Septic Tenosynovitis of the Hand: Factors Predicting Need for Subsequent Débridement.

BACKGROUND: Treatment of septic hand tenosynovitis is complex, and often requires multiple débridements and prolonged antibiotic therapy. The authors undertook this study to identify factors that might be associated with the need for subsequent débridement (after the initial one) because of persistence or secondary worsening of infection. METHODS: In this retrospective single-center study, the authors included all adult patients who presented to their emergency department from 2007 to 2010 with septic tenosynovitis of the hand. RESULTS: The authors identified 126 adult patients (55 men; median age, 45 years), nine of whom were immunosuppressed. All had community-acquired infection; 34 (27 percent) had a subcutaneous abscess and eight (6 percent) were febrile. All underwent at least one surgical débridement and had concomitant antibiotic therapy (median, 15 days; range, 7 to 82 days). At least one additional surgical intervention was required in 18 cases (median, 1.13 interventions; range, one to five interventions). All but four episodes (97 percent) were cured of infection on the first attempt after a median follow-up of 27 months. By multivariate analysis, only two factors were significantly associated with the outcome "subsequent surgical débridement": abscess (OR, 4.6; 95 percent CI, 1.5 to 14.0) and longer duration of antibiotic therapy (OR, 1.2; 95 percent CI, 1.1 to 1.2). CONCLUSION: In septic tenosynovitis of the hand, the only presenting factor that was statistically predictive of an increased risk of needing a second débridement was the presence of a subcutaneous abscess. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

How to monitor the brain in septic patients?

Brain injury is frequently observed after sepsis and may be primarily related to the direct effects of the septic insult on the brain (e.g., brain edema, ischemia, seizures) or to secondary/indirect injuries (e.g., hypotension, hypoxemia, hypocapnia, hyperglycemia). Management of brain injury in septic patients is first focused to exclude structural intracranial complications (e.g., ischemic/hemorrhagic stroke) and possible confounders (e.g., electrolyte alterations or metabolic disorders, such as dysglycemia). Sepsis-associated brain dysfunction is frequently a heterogeneous syndrome. Despite increasing understanding of main pathophysiologic determinants, therapy is essentially limited to protect the brain against further cerebral damage, by way of "simple" therapeutic manipulations of cerebral perfusion and oxygenation and by avoiding over-sedation. Non-invasive monitoring of cerebral perfusion and oxygenation with transcranial Doppler (TCD) and near-infrared spectroscopy (NIRS) is feasible in septic patients. Electroencephalography (EEG) allows detection of sepsis-related seizures and holds promise also as sedation monitoring. Brain CT-scan detects intra-cerebral structural lesions, while magnetic resonance imaging (MRI) provides important insights into primary mechanisms of sepsis-related direct brain injury, (e.g., cytotoxic vs. vasogenic edema) and the development of posterior reversible encephalopathy. Together with EEG and evoked potentials (EP), MRI is also important for coma prognostication. Emerging clinical evidence suggests monitoring of the brain in septic patients can be implemented in the ICU. The objective of this review was to summarize recent clinical data about the role of brain monitoring - including TCD, NIRS, EEG, EP, CT, and MRI - in patients with sepsis and to illustrate its potential utility for the diagnosis, management and prognostication.

Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia.

We and others have reported mutations in LONP1, a gene coding for a mitochondrial chaperone and protease, as the cause of the human CODAS (cerebral, ocular, dental, auricular and skeletal) syndrome (MIM 600373). Here, we delineate a similar but distinct condition that shares the epiphyseal, vertebral and ocular changes of CODAS but also included severe microtia, nasal hypoplasia, and other malformations, and for which we propose the name of EVEN-PLUS syndrome for epiphyseal, vertebral, ear, nose, plus associated findings. In three individuals from two families, no mutation in LONP1 was found; instead, we found biallelic mutations in HSPA9, the gene that codes for mHSP70/mortalin, another highly conserved mitochondrial chaperone protein essential in mitochondrial protein import, folding, and degradation. The functional relationship between LONP1 and HSPA9 in mitochondrial protein chaperoning and the overlapping phenotypes of CODAS and EVEN-PLUS delineate a family of "mitochondrial chaperonopathies" and point to an unexplored role of mitochondrial chaperones in human embryonic morphogenesis.

