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Leucocyte chemotaxis: physiological considerations and abnormalities.

Expression of the inflammatory process is dependent on mobilisation of leucocytes, which require leucocyte chemotaxis. Recent technological advances have enabled extensive in vitro biological characterisation of the chemotatic stimuli (factors) and the cellular events of migration. The chemotatic stimuli include products of complement activation, fibrinolytic and kinin generating systems, collagen products as well as products of bacterial growth and products released from virus-infected tissues. Chemotatic factors are also released as a result of lymphocyte activation and phagocytosis by neutrophils. Other neutrophils products released during phagocytosis activate the complement system. A complex mechanism for limiting production or activity of chemotactic factors has been identified. These antichemotatic agents include serum and cell-derived chemotactic factor inactivators as well as specific inhibitors of leucocyte migration and complement inactivators released from neutrophils during the phagocytic process. The mechanism by which cells respond to chemotatic factors is poorly understood by cell adherence to the substratum, cell deformability, random migration, and directed migration are required. These processes are complex and require modifications of the leucocyte surface, calcium and magnesium, activation of esterases, function of contractile elements and assembly of a cytoskeleton, which is probably modulated by cyclic nucleotide metabolism.

Animals↗

Embryonal cardiotoxicity of the Helicobacter pylori lipopolysaccharide.

Helicobacter (H.) pylori is the causative agent of the peptic ulcer disease and a co-factor in the development of gastric malignancies. Recently, it has been maintained that chronic H. pylori infections in adults are linked to a higher risk of coronary heart diseases. In this respect, the acute toxic effects of the H. pylori lipopolysaccharide (LPS) on embryonal cardiomyocytes at different developmental stages was evaluated. White Leghorn chick embryos and smooth (S)--form NCTC 11637 strain H. pylori organisms were used. Both whole heath-killed H. pylori suspensions (3.10(6) bacteria/egg) and isolated S-LPS (500 ng/egg) or S-Lipid A (500 ng/egg) were non-lethal to 4-day embryos, becoming moderately lethal (5% to 30%) to 6- and 8-day embryos and highly lethal (> 90%) to 10- to 17-day embryos. The contractile activity of isolated atrial fragments from 10-day embryos was completely inhibited, within 5 min, following treatments with heath-killed H. pylori (3 x 10(6)/ml), or S-LPS (500 ng/ml), or S-Lipid A (500 ng/ml); the block determined by S-LPS and S-Lipid A was irreversible, while the block by bacterial suspensions was completely reversible upon withdrawal. Following a 24-hour treatment with S-LPS or S-Lipid A of single-cell cultures of cardiomyocytes (isolated from 10-day embryos) a dose-dependent cell loss was observed, as assessed by total protein dosage and direct counting of adherent cells. Propidium Iodide/Annexin V FACS-analysis confirmed the occurrence of cellular necrosis, but did not show any evidence of apoptotic processes. The release of superoxide anion radicals by cultured cardiomyocytes was as follows: S-Lipid A (25 micrograms/ml) > S-LPS (25 micrograms/ml) > heath killed H. pylori suspensions (3 x 10(6)/ml); control cultures did not release detectable amounts of superoxide anion radicals. Furthermore, cultured cardiomyocytes produced increased amounts of NO (N-monomethylarginine-inhibitable) following stimulation with S-LPS (25 micrograms/ml) or S-Lipid A (25 micrograms/ml) (but not heath killed H. pylori 3 x 10(6)/ml suspensions). Under all the above experimental conditions S-polysaccharide proved to be non-toxic. Concluding, H. pylori LPS is relatively non-toxic to the less differentiated cardiomyocytes; cardiomyocytes which are more advanced in their biochemical differentiation become highly sensitive to LPS and produce ROS and NO. ROS are probably responsible for the early toxic actions, while both ROS and NO are likely to be involved in the later degenerative/necrotic effects.

Animals↗

Thoughts after reading Robert Jay Lifton's 'The Nazi Doctors'.

