A massive, cooling-flow-induced starburst in the core of a luminous cluster of galaxies.

In the cores of some clusters of galaxies the hot intracluster plasma is dense enough that it should cool radiatively in the cluster's lifetime, leading to continuous 'cooling flows' of gas sinking towards the cluster centre, yet no such cooling flow has been observed. The low observed star-formation rates and cool gas masses for these 'cool-core' clusters suggest that much of the cooling must be offset by feedback to prevent the formation of a runaway cooling flow. Here we report X-ray, optical and infrared observations of the galaxy cluster SPT-CLJ2344-4243 (ref. 11) at redshift z = 0.596. These observations reveal an exceptionally luminous (8.2 × 10(45) erg s(-1)) galaxy cluster that hosts an extremely strong cooling flow (around 3,820 solar masses a year). Further, the central galaxy in this cluster appears to be experiencing a massive starburst (formation of around 740 solar masses a year), which suggests that the feedback source responsible for preventing runaway cooling in nearby cool-core clusters may not yet be fully established in SPT-CLJ2344-4243. This large star-formation rate implies that a significant fraction of the stars in the central galaxy of this cluster may form through accretion of the intracluster medium, rather than (as is currently thought) assembling entirely via mergers.

Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target.

OBJECTIVES: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a "treat-to-target" clinical management strategy using an evidence-based expert consensus process. METHODS: A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7-10 on a 10-point rating scale (where 10=agree completely). RESULTS: The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn's disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0-1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target. CONCLUSIONS: Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients' quality of life.

Severe anaphylaxis caused by orally administered vancomycin to a patient with Clostridium difficile infection.

We report the first case of anaphylaxis to oral vancomycin in a cystic fibrosis patient with severe and relapsing Clostridium difficile infection (CDI) refractory to metronidazole. The patient's colitis has been successfully treated with a combination of intravenous metronidazole and tigecycline.

Pitfalls in surveillance for hepatocellular carcinoma: How successful is it in the real world?

BACKGROUND/AIMS: Surveillance for hepatocellular carcinoma (HCC) with ultrasound in high-risk populations is generally believed to improve opportunities for treatment. However, tumors are still missed due to various factors. This study explores success versus failure of HCC surveillance. METHODS: This is a retrospective study of 1,125 HCC cases. Categories considered for successful detection were largest tumor ≤3.0 cm, single tumors ≤3.0 cm and ≤2.0 cm, and adherence to Milan criteria. Examined factors were age <60 years, gender, rural residence, body-mass index (BMI), hepatitis infection, smoking, diabetes, hyperlipidemia, cirrhosis, ascites, and Model for End-Stage Liver Disease <10. RESULTS: HCC was found on surveillance in 257 patients with a mean tumor size of 3.17 cm; multiple tumors were seen in 28% of cases, bilateral tumors in 7.4%, and vascular invasion in 3.7%. Surveillance was successful in 61.5% of cases involving a largest tumor ≤3.0 cm, with BMI ≥35 negatively affecting detection (odds ratio [OR] 0.28, P=0.014) and cirrhosis positively affecting detection (OR 2.31, P=0.036). Ultrasound detected 19.1% of single tumors ≤2.0 cm with ascites improving the detection rate (OR 3.89, P=0.001). Finally, adherence to Milan criteria occurred in 75.1% of cases, revealing negative associations with diabetes (OR 0.48, P=0.044 and male gender (OR 0.49, P=0.08). CONCLUSIONS: Although surveillance is recommended for HCC, not all surveillance ultrasound are ideal. Tumor detection can depend on gender, BMI, diabetes, cirrhosis, and ascites and is achieved in 19.1-75% of cases depending on the definition of success. Closer follow-up or additional imaging might be necessary for some patient subgroups.

[Polyneuropathy involving cranial nerves associated with monoclonal IgM antibodies with anti-MAG/SGPG/SGPLG/sulfatides activity]. / Une polyneuropathie avec atteinte des nerfs crâniens associée à une IgM monoclonale à activité anti-MAG/SGPG/SGPLG/sulfatides.

