Like all sessile organisms, surface-attached communities of bacteria known as biofilms must release and disperse cells into the environment to colonize new sites. For many pathogenic bacteria, ...biofilm dispersal plays an important role in the transmission of bacteria from environmental reservoirs to human hosts, in horizontal and vertical cross-host transmission, and in the exacerbation and spread of infection within a host. The molecular mechanisms of bacterial biofilm dispersal are only beginning to be elucidated. Biofilm dispersal is a promising area of research that may lead to the development of novel agents that inhibit biofilm formation or promote biofilm cell detachment. Such agents may be useful for the prevention and treatment of biofilms in a variety of industrial and clinical settings. This review describes the current status of research on biofilm dispersal, with an emphasis on studies aimed to characterize dispersal mechanisms, and to identify environmental cues and inter- and intracellular signals that regulate the dispersal process. The clinical implications of biofilm dispersal and the potential therapeutic applications of some of the most recent findings will also be discussed.
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Antibiotic-induced biofilm formation KAPLAN, Jeffrey B
International journal of artificial organs,
09/2011, Volume:
34, Issue:
9
Journal Article
Peer reviewed
Surface-attached colonies of bacteria known as biofilms play a major role in the pathogenesis of device-related infections. Biofilm colonies are notorious for their resistance to suprainhibitory ...concentrations of antibiotics. Numerous studies have shown that subminimal inhibitory concentrations of some antibiotics can act as agonists of bacterial biofilm formation in vitro, a process that may have clinical relevance. This article reviews studies demonstrating that low-dose antibiotics induce bacterial biofilm formation. These studies have provided important information about the regulation of biofilm formation and the signaling pathways involved in global gene regulation in response to cell stressors. It is still unclear whether antibiotic-induced biofilm formation contributes to the inconsistent success of antimicrobial therapy for device infections.
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We studied the phenotype of late kidney graft failure in a prospective study of unselected kidney transplant biopsies taken for clinical indications. We analyzed histopathology, HLA antibodies and ...death‐censored graft survival in 234 consecutive biopsies from 173 patients, taken 6 days to 31 years posttransplant. Patients with late biopsies (>1 year) frequently displayed donor‐specific HLA antibody (particularly class II) and microcirculation changes, including glomerulitis, glomerulopathy, capillaritis, capillary multilayering and C4d staining. Grafts biopsied early rarely failed (1/68), whereas grafts biopsied late often progressed to failure (27/105) within 3 years. T‐cell‐mediated rejection and its lesions were not associated with an increased risk of failure after biopsy. In multivariable analysis, graft failure correlated with microcirculation inflammation and scarring, but C4d staining was not significant. When microcirculation changes and HLA antibody were used to define antibody‐mediated rejection, 17/27 (63%) of late kidney failures after biopsy were attributable to antibody‐mediated rejection, but many were C4d negative and missed by current diagnostic criteria. Glomerulonephritis accounted for 6/27 late losses, whereas T‐cell‐mediated rejection, drug toxicity and unexplained scarring were uncommon. The major cause of late kidney transplant failure is antibody‐mediated microcirculation injury, but detection of this phenotype requires new diagnostic criteria.
In patients presenting with indications for kidney transplant biopsy, antibody mediated rejection accounts for the majority of progression to late graft loss, but in many cases the diagnosis is missed by current criteria.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Calcineurin inhibitors (CNIs), including tacrolimus and cyclosporine, are immune‐modulating agents used in autoimmune disorders, glomerulonephritides, and after transplantation. CNIs are implicated ...as diabetogenic drugs but the mechanism is not clearly elucidated. Calcineurin is a cytosolic‐phosphatase critical for T‐lymphocyte activation. Calcineurin is widely distributed in different tissues responsible for glucose‐regulation including pancreas, liver, skeletal muscle, adipocytes, brain, and gut. We describe the pharmacologic effects of CNIs in different tissues and impact on glucose regulation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Post-traumatic stress disorder (PTSD) is a trauma-related condition that produces distressing fear memory intrusions, avoidance behaviors, hyperarousal/startle, stress responses and insomnia. This ...review focuses on the importance of the orexin neural system as a novel mechanism related to the pathophysiology of PTSD. Orexinergic neurons originate in the lateral hypothalamus and project widely to key neurotransmitter systems, autonomic neurons, the hypothalamic-pituitary-adrenal (HPA) axis, and fear-related neural circuits. After trauma or stress, the basolateral amygdala (BLA) transmits sensory information to the central nucleus of the amygdala (CeA) and in turn to the hypothalamus and other subcortical and brainstem regions to promote fear and threat behaviors. Orexin receptors have a prominent role in this circuit as fear conditioned orexin receptor knockout mice show decreased fear expression while dual orexin receptor antagonists (DORAs) inhibit fear acquisition and expression. Orexin activation of an infralimbic-amygdala circuit impedes fear extinction while DORA treatments enhance it. Increased orexin signaling to the amygdalo-cortical-hippocampal circuit promotes avoidance behaviors. Orexin has an important role in activating sympathetic nervous system (SNS) activity and HPA axis stress responses. Blockade of orexin receptors reduces fear-conditioned startle responses. In PTSD models, individuals demonstrate sleep disturbances such as increased sleep latency and more transitions to wakefulness. Increased orexin activity impairs sleep by promoting wakefulness and reducing total sleep time while DORA treatments enhance sleep onset and maintenance. The orexinergic neural system provides important mechanisms for understanding multiple PTSD behaviors and provides new medication targets to treat this often persistent and debilitating illness.