Robert Jay Lifton's remarkable book The Nazi Doctors and its tragic subject matter provided an opportunity to try and place the complicity of doctors in such barbarity in historical perspective. Massive episodes of killing of human beings by other human beings have been an ongoing saga for centuries. Misguided belief and misguided science, and the abuse of constantly advancing technology in the name of one or other nation-state, have made possible the acceleration of megadeath. The Nazi concentration and death camps were a particularly vicious manifestation within the spectrum of killing. Modern weaponry makes omnicide quite feasible. Our urgent need is to learn the lesson and to cultivate and promote planetary patriotism as promptly as possible. Adherence to an international code of human ethics is a compelling requirement. The origin of the International Committee of the Red Cross in 1863 was an inspiring and promising beginning. The formulation of the Declaration of Geneva by the World Medical Association in 1947 profoundly enhanced the value of the Hippocratic Oath and provides a sound ethical basis for the national and international guidance of the medical profession today. The International Physicians for the Prevention of Nuclear War establishes another firm step in the right direction.

Codes of Ethics↗

A novel anticancer effect of thalidomide: inhibition of intercellular adhesion molecule-1-mediated cell invasion and metastasis through suppression of nuclear factor-kappaB.

PURPOSE: Thalidomide has been reported to have antiangiogenic and antimetastatic effects. Intercellular adhesion molecule-1 (ICAM-1) was shown to be involved in monocyte adherence to epithelial cells and cancer cell invasion. In this study, we further investigated the role of ICAM-1 in tumorigenesis, including tumor formation and metastasis. ICAM-1 as a molecular target for cancer and the anticancer effect of thalidomide were investigated. EXPERIMENTAL DESIGN: Expression of ICAM-1 protein in human lung cancer specimens was assessed by immunohistochemistry. ICAM-1 overexpressing A549 cells (A549/ICAM-1) were established to investigate the direct effect of ICAM-1 on in vitro cell invasion and in vivo tumor metastasis. Transient transfection and luciferase assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation were done to assess the activity and binding of nuclear factor-kappaB to the ICAM-1 promoter. A xenograft model in nude mice was conducted to evaluate the anticancer effect of thalidomide. RESULTS: High expression of ICAM-1 in human lung cancer specimens was correlated with a greater risk of advanced cancers (stages III and IV). A549/ICAM-1 cells were shown to induce in vitro cell invasion and in vivo tumor metastasis. Anti-ICAM-1 antibody and thalidomide had inhibitory effect on these events. Thalidomide also suppressed tumor necrosis factor-alpha-induced ICAM-1 expression through inhibition of nuclear factor-kappaB binding to the ICAM-1 promoter. The in vivo xenograft model showed the effectiveness of thalidomide on tumor formation. CONCLUSION: These studies provide a framework for targeting ICAM-1 as a biologically based therapy for cancer, and thalidomide might be effective in human lung cancer.

Adenocarcinoma↗

The asthma consultation: what is important?

Sufficient time and effective communication are the main requirements in an ideal asthma consultation. One way of using limited time effectively is for patients to be offered more information prior to the consultation. Physician-patient communication during the consultation may be improved by patients receiving, in advance, pertinent information related to their appointment and leaflets may be used to encourage patients to list any questions, fears or concerns prior to the consultation. Directing patients to appropriate internet sites may also facilitate information transfer. Time is frequently wasted when patients fail to attend their consultation. Sending a reminder letter or phoning to remind patients of their appointment has been shown to significantly reduce non-attendance rates. During the consultation, time can be used more effectively by ensuring that patients understand their treatment regimens, by improving communication between the doctor and patient and by organising asthma services in a manner acceptable to patients; this includes avoiding delays, having a doctor that listens and seeing the same doctor on each occasion. After the consultation, advice given to patients should be reinforced as studies suggest that patients' ability to recall information given to them may influence patient adherence and patient satisfaction. The whole professional team should be involved in order to manage better limited time effectively and information given to patients should be reinforced, either by post-consultation leaflet/letter or via telephone or email. Most importantly, correct performance of the inhalation manoeuvre should be regularly checked, patients should be taught and trained how to manage their own condition and should be offered convenient follow-up options, all of which should improve patient satisfaction and compliance.

Asthma↗

Guidelines for environmental infection control in health-care facilities. Recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee (HICPAC).