L'année 2014 mise en perspective par les internistes hospitaliers [What is new in 2014 for the specialist in hospital internal medicine? The point of view of university hospital chief residents].

The year 2014 was rich in significant advances in all areas of internal medicine. Many of them have an impact on our daily practice and on the way we manage one problem or another. From the use of the ultrasound for the diagnosis of pneumonia to the choice of the site of venous access and the type of line, and the increasing complexity of choosing an oral anticoagulant agent, this selection offers to the readers a brief overview of the major advances. The chief residents in the Service of internal medicine of the Lausanne University hospital are pleased to share their readings.

The lipopolysaccharide of Aeromonas spp: structure-activity relationships.

Marine microorganisms, including Aeromonas, are a source of compounds for drug development that have generated great expectations in the last decades. Aeromonas infections produce septicaemia, and ulcerative and haemorrhagic diseases in fish. Among the pathogenic factors associated with Aeromonas, the lipopolysaccharides (LPS), a surface glyconconjugate unique to Gram-negative bacteria consisting of lipid A (lipid anchor of the molecule), core oligosaccharide and O-specific polysaccharide (O antigen), are key elicitors of innate immune responses. The chemical structure of these three parts has been characterized in Aeromonas. Based on the high variability of repeated units of O-polysaccharides, a total of 97 O-serogroups have been described in Aeromonas species, of which four of them (O:11; O:16; O:18 and O:34) account for more than 60% of the septicemia cases. The core of LPS is subdivided into two regions, the inner (highly conserved) and the outer core. The inner core of Aeromonas LPS is characterized by the presence of 3-deoxy-D-manno-oct-2-ulosonic (ketodeoxyoctonic) acid (Kdo) and L-glycero-D-manno-Heptoses (L,D-Hep), which are linked to the outer core, characterized by the presence of Glc, GlcN, Gal, and GalNAc (in Aeromonas salmonicida), D,D-Hep (in Aeromonas salmonicida), and L,D-Hep (in Aeromonas hydrophila). The biological relevance of these differences in the distal part of the outer core among these species has not been fully assessed to date. The inner core is attached to the lipid A, a highly conserved structure that confers endotoxic properties to the LPS when the molecule is released in blood from lysed bacteria, thus inducing a major systemic inflammatory response known as septic or endotoxic shock. In Aeromonas salmonicida subsp. salmonicida the Lipid A components contain three major lipid A molecules, differing in acylation patterns corresponding to tetra-, penta- and hexaacylated lipid A species and comprising of 4′-monophosphorylated β-2-amino-2-deoxy-D-glucopyranose-(1→6)-2-amino-2-deoxy-D-glucopyranose disaccharide. In the present review, we discuss the structure-activity relationships of Aeromonas LPS, focusing on its role in bacterial pathogenesis and its possible applications.

