simply produce compliance with the suggestions of investigators In two functional magnetic resonance imaging (fMRI) experiments, we found that placebo analgesia was related to decreased brain activity in pain-sensitive brain regions, including the thalamus, insula, and anterior cingulate cortex, and was associated with increased activity during anticipation of pain in the prefrontal cortex, providing evidence that placebos alter the experience of pain
1,820 citations
TL;DR: Different types of skeletal muscle atrophy share a common transcriptional program that is activated in many systemic diseases including diabetes, cancer, and renal failure, according to cDNA microarrays.
Abstract: Skeletal muscle atrophy is a debilitating response to starvation and many systemic diseases including diabetes, cancer, and renal failure. We had proposed that a common set of transcriptional adaptations underlie the loss of muscle mass in these different states. To test this hypothesis, we used cDNA microarrays to compare the changes in content of specific mRNAs in muscles atrophying from different causes. We compared muscles from fasted mice, from rats with cancer cachexia, streptozotocin-induced diabetes mellitus, uremia induced by subtotal nephrectomy, and from pair-fed control rats. Although the content of >90% of mRNAs did not change, including those for the myofibrillar apparatus, we found a common set of genes (termed atrogins) that were induced or suppressed in muscles in these four catabolic states. Among the strongly induced genes were many involved in protein degradation, including polyubiquitins, Ub fusion proteins, the Ub ligases atrogin-1/MAFbx and MuRF-1, multiple but not all subunits of the 20S proteasome and its 19S regulator, and cathepsin L. Many genes required for ATP production and late steps in glycolysis were down-regulated, as were many transcripts for extracellular matrix proteins. Some genes not previously implicated in muscle atrophy were dramatically up-regulated (lipin, metallothionein, AMP deaminase, RNA helicase-related protein, TG interacting factor) and several growth-related mRNAs were down-regulated (P311, JUN, IGF-1-BP5). Thus, different types of muscle atrophy share a common transcriptional program that is activated in many systemic diseases.
1,466 citations
TL;DR: Heyn et al. as discussed by the authors performed a meta-analysis to determine whether physical exercises are beneficial for people with dementia and related cognitive impairments, and they found that exercise training increases fitness, physical function, cognitive function, and positive behavior in elderly persons with dementia.
1,206 citations
TL;DR: Foot infections in patients with diabetes cause substantial morbidity and frequent visits to health care professionals and may lead to amputation of a lower extremity and, thus, the urgency and venue of management.
Abstract: Benjamin A. Lipsky, Anthony R. Berendt, H. Gunner Deery, John M. Embil, Warren S. Joseph, Adolf W. Karchmer, Jack L. LeFrock, Daniel P. Lew, Jon T. Mader, Carl Norden, and James S. Tan Medical Service, Veterans Affairs Puget Sound Health Care System, and Division of General Internal Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington; Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford, United Kingdom; Northern Michigan Infectious Diseases, Petoskey, Michigan; Section of Infectious Diseases, Department of Medicine, University of Manitoba, Winnipeg, Manitoba; Section of Podiatry, Department of Primary Care, Veterans Affairs Medical Center, Coatesville, Pennsylvania; Division of Infectious Diseases, Department of Medicine, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts; Dimensional Dosing Systems, Sarasota, Florida; Department of Medicine, Service of Infectious Diseases, University of Geneva Hospitals, Geneva, Switzerland; Department of Internal Medicine, The Marine Biomedical Institute, and Department of Orthopaedics and Rehabilitation, University of Texas Medical Branch, Galveston, Texas; Department of Medicine, New Jersey School of Medicine and Dentistry, and Cooper Hospital, Camden, New Jersey; and Department of Internal Medicine, Summa Health System, and Northeastern Ohio Universities College of Medicine, Akron, Ohio
991 citations
TL;DR: Albuminuria is an important factor predicting cardiovascular risk in patients with type 2 diabetic nephropathy, and reducing albuminuria in the first 6 months appears to afford cardiovascular protection in these patients.
