Minimally invasive repair of a pseudomeningocele caused by a sheared intrathecal catheter following implantation of a drug delivery system.

BACKGROUND: Shearing of an intrathecal catheter during implantation of a drug delivery system is an underreported complication that can be challenging to manage. CASE DESCRIPTION: A 53-year-old man with refractory cancer pain had an intrathecal pump system implanted. The procedure was complicated with catheter shear and retention in the intrathecal space. A second catheter was successfully placed but formation of a painful pseudomeningocele and ineffective pain relief complicated the outcome. A minimally invasive approach through a tubular retractor was employed to access the spinal canal via a laminotomy, the sheared catheter was removed and the dural defect repaired. Complete resolution of the pseudomeningocele and efficient pain control were observed at follow-up. CONCLUSION: Minimally invasive approach to the spine is demonstrated as a safe and effective alternative in this case of retained catheter induced cerebrospinal fluid (CSF) leak.

Exophytic bulbar pilocytic astrocytoma and post-operative cerebral salt wasting syndrome.

Cerebral salt wasting syndrome (CSWS) is a well-described consequence of several neurological disorders. Although the exact etiology of CSWS is still not completely elucidated, it is believed that the hypothalamus plays a pivotal role in the genesis of this disorder. We report for the first time 3 cases of CSWS occurring during the post-operative course following surgical resection of exophytic bulbar pilocytic astrocytomas in children. Since these 3 cases shared in common a medial implication of the medulla, we suggest that specific interconnectivity between the dorso-medial portion of the medulla oblongata and the hypothalamus might thus represent an anatomical pathway of interest in the pathogenesis of CSWS. Our findings suggest that the resection of medially located exophytic bulbar tumors might constitutes a risk factor in the development of CSWS. Particular care should thus be carried towards the prompt detection and treatment of CSWS in the post-operative courses of exophytic bulbar tumors.

An event-based hydrologic simulation model for bioretention systems.

Bioretention systems are designed to treat stormwater and provide attenuated drainage between storms. Bioretention has shown great potential at reducing the volume and improving the quality of stormwater. This study introduces the bioretention hydrologic model (BHM), a one-dimensional model that simulates the hydrologic response of a bioretention system over the duration of a storm event. BHM is based on the RECARGA model, but has been adapted for improved accuracy and integration of pollutant transport models. BHM contains four completely-mixed layers and accounts for evapotranspiration, overflow, exfiltration to native soils and underdrain discharge. Model results were evaluated against field data collected over 10 storm events. Simulated flows were particularly sensitive to antecedent water content and drainage parameters of bioretention soils, which were calibrated through an optimisation algorithm. Temporal disparity was observed between simulated and measured flows, which was attributed to preferential flow paths formed within the soil matrix of the field system. Modelling results suggest that soil water storage is the most important short-term hydrologic process in bioretention, with exfiltration having the potential to be significant in native soils with sufficient permeability.

Composition and uses of anaerobic digestion derived biogas from wastewater treatment facilities in North America.

A study was conducted to determine the current knowledge of biogas production and its use at municipal wastewater treatment plants (WWTPs) across North America. Information was provided by municipal WWTPs across Canada and the US. It was determined that hydrogen sulfide (H2S) and silicon (Si) compounds had sufficient variability to be of concern. The only biogas production trend that could be identified was a possible seasonal relationship with sludge input and biogas production. Secondary analysis was performed to observe trends in biogas usage in urban areas larger than 150,000 in the US and 50,000 in Canada; 66% of facilities had anaerobic digestion systems and, of those, only 35% had an energy recovery system. Climatic, population, and socio-political influences on the trends were considered. The primary conclusion was that more data is required to perform significant analyses on biogas production and composition variation.

Pathogen removal from domestic and swine wastewater by experimental constructed wetlands.

