Exercise combined with Acceptance and Commitment Therapy for chronic pain: One-year follow-up from a randomized controlled trial.

BACKGROUND: Acceptance and Commitment Therapy (ACT) is a type of Cognitive Behavioural Therapy, which has demonstrated positive outcomes in individuals with chronic pain. The purpose of this study was to compare the effect of an 8-week programme combining Exercise with Acceptance and Commitment Therapy (ExACT) with a standalone supervised exercise programme at 1-year follow-up. METHODS: One hundred and seventy-five people with chronic pain were randomly assigned to ExACT or supervised exercise only. The primary outcome was pain interference measured with the Brief Pain Inventory-Interference Scale. Secondary and treatment process outcomes included pain severity, depression, anxiety, pain catastrophizing, pain self-efficacy, fear avoidance, pain acceptance, committed action, healthcare utilization, patient satisfaction, and global impression of change. Estimates of treatment effects at 1-year follow-up were based on intention-to-treat analyses, implemented using a linear mixed-effects model. RESULTS: Eighty-three participants (47.4%) returned the outcome measures at 1-year follow-up. No significant difference was observed between the groups for the primary outcome, pain interference. There was a statistically significant difference between the groups, in favour of ExACT for pain catastrophizing. Within group improvements that were observed within both groups at earlier timepoints were maintained at 1-year follow-up for many of the secondary and treatment process outcomes. ExACT group participants reported higher levels of satisfaction with treatment and global perceived change. CONCLUSIONS: The study results showed no significant difference between the two groups for the primary outcome pain interference at 1-year follow-up. Future research could investigate factors that may predict and optimize outcomes from these types of intervention for people living with chronic pain. SIGNIFICANCE: Few previous randomized controlled trials investigating ACT for chronic pain have included long-term follow-up. This study found that Exercise combined with ACT was not superior to supervised exercise alone for reducing pain interference at 1-year follow-up. Further research is necessary to identify key processes of therapeutic change and to explore how interventions may be modified to enhance clinical outcomes for people with chronic pain.

Dynamic robotic tracking of underwater targets using reinforcement learning.

To realize the potential of autonomous underwater robots that scale up our observational capacity in the ocean, new techniques are needed. Fleets of autonomous robots could be used to study complex marine systems and animals with either new imaging configurations or by tracking tagged animals to study their behavior. These activities can then inform and create new policies for community conservation. The role of animal connectivity via active movement of animals represents a major knowledge gap related to the distribution of deep ocean populations. Tracking underwater targets represents a major challenge for observing biological processes in situ, and methods to robustly respond to a changing environment during monitoring missions are needed. Analytical techniques for optimal sensor placement and path planning to locate underwater targets are not straightforward in such cases. The aim of this study was to investigate the use of reinforcement learning as a tool for range-only underwater target-tracking optimization, whose promising capabilities have been demonstrated in terrestrial scenarios. To evaluate its usefulness, a reinforcement learning method was implemented as a path planning system for an autonomous surface vehicle while tracking an underwater mobile target. A complete description of an open-source model, performance metrics in simulated environments, and evaluated algorithms based on more than 15 hours of at-sea field experiments are presented. These efforts demonstrate that deep reinforcement learning is a powerful approach that enhances the abilities of autonomous robots in the ocean and encourages the deployment of algorithms like these for monitoring marine biological systems in the future.

Deep learning-based single image super-resolution for low-field MR brain images.

Low-field MRI scanners are significantly less expensive than their high-field counterparts, which gives them the potential to make MRI technology more accessible all around the world. In general, images acquired using low-field MRI scanners tend to be of a relatively low resolution, as signal-to-noise ratios are lower. The aim of this work is to improve the resolution of these images. To this end, we present a deep learning-based approach to transform low-resolution low-field MR images into high-resolution ones. A convolutional neural network was trained to carry out single image super-resolution reconstruction using pairs of noisy low-resolution images and their noise-free high-resolution counterparts, which were obtained from the publicly available NYU fastMRI database. This network was subsequently applied to noisy images acquired using a low-field MRI scanner. The trained convolutional network yielded sharp super-resolution images in which most of the high-frequency components were recovered. In conclusion, we showed that a deep learning-based approach has great potential when it comes to increasing the resolution of low-field MR images.

Characterization of displacement forces and image artifacts in the presence of passive medical implants in low-field (<100 mT) permanent magnet-based MRI systems, and comparisons with clinical MRI systems.