Abstract: Background— Albuminuria is an established risk marker for both cardiovascular and renal outcomes. Albuminuria can be reduced with drugs that block the renin-angiotensin system (RAS). We questioned whether the short-term drug-induced change in albuminuria would predict the long-term cardioprotective efficacy of RAS intervention. Methods and Results— We analyzed data from Reduction in Endpoints in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL), a double-blind, randomized trial in 1513 type 2 diabetic patients with nephropathy, focusing on the relationship between the prespecified cardiovascular end point (composite) or hospitalization for heart failure and baseline or reduction in albuminuria. Patients with high baseline albuminuria (≥3 g/g creatinine) had a 1.92-fold (95% CI, 1.54 to 2.38) higher risk for the cardiovascular end point and a 2.70-fold (95% CI, 1.94 to 3.75) higher risk for heart failure compared with patients with low albuminuria (<1.5 g/g). Amon...
724 citations
TL;DR: It is found that recombinant caspase-3 cleaves actomyosin, producing a characteristic, approximately 14-kDa actin fragment and other proteins that are degraded by the Ub-P'some system.
Abstract: With trauma, sepsis, cancer, or uremia, animals or patients experience accelerated degradation of muscle protein in the ATP-ubiquitin-proteasome (Ub-P'some) system. The initial step in myofibrillar proteolysis is unknown because this proteolytic system does not break down actomyosin complexes or myofibrils, even though it degrades monomeric actin or myosin. Since cytokines or insulin resistance are common in catabolic states and will activate caspases, we examined whether caspase-3 would break down actomyosin. We found that recombinant caspase-3 cleaves actomyosin, producing a characteristic, approximately 14-kDa actin fragment and other proteins that are degraded by the Ub-P'some. In fact, limited actomyosin cleavage by caspase-3 yields a 125% increase in protein degradation by the Ub-P'some system. Serum deprivation of L6 muscle cells stimulates actin cleavage and proteolysis; insulin blocks these responses by a mechanism requiring PI3K. Cleaved actin fragments are present in muscles of rats with muscle atrophy from diabetes or chronic uremia. Accumulation of actin fragments and the rate of proteolysis in muscle stimulated by diabetes are suppressed by a caspase-3 inhibitor. Thus, in catabolic conditions, an initial step resulting in loss of muscle protein is activation of caspase-3, yielding proteins that are degraded by the Ub-P'some system. Therapeutic strategies could be designed to prevent these events.
704 citations
TL;DR: Evidence from anatomical, neuroimaging, behavioral, electrophysiological, pharmacological, and biochemical data that implicate the amygdala in pain modulation and emotional responses to pain are reviewed.
Abstract: A reciprocal relationship exists between persistent pain and negative affective states such as fear, anxiety, and depression. Accumulating evidence points to the amygdala as an important site of such interaction. Whereas a key role of the amygdala in the neuronal mechanisms of emotionality and affective disorders has been well established, the concept of the amygdala as an important contributor to pain and its emotional component is still emerging. This article will review and discuss evidence from anatomical, neuroimaging, behavioral, electrophysiological, pharmacological, and biochemical data that implicate the amygdala in pain modulation and emotional responses to pain. The latero-capsular division of the central nucleus of the amygdala is now defined as the “nociceptive amygdala” and integrates nociceptive information with poly-modal information about the internal and external bodily environment. Dependent on environmental conditions and affective states, the amygdala appears to play a dual facilitato...
645 citations
TL;DR: Once-daily suppressive therapy with valacyclovir significantly reduces the risk of transmission of genital herpes among heterosexual, HSV-2-discordant couples.
Abstract: Background Nucleoside analogues against herpes simplex virus (HSV) have been shown to suppress shedding of HSV type 2 (HSV-2) on genital mucosal surfaces and may prevent sexual transmission of HSV. Methods We followed 1484 immunocompetent, heterosexual, monogamous couples: one with clinically symptomatic genital HSV-2 and one susceptible to HSV-2. The partners with HSV-2 infection were randomly assigned to receive either 500 mg of valacyclovir once daily or placebo for eight months. The susceptible partner was evaluated monthly for clinical signs and symptoms of genital herpes. Source partners were followed for recurrences of genital herpes; 89 were enrolled in a substudy of HSV-2 mucosal shedding. Both partners were counseled on safer sex and were offered condoms at each visit. The predefined primary end point was the reduction in transmission of symptomatic genital herpes. Results Clinically symptomatic HSV-2 infection developed in 4 of 743 susceptible partners who were given valacyclovir, as compared w...
