Degeneration of the intervertebral disc with new approaches for treating low back pain.

This review paper discusses the process of disc degeneration and the current understanding of cellular degradation in patients who present with low back pain. The role of surgical treatment for low back pain is analysed with emphasis on the proven value of spinal fusion. The interesting and novel developments of stem cell research in the treatment of low back pain are presented with special emphasis on the importance of the cartilaginous end plate and the role of IL-1 in future treatment modalities

Airway smooth muscle CXCR3 ligand production: Regulation by JAK-STAT1 and intracellular Ca²⁺

In asthma, airway smooth muscle (ASM) chemokine (C-X-C motif) receptor 3 (CXCR3) ligand production may attract mast cells or T lymphocytes to the ASM, where they can modulate ASM functions. In ASM cells (ASMCs) from people with or without asthma, we aimed to investigate JAK-STAT1, JNK, and Ca2+ involvement in chemokine (C-X-C motif) ligand (CXCL)10 and CXCL11 production stimulated by interferon-γ, IL-1β, and TNF-α combined (cytomix). Confluent, growth-arrested ASMC were treated with inhibitors for pan-JAK (pyridone-6), JAK2 (AG-490), JNK (SP-600125), or the sarco(endo)plasmic reticulum Ca2+ATPase (SERCA) pump (thapsigargin), Ca2+ chelator (BAPTA-AM), or vehicle before and during cytomix stimulation for up to 24 h. Signaling protein activation as well as CXCL10/CXCL11 mRNA and protein production were examined using immunoblot analysis, real-time PCR, and ELISA, respectively. Cytomix-induced STAT1 activation was lower and CXCR3 ligand mRNA production was more sensitive to pyridone-6 and AG-490 in asthmatic than nonasthmatic ASMCs, but CXCL10/CXCL11 release was inhibited by the same proportion. Neither agent caused additional inhibition of release when used in combination with the JNK inhibitor SP-600125. Conversely, p65 NF-κB activation was higher in asthmatic than nonasthmatic ASMCs. BAPTA-AM abolished early CXCL10/CXCL11 mRNA production, whereas thapsigargin reduced it in asthmatic cells and inhibited CXCL10/CXCL11 release by both ASMC types. Despite these inhibitory effects, neither Ca2+ agent affected early activation of STAT1, JNK, or p65 NF-κB. In conclusion, intracellular Ca2+ regulated CXCL10/CXCL11 production but not early activation of the signaling molecules involved. In asthma, reduced ASM STAT1-JNK activation, increased NF-κB activation, and altered Ca2+ handling may contribute to rapid CXCR3 ligand production and enhanced inflammatory cell recruitment. © 2013 the American Physiological Society

Hemoglobin Is a Vital Determinant of Arterial Oxygen Content in Hypoxemic Patients with Pulmonary Arteriovenous Malformations.

RATIONALE: Arterial partial pressure of oxygen (PaO2), and oxygen saturation (SaO2) are commonly measured in respiratory practice, but arterial oxygen content (CaO2) refers to the volume of oxygen delivered to the tissues per unit blood volume. CaO2 is calculated from SaO2 and the hemoglobin concentration in blood, recognizing that each gram of hemoglobin can transport approximately 1.34mls of oxygen when fully saturated. OBJECTIVES: To prospectively evaluate serial changes in CaO2 in man, incorporating and excluding dynamic changes to oxygenation and hemoglobin parameters that may occur during life. METHODS: A cohort of 497 consecutive patients at risk of both hypoxemia and anemia were recruited. The patients had radiologically-proven pulmonary arteriovenous malformations (PAVMs) which result in hypoxemia due to right-to-left shunting, and concurrent hereditary hemorrhagic telangiectasia (HHT) which placed them at risk of iron deficiency anemia due to recurrent hemorrhagic iron losses. Presentation SaO2 (breathing room air, by pulse oximetry), hemoglobin, red cell and iron indices were measured, and CaO2 calculated by SaO2*hemoglobin*1.34mls/gram. Serial measurements were evaluated in 100 cases spanning up to 32.1 (median 10.5) years. RESULTS: Presentation CaO2 ranged from 7.6-27.5 (median 17.6) mls/dL. CaO2 did not change appreciably across the SaO2 quartiles. In contrast, hemoglobin ranged from 5.9-21.8g/dL (median 14.1g/dL), with a linear increase in CaO2 across hemoglobin quartiles. Following PAVM embolization and an immediate increase in SaO2, hemoglobin fell and CaO2 was unchanged 1.6-12 (median 4) months later. When hemoglobin fell due to iron deficiency, there was no change in SaO2. Similarly, when hemoglobin rose after iron treatment, there was no change in SaO2, and the expected CaO2 increment was observed. These relationships were not evident during pregnancy when hemoglobin fell, and PAVMs usually deteriorated: In pregnancy SaO2 commonly increased, and serial CaO2 values (incorporating hemodilution/anemia) more accurately reflected deteriorating PAVM status. An apparent fall in CaO2 with age in females was attributable to the development of iron deficiency. There was an unexplained increase in CaO2 with age in males in follow up after embolization. CONCLUSIONS: Hemoglobin/CaO2 should be further incorporated into oxygenation considerations. More attention should be given to modest changes in hemoglobin that substantially modify CaO2