PURPOSE: To investigate the displacement forces and image artifacts associated with passive medical implants for recently-developed low-field (<100 mT) MRI systems, and to compare these with values from higher field strengths used for clinical diagnosis. METHODS: Setups were constructed to measure displacement forces in a permanent magnet-based Halbach array used for in vivo MRI at 50 mT, and results compared with measurements at 7 T. Image artifacts were assessed using turbo (fast) spin echo imaging sequences for four different passive medical implants: a septal occluder, iliac stent, pedicle screw and (ferromagnetic) endoscopic clip. Comparisons were made with artifacts produced at 1.5, 3 and 7 T. Finally, specific absorption rate (SAR) simulations were performed to determine under what operating conditions the limits might be approached at low-field. RESULTS: Displacement forces at 50 mT on all but the ferromagnetic implant were between 1 and 10 mN. Image artifacts at 50 mT were much less than at clinical field strengths for all passive devices, and with the exception of the ferromagnetic clip. SAR simulations show that very long echo train (>128) turbo spin echo sequences can be run with short inter-pulse times (5-10 ms) within SAR limits. CONCLUSIONS: This work presents the first evaluation of the effects of passive implants at field strengths less than 100 mT in terms of displacement forces, image artifacts and SAR. The results support previous claims that such systems can be used safely and usefully in challenging enviroments such as the intensive care unit.

Mobile robotic platforms for the acoustic tracking of deep-sea demersal fishery resources.

Knowing the displacement capacity and mobility patterns of industrially exploited (i.e., fished) marine resources is key to establishing effective conservation management strategies in human-impacted marine ecosystems. Acquiring accurate behavioral information of deep-sea fished ecosystems is necessary to establish the sizes of marine protected areas within the framework of large international societal programs (e.g., European Community H2020, as part of the Blue Growth economic strategy). However, such information is currently scarce, and high-frequency and prolonged data collection is rarely available. Here, we report the implementation of autonomous underwater vehicles and remotely operated vehicles as an aid for acoustic long-baseline localization systems for autonomous tracking of Norway lobster (Nephrops norvegicus), one of the key living resources exploited in European waters. In combination with seafloor moored acoustic receivers, we detected and tracked the movements of 33 tagged lobsters at 400-m depth for more than 3 months. We also identified the best procedures to localize both the acoustic receivers and the tagged lobsters, based on algorithms designed for off-the-shelf acoustic tags identification. Autonomous mobile platforms that deliver data on animal behavior beyond traditional fixed platform capabilities represent an advance for prolonged, in situ monitoring of deep-sea benthic animal behavior at meter spatial scales.

Three-dimensional MRI in a homogenous 27 cm diameter bore Halbach array magnet.

Modern clinical MRI systems utilise very high magnetic fields strengths to produce high resolution images of the human body. The high up-front and maintenance cost of these systems means that much of the world lacks access to this technology. In this paper we propose a low cost, head-only, homogenous Halbach magnet array with the potential for paediatric neuroimaging in low-resource settings. The homogeneity of the Halbach array is improved by allowing the diameter of the Halbach array to vary along its length, and also adding smaller internal shim magnets. The constructed magnet has a bore diameter of 27 cm, mean B0 field strength of 50.4 mT and a homogeneity of 2400 ppm over a 20 cm diameter spherical volume. The level of homogeneity of the system means that coil-based gradients can be used for spatial encoding which greatly increases the flexibility in image acquisition. 3D images of a "brain phantom" were acquired over a 22 × 22 × 22 cm field of view with a 3.5 mm isotropic resolution using a spin-echo sequence. Future development of a low-cost gradient amplifier and an open-source spectrometer has the potential of offering a fully open-source, low-cost MRI system for paediatric neuroimaging in low-resource settings.

Selective in vivo and in vitro effects of a small molecule inhibitor of cyclin-dependent kinase 4.