The health-care facility environment is rarely implicated in disease transmission, except among patients who are immunocompromised. Nonetheless, inadvertent exposures to environmental pathogens (e.g., Aspergillus spp. and Legionella spp.) or airborne pathogens (e.g., Mycobacterium tuberculosis and varicella-zoster virus) can result in adverse patient outcomes and cause illness among health-care workers. Environmental infection-control strategies and engineering controls can effectively prevent these infections. The incidence of health-care--associated infections and pseudo-outbreaks can be minimized by 1) appropriate use of cleaners and disinfectants; 2) appropriate maintenance of medical equipment (e.g., automated endoscope reprocessors or hydrotherapy equipment); 3) adherence to water-quality standards for hemodialysis, and to ventilation standards for specialized care environments (e.g., airborne infection isolation rooms, protective environments, or operating rooms); and 4) prompt management of water intrusion into the facility. Routine environmental sampling is not usually advised, except for water quality determinations in hemodialysis settings and other situations where sampling is directed by epidemiologic principles, and results can be applied directly to infection-control decisions. This report reviews previous guidelines and strategies for preventing environment-associated infections in health-care facilities and offers recommendations. These include 1) evidence-based recommendations supported by studies; 2) requirements of federal agencies (e.g., Food and Drug Administration, U.S. Environmental Protection Agency, U.S. Department of Labor, Occupational Safety and Health Administration, and U.S. Department of Justice); 3) guidelines and standards from building and equipment professional organizations (e.g., American Institute of Architects, Association for the Advancement of Medical Instrumentation, and American Society of Heating, Refrigeration, and Air-Conditioning Engineers); 4) recommendations derived from scientific theory or rationale; and 5) experienced opinions based upon infection-control and engineering practices. The report also suggests a series of performance measurements as a means to evaluate infection-control efforts.

Air Microbiology↗

Hepatic colon cancer metastases in mice: dynamic in vivo correlation with hypoechoic rims visible at US.

PURPOSE: To use videomicroscopy of tumor-bearing livers of live mice to depict tumors directly to determine the exact nature of rims seen on corresponding ultrasonographic (US) scans. MATERIALS AND METHODS: Seventy-six hepatic colorectal cancer metastases were studied in exteriorized livers of 18 mice by using intravital microscopy, US, and histologic examination of the same tumors. RESULTS: Hypoechoic rims correlated with distended sinusoidal spaces in vivo. These spaces surrounded only locally invasive tumors (mean diameter, 0.85 mm) that had obstructed the supplying terminal portal venules. These spaces, containing adherent leukocytes and tumor cells, gave rise to new tumor vasculature. Results of histologic examination of rims (portal inflammation, congested or compressed sinusoids, cell atrophy) correlated with leukocyte endothelial adherence, occluded sinusoids, and new vessel formation in vivo. CONCLUSION: Unlike results from previous studies, dynamic in vivo observations of peritumoral rims demonstrated distended sinusoidal spaces giving rise to new tumor-penetrating vessels. These sinusoids arose around locally invasive tumors and were associated with more advanced intrahepatic disease. These dynamic observations provide a pathophysiologic explanation for previous histologic correlates of peritumoral rims.

Analysis of Variance↗

Substitution of doctors by nurses in primary care.