The lipopolysaccharide of Aeromonas spp: structure-activity relationships

Marine microorganisms, including Aeromonas, are a source of compds. for drug development that have generated great expectations in the last decades. Aeromonas infections produce septicemia, and ulcerative and haemorrhagic diseases in fish. Among the pathogenic factors assocd. with Aeromonas, the lipopolysaccharides (LPS)​, a surface glyconconjugate unique to Gram-​neg. bacteria consisting of lipid A (lipid anchor of the mol.)​, core oligosaccharide and O-​specific polysaccharide (O antigen)​, are key elicitors of innate immune responses. The chem. structure of these three parts has been characterized in Aeromonas. Based on the high variability of repeated units of O-​polysaccharides, a total of 97 O-​serogroups have been described in Aeromonas species, of which four of them (O:11; O:16; O:18 and O:34) account for more than 60​% of the septicemia cases. The core of LPS is subdivided into two regions, the inner (highly conserved) and the outer core. The inner core of Aeromonas LPS is characterized by the presence of 3-​deoxy-​d-​manno-​oct-​2-​ulosonic (ketodeoxyoctonic) acid (Kdo) and l-​glycero-​d-​manno-​Heptoses (l,​d-​Hep)​, which are linked to the outer core, characterized by the presence of Glc, GlcN, Gal, and GalNAc (in Aeromonas salmonicida)​, d,​d-​Hep (in Aeromonas salmonicida)​, and l,​d-​Hep (in Aeromonas hydrophila)​. The biol. relevance of these differences in the distal part of the outer core among these species has not been fully assessed to date. The inner core is attached to the lipid A, a highly conserved structure that confers endotoxic properties to the LPS when the mol. is released in blood from lysed bacteria, thus inducing a major systemic inflammatory response known as septic or endotoxic shock. In Aeromonas salmonicida subsp. salmonicida the Lipid A components contain three major lipid A mols., differing in acylation patterns corresponding to tetra-​, penta- and hexa-​acylated lipid A species and comprising of 4'-​monophosphorylated β-​2-​amino-​2-​deoxy-​d-​glucopyranose-​(1→6)​-​2-​amino-​2-​deoxy-​d-​glucopyranose disaccharide. In the present review, we discuss the structure-​activity relationships of Aeromonas LPS, focusing on its role in bacterial pathogenesis and its possible applications.

The lipopolysaccharide of Aeromonas spp: structure-activity relationships

Marine microorganisms, including Aeromonas, are a source of compds. for drug development that have generated great expectations in the last decades. Aeromonas infections produce septicemia, and ulcerative and haemorrhagic diseases in fish. Among the pathogenic factors assocd. with Aeromonas, the lipopolysaccharides (LPS)​, a surface glyconconjugate unique to Gram-​neg. bacteria consisting of lipid A (lipid anchor of the mol.)​, core oligosaccharide and O-​specific polysaccharide (O antigen)​, are key elicitors of innate immune responses. The chem. structure of these three parts has been characterized in Aeromonas. Based on the high variability of repeated units of O-​polysaccharides, a total of 97 O-​serogroups have been described in Aeromonas species, of which four of them (O:11; O:16; O:18 and O:34) account for more than 60​% of the septicemia cases. The core of LPS is subdivided into two regions, the inner (highly conserved) and the outer core. The inner core of Aeromonas LPS is characterized by the presence of 3-​deoxy-​d-​manno-​oct-​2-​ulosonic (ketodeoxyoctonic) acid (Kdo) and l-​glycero-​d-​manno-​Heptoses (l,​d-​Hep)​, which are linked to the outer core, characterized by the presence of Glc, GlcN, Gal, and GalNAc (in Aeromonas salmonicida)​, d,​d-​Hep (in Aeromonas salmonicida)​, and l,​d-​Hep (in Aeromonas hydrophila)​. The biol. relevance of these differences in the distal part of the outer core among these species has not been fully assessed to date. The inner core is attached to the lipid A, a highly conserved structure that confers endotoxic properties to the LPS when the mol. is released in blood from lysed bacteria, thus inducing a major systemic inflammatory response known as septic or endotoxic shock. In Aeromonas salmonicida subsp. salmonicida the Lipid A components contain three major lipid A mols., differing in acylation patterns corresponding to tetra-​, penta- and hexa-​acylated lipid A species and comprising of 4'-​monophosphorylated β-​2-​amino-​2-​deoxy-​d-​glucopyranose-​(1→6)​-​2-​amino-​2-​deoxy-​d-​glucopyranose disaccharide. In the present review, we discuss the structure-​activity relationships of Aeromonas LPS, focusing on its role in bacterial pathogenesis and its possible applications.