BACKGROUND: Cyclin-dependent kinase 4 (Cdk4) represents a prime target for the treatment of cancer because most human cancers are characterized by overexpression of its activating partner cyclin D1, loss of the natural Cdk4-specific inhibitor p16, or mutation(s) in Cdk4's catalytic subunit. All of these can cause deregulated cell growth, resulting in tumor formation. We sought to identify a small molecule that could inhibit the kinase activity of Cdk4 in vitro and to then ascertain the effects of that inhibitor on cell growth and tumor volume in vivo. METHODS: A triaminopyrimidine derivative, CINK4 (a chemical inhibitor of Cdk4), was identified by screening for compounds that could inhibit Cdk4 enzyme activity in vitro. Kinase assays were performed on diverse human Cdks and on other kinases that were expressed in and purified from insect cells to determine the specificity of CINK4. Cell cycle effects of CINK4 on tumor and normal cells were studied by flow cytometry, and changes in phosphorylation of the retinoblastoma protein (pRb), a substrate of Cdk4, were determined by western blotting. The effect of the inhibitor on tumor growth in vivo was studied by use of tumors established through xenografts of HCT116 colon carcinoma cells in mice. Statistical tests were two-sided. RESULTS: CINK4 specifically inhibited Cdk4/cyclin D1 in vitro. It caused growth arrest in tumor cells and in normal cells and prevented pRb phosphorylation. CINK4 treatment resulted in statistically significantly (P: =.031) smaller mean tumor volumes in a mouse xenograft model. CONCLUSIONS: Like p16, the natural inhibitor of Cdk4, CINK4 inhibits Cdk4 activity in vitro and slows tumor growth in vivo. The specificity of CINK4 for Cdk4 raises the possibility that this small molecule or one with a similar structure could have therapeutic value.

Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine class.

Glioblastoma multiforme is the most common primary human brain tumor, and it is, for all practical purposes, incurable in adult patients. The high mortality rates reflect the fact that glioblastomas are resistant to adjuvant therapies (radiation and chemicals), the mode of action of which is cytotoxic. We show here that an p.o.-active small molecule kinase inhibitor of the 2-phenylaminopyrimidine class may have therapeutic potential for glioblastomas. STI571 inhibits the growth of U343 and U87 human glioblastoma cells that have been injected into the brains of nude mice, but it does not inhibit intracranial growth of ras-transformed cells. Studies on a broad panel of genetically validated human and animal cell lines show that STI571 acts by disruption of the ligand:receptor autocrine loops for platelet-derived growth factor that are a pervasive feature of malignant astrocytoma. The cellular response of glioblastoma cells to STI571 does not appear to involve an apoptotic mechanism.

PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration.

PTK787/ZK 222584 (1-[4-chloroanilino]-4-[4-pyridylmethyl] phthalazine succinate) is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, such as the platelet-derived growth factor (PDGF) receptor beta tyrosine kinase, c-Kit, and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families, such as epidermal growth factor receptor, fibroblast growth factor receptor-1, c-Met, and Tie-2, or intracellular kinases such as c-Src, c-Abl, and protein kinase C-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of kinase insert domain-containing receptor (KDR), endothelial cell proliferation, migration, and survival in the nanomolar range in cell-based assays. In concentrations up to 1 microM, PTK787/ZK 222584 does not have any cytotoxic or antiproliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once-daily oral dosing (25-100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown s.c. in nude mice, as well as a murine renal carcinoma and its metastases in a syngeneic, orthotopic model. Histological examination of tumors revealed inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent or impair hematopoetic recovery after concomitant cytotoxic anti-cancer agent challenge. This novel compound has therapeutic potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.

Practical improvements in the design of high permittivity pads for dielectric shimming in neuroimaging at 7T.

Improvements are proposed for practical design and use of high permittivity materials in high field neuroimaging in three different areas: (i) a simple formula to predict the permittivity of tri-component aqueous-based perovskite suspensions with relative permittivities between 110 and 300, (ii) characterization of addition of a hydroxyethyl-cellulose gelling agent to improve the long-term stability and material properties of "dielectric pads", and (iii) investigation of the integration of, for example, headphones into the dielectric pads to increase patient comfort within tightly-fitting receive coil arrays.

Inhibitors of protein kinases: CGP 41251, a protein kinase inhibitor with potential as an anticancer agent.

CGP 41251 was originally identified as an inhibitor of protein kinase C (PKC), inhibiting mainly the conventional PKC subtypes, and subsequently shown to inhibit the vascular endothelial growth factor (VEGF) receptor kinase insert domain-containing receptor, which is involved in angiogenesis. CGP 41251 inhibits reversibly intracellular PKC activity, induction of c-fos and the corresponding activation of the mitogen-activated protein kinase induced by either tumor promoting phorbol esters, platelet-derived growth factor, or basic fibroblast growth factor, but not by the epidermal growth factor. CGP 41251 inhibited the ligand-induced autophosphorylation of the receptors for platelet-derived growth factor, stem cell factor, and VEGF (kinase insert domain-containing receptor) that correlated with the inhibition of the mitogen-activated protein kinase activation, but did not affect the ligand-induced autophosphorylation of the receptors for insulin, insulin-like growth factor-I, or epidermal growth factor. CGP 41251 showed broad antiproliferative activity against various tumor and normal cell lines in vitro, and is able to reverse the p-glycoprotein-mediated multidrug resistance of tumor cells in vitro. CGP 41251 showed in vivo antitumor activity as single agent and inhibited angiogenesis in vivo. Thus, CGP 41251 may suppress tumor growth by inhibiting tumor angiogenesis (via its effects on the VEGF receptor tyrosine kinases) in addition to directly inhibiting tumor cell proliferation (via its effects on PKCs).