INTRODUCTION: A typically distal and symmetrical, slowly progressive sensorimotor demyelinating neuropathy is caused by monoclonal IgM against myelin-associated glycoprotein (MAG) and SGPG, SGLPG glycolipids in the context of a benign IgM paraproteinemia. We studied a patient with a neuropathy that fulfilled the diagnostic criteria for CIDP in whom IgM kappa anti-MAG/SGPG/SGLPG were detected. OBSERVATION: The patient was a 57-year-old man who had developed a slowly progressive distal sensorimotor neuropathy, involving the lower then upper limbs, with cranial nerves palsies (oro-pharyngo-laryngo territory). ENMG showed a demyelinating neuropathy with a disproportionate slowing of conduction in distal segments of motor and axonal features in the lower limbs. The first routine laboratory analysis revealed negative or normal findings. Several serum protein electrophoreses were normal. The third cerebrospinal fluid examination demonstrated a moderate and late rise in CSF protein level with no cells. Monoclonal IgM-kappa against MAG/SGPG/SGLPG, was detected; anti-MAG antibody titre in the serum was 20 059 BTU (N<1000). A small IgM-kappa paraprotein was identified by immunofixation. Electron microscopy failed to show nerve fibers with widening of outer lamellae of the myelin. There is no clinical improvement after different treatments, immunoglobulins IV, cortisteroids, plasma exchange, rituximab. CONCLUSION: It is not known whether this neuropathy is an atypical form of PNMAG or an CIDP associated with anti-MAG. When ENMG show a disproportionate slowing of conduction in distal segments of motor nerves, one should screen the serum with immunofixation to identify small monoclonal components. If IgM-MGUS is present, search should be undertaken for anti-MAG/SGPG/SGLPG antibodies. Diagnosis enables optimal treatment using, in severe cases, expensive current strategies with immunoglobulins IV, plasma exchange, and corticosteroids, or, in the event of no response, rituximab before resorting to more toxic drugs like cyclophosphamide.

Effects of neonatal hypo- and hyperthyroidism on pituitary growth hormone content in the rat.

Thyroid hormones play an important role in growth and development. Therefore, we investigated the effects of neonatal hypo- and hyperthyroidism on pituitary GH content in the rat. In control rats, pituitary GH content increased from 4.16 +/- 0.34 at 2 days to 43.7 +/- 4.2 microgram/gland (mean +/- SE) at 15 days of age, with a t 1/2 of increment of 3.48 +/- 0.40 days. Between 18-60 days of age, pituitary GH content increased from 56.9 +/- 4.0 to 300 +/- 28 microgram/gland, with a t 1/2 of 18.2 +/- 1.5 days. The administration of T3 had no significant effect on the pituitary GH content of these animals. In neonatal hypothyroid rats, pituitary GH content was significantly lower than that of controls at 2 days of age (P < 0.01) and decreased from 8 days on, with a t 1/2 of 3.71 +/- 0.25 days. However, 24 h after the administration of T3 (100 microgram/100 g BW), pituitary GH content was significantly increased in these animals. Similarly, the administration of T3 (0.4 microgram/100 g BW) to 14-day-old hypothyroid rats restored the pituitary GH content to 70-80% of normal after 5 days of therapy. Conversely, hyperthyroidism induced in 14-day-old normal or hypothyroid rats resulted in a significant decrease in their pituitary GH contents after 5 days of treatment. Therefore, the present results indicate that during the neonatal period, thyroid hormones play a primary role in the control of GH accumulation in the pituitary. Furthermore, the lack of increase in pituitary GH content after the administration of T3 during development might suggest that the rate of formation of GH is already maximum during this period of life in the rat, or, alternatively, that the pituitary nuclear T3 receptors are near full saturation during development. Finally, a generally similar effect of T3 on pituitary GH response was observed in the neonatal rat as well as in the adult animal.

