Biorefinery potential of sustainable municipal wastewater treatment using fast-growing willow.

The use of willow plantations can be a sustainable approach for treating primary municipal wastewater, potentially reducing both the environmental and economic burdens associated with conventional treatment. However, the impact of wastewater irrigation upon the willow biorefinery potential has not yet been established. To investigate this effect, three-year-old field grown willows were harvested from plots kept as either controls or irrigated with primary municipal wastewater effluent at 29.5 million L ha-1 yr-1. Biomass compositional analysis, ionic liquid pretreatment and enzymatic saccharification were assessed and differential abundance of persistent extractable phytochemicals was evaluated using untargeted metabolite profiling. Glucan significantly increased by 8% in wastewater treated trees, arabinose and galactose were significantly decreased by 8 and 29%, respectively, while xylose, mannose and lignin content were unaltered. Ionic liquid pretreatment and enzymatic saccharification efficiencies did not vary significantly, releasing >95% of the cell wall glucose and recovering 35% of the lignin. From a total of 213 phytochemical features, 83 were significantly depleted and 14 were significantly enriched due to wastewater irrigation, including flavonoids and lignan derivatives. Considered alongside increased biomass yield from wastewater irrigation (+200%), lignocellulosic bioenergy yields increased to 8.87 t glucose ha-1 yr-1 and 1.89 t ha-1 yr-1 recovered lignin, while net extractives yields increased to 1.48 t ha-1 yr-1, including phytochemicals of interest. The maintenance of glucose accessibility after low-cost ionic liquid pretreatment is promising evidence that sustainable lignocellulose bioenergy production can complement wastewater treatment. Untargeted metabolite assessment revealed some of the phytochemical toolkit employed by wastewater irrigated willows, including accumulation of flooding and salinity tolerance associated flavonoids glabraoside A and glabrene. The extractable phytochemicals underpin a novel high biomass phenotype in willow and, alongside lignocellulosic yields, could help enhance the economic feasibility of this clean wastewater treatment biotechnology through integration with sustainable biorefinery.

Embolisation of symptomatic pelvic veins in women presenting with non-saphenous varicose veins of pelvic origin - three-year follow-up.

AIM: To evaluate the clinical results of embolisation of symptomatic, incompetent pelvic veins in women presenting with perineal veins. PATIENTS AND METHODS: Twenty-four women presenting with non-saphenous perineal varicose veins and who experienced pelvic vein syndrome were treated. Symptoms was scored on a visual analogue scale assessing dyspareunia, pelvic and lower limb pain. Lower limb varices were investigated by duplex ultrasonography. Pelvic veins were studied by pelvic vein angiography with simultaneous embolisation of incompetent veins. Ovarian and internal iliac veins were systematically embolised when incompetent. Follow-up assessment of symptoms and varices was carried out at 1, 2 and 3 years. RESULTS: All patients presented with perineal veins, 2 with sciatic vein incompetence and 2 with a perforator of the thigh or buttock. Pelvic venous angiography was performed via right femoral access in 87% of the cases and confirmed the presence of incompetent ovarian and internal iliac veins. The mean number of coils used per vein was 6 and all were successfully embolised. No serious complications were encountered. The mean clinical improvement score was 80%, 77%, 80% and 76% at respectively 45 days, 1, 2 and 3-year follow-up. CONCLUSION: In women of reproductive age, non-saphenous varicose veins associated with pelvic venous incompetence (PVI) should undergo pelvic vein investigation. In this clinical series we achieved a satisfactory improvement in symptoms after 3 years following treatment of incompetent pelvic veins.

ZM323881, a novel inhibitor of vascular endothelial growth factor-receptor-2 tyrosine kinase activity.