BACKGROUND: Demand for primary care services has increased in developed countries due to population ageing, rising patient expectations, and reforms that shift care from hospitals to the community. At the same time, the supply of physicians is constrained and there is increasing pressure to contain costs. Shifting care from physicians to nurses is one possible response to these challenges. The expectation is that nurse-doctor substitution will reduce cost and physician workload while maintaining quality of care. OBJECTIVES: Our aim was to evaluate the impact of doctor-nurse substitution in primary care on patient outcomes, process of care, and resource utilisation including cost. Patient outcomes included: morbidity; mortality; satisfaction; compliance; and preference. Process of care outcomes included: practitioner adherence to clinical guidelines; standards or quality of care; and practitioner health care activity (e.g. provision of advice). Resource utilisation was assessed by: frequency and length of consultations; return visits; prescriptions; tests and investigations; referral to other services; and direct or indirect costs. SEARCH STRATEGY: The following databases were searched for the period 1966 to 2002: Medline; Cinahl; Bids, Embase; Social Science Citation Index; British Nursing Index; HMIC; EPOC Register; and Cochrane Controlled Trial Register. Search terms specified the setting (primary care), professional (nurse), study design (randomised controlled trial, controlled before-and-after-study, interrupted time series), and subject (e.g. skill mix). SELECTION CRITERIA: Studies were included if nurses were compared to doctors providing a similar primary health care service (excluding accident and emergency services). Primary care doctors included: general practitioners, family physicians, paediatricians, general internists or geriatricians. Primary care nurses included: practice nurses, nurse practitioners, clinical nurse specialists, or advanced practice nurses. DATA COLLECTION AND ANALYSIS: Study selection and data extraction was conducted independently by two reviewers with differences resolved through discussion. Meta-analysis was applied to outcomes for which there was adequate reporting of intervention effects from at least three randomised controlled trials. Semi-quantitative methods were used to synthesize other outcomes. MAIN RESULTS: 4253 articles were screened of which 25 articles, relating to 16 studies, met our inclusion criteria. In seven studies the nurse assumed responsibility for first contact and ongoing care for all presenting patients. The outcomes investigated varied across studies so limiting the opportunity for data synthesis. In general, no appreciable differences were found between doctors and nurses in health outcomes for patients, process of care, resource utilisation or cost. In five studies the nurse assumed responsibility for first contact care for patients wanting urgent consultations during office hours or out-of-hours. Patient health outcomes were similar for nurses and doctors but patient satisfaction was higher with nurse-led care. Nurses tended to provide longer consultations, give more information to patients and recall patients more frequently than did doctors. The impact on physician workload and direct cost of care was variable. In four studies the nurse took responsibility for the ongoing management of patients with particular chronic conditions. The outcomes investigated varied across studies so limiting the opportunity for data synthesis. In general, no appreciable differences were found between doctors and nurses in health outcomes for patients, process of care, resource utilisation or cost. AUTHORS' CONCLUSIONS: The findings suggest that appropriately trained nurses can produce as high quality care as primary care doctors and achieve as good health outcomes for patients. However, this conclusion should be viewed with caution given that only one study was powered to assess equivalence of care, many studies had methodological limitations, and patient follow-up was generally 12 months or less. While doctor-nurse substitution has the potential to reduce doctors' workload and direct healthcare costs, achieving such reductions depends on the particular context of care. Doctors' workload may remain unchanged either because nurses are deployed to meet previously unmet patient need or because nurses generate demand for care where previously there was none. Savings in cost depend on the magnitude of the salary differential between doctors and nurses, and may be offset by the lower productivity of nurses compared to doctors.

Family Practice↗

Combinatorial protein display for the cell-based screening of biomaterials that direct neural stem cell differentiation.

Neural stem cell (NSC) has emerged as a potential source for cell replacement therapy following traumatic injuries and degenerative diseases of the central nervous system. However, clinical applications of NSC further require technological advances especially for controlling differentiation of NSC. This study aimed at developing biomaterials that serve to expand undifferentiated NSC or to induce cells with specific phenotypes. Our approach is to construct composite biomaterials that consist of extracellular matrix components and growth factors. In order to optimize matrix-growth factor combinations, we conducted the parallel and rapid screening of composite biomaterials through assays using cell-based arrays. The photo-assisted patterning of an alkanethiol self-assembled monolayer was employed to achieve site-addressable combinatorial immobilization of natural and synthetic matrices incorporated with growth factors including epidermal growth factor (EGF), ciliary neurotrophic factor (CNTF), nerve growth factor (NGF), and neurotrophin-3 (NT-3). NSC obtained from the rat embryonic striatum was cultured directly on the array to screen for cell adhesion, proliferation, and promotion of neuronal and glial specification. The results showed that the significant number of cells adhered to laminin-1, fibronectin, ProNectin, and poly(ethyleneimine). It was found that cells proliferated most extensively on a spot with immobilized EGF among the spots with different matrix-growth factor combinations. The results also showed that neuronal differentiation was promoted on the spots with immobilized NGF or NT-3, and astroglial differentiation with CNTF. Importantly, observed effects of growth factors were frequently altered depending on the type of co-immobilized matrices, suggesting synergic effects of adhesion and growth factor signals.

Adsorption↗

[Percutaneous diagnostic angioscopy. Primary lesions].