635 citations
TL;DR: The mechanisms of disease emergence that are related to the host-range specificity of selected mosquito-borne alphaviruses and flaviviruses are reviewed.
Abstract: Many pandemics have been attributed to the ability of some RNA viruses to change their host range to include humans. Here, we review the mechanisms of disease emergence that are related to the host-range specificity of selected mosquito-borne alphaviruses and flaviviruses. We discuss viruses of medical importance, including Venezuelan equine and Japanese encephalitis viruses, dengue viruses and West Nile viruses.
571 citations
TL;DR: Results do not support the role of A. cooperi in the ecology of R. rickettsii in the area studied, but they add two more species of ricksettsiae to the poorly developed list of species occurring in ticks in South America.
Abstract: Owing to the potential role of the tick Amblyomma cooperi in the enzootic cycle of Rickettsia rickettsii, the etiologic agent of Brazilian spotted fever (BSF), this study evaluated infection by Rickettsia species in A. cooperi ticks collected from an area in Brazil where BSF is endemic. Among a total of 40 A. cooperi adult ticks collected in an area of BSF endemicity in the state of Sao Paulo, PCR analysis detected DNA of Rickettsia bellii in 16 ticks (40%), and 3 other ticks (7.5%) were positive for a previously unidentified spotted-fever-group (SFG) rickettsia. Cultivation in Vero cell cultures by the shell vial technique with individual A. cooperi ticks resulted in two isolates of R. bellii and one isolate genotypically characterized as an SFG rickettsia. The two R. bellii isolates were established in Vero cell cultures in the laboratory and were confirmed to be R. bellii by molecular analysis of the gltA and 17-kDa protein-encoding genes and by electron microscopic analysis. The SFG rickettsial isolate could not be stably passaged in cell culture in the laboratory, but molecular analysis of early passages suggested that it was closely related to Rickettsia parkeri, Rickettsia africae, and Rickettsia sibirica. These results do not support the role of A. cooperi in the ecology of R. rickettsii in the area studied, but they add two more species of rickettsiae to the poorly developed list of species occurring in ticks in South America.
551 citations
TL;DR: Low pregnancy-associated plasma protein A levels in the first trimester were associated strongly with a number of adverse pregnancy outcomes, and low free-beta subunit human chorionic gonadotropin levels and large nuchal translucency were both associated with early fetal loss.
TL;DR: Sequence analysis of GALNT3 identified biallelic deleterious mutations in all individuals with FTC, suggesting that defective post-translational modification underlies the disease.
Abstract: Familial tumoral calcinosis (FTC; OMIM 211900) is a severe autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Using linkage analysis, we mapped the gene underlying FTC to 2q24-q31. This region includes the gene GALNT3, which encodes a glycosyltransferase responsible for initiating mucin-type O-glycosylation. Sequence analysis of GALNT3 identified biallelic deleterious mutations in all individuals with FTC, suggesting that defective post-translational modification underlies the disease.
TL;DR: An overview of recent advances in understanding of feedback mechanisms that serve to limit P450 production of ROS is provided, including those that affect physiological and cellular effects of P450 generation of ROS.
TL;DR: The data indicate that activation of the hedgehog pathway, through loss of Su(Fu) or overexpression of sonic hedgehog, may involve tumor progression and metastases of prostate cancer.
Abstract: The hedgehog pathway plays a critical role in the development of prostate. However, the role of the hedgehog pathway in prostate cancer is not clear. Prostate cancer is the second most prevalent cause of cancer death in American men. Therefore, identification of novel therapeutic targets for prostate cancer has significant clinical implications. Here we report that activation of the hedgehog pathway occurs frequently in advanced human prostate cancer. We find that high levels of hedgehog target genes, PTCH1 and hedgehog-interacting protein (HIP), are detected in over 70% of prostate tumors with Gleason scores 8–10, but in only 22% of tumors with Gleason scores 3–6. Furthermore, four available metastatic tumors all have high expression of PTCH1 and HIP. To identify the mechanism of the hedgehog signaling activation, we examine expression of Su(Fu) protein, a negative regulator of the hedgehog pathway. We find that Su(Fu) protein is undetectable in 11 of 27 PTCH1 positive tumors, two of them contain somatic loss-of-function mutations of Su(Fu). Furthermore, expression of sonic hedgehog protein is detected in majority of PTCH1 positive tumors (24 out of 27). High levels of hedgehog target genes are also detected in four prostate cancer cell lines (TSU, DU145, LN-Cap and PC3). We demonstrate that inhibition of hedgehog signaling by smoothened antagonist, cyclopamine, suppresses hedgehog signaling, down-regulates cell invasiveness and induces apoptosis. In addition, cancer cells expressing Gli1 under the CMV promoter are resistant to cyclopamine-mediated apoptosis. All these data suggest a significant role of the hedgehog pathway for cellular functions of prostate cancer cells. Our data indicate that activation of the hedgehog pathway, through loss of Su(Fu) or overexpression of sonic hedgehog, may involve tumor progression and metastases of prostate cancer. Thus, targeted inhibition of hedgehog signaling may have significant implications of prostate cancer therapeutics.