Patupilone (epothilone B, EPO906) and imatinib (STI571, Glivec) in combination display enhanced antitumour activity in vivo against experimental rat C6 glioma.

PURPOSE: The microtubule-stabilizing agent patupilone (epothilone B, EPO906) and the tyrosine kinase inhibitor imatinib (STI571, Glivec) which primarily inhibits Bcr-Abl, PDGF and c-Kit tyrosine kinase receptors, were combined in vivo to determine if any interaction would occur with respect to antitumour effect and tolerability using rat C6 glioma xenografted into nude mice. METHODS: Patupilone and imatinib were administered alone or in combination at suboptimal doses. Imatinib treatment (orally once daily) was initiated 4 days after s.c. injection of rat C6 glioma cells into athymic nude mice and patupilone administration (i.v. once per week) was started 3 or 4 days after imatinib treatment. RESULTS: As a single agent, imatinib was inactive in the regimens selected (100 mg/kg: T/C 86% and 116%; 200 mg/kg: T/C 68% and 84%; two independent experiments), but well tolerated (gain in body weight and no mortalities). Patupilone weekly monotherapy demonstrated dose-dependent antitumour effects (1 mg/kg: T/C 67% and 70%; 2 mg/kg: T/C 32% and 63%; 4 mg/kg: T/C 3% and 46%). As expected, dose-dependent body weight losses occurred (final body weight changes at 1 mg/kg were -7% and -3%; at 2 mg/kg were -23% and -13%; and at 4 mg/kg were -33% and -15%). Combining 2 mg/kg patupilone and 200 mg/kg per day imatinib in one experiment produced a non-statistically significant trend for an improved antitumour effect over patupilone alone (combination, T/C 9%), while in the second experiment, enhancement was seen with the combination and reached statistical significance versus patupilone alone (combination, T/C 22%; P=0.008). Reduction of the imatinib dose to 100 mg/kg per day resulted in no enhancement of antitumour activity in combination with 2 mg/kg patupilone. Reduction of the patupilone dose to 1 mg/kg resulted in a reduced antitumour effect, and only a trend for synergy with either imatinib dose (combination, T/C 46% and 40%). Pooling the data from the two experiments confirmed a significant synergy for the combination of 2 mg/kg patupilone and 200 mg/kg per day imatinib (P=0.032), and a trend for synergy at the 1 mg/kg patupilone dose. Reduction in the imatinib dose to 100 mg/kg per day resulted only in additivity with either dose of patupilone. Body weight losses were dominated by the effect of patupilone, since no greater body weight loss was observed in the combination groups. CONCLUSION: Combining patupilone with high-dose imatinib produced an increased antitumour effect without affecting the tolerability of treatment in a relatively chemoresistant rat C6 glioma model. Such results indicate that further evaluation is warranted, in particular to elucidate possible mechanisms of combined action.

Unique chemical reactivity of His-21 of CRM-197, a mutated diphtheria toxin.

CRM-197 is a mutated diphtheria toxin (63000 Da) widely used as a carrier protein of conjugated vaccines. Among the 14 histidines of CRM-197, His-21 was found to be modified selectively with iodoacetamide based reagents. This finding suggests a simplified method for the preparation of conjugate vaccines crosslinked to CRM-197. A bifunctional iodoacetamide, N,N'-(2-hydroxy-1,3-propanediyl)-bis-12-iodoacetamidel (I-CH2-CONH-CH2-CH(OH)-CH2-NHCO-CH2-I) (HPBIA), was synthesized and allowed to react with CRM-197. In the alkaline buffer of pH 8.0-8.4, HPBIA was shown to react and intra-bridge His-21 and Lys-24 of CRM-197 sequentially. At lower pH (7.1-7.5) in the phosphate buffer, the reactivity of Lys-24 toward HPBIA was suppressed drastically. Under these conditions, His-21 could be specifically labeled with HPBIA. Initial experiments have demonstrated that HPBIA modified CRM-197 is able to crosslink to a cysteine-containing peptide. These results offer a potential route for improving the homogeneity of CRM-197 based protein-peptide as well as protein-polysaccharide conjugates.