This study examined the performance of subsurface flow horizontal wetlands in total coliforms, faecal coliforms, enterococci and Salmonella removal from swine and domestic wastewaters. The effects of organic loading rate, contact time (CT) and the presence of aquatic macrophytes, Typha dominguensis and Typha latifolia, on treatment performance were evaluated. In general, chemical oxygen demand (COD) and total suspended solids (TSS) were reduced by 66 and 72% after 24 h and 75 and 84% after 48 h in domestic wastewaters, and 73 and 71% after 24 h and 72 and 78% after 48 h in swine wastewater. Total coliform and faecal coliform reductions of 70-83% and 65-78% were observed in the vegetated systems after 24 h of CT, while after 48 h, total coliform and faecal coliform reductions of 80-82% and 86-91% were noted.

Biogas production performance of mesophilic and thermophilic anaerobic co-digestion with fat, oil, and grease in semi-continuous flow digesters: effects of temperature, hydraulic retention time, and organic loading rate.

Anaerobic co-digestions with fat, oil, and grease (FOG) were investigated in semi-continuous flow digesters under various operating conditions. The effects of hydraulic retention times (HRTs) of 12 and 24 days, organic loading rates (OLRs) between 1.19 and 8.97 gTVS/Ld, and digestion temperatures of 37 degrees C and 55 degrees C on biogas production were evaluated. It was proposed that, compared to anaerobic digestion with wastewater treatment plant sludge (primary raw sludge), semi-continuous flow anaerobic co-digestion with FOG could effectively enhance biogas and methane production. Thermophilic (55 degrees C) co-digestions exhibited higher biogas production and degradation of organics than mesophilic co-digestions. The best biogas production rate of 17.4 +/- 0.86 L/d and methane content 67.9 +/- 1.46% was obtained with a thermophilic co-digestion at HRT = 24 days and OLR = 2.43 +/- 0.15 g TVS/Ld. These were 32.8% and 7.10% higher than the respective values from the mesophilic co-digestion under similar operating conditions.

A mechanism for NaCl inhibition of Reactive Blue 19 decolorization and ABTS oxidation by laccase.

Laccases produced by white rot fungi have been extensively evaluated for their potential to decolorize textile wastewaters which contain salts like sodium chloride and sodium sulfate. The effect of sodium chloride and sodium sulfate on Trametes versicolor laccase during the decolorization of an anthraquinone dye (Reactive Blue 19) and the oxidation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) were evaluated by steady-state kinetic analysis. The results showed that, while sodium sulfate did not affect laccase activity, sodium chloride inhibited both ABTS oxidation and dye decolorization. However, the type of inhibition was substrate-dependent: it was hyperbolic, noncompetitive with ABTS and parabolic, noncompetitive with Reactive Blue 19. Furthermore, the results suggested that two chlorides may bind to laccase in the presence of the dye unlike recent inhibition models which suggest that there is only one inhibition site. This investigation is the first to provide evidence for and to propose a two-site model of laccase inhibition, providing new insight into NaCl inhibition of laccase. The proposed model is also useful to predict decolorization rates in the presence of sodium chloride and to determine operating conditions that will minimize inhibition.

Mn(II), Cu(II) and Cd(II) p-coumarates: FT-IR, FT-Raman, ¹H and ¹³C NMR and thermogravimetric studies.

Manganese(II), copper(II) and cadmium(II) complexes of p-coumaric acid (p-hydroxycinnamic acid) were synthesized. Their composition was established by means of elementary and thermogravimetric analysis. To study the molecular structure of synthesized compounds many miscellaneous analytical methods, which complement one another, were used: infrared (FT-IR), Raman (FT-Raman) and nuclear magnetic resonance ((1)H, (13)C NMR). The spectroscopic studies lead to conclusions concerning the distribution of the electronic charge in complexes in comparison with p-coumaric acid molecule and the type of metal ion coordination.

Dye decolorization and detoxification by laccase immobilized on porous glass beads.

The decolorization and detoxification of textile dyes by fungal laccase immobilized on porous glass beads were evaluated. Anthraquinone (Reactive blue 19 and Dispersed blue 3) and indigoid (Acid blue 74) dyes were degraded more rapidly than the azo dyes (Acid red 27 and Reactive black 5). There was no dye sorption to the enzyme bed when decolorization rates were high (>12 microM dye/U-h) but at moderate rates (8 to>0.06 microM/U-h), there was a transient color which disappeared upon prolonged exposure. With Reactive black 5, permanent adsorption occurred most likely because laccase had been totally inactivated. Although laccase treatment was more efficient at decolorizing the anthraquinone dyes, their toxicity (as determined by the Microtox assay) increased while the less efficiently decolorized solutions of azo and indigoid dyes became less toxic. These results demonstrate the potential and limitations of using immobilized laccase to enzymatically decolorize a range of different dye classes and reduce dye toxicity in a single step.