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The microbiota of the human lower intestinal tract helps maintain healthy host physiology, for example through nutrient acquisition and bile acid recycling, but specific positive contributions of the ...oral microbiota to host health are not well established. Nitric oxide (NO) homeostasis is crucial to mammalian physiology. The recently described entero-salivary nitrate-nitrite-nitric oxide pathway has been shown to provide bioactive NO from dietary nitrate sources. Interestingly, this pathway is dependent upon oral nitrate-reducing bacteria, since humans lack this enzyme activity. This pathway appears to represent a newly recognized symbiosis between oral nitrate-reducing bacteria and their human hosts in which the bacteria provide nitrite and nitric oxide from nitrate reduction. Here we measure the nitrate-reducing capacity of tongue-scraping samples from six healthy human volunteers, and analyze metagenomes of the bacterial communities to identify bacteria contributing to nitrate reduction. We identified 14 candidate species, seven of which were not previously believed to contribute to nitrate reduction. We cultivated isolates of four candidate species in single- and mixed-species biofilms, revealing that they have substantial nitrate- and nitrite-reduction capabilities. Colonization by specific oral bacteria may thus contribute to host NO homeostasis by providing nitrite and nitric oxide. Conversely, the lack of specific nitrate-reducing communities may disrupt the nitrate-nitrite-nitric oxide pathway and lead to a state of NO insufficiency. These findings may also provide mechanistic evidence for the oral systemic link. Our results provide a possible new therapeutic target and paradigm for NO restoration in humans by specific oral bacteria.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We analyze the chiral magnetic effect in a homogeneous neutral plasma from the point of view of energy conservation, and construct an effective potential for the growth of maximally helical ...perturbations of the electromagnetic field. We show that a negative curvature at the origin of the potential, indicating instability of the plasma, is induced by a chiral asymmetry in electron Fermi energy, as opposed to number density, while the potential grows at large field value. It follows that the ground state for a plasma has zero magnetic helicity; a nonzero electron mass will allow an excited state of a plasma with nonzero helicity to relax to that ground state quickly. We conclude that a chiral plasma instability triggered by weak interactions is not a viable mechanism for explaining magnetic fields in stars except possibly when dynamics drives the system far from equilibrium.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
BIOFILM FORMATION AS MICROBIAL DEVELOPMENT O'Toole, George; Kaplan, Heidi B; Kolter, Roberto
Annual review of microbiology,
01/2000, Volume:
54, Issue:
1
Journal Article
Peer reviewed
Biofilms can be defined as communities of microorganisms attached to a
surface. It is clear that microorganisms undergo profound changes during their
transition from planktonic (free-swimming) ...organisms to cells that are part of
a complex, surface-attached community. These changes are reflected in the new
phenotypic characteristics developed by biofilm bacteria and occur in response
to a variety of environmental signals. Recent genetic and molecular approaches
used to study bacterial and fungal biofilms have identified genes and
regulatory circuits important for initial cell-surface interactions, biofilm
maturation, and the return of biofilm microorganisms to a planktonic mode of
growth. Studies to date suggest that the planktonic-biofilm transition is a
complex and highly regulated process. The results reviewed in this article
indicate that the formation of biofilms serves as a new model system for the
study of microbial development.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prognostic models for overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC) are dated and do not reflect significant advances in treatment options available ...for these patients. This work developed and validated an updated prognostic model to predict OS in patients receiving first-line chemotherapy.
Data from a phase III trial of 1,050 patients with mCRPC were used (Cancer and Leukemia Group B CALGB-90401 Alliance). The data were randomly split into training and testing sets. A separate phase III trial served as an independent validation set. Adaptive least absolute shrinkage and selection operator selected eight factors prognostic for OS. A predictive score was computed from the regression coefficients and used to classify patients into low- and high-risk groups. The model was assessed for its predictive accuracy using the time-dependent area under the curve (tAUC).
The model included Eastern Cooperative Oncology Group performance status, disease site, lactate dehydrogenase, opioid analgesic use, albumin, hemoglobin, prostate-specific antigen, and alkaline phosphatase. Median OS values in the high- and low-risk groups, respectively, in the testing set were 17 and 30 months (hazard ratio HR, 2.2; P < .001); in the validation set they were 14 and 26 months (HR, 2.9; P < .001). The tAUCs were 0.73 (95% CI, 0.70 to 0.73) and 0.76 (95% CI, 0.72 to 0.76) in the testing and validation sets, respectively.
An updated prognostic model for OS in patients with mCRPC receiving first-line chemotherapy was developed and validated on an external set. This model can be used to predict OS, as well as to better select patients to participate in trials on the basis of their prognosis.
Surface-attached colonies of bacteria known as biofilms play a major role in the pathogenesis of medical device infections. Biofilm colonies are notorious for their resistance to antibiotics and host ...defenses, which makes most device infections difficult or impossible to eradicate. Bacterial cells in a biofilm are held together by an extracellular polymeric matrix that is synthesized by the bacteria themselves. Enzymes that degrade biofilm matrix polymers have been shown to inhibit biofilm formation, detach established biofilm colonies, and render biofilm cells sensitive to killing by antimicrobial agents. This review discusses the potential use of biofilm matrix-degrading enzymes as anti-biofilm agents for the treatment and prevention of device infections. Two enzymes, deoxyribonuclease I and the glycoside hydrolase dispersin B, will be reviewed in detail. In vitro and in vivo studies demonstrating the anti-biofilm activities of these two enzymes will be summarized, and the therapeutic potential and possible drawbacks of using these enzymes as clinical agents will be discussed.
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