A massive reservoir of low-excitation molecular gas at high redshift

Molecular hydrogen is an important component of galaxies because it fuels star formation and accretion onto AGN, the two processes that generate the large infrared luminosities of gas-rich galaxies. Observations of spectral-line emission from the tracer molecule CO are used to probe the properties of this gas. But the lines that have been studied in the local Universe, mostly the lower rotational transitions of J = 1-0 and J = 2-1, have hitherto been unobservable in high-redshift galaxies. Instead, higher transitions have been used, although the densities and temperatures required to excite these higher transitions may not be reached by much of the gas. As a result, past observations may have underestimated the total amount of molecular gas by a substantial amount. Here we report the discovery of large amounts of low-excitation molecular gas around the infrared-luminous quasar, APM 08279+5255 at z = 3.91, using the two lowest excitation lines of 12CO (J = 1-0 and J = 2-1). The maps confirm the presence of hot and dense gas near the nucleus, and reveal an extended reservoir of molecular gas with low excitation that is 10 to 100 times more massive than the gas traced by higher-excitation observations. This raises the possibility that significant amounts of low-excitation molecular gas may lurk in the environments of high-redshift (z > 3) galaxies.Comment: To appear as a Letter to Nature, 4th January 200

Intermittent aeration to improve wastewater treatment efficiency in pilot-scale constructed wetland

Forced aeration of horizontal subsurface flow constructed wetlands (HSSF CWs) is nowadays a recognized method to improve treatment efficiency, mainly in terms of ammonium removal. While numerous investigations have been reported testing constant aeration, scarce information can be found about the efficiency of intermittent aeration. This study aims at comparing continuous and intermittent aeration, establishing if there is an optimal regime that will increase treatment efficiency of HSSF CWs whilst minimizing the energy requirement. Full and intermittent aeration were tested in a pilot plant of three HSSF CWs (2.64 m2 each) fed with primary treated wastewater. One unit was fully aerated; one intermittently aerated (i.e. by setting a limit of 0.5 mg/L dissolved oxygen within the bed) with the remaining unit not aerated as a control. Results indicated that intermittent aeration was the most successful operating method. Indeed, the coexistence of aerobic and anoxic conditions promoted by the intermittent aeration resulted in the highest COD (66%), ammonium (99%) and total nitrogen (79%) removals. On the other hand, continuous aeration promotes ammonium removal (99%), but resulted in nitrate concentrations in the effluent of up to 27 mg/L. This study demonstrates the high potential of the intermittent aeration to increase wastewater treatment efficiency of CWs providing an extreme benefit in terms of the energy consumption

The British antibiotic and silver-impregnated catheters for ventriculoperitoneal shunts multi-centre randomised controlled trial (the BASICS trial): study protocol

BACKGROUND: Insertion of a ventriculoperitoneal shunt (VPS) for the treatment of hydrocephalus is one of the most common neurosurgical procedures in the UK, but failures caused by infection occur in approximately 8% of primary cases. VPS infection is associated with considerable morbidity and mortality and its management results in substantial cost to the health service. Antibiotic-impregnated (rifampicin and clindamycin) and silver-impregnated VPS have been developed to reduce infection rates. Whilst there is some evidence showing that such devices may lead to a reduction in VPS infection, there are no randomised controlled trials (RCTs) to support their routine use. METHODS/DESIGN: Overall, 1,200 patients will be recruited from 17 regional neurosurgical units in the UK and Ireland. Patients of any age undergoing insertion of their first VPS are eligible. Patients with previous indwelling VPS, active and on-going cerebrospinal fluid (CSF) or peritoneal infection, multiloculated hydrocephalus requiring multiple VPS or neuroendoscopy, and ventriculoatrial or ventriculopleural shunt planned will be excluded. Patients will be randomised 1:1:1 to either standard silicone (comparator), antibiotic-impregnated, or silver-impregnated VPS. The primary outcome measure is time to VPS infection. Secondary outcome measures include time to VPS failure of any cause, reason for VPS failure (infection, mechanical failure, or patient failure), types of bacterial VPS infection (organism type and antibiotic resistance), and incremental cost per VPS failure averted. DISCUSSION: The British antibiotic and silver-impregnated catheters for ventriculoperitoneal shunts multi-centre randomised controlled trial (the BASICS trial) is the first multi-centre RCT designed to determine whether antibiotic or silver-impregnated VPS reduce early shunt infection compared to standard silicone VPS. The results of this study will be used to inform current neurosurgical practice and may potentially benefit patients undergoing shunt surgery in the future. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number: ISRCTN49474281