Methods for construction and analysis of computational models in systems biology : applications to the modelling of the heat shock response and the self-assembly of intermediate filaments

Systems biology is a new, emerging and rapidly developing, multidisciplinary research field that aims to study biochemical and biological systems from a holistic perspective, with the goal of providing a comprehensive, system- level understanding of cellular behaviour. In this way, it addresses one of the greatest challenges faced by contemporary biology, which is to compre- hend the function of complex biological systems. Systems biology combines various methods that originate from scientific disciplines such as molecu- lar biology, chemistry, engineering sciences, mathematics, computer science and systems theory. Systems biology, unlike “traditional” biology, focuses on high-level concepts such as: network, component, robustness, efficiency, control, regulation, hierarchical design, synchronization, concurrency, and many others. The very terminology of systems biology is “foreign” to “tra- ditional” biology, marks its drastic shift in the research paradigm and it indicates close linkage of systems biology to computer science. One of the basic tools utilized in systems biology is the mathematical modelling of life processes tightly linked to experimental practice. The stud- ies contained in this thesis revolve around a number of challenges commonly encountered in the computational modelling in systems biology. The re- search comprises of the development and application of a broad range of methods originating in the fields of computer science and mathematics for construction and analysis of computational models in systems biology. In particular, the performed research is setup in the context of two biolog- ical phenomena chosen as modelling case studies: 1) the eukaryotic heat shock response and 2) the in vitro self-assembly of intermediate filaments, one of the main constituents of the cytoskeleton. The range of presented approaches spans from heuristic, through numerical and statistical to ana- lytical methods applied in the effort to formally describe and analyse the two biological processes. We notice however, that although applied to cer- tain case studies, the presented methods are not limited to them and can be utilized in the analysis of other biological mechanisms as well as com- plex systems in general. The full range of developed and applied modelling techniques as well as model analysis methodologies constitutes a rich mod- elling framework. Moreover, the presentation of the developed methods, their application to the two case studies and the discussions concerning their potentials and limitations point to the difficulties and challenges one encounters in computational modelling of biological systems. The problems of model identifiability, model comparison, model refinement, model inte- gration and extension, choice of the proper modelling framework and level of abstraction, or the choice of the proper scope of the model run through this thesis.

Role and regulatory mechanisms of heat shock factor 2

Protein homeostasis is essential for cells to prosper and survive. Various forms of stress, such as elevated temperatures, oxidative stress, heavy metals or bacterial infections cause protein damage, which might lead to improper folding and formation of toxic protein aggregates. Protein aggregation is associated with serious pathological conditions such as Alzheimer’s and Huntington’s disease. The heat shock response is a defense mechanism that protects the cell against protein-damaging stress. Its ancient origin and high conservation among eukaryotes suggest that the response is crucial for survival. The main regulator of the heat shock response is the transcription factor heat shock factor 1 (HSF1), which induces transcription of genes encoding protective molecular chaperones. In vertebrates, a family of four HSFs exists (HSF1-4), with versatile functions not only in coping with acute stress, but also in development, longevity and cancer. Thus, knowledge of the HSFs will aid in our understanding on how cells survive suboptimal circumstances, but will also provide insights into normal physiological processes as well as diseaseassociated conditions. In this study, the function and regulation of HSF2 have been investigated. Earlier gene inactivation experiments in mice have revealed roles for HSF2 in development, particularly in corticogenesis and spermatogenesis. Here, we demonstrate that HSF2 holds a role also in the heat shock response and influences stress-induced expression of heat shock proteins. Intriguingly, DNA-binding activity of HSF2 upon stress was dependent on the presence of intact HSF1, suggesting functional interplay between HSF1 and HSF2. The underlying mechanism for this phenomenon could be configuration of heterotrimers between the two factors, a possibility that was experimentally verified. By changing the levels of HSF2, the expression of HSF1-HSF2 heterotrimer target genes was altered, implementing HSF2 as a modulator of HSF-mediated transcription. The results further indicate that HSF2 activity is dependent on its concentration, which led us to ask the question of how accurate HSF2 levels are achieved. Using mouse spermatogenesis as a model system, HSF2 was found to be under direct control of miR-18, a miRNA belonging to the miR-17~92 cluster/Oncomir-1 and whose physiological function had remained unclear. Investigations on spermatogenesis are severely hampered by the lack of cell systems that would mimic the complex differentiation processes that constitute male germ cell development. Therefore, to verify that HSF2 is regulated by miR-18 in spermatogenesis, a novel method named T-GIST (Transfection of Germ cells in Intact Seminiferous Tubules) was developed. Employing this method, the functional consequences of miR-18-mediated regulation in vivo were demonstrated; inhibition of miR- 18 led to increased expression of HSF2 and altered the expression of HSF2 target genes Ssty2 and Speer4a. Consequently, the results link miR-18 to HSF2-mediated processes such as germ cell maturation and quality control and provide miR-18 with a physiological role in gene expression during spermatogenesis.Taken together, this study presents compelling evidence that HSF2 is a transcriptional regulator in the heat shock response and establishes the concept of physical interplay between HSF2 and HSF1 and functional consequences thereof. This is also the first study describing miRNA-mediated regulation of an HSF.