TL;DR: A model of medical decision making was used to build a model of informed consent, which was then used to analyze the difference between informed consent and shared decision making, and it is hoped that this analysis will provide clinicians with helpful insights.
Abstract: Enhancing patient choice is a central theme of medical ethics and law. Informed consent is the legal process used to promote patient autonomy; shared decision making is a widely promoted ethical approach. These processes may most usefully be seen as distinct in clinically and ethically important respects. The approach outlined in this article uses a model that arrays all medical decisions along 2 axes: risk and certainty. At the extremes of these continua, 4 decision types are produced, each of which constrains the principal actors in predictable ways. Shared decision making is most appropriate in situations of uncertainty, in which 2 or more clinically reasonable alternatives exist. When there is only 1 realistic choice, patient and physician may gather and exchange information; however, the patient cannot be empowered to make choices that do not exist. In contrast, informed consent does not require the presence of clinical choice; it is appropriate for all decisions of significant risk, even if there is only one option. When a clinical decision contains both risk and uncertainty, shared decision making and informed consent are both appropriate. For decisions of lower risk, consent should still be present, but it can be simple rather than informed. Clinicians may use this analysis as a guide to their own interactions with patients. In the continuing effort to provide patients with appropriate decisional authority over their own medical choices, shared decision making, informed consent, and simple consent each has a distinct role to play.
TL;DR: Despite differences in the time course of plasma phenylalanine kinetics and a greater residual IC phenylAlanine concentration, amino acid supplementation acutely stimulated muscle protein synthesis in both young and elderly individuals.
Abstract: We recently demonstrated that muscle protein synthesis was stimulated to a similar extent in young and elderly subjects during a 3-h amino acid infusion. We sought to determine if a more practical ...
TL;DR: Second messenger cAMP regulates many cellular functions through its effectors, such as cAMP-dependent protein kinase (PKA) and Epac (exchange proteins directly activated by cAMP), which are precisely controlled spatiotemporally in vivo.
Abstract: Second messenger cAMP regulates many cellular functions through its effectors, such as cAMP-dependent protein kinase (PKA) and Epac (exchange proteins directly activated by cAMP). Spatial and temporal control of cAMP signaling is crucial to differential regulation of cellular targets involved in various signaling cascades. To investigate the compartmentalized cAMP signaling, we constructed fluorescent indicators that report intracellular cAMP dynamics and Epac activation by sandwiching the full-length Epac1 between cyan and yellow mutants of GFP. Elevations of cAMP decreased FRET and increased the ratio of cyan-to-yellow emissions by 10–30% in living mammalian cells. This response can be reversed by removing cAMP-elevating agents and abolished by mutating the critical residue responsible for cAMP binding. Targeting of the reporter to the plasma membrane, where cAMP is produced in response to the activation of β-adrenergic receptor, revealed a faster cAMP response at the membrane than in the cytoplasm and mitochondria. Simultaneous imaging with targeted cAMP indicator and PKA activity reporter allowed the detection of a much delayed PKA response in the nucleus after the rapid accumulation of cAMP at the plasma membrane of the same cell, despite the immediate presence of a pool of cAMP in the nucleus. Thus, cAMP dynamics and the activation of its effectors are precisely controlled spatiotemporally in vivo.
TL;DR: It is shown that in mammalian cells, removal of the 3' phosphate is dependent on polynucleotide kinase (PNK), and not APE, and that NEIL1/PNK could also repair the products of other DNA glycosylases, suggesting a broad role for this APE-independent BER pathway in mammals.