Efficacy of percutaneous treatments of arterial affections requires the correct choice of indications, necessitating precise knowledge of elementary arterial lesions. Arterial endoscopy appears to be more specific than angiography for this use, since it allows direct vision in vivo of the lesion, a histopathologic approach compared with the non univocal images produced by angiography (for example, an arterial obstruction can result from varied causes). Different accidents to the endothelial surface can be observed: golden yellow atheromatous elevations on a straw yellow background, intimal flaps, mobile intra-luminal vegetations. Established atheromatous stenosis are smooth and regular, or on the contrary ulcerated and edged with irregular flaps capable of provoking an eccentric residual lumen. The vegetating atheromatous lesions may project into the lumen, often as calcified and thus pearly white scales adhering to the wall, or as larger occlusive lesions. When capable of being isolated, a thrombus often completes the stenosis: its recognition is therefore fundamental since its removal exposes the subjacent lesions to be treated. The fresh clot is coral shaped, bright red and mobile in the blood flow. Established clots are compact and greenish brown. At an advanced stage of atheroma the surface of the occluding clot is covered with a regular straw yellow endothelium. In the presence of a dissecting vessel the fibroscope may be introduced into the false channel, no longer showing typical endothelium but a coagulated mass interspersed with fibrous bands. Prosthetic stenosis result from either intimal hyperplasia or a suturing fault with plication.

Angiography↗

HDAC6 inhibition reduces Pseudomonas aeruginosa adherence and internalization in cystic fibrosis epithelial cells via microtubule stabilization.

Pseudomonas aeruginosa is a common opportunistic pathogen that causes chronic lung infections in individuals with cystic fibrosis. Despite advances in therapies that restore cystic fibrosis transmembrane conductance regulator function, persistent colonization of the airway remains a major clinical challenge. Reduced clearance of P. aeruginosa from the cystic fibrosis airway has been associated with the increased activity of histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase that decreases microtubule acetylation and stability. In this study, we investigated the role of HDAC6 in modulating interactions between P. aeruginosa and cystic fibrosis airway epithelial cells. Pharmacologic inhibition of HDAC6 significantly reduced bacterial adherence in both mouse and human cystic fibrosis epithelial cells. Genetic deletion of HDAC6 produced similar effects, while knockout of a microtubule-stabilizing protein increased bacterial adherence, mimicking the cystic fibrosis phenotype. HDAC6 inhibition also reduced bacterial internalization, although to a lesser extent compared to adherence. These results suggest that microtubule destabilization contributes to the enhanced colonization of cystic fibrosis airways by P. aeruginosa. Targeting host microtubule regulatory pathways, particularly by inhibiting HDAC6, may represent a promising host-directed strategy to limit early bacterial attachment and reduce the risk of chronic infection in cystic fibrosis.

Pseudomonas aeruginosa↗

Biopotential fiber sensor.

UNLABELLED: We have developed a new biopotential fiber sensor (BFS) technology as an alternative to traditional wet-gel Ag/AgCl electrodes in long-term monitoring applications. Biopotential fiber sensor technology uses proprietary method of bonding copper sulfide to the surface of acrylic fibers, thus creating an electrically conductive medium (10(-1) ohms/cm). Surface modified bundles of acrylic fibers form stable biopotential sensors when doped with proprietary ink comprising organic acids and nano particles of Ag and AgCl. Biopotential fiber sensors are characterized by a small footprint 0.1 mm2 and low mass of 0.005 g. Biopotential fiber sensor systems are disposable 1-piece assemblies combining the functions of the electrodes, lead wires and a patient cable. METHODS: The electric performance characteristics of BFS were obtained according to American National Standards Institute/Association for the Advancement of Medical Instrumentation EC-12:2000 standard and compared with Ag/AgCl wet-gel electrodes. The noise characteristics were determined from 250 hours of 3-lead electrocardiographic (ECG) data recorded with BFS over a period of 10 days from healthy volunteers. RESULTS: The BFS direct current offset voltage was 0.11 mV and alternate current impedance at 10 Hz was 22 ohms. The sensors average longevity on the body surface with no detachments was at least 7 days. BFS demonstrated high immunity to motion and electric field-induced artifacts. CONCLUSIONS: Biopotential fiber sensors are well suited for routine long-term ECG monitoring applications because of increased patient comfort through integration of the electrode, lead wire, and a patient cable, which function into one disposable BFS fiber assembly. Biopotential fiber sensor have electrical characteristics comparable to Ag/AgCl wet electrodes. We observed an improved ECG signal quality, reduced frequent electrode detachments, reduced wire clutter and entanglement, and improved sensor adherence to the skin over longer periods of time.