A rat model of bone cancer pain.

This study describes the first known model of bone cancer pain in the rat. Sprague-Dawley rats receiving intra-tibial injections of syngeneic MRMT-1 rat mammary gland carcinoma cells developed behavioural signs indicative of pain, including: mechanical allodynia, difference of weight bearing between hind paws and mechanical hyperalgesia. The development of the bone tumour and structural damage to the bone was monitored by radiological analysis, quantitative measurement of mineral content and histology. Intra-tibial injections of 3 x 10(3) or 3 x 10(4) syngeneic MRMT-1 cells produced a rapidly expanding tumour within the boundaries of the tibia, causing severe remodelling of the bone. Radiographs showed extensive damage to the cortical bone and the trabeculae by day 10-14 after inoculation of 3 x 10(3) MRMT-1 cells, and by day 20, the damage was threatening the integrity of the tibial bone. While both mineral content and mineral density decreased significantly in the cancerous bone, osteoclast numbers in the peritumoural compact bone remained unchanged. However, tartarate-resistant acid phosphatase staining revealed a large number of polykariotic cells, resembling those of osteoclasts within the tumour. No tumour growth was observed after the injection of heat-killed MRMT-1 cells. Intra-tibial injections of 3 x 10(3) or 3 x 10(4) MRMT-1 cells, heat-killed cells or vehicle did not show changes in body weight and core temperature over 19-20 days. The general activity of animals after injection with live or heat-killed MRMT-1 cells was higher than that of the control group, however, the activity of the MRMT-1 treated group declined during the progress of the disease. Rats receiving intra-tibial injections of MRMT-1 cells displayed the gradual development of mechanical allodynia and mechanical hyperalgesia/reduced weight bearing on the affected limb, beginning on day 12-14 or 10-12 following injection of 3 x 10(3) or 3 x 10(4) cells, respectively. These symptoms were not observed in rats receiving heat-killed cells or vehicle. Behavioural data suggest a reasonable time window for evaluation of anti-nociceptive agents between day 14 and 20 after cancer cell inoculation in this model. Acute treatment with morphine (1-3mg/kg, subcutanously (s.c.)) produced a dose-dependent reduction in the response frequency of hind paw withdrawal to von Frey filament stimulation 17 or 19 days following intra-tibial injections of 3 x 10(3) MRMT-1 cells. A significant reduction in the difference in hind limb weight bearing was also observed. Acute treatment with celebrex (10-30 mg/kg, s.c.) did not affect mechanical allodynia or difference in weight bearing in rats 20 days following treatment with 3 x 10(3) MRMT-1 cells. Although the pathophysiology of cancer pain is largely unknown, significant enhancement of glial fibrillary acidic protein (GFAP) staining in the corresponding segments of the ipsilateral spinal cord highlights the possible involvement of astrocytes. In summary, the induction of bone cancer in the rat by the syngeneic MRMT-1 mammary tumour cell line provides a valid pre-clinical model for pain associated with bone metastases. Significant mechanical hyperalgesia and allodynia develops in association with the progression of the tumour in the bone marrow cavity, while the general condition of the animal remains satisfactory. While acute treatment with morphine has some analgesic effect on hind limb sparing the selective COX-2 inhibitor, celebrex, has no influence on the pain-related behavioural changes in this model.

The effect of calcium channel blockade with nifedipine on splanchnic and systemic haemodynamics in cirrhosis.

The splanchnic and systemic haemodynamic effects of a single sublingual dose of nifedipine (slow calcium channel blocker) in nine patients with cirrhosis of the liver and portal hypertension were studied. Nifedipine produced a significant reduction in the mean arterial blood pressure (98 +/- 5.3 vs. 86 +/- 5 mmHg, P less than 0.05) but did not alter the mean heart rate, portal venous pressure or total liver blood flow. The systemic antihypertensive effect of nifedipine can be achieved without altering liver blood-flow in patients with chronic liver disease and portal hypertension.

Measurement of total bile acids in gastric juice.