TL;DR: NIR-LED photobiomodulation represents an innovative and non-invasive therapeutic approach for the treatment of tissue injury and disease processes in which mitochondrial dysfunction is postulated to play a role including diabetic retinopathy, age-related macular degeneration, Leber's hereditary optic neuropathy and Parkinson's disease.
TL;DR: Systemic injection of a ROS scavenger, phenyl‐N‐tert‐butylnitrone (PBN), relieves SNL‐induced mechanical allodynia in a dose‐dependent manner, and systemic administration of non‐toxic doses of free radical scavengers could be useful for treatment of neuropathic pain.
Abstract: Reactive oxygen species (ROS) are free radicals produced in biological systems that are involved in various degenerative brain diseases. The present study tests the hypothesis that ROS also play an important role in neuropathic pain. In the rat spinal nerve ligation (SNL) model of neuropathic pain, mechanical allodynia develops fully 3 days after nerve ligation and persists for many weeks. Systemic injection of a ROS scavenger, phenyl-N-tert-butylnitrone (PBN), relieves SNL-induced mechanical allodynia in a dose-dependent manner. Repeated injections cause no development of tolerance or no loss of potency. Preemptive treatment with PBN is also effective in preventing full development of neuropathic pain behavior. Systemic injection was mimicked by intrathecal injection with a little less efficacy, while intracerebroventricular administration produced a much smaller effect. These data suggest that PBN exerts its anti-allodynic action mainly by spinal mechanisms. Systemic treatment with other spin-trap reagents, 5,5-dimethylpyrroline-N-oxide and nitrosobenzene, showed similar analgesic effects, suggesting that ROS are critically involved in the development and maintenance of neuropathic pain. Thus this study suggests that systemic administration of non-toxic doses of free radical scavengers could be useful for treatment of neuropathic pain.
TL;DR: It is reported that the sensitivity to TGF-β-induced apoptosis is regulated by crosstalk between the Akt/PKB serine/threonine kinase and Smad3 through a mechanism that is independent of Akt kinase activity.
Abstract: Transforming growth factor beta (TGF-beta) induces both apoptosis and cell-cycle arrest in some cell lines, but only growth arrest in others. It is not clear how this differential response to TGF-beta is specified. Smad proteins are critical mediators of TGF-beta signalling. After stimulation by TGF-beta, Smad2 and Smad3 become phosphorylated by the activated TGF-beta receptor kinases, oligomerize with Smad4, translocate to the nucleus and regulate the expression of TGF-beta target genes. Here we report that the sensitivity to TGF-beta induced apoptosis is regulated by crosstalk between the Akt/PKB serine/threonine kinase and Smad3 through a mechanism that is independent of Akt kinase activity. Akt interacts directly with unphosphorylated Smad3 to sequester it outside the nucleus, preventing its phosphorylation and nuclear translocation. This results in inhibition of Smad3-mediated transcription and apoptosis. Furthermore, the ratio of Smad3 to Akt correlates with the sensitivity of cells to TGF-beta induced apoptosis. Alteration of this ratio changes the apoptotic, but not the growth-inhibitory, responses of cells to TGF-beta. These findings identify an important determinant of sensitivity to TGF-beta-induced apoptosis that involves crosstalk between the TGF-beta and phosphatidylinositol-3-OH kinase (PI(3)K) pathways.
TL;DR: Sociocultural advantages conferred on Mexican Americans by living in high-density Mexican American neighborhoods outweigh the disadvantages conferred by the high poverty of those neighborhoods.
Abstract: Objectives. We examined whether Mexican Americans living in high-density Mexican American neighborhoods experience increased morbidity and mortality compared with the rates observed among Mexican Americans living in low-density areas.Methods. We conducted a prospective analysis of a cohort of 3050 Mexican Americans aged 65 years or older. We examined prevalence of 6 medical conditions and survival over 7 years of follow-up in relation to percentage of Mexican Americans in the census tract.Results. With adjustment for covariates, odds for disease prevalence among older Mexican Americans as a function of percentage of Mexican Americans in the census tract were 0.33 (95% confidence interval [CI]=0.16, 0.71) for stroke, 0.28 (95% CI= 0.11, 0.70) for cancer, and 0.31 (95% CI=0.10, 0.98) for hip fracture. The hazard ratio for all-cause mortality over 7 years’ follow-up was 0.64 (95% CI=0.42, 0.96).Conclusions. Sociocultural advantages conferred on Mexican Americans by living in high-density Mexican American nei...