Hydraulic performance of a mature wetland treating milkhouse wastewater and agricultural runoff.

A tracer study is an efficient method of determining flow dynamics within a constructed wetland. In previous studies, a number of tracer studies have been carried out on various constructed wetlands covering a wide range of configurations. From these tracer studies it is evident that all constructed wetlands perform differently and generally with less efficiency than assumed by theoretical design computations. During the summer of 2004, a tracer study was performed on a constructed wetland located in Embrun, Ontario (Canada) treating milkhouse wastewater and agricultural runoff to determine its actual hydraulic performance. Sediment height and vegetation density profiles were also obtained and examined to explain the preferential flow pathways that were observed during the tracer analysis. It was determined that the constructed wetland had an effective treatment area representing 79% of the total area, and that the hydraulic efficiency of the system was 74%. Examination of the sediment height and vegetation density profiles resulted in no evidence of physical pathways that could be attributed to the establishment of preferential flow. The hydraulic efficiency was therefore attributed to the inflow and outflow layout of the constructed wetland cell, combined with wind induced mixing.

Reactive blue 19 decolouration by laccase immobilized on silica beads.

Laccase (31.5 U of activity/g or 4.39 mug of protein/m(2)) from Trametes versicolor was immobilized on controlled-porosity-carrier silica beads and evaluated for the decolouration of Reactive blue 19, an anthraquinone dye. Although there was an initial, rapid adsorption of the dye to the packed bed in a recirculating reactor, about 97.5% of Reactive blue 19 removal was due to enzymatic degradation. The free enzyme lost 52% of its activity in 48 h. However, the activity of the immobilized laccase was unchanged after 4 months of storage in phosphate buffer under ambient conditions followed by three successive decolourations over 120 h. Treating the laccase immobilized beads with ethanolamine reduced dye adsorption by 40%.

Neovastat (AE-941) in refractory renal cell carcinoma patients: report of a phase II trial with two dose levels.

BACKGROUND: renal cell carcinoma (RCC) is a potential target for anti-angiogenic drugs because of its high vascularization. Neovastat (AE-941) is an inhibitor of angiogenesis with a mechanism of action that could prove beneficial in the treatment of RCC. Patients and design A phase II trial was conducted to identify the long-term safety profile of Neovastat in advanced cancer patients and to obtain preliminary information on its efficacy in solid tumors refractory to standard treatments. Neovastat (60 or 240 ml/day) was administered orally (b.i.d.) to 144 patients with solid tumors refractory to standard therapies or for whom no standard treatments were available. RESULTS: A survival analysis was conducted on 22 patients with a primary diagnosis of refractory RCC to determine whether the dose of Neovastat had any effect. A significant relationship between dose and survival was observed; the median survival time was significantly longer (16.3 versus 7.1 months; P = 0.01) in patients treated with Neovastat 240 ml/day (n = 14) compared with patients receiving 60 ml/day (n = 8). No dose-limiting toxicity was reported. The most frequent adverse event was taste alteration (13.6%). CONCLUSIONS: Neovastat is well tolerated by advanced cancer patients at doses of 60 and 240 ml/day. The higher dose of Neovastat administered in this trial is associated with a survival benefit in RCC, which is not explained by differences in major prognostic factors.

Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials.