Action Potentials↗

Modulation of chondrocyte phenotype for tissue engineering by designing the biologic-polymer carrier interface.

Therapeutic strategies based on cell and tissue engineering can be advanced by developing material substrates that effectively interrogate the biological compartment, with or without the complimentary local release of growth factors. Poly(ether ester) segmented copolymers were engineered as model material systems to elucidate the interfacial molecular events that govern the function of adhered cells. Surface chemistry was modulated by varying poly(ethylene glycol) (PEG) length and mole fraction with poly(butylene terephthalate) (PBT), leading to differential competitive protein adsorption of fibronectin and vitronectin from serum and consequently to different cell attachment modes. Adhesion within the hydrogel-like milieu of longer surface PEG was mediated via binding to the CD44 transmembrane receptor, rather than the RGD-integrin mechanism, whereas greater substrate-bound fibronectin resulted in cell adhesion via integrins. These adhesion modalities differentially impacted morphological cell phenotype (spread or spheroid) and the subsequent expression of mRNA transcripts (collagen types II, I) characteristic of phenotypically differentiated or dedifferentiated chondrocytes, respectively. These results demonstrate that materials can be designed to directly elicit the membrane bound receptor apparatus desired for downstream cellular response, without requiring exogenous biological growth factors to enable differentiated potential.

Blotting, Western↗

A neuropsychological model relating self-awareness to hostility.

Neuropsychological advances may help researchers better understand the relationship between psychological constructs. This paper proposes a neuropsychological model explaining the negative relationship between hostility and "self-awareness," which has been suggested by previous research [H. A. Demaree and D. W. Harrison (1995a) "Behavioral, Physiological, and Neuropsychological Correlates of Hostility," manuscript submitted for publication; L. H. Epstein and P. A. Cluss (1982) "A Behavioral Medicine Perspective on Adherence to Long-Term Medical Regimes," Journal of Consulting and Clinical Psychology, Vol. 50, pp. 950-971; M. F. Scheier et al. (1974) "Self-Awareness and Physical Aggression," Journal of Experimental and Social Psychology, Vol. 10, pp. 254-273]. The authors review the role of the right cerebrum in both hostility and "self-awareness"--including arousal, perceptual, expressive, and integrative processes. Using identifiable tracts in the brain, the model suggests how deficits in "self-awareness"--poor awareness of physiological arousal, natural and emotional environment, etc.--may enhance the probability of hostility expression. This model is supported by previous empirical research and provides direction for future neuropsychological investigation.

Awareness↗

Harnessing motivational forces in the promotion of physical activity: the Community Health Advice by Telephone (CHAT) project.

Physical inactivity among middle- and older-aged adults is pervasive, and is linked with numerous chronic conditions that diminish health and functioning. Counselor-directed physical activity programs may enhance extrinsic motivation (reflected in social influence theories, such as self-presentation theory) and, in turn, physical activity adherence, while the counselor is in charge of program delivery. However, external influences can undermine intrinsic motivation, making it more difficult to maintain physical activity once counselor-initiated contact ends. In contrast, programs that diminish the socially evaluative and controlling aspects of the counseling interchange may promote intrinsic motivation (described in cognitive evaluation theory), and, thus, physical activity maintenance, even when counselor-initiated contact ceases. The objective of the Community Health Advice by Telephone (CHAT) project is to compare these two theories by conducting a randomized controlled trial evaluating the effects of a telephone-administered counseling program delivered by a person (social influence enhancement) or computer (cognitive evaluation enhancement) on physical activity adoption and maintenance over 18 months. Healthy, sedentary adults (n = 225) aged 55 years and older are randomized to one of these programs or to a control arm. This study will contribute to advancing motivational theory as well as provide information on the sustained effectiveness of interventions with substantial public health applicability.

Aged↗

New developments in systemic chemotherapy in advanced colorectal cancer.