TL;DR: It is shown that in addition to normal PMN (PMN-N), there are at least two distinct subsets of PMNs (PMn-I and PMN-II) distinguished as follows: cytokine and chemokine production and surface antigen expression.
TL;DR: Acute ingestion of both WH and CS after exercise resulted in similar increases in muscle protein net balance, resulting in net muscle protein synthesis despite different patterns of blood amino acid responses.
Abstract: TIPTON, K. D., T. A. ELLIOTT, M. G. CREE, S. E. WOLF, A. P. SANFORD, and R. R. WOLFE. Ingestion of Casein and Whey Proteins Result in Muscle Anabolism after Resistance Exercise. Med. Sci. Sports Exerc., Vol. 36, No. 12, pp. 2073–2081, 2004. Purpose: Determination of the anabolic response to exercise and nutrition is important for individuals who may benefit from increased muscle mass. Intake of free amino acids after resistance exercise stimulates net muscle protein synthesis. The response of muscle protein balance to intact protein ingestion after exercise has not been studied. This study was designed to examine the acute response of muscle protein balance to ingestion of two different intact proteins after resistance exercise. Methods: Healthy volunteers were randomly assigned to one of three groups. Each group consumed one of three drinks: placebo (PL; N 7), 20 g of casein (CS; N 7), or whey proteins (WH; N 9). Volunteers consumed the drink 1 h after the conclusion of a leg extension exercise bout. Leucine and phenylalanine concentrations were measured in femoral arteriovenous samples to determine balance across the leg. Results: Arterial amino acid concentrations were elevated by protein ingestion, but the pattern of appearance was different for CS and WH. Net amino acid balance switched from negative to positive after ingestion of both proteins. Peak leucine net balance over time was greater for WH (347 50 nmol·min 1 ·100 mL 1 leg) than CS (133 45 nmol·min 1 ·100 mL 1 leg), but peak phenylalanine balance was similar for CS and WH. Ingestion of both CS and WH stimulated a significantly larger net phenylalanine uptake after resistance exercise, compared with the PL (PL 5 15 mg, CS 84 10 mg, WH 62 18 mg). Amino acid uptake relative to amount ingested was similar for both CS and WH (10–15%). Conclusions: Acute ingestion of both WH and CS after exercise resulted in similar increases in muscle protein net balance, resulting in net muscle protein synthesis despite different patterns of blood amino acid responses. Key Words: MUSCLE PROTEIN SYNTHESIS, ARTERIOVENOUS BALANCE, NET MUSCLE PROTEIN BALANCE, MUSCLE BIOPSIES
TL;DR: Essential amino acid and carbohydrate supplementation may represent a viable intervention for individuals at risk of sarcopenia due to immobility or prolonged bedrest.
Abstract: We determined whether essential amino acid and carbohydrate supplementation could offset the catabolic response to prolonged inactivity. Major outcome measures included mixed muscle fractional synthetic rate (FSR), phenylalanine net balance, lean leg mass, and leg extension strength. On d 1 and 28, vastus lateralis muscle biopsies and femoral arterio-venous blood samples were obtained during a primed constant infusion of l-[ring-(2)H(5)]phenylalanine. Net balance and FSR were calculated over 16 h, during which the control group (CON) received a nutritionally mixed meal every 5 h (0830, 1330, and 1830 h). The experimental group (EXP) also consumed 16.5 g essential amino acids and 30 g carbohydrate (1100, 1600, and 2100 h). The dietary regimen was maintained during bedrest. FSR was higher in the EXP group on d 1 (EXP, 0.099 +/- 0.008%/h; CON: 0.075 +/- 0.005%/h) and d 28 (EXP, 0.093 +/- 0.006%/h; CON, 0.055 +/- 0.007%/h). Lean leg mass was maintained throughout bedrest in the EXP group (+0.2 +/- 0.3 kg), but fell in the CON group (-0.4 +/- 0.1 kg). Strength loss was more pronounced in the CON group (EXP, -8.8 +/- 1.4 kg; CON, -17.8 +/- 4.4 kg). Essential amino acid and carbohydrate supplementation may represent a viable intervention for individuals at risk of sarcopenia due to immobility or prolonged bedrest.