OBJECTIVE: Vascular endothelial growth factor (VEGF) increases vascular permeability and angiogenesis in many pathological conditions including cancer, arthritis, and diabetes. VEGF activates VEGF-Receptor 1(VEGF-R1) and VEGF-Receptor 2 (VEGF-R2), which autophosphorylate to initiate a signaling cascade resulting in angiogenesis and increased microvascular permeability. Here we describe a novel VEGF-R2 selective inhibitor, ZM323881 (5-[[7-(benzyloxy) quinazolin-4-yl]amino]-4-fluoro-2-methylphenol), that is a potent and selective inhibitor of VEGF-R2 tyrosine kinase in vitro (IC(50) < 2 nM), compared with other receptor tyrosine kinases, including VEGF-R1 (IC(50) > 50 microM). METHODS: Endothelial cell proliferation was assayed by (3)H-thymidine incorporation in response to VEGF-A +/- ZM323881. The effect of ZM323881 on VEGF-mediated permeability was measured in frog microvessels using the Landis Michel technique. To ensure that ZM323881 was effective in frogs, western analysis was performed on protein extracted from frog lungs incubated in the presence or absence of VEGF-A or VEGF-A with ZM323881. RESULTS: ZM323881 inhibits VEGF-A-induced endothelial cell proliferation (IC(50) = 8 nM) and VEGF-R2 tyrosine phosphorylation in vitro. VEGF-A-mediated increases in vascular permeability in perfused mesenteric microvessels in vivo were reversibly abolished by both ZM323881 and the class III receptor tyrosine kinase inhibitor PTK787/ZK222584. CONCLUSIONS: These data suggest that VEGF-R2 phosphorylation is necessary for VEGF-A-mediated increases in microvascular permeability in vivo.

ZD4190: an orally active inhibitor of vascular endothelial growth factor signaling with broad-spectrum antitumor efficacy.

There is evidence that vascular endothelial growth factor (VEGF) contributes to solid tumor growth through the promotion of both angiogenesis and tumor vascular permeability. To abrogate VEGF signaling, we developed a small molecular weight inhibitor of VEGF receptor tyrosine kinase (RTK) activity that was compatible with chronic oral administration. ZD4190, a substituted 4-anilinoquinazoline, is a potent inhibitor of KDR and Flt-1 RTK activity, and VEGF stimulated HUVEC proliferation in vitro. Chronic once-daily oral dosing of ZD4190 to young rats produced a dose-dependent increase in the femoral epiphyseal growth plate area, which may be attributed to the inhibition of VEGF signaling in vivo because vascular invasion of cartilage is a prerequisite to the process of ossification. Once-daily oral dosing of ZD4190 to mice bearing established (approximately 0.5 cm3) human tumor xenografts (breast, lung, prostate, and ovarian) elicited significant antitumor activity and at doses that would not be expected to have any direct antiproliferative effect on tumor cells. Prolonged tumor cytostasis was further demonstrated in a PC-3 xenograft model with 10 weeks of ZD4190 dosing, and upon withdrawal of therapy, tumor growth resumed after a short delay. These observations are entirely consistent with the proposed mode of action. ZD4190 is one of a series of VEGF RTK inhibitors that may have utility in the treatment of a range of histologically diverse solid tumor types.

Design and synthesis of potent non-polyglutamatable quinazoline antifolate thymidylate synthase inhibitors.

The synthesis is described of a series of analogues of the potent thymidylate synthase (TS) inhibitor, N-[4-[N-[(3,4-dihydro-2, 7-dimethyl-4-oxo-6-quinazolinyl)methyl]-N-prop-2-ynylamino]-2-f luorob enzoyl]-L-glutamic acid (4, ZM214888), in which the glutamic acid moiety is replaced by homologous amino acids and alpha-amino acids where the omega-carboxylate is replaced by acylsulfonamides and acidic heterocycles. In general these modifications when compared to 4 gave compounds with increased potency as inhibitors of isolated TS and as cytotoxic agents against murine tumor cell lines. The new compounds require transport by the reduced folate carrier for entry into cells but are not converted intracellularly into polyglutamated species. Agents with this profile are expected to show activity against tumors that are resistant to classical antifolates due to low expression of folylpolyglutamate synthetase. The analogue (S)-2-[4-[N-[(3,4-dihydro-2, 7-dimethyl-4-oxo-6-quinazolinyl)methyl]-N-prop-2-ynylamino]-2-f luorob enzamido]-4-(1H-1,2,3,4-tetrazol-5-yl)butyric acid (35, ZD9331) has been selected as a clinical development candidate and is currently undergoing phase I studies.

Design and structure-activity relationship of a new class of potent VEGF receptor tyrosine kinase inhibitors.