Recent studies have indicated that bone marrow angiogenesis is increased in multiple myeloma, suggesting that treatment with an antiangiogenic agent might be useful. Among the new antiangiogenic drugs in development, Neovastat (AE-941; Aeterna Laboratories, Quebec City, Canada) can be classified as a naturally occurring multifunctional antiangiogenic agent. It has a marked inhibitory effect on the formation of blood vessels in the chicken embryo vascularization assay (EVT) and endothelial cell proliferation. Furthermore, in vivo experiments showed that oral administration of Neovastat blocks the formation of blood vessels in Matrigel implants containing basic fibroblast growth factor (bFGF). The antiangiogenic activity of Neovastat was found to be associated with two mechanisms of action. In addition to the inhibition of the matrix metalloproteinase activities (MMP-2, MMP-9, and MMP-12), Neovastat inhibits vascular endothelial growth factor (VEGF) binding to endothelial cells, VEGF-dependent tyrosine phosphorylation, and VEGF-induced vascular permeability in mice. Neovastat was also found to have a significant antitumor activity. Oral administration of Neovastat in mice with subcutaneous grafted breast cancer (DA3) cells showed a significant reduction in tumor volume. Neovastat also decreased the number of lung metastases in the Lewis lung carcinoma model. Interestingly, the effect of Neovastat was additive to cisplatin in this model. Furthermore, no treatment-related mortality or loss of body weight was observed. Also, toxicology studies in rats and monkeys demonstrate no dose-limiting toxicity or target organ damage after 1 year of chronic exposure, thus suggesting that Neovastat could be safely administered in humans. Four clinical studies have been conducted to establish the dosing, safety, and early efficacy of Neovastat administered orally. In the oncology field, 482 patients have received Neovastat, of which 146 with solid tumors were exposed to the drug for more than 6 months. Two phase III clinical trials are currently underway. A phase III double-blind placebo-controlled study is being conducted to evaluate the efficacy of Neovastat in addition to induction chemotherapy/radiotherapy combined modality treatment in patients with unresectable non-small cell lung cancer stage IIIA and IIIB. A second phase III randomized, double-blind placebo-controlled study evaluates the efficacy of Neovastat as a monotherapy in metastatic renal cell carcinoma patients who have progressed following a first-line immunotherapy. Neovastat efficacy is also being evaluated in a registration phase II trial in patients with early relapse or refractory multiple myeloma.

Skewed maturation of memory HIV-specific CD8 T lymphocytes.

Understanding the lineage differentiation of memory T cells is a central question in immunology. We investigated this issue by analysing the expression of the chemokine receptor CCR7, which defines distinct subsets of naive and memory T lymphocytes with different homing and effector capacities and antiviral immune responses to HIV and cytomegalovirus. Ex vivo analysis of the expression of CD45RA and CCR7 antigens, together with in vitro analysis of the cell-division capacity of different memory CD8+ T-cell populations, identified four subsets of HIV- and CMV-specific CD8+ T lymphocytes, and indicated the following lineage differentiation pattern: CD45RA+ CCR7+ --> CD45RA- CCR7+ --> CD45RA- CCR7- --> CD45RA+ CCR7-. Here we demonstrate through analysis of cell division (predominantly restricted to the CCR7+ CD8+ T-cell subsets) that the differentiation of antigen-specific CD8+ T cells is a two-step process characterized initially by a phase of proliferation largely restricted to the CCR7+ CD8+ cell subsets, followed by a phase of functional maturation encompassing the CCR7- CD8+ cell subsets. The distribution of these populations in HIV- and CMV-specific CD8+ T cells showed that the HIV-specific cell pool was predominantly (70%) composed of pre-terminally differentiated CD45RA- CCR7- cells, whereas the CMV-specific cell pool consisted mainly (50%) of the terminally differentiated CD45RA+ CCR7- cells. These results demonstrate a skewed maturation of HIV-specific memory CD8+ T cells during HIV infection.

Learning to remember: generation and maintenance of T-cell memory.

Immunologic memory results from a carefully coordinated interplay between cells of the immune system. In this review, we explore various aspects of the nature, generation, and maintenance of T lymphocyte-mediated immunologic memory. In light of the demonstrated heterogeneity of the memory T-cell pool, we hypothesize that subsets of memory T cells instructed to mature to distinct differentiation stages may differ, not only in functional and homing properties, but also in the conditions they require for survival, including antigen persistence and cytokine environment. Hence, according to this hypothesis, distinct memory T-cell subsets result from the nature and timing of the signals provided by the immune environment and occupy distinct niches. Intracellular and extracellular molecular mechanisms that underlie and modulate T-cell memory are discussed.