TL;DR: The authors found in diabetic muscle that mRNA of the forkhead transcriptional factor, its nuclear translocation, and binding to the atrogin-1/MAFbx promoter were increased, and this mechanism could increase muscle atrophy in conditions with impaired insulin responsiveness.
Abstract: Muscle proteolysis from catabolic conditions, including chronic kidney disease, requires coordinated activation of both the apoptotic and ATP-ubiquitin-proteasome systems (Ub-P'some), including upregulation of components of the Ub-P'some system. Activation of the apoptotic system is required because caspase-3 initially cleaves myofibrils, yielding substrates for the Ub-P'some system plus a characteristic 14-kD actin fragment. The authors studied insulin deficiency, a model of accelerated muscle atrophy, to understand how regulation of the apoptotic and the Ub-P'some systems could be coordinated. As expected, phosphatidylinositol 3 kinase activity (PI3K) was suppressed in muscle; in addition to decreased insulin, the mechanism includes IRS-1 phosphorylation at serine-307. Caspase-3 activity was also increased, and the authors linked it to a low PI3K-induced activation of the apoptotic system that includes a conformational change in Bax and release of cytochrome C. Coordinated atrogin-1/MAFbx expression is required as a critical factor for Ub-P'some system-dependent muscle proteolysis in diabetes and other catabolic states. The mechanism that regulates atrogin-1/MAFbx expression is unknown. Atrogin-1/MAFbx expression increased when the authors suppressed PI3K activity in muscle cells. The forkhead transcriptional factor, a downstream substrate of PI3K, stimulated atrogin-1/MAFbx promoter transcriptional activity markedly. The authors found in diabetic muscle that mRNA of the forkhead transcriptional factor, its nuclear translocation, and binding to the atrogin-1/MAFbx promoter were increased. When PI3K activity is low, both apoptotic and Ub-P'some pathways are activated coordinately to cause muscle proteolysis. This mechanism could increase muscle atrophy in conditions with impaired insulin responsiveness.
TL;DR: Experimental data together with theoretical analysis demonstrate the feasibility of detection of deeply seeded small tumors that express tumor associated antigens using targeted gold NPs and OAT.
Abstract: Purpose Optoacoustic tomography (OAT) is a novel medical imaging method that uses optical illumination and ultrasonic detection to produce deep tissue images based on their light absorption. Abnormal angiogenesis in advanced tumors, that increases the blood content of the tumor, is an endogenous contrast agent for OAT. In early stages, however, angiogenesis is not sufficient to differentiate a tumor from normal tissue; justifying the application of an exogenous contrast agent. We have developed a molecular based contrast agent composed of gold nanoparticles conjugated to a monoclonal antibody that improves OAT imaging to potentiate its use in imaging deep tumors in early stages of cancer or metastatic lesions. Procedure Due to their strong optoacoustic signal, we used gold nanoparticles (NPs) as a contrast agent. To target NPs to breast cancer cells, we conjugated NPs to a monoclonal antibody that specifically binds cell surface receptors known to be overexpressed in human breast tumors. Results In a series of in vitro experiments, Herceptin® (monoclonal antibody that binds HER2/neu) conjugated to 40nm NPs (Mab/NPs) selectively targeted human SK-BR-3 breast cancer cells. The breast cancer cells were detected and imaged by OAT in a gelatin phantom that optically resembled breast tissue. Sensitivity experiments showed that a concentration as low as 10 9 NPs per ml were detectable at a depth of 6 cm. Conclusion Experimental data together with theoretical analysis demonstrate the feasibility of detection of deeply seeded small tumors that express tumor associated antigens using targeted gold NPs and OAT.
TL;DR: Visual and auditory cues improved gait performance in patients with PD, but they did so in different ways and the simultaneous use of auditory and visual cues did not improve gait significantly more than each cue alone.
01 Jan 2004
TL;DR: The two-feedback-loop regulatory module of nuclear factor kappaB (NF-kappaB) signaling pathway is modeled by means of ordinary differential equations and gives the predictions of the possible responses of whole kinetics to the change in the level of a given activator or inhibitor.