A series of substituted 4-anilinoquinazolines and related compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt and KDR) tyrosine kinase activity. Enzyme screening indicated that a narrow structure-activity relationship (SAR) existed for the bicyclic ring system, with quinazolines, quinolines, and cinnolines having activity and with quinazolines and quinolines generally being preferred. Substitution of the aniline was investigated and clearly indicated that small lipophilic substituents such as halogens or methyl were preferred at the C-4' position. Small substituents such as hydrogen and fluorine are preferred at the C-2' position. Introduction of a hydroxyl group at the meta position of the aniline produced the most potent inhibitors of Flt and KDR tyrosine kinases activity with IC(50) values in the nanomolar range (e.g. 10, 12, 13, 16, and 18). Investigation of the quinazoline C-6 and C-7 positions indicates that a large range of substituents are tolerated at C-7, whereas variation at the C-6 is more restricted. At C-7, neutral, basic, and heteroaromatic side chains led to very potent compounds, as illustrated by the methoxyethoxy derivative 13 (IC(50) < 2 nM). Our inhibitors proved to be very selective inhibitors of Flt and KDR tyrosine kinase activity when compared to that associated with the FGF receptor (50- to 3800-fold). Observed enzyme profiles translated well with respect to potency and selectivity for inhibition of growth factor stimulated proliferation of human umbilical vein endothelial cells (HUVECs). Oral administration of selected compounds to mice produced total plasma levels 6 h after dosing of between 3 and 49 microM. In vivo efficacy was demonstrated in a rat uterine oedema assay where significant activity was achieved at 60 mg/kg with the meta hydroxy anilinoquinazoline 10. Inhibition of growth of human tumors in athymic mice has also been demonstrated: compound 34 inhibited the growth of established Calu-6 lung carcinoma xenograft by 75% (P < 0.001, one tailed t-test) following daily oral administration of 100 mg/kg for 21 days.

[Prognostic factors of Pneumocystis carinii pneumonia in AIDS]. / Facteurs pronostiques de la pneumocystose au cours du SIDA.

OBJECTIVES: Identify prognosis factors in Pneumocystis carinii pneumonia at diagnosis and construct a model to predict mortality according to these prognosis factors. METHODS: Seventy-seven consecutive cases of proven AIDS-related Pneumocystis carinii pneumonia (67 men, 10 women, mean age 37.2 years) were reviewed to determine the most accurate initial prognostic factors and estimate an individual prediction of death. A stepwise logistic regression analysis was performed. Three kinds of data were entered into the logistic model: historical data, clinical and laboratory data obtained within the first 24 hours of diagnosis, and specific data related to chest X-ray and bronchoalveolar lavage results. RESULTS: The sum of arterial partial pressure of oxygen and carbon dioxide (PaO2 + PaCO2) and serum albumin level best predicted a fatal outcome in multivariate analysis. CONCLUSION: The logistic equation provided by the model might be used to accurately and quickly identify the patients with severe Pneumocystis carinii pneumonia who might benefit from supportive intensive care.

Quinazoline antifolates thymidylate synthase inhibitors: lipophilic analogues with modification to the C2-methyl substituent.

Modification of the potent thymidylate synthase (TS) inhibitor 1-[[N-[4-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]-N- prop-2-ynylamino]benzoyl]amino]methyl]-3-nitrobenzene (4a) has led to the synthesis of quinazolinone antifolates bearing functionalized alkyl substituents at C2. A general synthetic route was developed which involved coupling the appropriate 1-[[N-[4-(alkylamino)benzoyl)amino]methyl]-3-nitrobenzene 20-22 with a 6-(bromomethyl)-2-(acetoxymethyl)-3,4-dihydro-4-oxoquinazoline 9 or 10. Replacement of the 2-acetoxy group by a chlorine atom followed by the displacement of the halogen of 25a-c by various nucleophiles led to compounds 26-40. Good TS (IC50 < 1 microM) and growth inhibition (IC50 0.1-1 microM) were found with most of these new antifolates. TS inhibitors in this series do not apparently require the reduced folate carrier (RFC) for cell entry (they most likely penetrate the cell membrane by passive diffusion) and are not polyglutamated. N, O, S, Cl, and CN as well as large amino and mercapto substituents were tolerated by the enzyme. The simultaneous incorporation of 7-methyl and 2'-F substituents gave a series of highly potent agents inhibiting cell growth at concentrations < 1 microM (24, 27bc; 30-32b, 35b). The incorporation of suitable C2 substituents has overcome the decrease in aqueous solubility observed with lipophilic quinazoline antifolates. This is best illustrated by compound 31a, where up to a 54-fold increase in solubility has been achieved by the incorporation of an N-methylpiperazine nucleus into the C2-methyl group of 4a.