Numerical study of wedge supported oblique shock wave-oblique detonation wave transitions

The results of a numerical study of premixed Hydrogen-air flows ignition by an oblique shock wave (OSW) stabilized by a wedge are presented, in situations when initial and boundary conditions are such that transition between the initial OSW and an oblique detonation wave (ODW) is observed. More precisely, the objectives of the paper are: (i) to identify the different possible structures of the transition region that exist between the initial OSW and the resulting ODW and (ii) to evidence the effect on the ODW of an abrupt decrease of the wedge angle in such a way that the final part of the wedge surface becomes parallel to the initial flow. For such a geometrical configuration and for the initial and boundary conditions considered, the overdriven detonation supported by the initial wedge angle is found to relax towards a Chapman-Jouguet detonation in the region where the wedge surface is parallel to the initial flow. Computations are performed using an adaptive, unstructured grid, finite volume computer code previously developed for the sake of the computations of high speed, compressible flows of reactive gas mixtures. Physico-chemical properties are functions of the local mixture composition, temperature and pressure, and they are computed using the CHEMKIN-II subroutines.

Choosing the target loci : heat shock factors HSF1 and HSF2 as regulators of cell stress and development

Heat shock factors (HSFs) are an evolutionarily well conserved family of transcription factors that coordinate stress-induced gene expression and direct versatile physiological processes in eukaryote organisms. The essentiality of HSFs for cellular homeostasis has been well demonstrated, mainly through HSF1-induced transcription of heat shock protein (HSP) genes. HSFs are important regulators of many fundamental processes such as gametogenesis, metabolic control and aging, and are involved in pathological conditions including cancer progression and neurodegenerative diseases. In each of the HSF-mediated processes, however, the detailed mechanisms of HSF family members and their complete set of target genes have remained unknown. Recently, rapid advances in chromatin studies have enabled genome-wide characterization of protein binding sites in a high resolution and in an unbiased manner. In this PhD thesis, these novel methods that base on chromatin immunoprecipitation (ChIP) are utilized and the genome-wide target loci for HSF1 and HSF2 are identified in cellular stress responses and in developmental processes. The thesis and its original publications characterize the individual and shared target genes of HSF1 and HSF2, describe HSF1 as a potent transactivator, and discover HSF2 as an epigenetic regulator that coordinates gene expression throughout the cell cycle progression. In male gametogenesis, novel physiological functions for HSF1 and HSF2 are revealed and HSFs are demonstrated to control the expression of X- and Y-chromosomal multicopy genes in a silenced chromatin environment. In stressed human cells, HSF1 and HSF2 are shown to coordinate the expression of a wide variety of genes including genes for chaperone machinery, ubiquitin, regulators of cell cycle progression and signaling. These results highlight the importance of cell type and cell cycle phase in transcriptional responses, reveal the myriad of processes that are adjusted in a stressed cell and describe novel mechanisms that maintain transcriptional memory in mitotic cell division.