A monoclonal antibody to the rat nuclear triiodothyronine receptor: production and characterization.

The nuclear T3 receptor (NTR) was affinity-labeled with bromoacetyl-[125I]T3, purified by preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and used to immunize BALB/c mice. Spleen cells from one strongly immunoreactive mouse were fused with Sp2 mouse myeloma cells, and 328 hybridomas were screened by a dot-blot immunoassay using as antigen, a preparation of NTR partially purified by diethylaminoethyl-Sephadex chromatography. Four positive cultures were thus found; three of which were confirmed by comparing Western blotting patterns with the electrophoretic mobility of the affinity-labeled NTR. One of these 3 hybridomas was further subcloned by limiting dilution and gave rise to the 2B3 clone, which produces an immunoglobulin of the immunoglobulin G1 subclass. Several lines of evidence indicated that the 2B3 monoclonal antibody was indeed directed against the NTR. The antibody recognized a protein with the same electrophoretic mobility as the affinity-labeled receptor. Thus, Western blotting revealed a predominant protein with a mol wt of 57,000 and a less abundant 45,000 component on sodium dodecyl sulfate gels, and multiple isoelectric variants of the 57,000 protein, with a predominant form at pI 6.2, were detected on two-dimensional gels. Incubation of the 2B3 antibody with the NTR labeled with [125I]T3 resulted in the formation of an antibody-receptor complex, as indicated by a shift of the radioactivity peak upon gel filtration on Sephacryl S-300. In contrast, control ascitic fluid did not change the elution profile of the labeled NTR. The 2B3 antibody is able to remove the T3-binding activity from rat liver nuclear extracts. Finally, in accordance with previous T3-binding experiments, expected amounts of NTR were found in pituitary, liver, brain, kidney, spleen, and testis with the use of the Western blotting technique and immunohistochemistry on frozen tissue sections. This antibody should prove useful in the characterization and purification of the NTR and also in the study of its distribution in different tissues and cell types.

The selective AMPA receptor antagonist GYKI 53784 blocks action potential generation and excitotoxicity in the guinea pig cochlea.

The role of AMPA receptors in cochlear synaptic transmission and excitotoxicity was investigated by comparing the actions of a selective AMPA antagonist GYKI 53784 (LY303070) with additional AMPA/kainate antagonists, GYKI 52466 and DNQX, and the NMDA antagonist, D-AP5, in several electrophysiological, neurotoxicological and histochemical tests. GYKI 53784 had the same potency as DNQX and was 10 times more potent than GYKI 52466 in reducing auditory nerve activity. The NMDA antagonist D-AP5 had no effect on auditory nerve activity. When single-fiber activity was blocked with GYKI 53784, the effects of AMPA or kainate were also antagonized. GYKI 53784 completely blocked excitotoxicity (i.e. destruction of the afferent nerve endings) induced by AMPA and kainate. The histochemical detection of Co(2+) uptake was used to study Ca(2+) influx within the primary auditory nerve cells. Application of AMPA induced no significant Co(2+) uptake into the cells, suggesting that these receptors normally have a very low permeability to Ca(2+). Application of kainate induced significant Co(2+) uptake that was blocked by the AMPA receptor antagonist GYKI 53784 suggesting that kainate stimulated Ca(2+) entry through AMPA receptor channels. Results suggest that AMPA-preferring receptors are functionally located at the sensory cell-afferent synapse whereas NMDA and kainate receptors are not.

Regulation of protein phosphorylation by triiodothyronine (T3) in neural cell cultures. Part I: Astrocytes.