Superior vena cava stent placement: results with the Wallstent endoprosthesis.

PURPOSE: To assess the clinical success and short-term patency of the Wallstent endoprosthesis in the treatment of superior vena cava (SVC) syndrome. MATERIALS AND METHODS: Twenty-one 14-mm-diameter endoprostheses were implanted in 15 patients (mean age, 60 years) treated for SVC syndrome due to malignant compression (n = 14) or postirradiation fibrotic stenosis (n = 1) of the SVC. RESULTS: Immediate technical success was achieved in all patients. Two early complications occurred: retroperitoneal hemorrhage due to venous iliac tear and early stent thrombosis. In the 14 patients without early stent occlusion, stent placement resulted in complete relief of SVC syndrome; clinical success was 93%. SVC syndrome did not recur from 1 to 14 months, until the patient died (n = 11) or until the end of the study (n = 3). Helical CT showed a patent stent in five patients, respectively, at 3, 6, 8, 10, and 11 months. CONCLUSION: SVC stent placement has good clinical results and a high patency rate at short-term follow-up in patients with SVC syndrome.

Renal artery stent placement: long-term results with the Wallstent endoprosthesis.

PURPOSE: To evaluate clinical success and long-term patency of a Wallstent in the renal artery. MATERIALS AND METHODS: Twenty-five Wallstents were placed in 21 patients to treat delayed restenosis after previous balloon angioplasty (n = 13) or inadequate immediate postangioplasty response (n = 8). Indications for angioplasty were hypertension in all patients and renal preservation in seven. Stenosis was atheromatous in 15 patients, involving ostium in seven. RESULTS: Stent placement was successful in all patients. At follow-up angiography (range, 12-60 months), four patients (20%) had stent restenosis. Of these, three had undergone treatment for restenosis after angioplasty and three had ostial lesions. Cumulative primary patency rate was 95%, 85%, and 77% at 7, 9, and 15 months, respectively. Hypertension was cured in three patients and improved in 18. CONCLUSION: Arterial stent placement has good clinical results and high long-term patency rates after conventional renal angiography or delayed restenosis, especially in ostial lesions.

[Techniques and complications of interventional radiology in vascular diseases of transplanted kidneys]. / Techniques et complications de la radiologie interventionnelle des affections vasculaires des reins transplantés.

The authors present a general review on the various techniques of interventional radiology in the treatment of vascular complications of renal transplants. Arterial stenosis require generally percutaneous transluminal angioplasty; arterial stenting is justified in cases of multiple restenosis and occluding dissection. Arterial thrombosis is treated by fibrinolysis or clot aspiration. Treatment of venous complications, such as stenosis or thrombosis, require analogous methods. Arterio-venous fistula and arterial aneurysms due to renal biopsy can be obliterated by dissection with a guide wire, or dropping of metallic coils, or electrical embolization. The authors emphasize the technical aspects, the difficulties and the complications of these procedures. The most frequent complication is the spasm of the renal transplant artery, which may lead to thrombosis. Arterial wall rupture and dissections are very rare. Hematoma at the puncture site of the arterial access are frequent; they may lead to false aneurysm, which can be treated also by noninvasive methods of interventional radiology.

Synthesis and biological activity of C-3' ortho dihydroxyphthalimido cephalosporins.

A series of C-3' ortho dihydroxyphthalimido cephalosporins 3-7 has been prepared by reaction of C-3' aminomethyl cephalosporin 41 with the corresponding N-carboethoxyphthalimides 23-25, 37, 38. These new cephalosporins exhibit excellent in vitro Gram-negative activities, including Pseudomonas aeruginosa, excellent beta-lactamases stability and pharmacokinetics equivalent or better than ceftriaxone.