BACKGROUND: The majority of patients with newly diagnosed colorectal cancer who present with concurrent metastases are considered to be incurable from the disease. For their treatment, these patients depend on systemic anticancer therapy and supportive care. METHODS: This article reviews recent developments in systemic treatment of disseminated colorectal cancer. RESULTS: Until recently, the fluoropyrimidines were the only cytotoxic drugs available, but during recent years three other classes of active conventional cytotoxic drugs and a new class of target-directed drugs have become available. New cytotoxic drug therapies include raltitrexed, irinotecan and oxaliplatin. Patients receiving irinotecan experience a better quality of life than those treated with best supportive care alone. Irinotecan or oxaliplatin in combination with 5-fluoro-uracil (5-FU) and leucovorin are currently the most active treatment regimens. Oral prodrugs of 5-FU, such as capecitabine and uracil, have been developed in order to mimic the protracted infusion schedule of 5-FU, and these drugs may change the daily practice of palliative chemotherapy for colorectal cancer in the coming years. Therapeutic agents that target specific molecular processes that promote proliferation, vascularization and metastasis, and inhibit apoptosis, are being designed and may offer a rational approach to anticancer therapy. Examples of this novel approach are monoclonal antibodies and small molecules adhering to the epithelial growth factor receptor and vascular endothelial growth factor receptor in order to inhibit growth stimulation and angiogenesis. CONCLUSION: The current debate is no longer whether to use palliative chemotherapy in metastatic colorectal, but which patient will benefit from which combination and in what sequence.

Administration, Oral↗

Vesicle-mediated trafficking of parasite proteins to the host cell cytosol and erythrocyte surface membrane in Plasmodium falciparum infected erythrocytes.

During the development of the asexual stage of the malaria parasite, Plasmodium falciparum, the composition, structure and function of the host cell membrane is dramatically altered, including the ability to adhere to vascular endothelium. Crucial to these changes is the transport of parasite proteins, which become associated with or inserted into the erythrocyte membrane. Protein and membrane targeting beyond the parasite plasma membrane must require unique pathways, given the parasites intracellular location within a parasitophorous vacuolar membrane and the lack of organelles and biosynthetic machinery in the host cell necessary to support a secretory system. It is not clear how these proteins cross the parasitophorous vacuolar membrane or how they traverse the erythrocyte cytosol to reach their final destinations. The identification of: (1) a P. falciparum homologue of the protein Sar1p, which is an essential component of the COPII-based secretory system in mammalian cells and yeast and (2) electron-dense, possibly coated, secretory vesicles bearing P. falciparum erythrocyte membrane protein 1 and P. falciparum erythrocyte membrane protein 3 in the host cell cytosol of P. falciparum infected erythrocytes recently provided the first direct evidence of a vesicle-mediated pathway for the trafficking of some parasite proteins to the erythrocyte membrane. The major advance in uncovering the parasite-induced secretory pathway was made by incubating infected erythrocytes with aluminium tetrafluoride, an activator of guanidine triphosphate-binding proteins, which resulted in the accumulation of the vesicles into multiple vesicle strings. These vesicle complexes were often associated with and closely abutted the erythrocyte membrane, but were apparently prevented from fusing by the aluminium fluoride treatment, making their capture by electron microscopy possible. It appears that malaria parasites export proteins into the host cell cytosol to support a vesicle-mediated protein trafficking pathway.

Animals↗

Advanced practice nurse strategies to improve outcomes and reduce cost in elders with heart failure.

The aim of this study was to investigate whether, in a randomized controlled trial (RCT) of vulnerable elders with heart failure (HF), advanced practice nurses (APNs) who were coordinating care in the transition from hospital to home could improve outcomes, prevent rehospitalizations, and reduce costs when compared with usual care. The APN strategies focused on improving patient and family or caregiver effectiveness in managing their illnesses, strengthening the patient-provider relationship, and managing comorbid conditions while improving overall health. The results were positive. By capitalizing on the patient's desire to achieve their identified goals, APNs successfully educated patients about the meaning of their symptoms and appropriate self-management strategies; improved patient-provider communication patterns; and marshaled caregiver and community resources to maximize patient adherence to the treatment plan and overall quality of life. While HF was the primary reason for enrollment in the study, optimal health outcomes demanded a strong focus on integrating management of comorbid conditions and other long-standing health problems. Specific strategies used by the APN to achieve these positive outcomes are addressed in this report. These strategies are compared with nursing interventions used in other RCTs of HF home management. Directions for future research are explored.

Aged↗