Dissociated cells from 2-day-old rat cerebral hemispheres were cultured for 17 days in absence of thyroid hormones using conditions yielding mainly glial cells. Triiodothyronine (10(-8) M) was added for 0-72 h before the end of the incubation and [32P]phosphate was added for the last 4 h. Soluble (105,000 X g supernatant), particulate (105,000 X g pellet) and HMG (high mobility group; 0.75 M perchloric acid-soluble proteins) fractions were prepared and phosphorylated proteins in each fraction were analyzed by polyacrylamide gel electrophoresis. In the soluble fraction a protein (Mr = 19,000) incorporates less [32P]phosphate after only 4 h of T3 treatment. The maximal effect is attained after 7 h (-42%) and remains unchanged up until 72 h. In this fraction, the phosphorylation of some other proteins is increased but the maximal effect is observed 48 and 72 h after T3 administration. In the particulate fraction, exposure to T3 rapidly (4 h) increases the amount of a protein (Mr = 45,000) identified as beta-actin. Protein phosphorylation in this fraction is slightly, or not at all, affected by T3. In contrast, a rapid (between 4 and 7 h) increased phosphorylation of a 17 kDa protein in the HMG fraction is observed following T3 stimulation. This nuclear protein was further characterized as HMG 14. These results show that thyroid hormones can produce direct effects (not mediated by neurons) on the phosphorylation of specific proteins in cultured glial cells. Possible functional implications of the observed protein changes are discussed in this paper.

Regulation of protein phosphorylation by triiodothyronine (T3) in neural cell cultures. Part II: Neurons.

Cerebral hemisphere from 16- to 18-day-old rat fetuses were dissociated and cells were cultured in absence of thyroid hormones. Neuron-enriched cultures were obtained either by using cells after 6 days of culture (before extensive glial cell proliferation) or by adding cytosine arabinoside for 48 h after 4 days of culture and using cells on day 9. Cells were incubated with T3 (10(-8) M) for 0-72 h and [32P]phosphate was added for the last 4 h of incubation. HMG (high mobility group; 0.75 M perchloric acid-soluble proteins) were prepared and phosphorylated proteins were analyzed by polyacrylamide gel electrophoresis. T3 rapidly (4-7 h) increased the phosphorylation of histone H1 and of a protein with apparent molecular mass of 17000 Da identified as HMG 14. In addition, in cells not treated with cytosine arabinoside, histone H1 was resolved into 3 subfractions and each of these responded to the hormone with a different time course. These results indicate that thyroid hormones act on the phosphorylation of specific nuclear proteins and therefore may influence chromatin structure and gene expression in primary neuronal cell cultures.

Antisense oligonucleotides to the GluR2 AMPA receptor subunit modify excitatory synaptic transmission in vivo.

In the brain, fast wxcitatory synaptic transmission is mostly mediated by the alpha-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) subtype of the glutamate receptors. Molecular cloning has revealed that four subunits, GluR1, GluR2, GluR3, and GluR4 form heteromeric receptors with high affinity for AMPA. Because antagonists and agonists do not discriminate between individual AMPA receptor subunits, we decided to use antisense oligonucleotides to block the expression of the GluR2 subunit within the receptor complex in adult animals. In the present study, we exploited several advantages afforded by the guinea pig cochlea to determine whether an antisense oligonucleotide directed to the mRNA of the GluR2 subunit could modify primary auditory neurotransmission. While a random probe with the same base composition had no effect, a GluR2 antisense oligonucleotide, continuously delivered into the cochlea, transiently reduced the compound action potential and diminished spontaneous activity of single auditory nerve fibers. Although antisense oligonucleotides penetrated a variety of cells, their effect could be physiologically localized to a single site of GluR2 antisense probe action, the primary auditory neuron. Subunit specificity of this effect was confirmed by a significant reduction in GluR2/3, but not GluR4 immunoreactivity in primary auditory neurons. Besides being the first demonstration that transient knockout of GluR2 subunit in adult animal modifies excitatory synaptic transmission in vivo, these results support the use of the antisense strategy as a powerful tool for blocking expression of any gene in the cochlea.

Endothelial cells exposed to erythrocytes under shear stress: an in vitro study.