[Absence of mitral valve prolapse during panic attacks induced by sodium lactate]. / Absence de prolapsus mitral au cours d'attaques de panique provoquées par lactate de sodium.

The recent identification of a new type of anxiety state, panic attack, has drawn attention to common pathways between panic disorder and cardiac somatization, particularly mitral valve collapse. A double-blind study was set up, using doppler-echocardiography during a panic attack induced by sodium lactate infusion. The results showed that there was no relationship between panic attack and mitral valve collapse, and that the lactate infusion-anxiety rate was only 35 percent.

[Viral pneumopathies after heart transplantation. Radioclinical analysis]. / Pneumopathies virales après transplantation cardiaque. Analyse radioclinique.

From a retrospective study of 80 cases of heart transplantation, the contribution of chest X-rays to the diagnosis of viral pneumonia was studied. Among 66 episodes of pneumonia, a viral cause was proved in 16 cases (CMV: 9, Herpes: 7), with 13 cases during the first 4 months. CMV pneumonia was revealed in 3 cases by a diffuse pulmonary infiltrate with a rapidity fatal outcome and in 6 cases by focal infiltrates that disappeared within 1 and 7 weeks. Herpes pneumonia was immediately revealed, in 5 cases, by a diffuse infiltrate. In 11 out of 16 cases, the viral pneumonia improved but its course was complicated by the development of another pneumonia.

[Imaging of cervical and thoracic chordoma. Apropos of 2 cases]. / Imagerie des chordomes cervicaux et thoraciques. A propos de 2 observations.

Chordoma is a rare tumor in spine. Two cases, exceptional in adolescents, are reported. The clinical evolution is slow and progressive. CT shows a lobulated tumor, precises the degree of vertebral osteolysis and detects intra-tumoral calcifications. MRI is useful to determine especially in high in soft tissues and the vertebral canal. Arteriography is realised in pre-operative time and permits an embolization when the tumor is hypervascularised.

Improved subtraction technique in intravenous digital left ventriculography: comparison with radionuclide studies.

Adequate processing of left ventricular angiograms depends on the visualisation of all segments of the ventricular wall. At the same time, subtraction of different images can enhance different heart segments but commercially available methods do not allow simultaneous viewing of several images masked by different processes. Using our software, for each studied frame, a four quadrant display permits the simultaneous visualisation of a mask mode image, a diastolic-systolic difference image, an image obtained by subtraction of a frame at the same cycle time and a composite mask subtracted image. The composite mask image is obtained by weighting three images according to videodensitometric measurements by reference to previously acquired data. This method facilitates contour delineation and computation of the ejection fraction by area-length method. Correlation with radionuclide estimates of left ventricular ejection fraction is higher (n = 60, r = 0.90, SEE = 8%) than using the classical mask mode display (n = 60, r = 0.82, SEE = 11%). In a subgroup of 30 patients the contrast medium was injected in an antecubital vein and the correlation coefficient remained satisfactory (n = 30, r = 0.89, SEE = 7%) when compared with the classical subtraction technique (n = 30, r = 0.70, SEE = 12%). We therefore conclude that the composite mask method gives comparatively similar values for left ventricular ejection fraction to those acquired by radionuclide angiography.

[Value of digital subtraction of left ventriculographies by the venous route. Comparison with balanced scintigraphy of the heart cavities]. / Intérêt de la numérisation des ventriculographies gauches par voie veineuse. Comparison avec la scintigraphie des cavités à l'équilibre.

The development of numerisation material in radiology currently permits to perform usual cardiovascular tests. The authors report a series of 48 patients who benefited from the determination by numerised left ventriculography, of their stroke volume (SV). In 37 cases, the peripheral venous route is used while in 11 cases the central venous route is used, in the pulmonary artery trunk. The SV values obtained with both methods (one advocated by the manufacture and another one developed by the authors), are correlated with the SV values obtained with the isotopic method, used as reference. The correlations are satisfactory, approximately 0.79 for all patients of the study, and markedly improve when the injection of the contrast material is performed in the pulmonary artery (approximately 0.95). The authors conclude that determination of the left ventricle SV by numerisation is an interesting technique in centers where there is no department of nuclear medicine, and is absolutely necessary to complement right catheterisation.