An established method for the assay of total bile acids was validated for use in fasting and post-prandial gastric juice samples. Fasting and post-prandial intragastric bile acid concentrations were measured in 29 healthy volunteers, 15 patients after vagotomy and gastrojejunostomy (V and GJ) and 15 patients after vagotomy and pyloroplasty (V and P). Healthy female volunteers had higher post-prandial bile acid concentrations than age matched healthy males (p less than 0.02). Patients with V and GJ had higher fasting and post-prandial bile acid concentrations than age and sex matched control subjects (p less than 0.01). Patients with V and P had higher bile acid concentrations than control subjects only in post-prandial samples (p less than 0.05).

Neutrophil intracellular kill following thermal injury. Different bactericidal capability for patients' organisms and laboratory organisms.

Sixteen patients with septic complications of severe thermal injury were studied with respect to neutrophil intracellular-killing power against clinical isolates from the patients themselves and against other laboratory organisms. Simultaneous measurements of neutrophil chemotaxis, helper/suppressor lymphocyte ratios, and serum IgG concentrations were also carried out. Neutrophils from patients who survived had diminished intracellular-killing capacity for their own organisms, but normal capacity for killing laboratory organisms either matched or unmatched with the patients' own isolate's species. In these patients, the chemotactic index, the lymphocyte helper/suppressor ratio, and the serum IgG concentration remained within normal limits. Neutrophils from patients who died failed to kill their own, as well as laboratory, organisms. In these patients, the chemotactic index, lymphocyte helper/suppressor ratio, and IgG concentration were significantly diminished. The biological implications of these findings are noted.

Porphyrin ring source can alter the outer membrane protein profile of non-typable Haemophilus influenzae.

Porphyrin ring source appears to alter the outer membrane protein (OMP) profile of some, but not all, non-typable (NT) Haemophilus influenzae strains isolated from sputum. When haemin was replaced with protoporphyrin IX, 41% of strains examined produced increased amounts of a polypeptide of 84 Kda and new OMPs of either 120 or 150 Kda. Immunoblotting with paired patient's sera revealed that antibodies reactive with these proteins were present, demonstrating OMP antigenicity and expression in vivo and indicating that these isolates of NT H. influenzae may display an altered OMP phenotype when growing in the human lung.

Rat model of chronic lung infections caused by non-typable Haemophilus influenzae.

Patients with chronic obstructive pulmonary disease (COPD) often have chronic or recurrent pulmonary infections with non-typable Haemophilus influenzae. A model of these infections exploited agar bead vehicles to protect the inoculum from rapid clearance, and a chronic lung infection of at least 42 days duration was established in rats. This infection induced increases in serum IgG titres to outer-membrane (OM) and lipo-oligosaccharide (LOS) antigens; immunoblotting demonstrated that this humoral response was directed partly against the outer-membrane proteins (OMPs). Lung lavage fluid also contained an increased titre of IgG antibodies to OM and LOS 42 days after infection. Antibodies produced during infection with one strain of H. influenzae cross-reacted with OMPs from another, non-typable H. influenzae strain. Despite their encasement in agar beads, pulmonary H. influenzae remained susceptible to amoxycillin. This model of chronic pulmonary infections due to non-typable H. influenzae appears to resemble the situation in COPD patients and may be useful for experimental therapeutic studies.

Dexamethasone treatment of lipopolysaccharide-induced meningitis in rabbits that mimics magnification of inflammation following antibiotic therapy.

The objective of adjunct anti-inflammatory therapy of bacterial meningitis is the containment of heightened inflammation caused by lysis of bacteria by antibiotics. This can be modelled by giving two consecutive intra-cisternal injections of lipopolysaccharide (LPS) to rabbits, the first at 0 h to induce inflammation to mimic that occurring during the proliferation of bacteria in the cerebrospinal fluid (CSF), and the second at 6 h to mimic inflammation subsequent to antibiotic-induced bacterial lysis. Injection of 2.5 ng of LPS induced pleocytosis at 4 h which was preceded by a peak of tumour necrosis factor (TNF) activity at 2 h. A subsequent injection of 25 ng of LPS at 6 h induced second peaks of pleocytosis and CSF TNF. Dexamethasone (1.5 mg/kg, i.v.) administered 15 min or 1 h before the second injection of LPS tended only to reduce CSF TNF, but effectively prohibited further pleocytosis. Brain TNF alpha mRNA levels were unchanged at 6 and 7 h after LPS injection, and were unaffected by dexamethasone. These results indicate that the subarachnoid space is distinct from the general circulation in that the TNF-producing cells present do not display a hypo-responsive state towards LPS as occurs when LPS is injected systemically. Furthermore, dexamethasone is able to attenuate the secondary inflammatory response resulting from a second LPS injection without eliminating a second peak of TNF activity.