After injury and vascular replacement, endothelial cell recovery is limited and could lead to thrombosis. Seeding small diameter vascular prosthesis with endothelial cells has been proposed to fulfil cell lining and improve surface hemocompatibility. However, detachment of seeded cells occurs following implantation. Previous in vitro studies have looked at the fluid shear stress as a major cause of cell detachment. To our knowledge, the role of erythrocyte collisions has not been investigated. The present in vitro study aims at investigating whether endothelial cell adhesion depends on (i) the presence of erythrocytes in flow and (ii) the latent culture period (1, 24 and 48 h) between seeding and exposure to flow. Endothelial cells were exposed to culture media containing different erythrocyte concentrations using a steady laminar flow of 1350 ml min(-1) in a parallel plate flow chamber. Endothelial cell morphology in dynamic conditions was quantified and compared to that in static conditions. The projected area of cells were mostly found smaller under dynamic than static conditions, particularly at a wall shear stress of 23 dyn cm(-2). Cells from the 1 h latent culture period were oriented parallel to the flow axis and were more elongated than under static conditions. Conversely, endothelial cell shape was slightly modified when either the latent period or the wall shear stress was increased. Disparate orientation was observed on confluent endothelial cells (24-48 h latent period) exposed to shear stress with or without erythrocytes. Increasing fluid viscous forces due to erythrocytes play a critical role on the behaviour of freshly seeded endothelial cells upon exposure to blood flow.

Excitotoxicity and repair of cochlear synapses after noise-trauma induced hearing loss.

Guinea-pigs were exposed to a traumatic sound inducing up to 80 dB hearing loss. Beside the well described mechanical damage to outer hair cells, a total disruption of inner hair cell (IHC)-auditory nerve synapses was acutely observed within the traumatized area. To test the hypothesis that synaptic damage is due to an excessive release of glutamate by the IHCs, we examined the protective effect of the glutamate antagonist kynurenate on noise-induced hearing loss. The high degree of protection observed with kynurenate attests that dendritic damage is an important component in noise-induced hearing loss. Moreover, we demonstrate that a synaptic repair mechanism occurring within the first few days post-exposure is partly responsible for the recovery of temporary threshold shifts after an acoustic trauma.

Triiodothyronine increases glutamine synthetase activity in primary cultures of rat cerebellum.

Dissociated cells from 2-3 day-old rat cerebella were cultured in absence of thyroid hormones using conditions yielding mainly glial cells. After 7, 14 and 21 days in vitro, triiodothyronine (60 nM) was added to a set of dishes and glutamine synthetase activity was measured after 24, 48, and 72 h in both control and triiodothyronine-treated cultures. Basal glutamine synthetase activity increased more than 6 X between 7 and 21 days of culture. Triiodothyronine produced significant increases of glutamine synthetase activity after 72 h in 7-day-old cultures (+ 16%), after 48 h in 14-day-old cultures (+ 45%) and after 24 h in 21-day-old cultures (+ 27%). This effect depends on the initial plating density and is not observed if cells are plated at less than 1 cerebellum equivalent per 60 mm dish. Dose-response experiments indicated that 10(-8) M of triiodothyronine induces maximal response whereas half-maximal response is achieved around 10(-10) M. These results show that physiological amounts of thyroid hormone can influence the maturation of astrocytes in culture.

Implication of NMDA type glutamate receptors in neural regeneration and neoformation of synapses after excitotoxic injury in the guinea pig cochlea.