Thalidomide protects mice against LPS-induced shock

Thalidomide has been shown to selectively inhibit TNF-a production in vitro by lipopolysaccharide (LPS)-stimulated monocytes. TNF-a has been shown to play a pivotal role in the pathophysiology of endotoxic shock. Using a mouse model of LPS-induced shock, we investigated the effects of thalidomide on the production of TNF-a and other cytokines and on animal survival. After injection of 100-350 µg LPS into mice, cytokines including TNF-a, IL-6, IL-10, IL-1ß, GM-CSF and IFN-g were measured in the serum. Administration of 200 mg/kg thalidomide to mice before LPS challenge modified the profile of LPS-induced cytokine secretion. Serum TNF-a levels were reduced by 93%, in a dose-dependent manner, and TNF-a mRNA expression in the spleens of mice was reduced by 70%. Serum IL-6 levels were also inhibited by 50%. Thalidomide induced a two-fold increase in serum IL-10 levels. Thalidomide treatment did not interfere with the production of GM-CSF, IL-1ß or IFN-g. The LD50 of LPS in this model was increased by thalidomide pre-treatment from 150 µg to 300 µg in 72 h. Thus, at otherwise lethal doses of LPS, thalidomide treatment was found to protect animals from death

Acetylcholinesterase activity in the pons and medulla oblongata of rats after chronic electroconvulsive shock

An imbalance between cholinergic and noradrenergic neurotransmission has been proposed for the etiology of affective disorders. According to this hypothesis, depression would be the result of enhanced cholinergic and reduced noradrenergic neurotransmission. Repeated electroconvulsive shock (ECS) is an effective treatment for depression; moreover, in laboratory animals it induces changes in brain noradrenergic neurotransmission similar to those obtained by chronic treatment with antidepressant drugs (down-regulation of beta-adrenergic receptors). The aim of the present study was to determine whether repeated ECS in rats changes acetylcholinesterase (Achase) activity. Achase controls the level of acetylcholine (Ach) in the synaptic cleft and its levels seem to be regulated by the interaction between Ach and its receptor. Thus, a decrease in Achase activity would suggest decreased cholinergic activity. Adult male Wistar rats received one ECS (80 mA, 0.2 s, 60 Hz) daily for 7 days. Control rats were handled in the same way without receiving the shock. Rats were sacrificed 24 h after the last ECS and membrane-bound and soluble Achase activity was assayed in homogenates obtained from the pons and medulla oblongata. A statistically significant decrease in membrane-bound Achase activity (nmol thiocholine formed min-1 mg protein-1) (control 182.6 ± 14.8, ECS 162.2 ± 14.2, P<0.05) and an increase in soluble Achase activity in the medulla oblongata (control 133.6 ± 4.2, ECS 145.8 ± 12.3, P<0.05) were observed. No statistical differences were observed in Achase activity in the pons. Although repeated ECS induced a decrease in membrane-bound Achase activity, the lack of changes in the pons (control Achase activity: total 231.0 ± 34.5, membrane-bound 298.9 ± 18.5, soluble 203.9 ± 30.9), the region where the locus coeruleus, the main noradrenergic nucleus, is located, does not seem to favor the existence of an interaction between cholinergic and noradrenergic neurotransmission after ECS treatment

Anterograde effects of a single electroconvulsive shock on inhibitory avoidance and on cued fear conditioning

A single electroconvulsive shock (ECS) or a sham ECS was administered to male 3-4-month-old Wistar rats 1, 2, and 4 h before training in an inhibitory avoidance test and in cued classical fear conditioning (measured by means of freezing time in a new environment). ECS impaired inhibitory avoidance at all times and, at 1 or 2 h before training, reduced freezing time before and after re-presentation of the ECS. These results are interpreted as a transient conditioned stimulus (CS)-induced anxiolytic or analgesic effect lasting about 2 h after a single treatment, in addition to the known amnesic effect of the stimulus. This suggests that the effect of anterograde learning impairment is demonstrated unequivocally only when the analgesic/anxiolytic effect is over (about 4 h after ECS administration) and that this impairment of learning is selective, affecting inhibitory avoidance but not classical fear conditioning to a discrete stimulus.