Generation and characterization of malaria-specific human CD8(+) lymphocyte clones: effect of natural polymorphism on T cell recognition and endogenous cognate antigen presentationby liver cells.

CD8(+) cytolytic T lymphocytes (CTL) play a fundamental role in the clearance of malaria parasites from the liver in mouse models. In humans, however, only low levels of parasite-specific CD8(+) T lymphocytes have been observed in individuals living in endemic areas. In the present study, we identified high levels of circulating CD8(+) T lymphocytes specific for a previously described HLA-A2-restricted CTL epitope of the circumsporozoite (CS) protein of Plasmodium falciparum in an adult living in Burkina Faso, as evidenced by IFN-gamma ELISPOT assay and MHC-tetramer technology. After cloning by limiting dilution culture, T cell recognition of natural CS variants of P. falciparum was studied. The results demonstrate that naturally occurring variations drastically affect residues critical for T cell recognition as only two out of nine sequences analyzed were efficiently recognized by the CTL clones. These clones were also used to analyze T cell recognition of the endogenously presented cognate antigen. We observed efficient antigen recognition of both HLA-A*0201-transfected murine antigen presenting cells and liver cells from HLA-A*0201/K(b)-transgenic mice upon infection with recombinant vaccinia virus encoding the CS protein (WR-CS). More importantly, we demonstrate for the first time efficient recognition of WR-CS-infected human liver cells.

Naturally occurring human lymphocyte antigen-A2 restricted CD8+ T-cell response to the cancer testis antigen NY-ESO-1 in melanoma patients.

Cancer testis (CT) antigens are particularly interesting candidates for cancer vaccines. However, T-cell reactivity to CT antigens has been detected only occasionally in cancer patients, even after vaccination. A new group of CT antigens has been recently identified using the SEREX technique based on immunoscreening of tumor cDNA expression libraries with autologous sera. We have used fluorescent HLA-A2/peptide tetramers containing an optimized antigenic peptide to directly identify HLA-A2-restricted CD8+ T cells specific for the SEREX-defined CT antigen NY-ESO-1 in melanoma patients. High frequencies of NY-ESO-1-specific CD8+ T cells were readily detected in peptide-stimulated peripheral blood mononuclear cells as well as in lymphocytes infiltrating melanoma lesions from patients with measurable antibody responses to NY-ESO-1. NY-ESO-1-specific CD8+ T cells were also detectable in peptide-stimulated peripheral blood mononuclear cells from some seronegative patients. Whereas the frequencies of NY-ESO-1-specific CD8+ T cells in circulating lymphocytes were usually below the limit of detection by tetramer staining, the presence of NY-ESO-1 CD8+ T cells displaying a memory phenotype was clearly detectable ex vivo in blood from a seropositive patient over an extended period of time. These results indicate that sustained CD8+ T-cell responses to CT antigens can naturally occur both locally and systemically in melanoma patients.

Transient T cell receptor beta-chain variable region-specific expansions of CD4+ and CD8+ T cells during the early phase of pediatric human immunodeficiency virus infection: characterization of expanded cell populations by T cell receptor phenotyping.

T cell receptor (TCR) repertoire perturbations are commonly detected in CD8+ T cells during adult primary human immunodeficiency virus (HIV) infection and have been associated with HIV-specific cytotoxic T cell responses. By use of flow cytometry, transient high-level TCR beta-chain variable region-specific expansions of CD4+ and CD8+ T cells were observed more frequently in HIV-infected children than in children exposed to HIV who remained uninfected. TCR beta-chain diversity analysis and diversity-specific polymerase chain reaction were used to study the clonality of expanded CD4+ and CD8+ subsets. In CD8+ T cells, structural features of the complement-determining regions 3 were altered during the course of the expansion, and persistent TCR clonotypes were observed, consistent with antigen-driven selection. In contrast, TCR beta-chain variable region-specific expansions without clonotypic overrepresentation or persistence were observed in CD4+ T cells, possibly related to HIV-specific helper T cell responses or to the progressive destruction of the CD4+ cell compartment.