In the adult mammalian cochlea, the ability of nerve fibres to regenerate has been observed following disruption of the organ of Corti by various means, or transsection of the cochlear nerve in the internal auditory meatus. Based upon the implication of glutamate as a neurotransmitter at synapses between sensory hair cells and terminal dendrites of the auditory nerve in the mammalian cochlea, we have developed, in a previous study, an in vivo model of neural regeneration and formation of synapses after the destruction of the afferent nerve endings by local application of the glutamate agonist alpha-amino-3-hydroxy-5-methyl-isoxazol-propionic acid (AMPA). In situ hybridization experiments performed during the re-innervation process revealed an overexpression of mRNA coding for NR1 subunit of N-methyl-D-aspartate (NMDA) receptors in the spiral ganglion neurons, suggesting that these receptors are implicated in neural regenerative processes. The present study has been designed to study the functional implication of NMDA receptors in the regrowth and synaptic repair of auditory dendrites in the guinea pig cochlea, by blocking the NMDA receptors during the period of normal functional recovery. In a first set of experiments, we recorded compound action potential after acute perilymphatic perfusion of cumulative doses (0.03-10mM) of DL 2-amino-5-phosphonovalerate (D-AP5), a NMDA antagonist, to determine the efficiency of the drug. In a second set of experiments, the auditory dendrites were destroyed by local application of the glutamate agonist AMPA. The blockage of NMDA by the antagonist D-AP5 applied with an osmotic micropump delayed the functional recovery and the regrowth of auditory dendrites. The findings of our study support the hypothesis that, in addition to acting as a fast transmitter, glutamate has a neurotrophic role via the activation of NMDA receptors.

Residual visual capacities in a case of cortical blindness.

A case of cortical blindness resulting from a dense ischemic lesion of both calcarine cortices (as seen on CAT Scan) was studied up till the seventh month after the initial stroke. By using mainly forced-choice procedures, similar to those previously used for testing hemianopic subjects, we were able to demonstrate the reappearance of some visual capacities, even though the patient still behaved as if completely blind in everyday life and the lesion remained as it was first seen. First, an ability to detect moving stimuli reappeared then bright flashes could be detected. At last, the patient could localize flickering spots approximately, by pointing with his hand, despite the fact that he did not really see them. As was hypothesized in cases of unilateral occipital lesions, such residual vision would likely to be subserved by extrageniculostriate pathways.

Survey of methadone patients in Canada.

We present the results of a survey outlining the frequency of certain activities associated with drug-seeking behaviour, e.g. needle sharing, illicit activity. The data presented are based upon information concerning 1,000 patients receiving long-term Methadone as a treatment for opioid dependence. These data are unique in that specific information of this nature has never before been made available in Canada, and are of interest in view of the AIDS epidemic.

Development of a parallel plate flow chamber for studying cell behavior under pulsatile flow.

The design of a new parallel plate perfusion chamber for cell behavior studies involving pulsatile flowrates is presented. It was based on fluid mechanical considerations to ensure a region of regular and uniform shear stress at the wall. A numeric solution of the flow was performed to study the effect of pulsating flow on the entrance length. Dye injection investigations in the chamber showed laminar and uniform flow in the culture region under steady state conditions.

Synaptic repair mechanisms responsible for functional recovery in various cochlear pathologies.

In some cochlear pathologies, temporary hearing loss can be followed by complete or partial functional recovery. Our previous findings suggest the involvement of an excitotoxic (glutamate-related) disruption of inner hair cell (IHC)-auditory nerve synapses, followed by synaptic regeneration. It is essential to understand the molecular mechanisms responsible for this synaptic repair if new therapeutic strategies are to be developed. In guinea pig cochleas, acute synaptic excitotoxic damage (mimicking what occurs with acoustic trauma or local ischemia) is achieved by locally applying AMPA, a glutamate agonist. This results in a total disruption of all IHC-auditory dendrite synapses, together with a disappearance of cochlear potentials. Within the next 5 days, however, a recovery of both the normal pattern of IHC innervation and the physiological responses is observed. The fact that the blockage of the NMDA receptors during functional recovery delayed the regrowth of neurites and the restoration of hearing suggests that glutamate plays a neurotrophic role via activation of NMDA receptors. Experiments are in progress to investigate, among other factors, the role of other glutamate receptor subunits. A reversible in vivo antisense strategy is being developed to overcome the lack of specificity of some antagonists. First results bode well for future pharmacological therapies in cochlear pathologies where glutamatergic synapses are likely to be involved; i.e., noise trauma, ischemia-related sudden deafness, and neural presbycusis.