The space group classification of topological band insulators

Topological band insulators (TBIs) are bulk insulating materials which feature topologically protected metallic states on their boundary. The existing classification departs from time-reversal symmetry, but the role of the crystal lattice symmetries in the physics of these topological states remained elusive. Here we provide the classification of TBIs protected not only by time-reversal, but also by crystalline symmetries. We find three broad classes of topological states: (a) Gamma-states robust against general time-reversal invariant perturbations; (b) Translationally-active states protected from elastic scattering, but susceptible to topological crystalline disorder; (c) Valley topological insulators sensitive to the effects of non-topological and crystalline disorder. These three classes give rise to 18 different two-dimensional, and, at least 70 three-dimensional TBIs, opening up a route for the systematic search for new types of TBIs.Comment: Accepted in Nature Physic

Early growth response 2 (EGR2) is a novel regulator of the senescence programme.

Senescence, a state of stable growth arrest, plays an important role in ageing and age-related diseases in vivo. Although the INK4/ARF locus is known to be essential for senescence programmes, the key regulators driving p16 and ARF transcription remain largely underexplored. Using siRNA screening for modulators of the p16/pRB and ARF/p53/p21 pathways in deeply senescent human mammary epithelial cells (DS HMECs) and fibroblasts (DS HMFs), we identified EGR2 as a novel regulator of senescence. EGR2 expression is up-regulated during senescence, and its ablation by siRNA in DS HMECs and HMFs transiently reverses the senescent phenotype. We demonstrate that EGR2 activates the ARF and p16 promoters and directly binds to both the ARF and p16 promoters. Loss of EGR2 down-regulates p16 levels and increases the pool of p16- p21- 'reversed' cells in the population. Moreover, EGR2 overexpression is sufficient to induce senescence. Our data suggest that EGR2 is a direct transcriptional activator of the p16/pRB and ARF/p53/p21 pathways in senescence and a novel marker of senescence

c-di-GMP modulates type IV MSHA pilus retraction and surface attachment in Vibrio cholerae.

Biofilm formation by Vibrio cholerae facilitates environmental persistence, and hyperinfectivity within the host. Biofilm formation is regulated by 3',5'-cyclic diguanylate (c-di-GMP) and requires production of the type IV mannose-sensitive hemagglutinin (MSHA) pilus. Here, we show that the MSHA pilus is a dynamic extendable and retractable system, and its activity is directly controlled by c-di-GMP. The interaction between c-di-GMP and the ATPase MshE promotes pilus extension, whereas low levels of c-di-GMP correlate with enhanced retraction. Loss of retraction facilitated by the ATPase PilT increases near-surface roaming motility, and impairs initial surface attachment. However, prolonged retraction upon surface attachment results in reduced MSHA-mediated surface anchoring and increased levels of detachment. Our results indicate that c-di-GMP directly controls MshE activity, thus regulating MSHA pilus extension and retraction dynamics, and modulating V. cholerae surface attachment and colonization

Wolbachia in the flesh: symbiont intensities in germ-line and somatic tissues challenge the conventional view of Wolbachia transmission routes

Symbionts can substantially affect the evolution and ecology of their hosts. The investigation of the tissue-specific distribution of symbionts (tissue tropism) can provide important insight into host-symbiont interactions. Among other things, it can help to discern the importance of specific transmission routes and potential phenotypic effects. The intracellular bacterial symbiont Wolbachia has been described as the greatest ever panzootic, due to the wide array of arthropods that it infects. Being primarily vertically transmitted, it is expected that the transmission of Wolbachia would be enhanced by focusing infection in the reproductive tissues. In social insect hosts, this tropism would logically extend to reproductive rather than sterile castes, since the latter constitute a dead-end for vertically transmission. Here, we show that Wolbachia are not focused on reproductive tissues of eusocial insects, and that non-reproductive tissues of queens and workers of the ant Acromyrmex echinatior, harbour substantial infections. In particular, the comparatively high intensities of Wolbachia in the haemolymph, fat body, and faeces, suggest potential for horizontal transmission via parasitoids and the faecal-oral route, or a role for Wolbachia modulating the immune response of this host. It may be that somatic tissues and castes are not the evolutionary dead-end for Wolbachia that is commonly thought