Re-thinking sludge management within the Sustainable Development Goal 6.2.

Sustainable Development Goal 6.2 of the Agenda 2030 is addressed to achieve access to adequate and equitable sanitation and hygiene for all. Further, one of the major principles underlying the Lisbon Charter is that sustainable and safe management of wastewaters are fundamental to the health of communities and their sustainable socio-economic development. Within this framework, the management of sewage sludge in a sustainable manner is one of the critical issues facing modern society, due to the growing rise of its production, increasing difficulties in properly locating treatment and disposal works, and complying with more stringent environmental quality requirements, thus requiring a re-thinking of its management. This paper discusses major concepts and principles for re-thinking the sludge management in order to achieve the above-mentioned objectives.

Second-line nivolumab in relapsed small-cell lung cancer: CheckMate 331☆.

BACKGROUND: Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC. PATIENTS AND METHODS: CheckMate 331 is a randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS). RESULTS: Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy [median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P = 0.11]. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase ≤ upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score ≥1% versus <1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%. CONCLUSION: Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.

Temperature Mediated Morphological Transition during Drying of Spray Colloidal Droplets.

Understanding how a tiny dilute evaporative colloidal spray droplet gets transformed into a microgranule with a characteristic morphology is crucial from scientific as well as technological points of view. In the present work, it is demonstrated that the morphology and the size distribution of the microcapsules can be tuned simply by adjusting the drying temperature. Shape and size of the capsules are quantified at four different drying temperatures. It is shown that the morphology transits gradually from sphere to toroid with increasing temperature keeping the average volume-fraction of the correlated nanoparticles nearly unaffected for the synthesized granules. A plausible mechanism for the chronological pathway of such morphological transformation is illustrated. Computer simulation corroborates the experimentally observed morphological transition. The variation in hollowness and buckling tendency of the capsules are elucidated by scattering and imaging techniques.

Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab.

Daratumumab is an anti-CD38 monoclonal antibody with lytic activity against multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity). Owing to a marked heterogeneity of response to daratumumab therapy in MM, we investigated determinants of the sensitivity of MM cells toward daratumumab-mediated ADCC and CDC. In bone marrow samples from 144 MM patients, we observed no difference in daratumumab-mediated lysis between newly diagnosed or relapsed/refractory patients. However, we discovered, next to an expected effect of effector (natural killer cells/monocytes) to target (MM cells) ratio on ADCC, a significant association between CD38 expression and daratumumab-mediated ADCC (127 patients), as well as CDC (56 patients). Similarly, experiments with isogenic MM cell lines expressing different levels of CD38 revealed that the level of CD38 expression is an important determinant of daratumumab-mediated ADCC and CDC. Importantly, all-trans retinoic acid (ATRA) increased CD38 expression levels but also reduced expression of the complement-inhibitory proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted in a significant enhancement of the activity of daratumumab in vitro and in a humanized MM mouse model as well. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients.

Commentary on Cochrane review of neuraminidase inhibitors for preventing and treating influenza in healthy adults and children.

In recent years there has been much debate and controversy surrounding the efficacy and safety of neuraminidase inhibitors for influenza, in part because the data underlying certain efficacy claims were not available for independent scrutiny. In 2014, a Cochrane review was published, based exclusively on an almost complete set of clinical study reports and other regulatory documents. Clinical study reports can run to thousands of pages, providing an extensive amount of information on the planning, conduct and results of each trial. After a protracted campaign to obtain the reports, the manufacturers of the medications provided them unconditionally. The review authors subsequently published the underlying documents simultaneously with the Cochrane review, endorsing the concept of open science. In the following commentary, the background to and results of this review are summarized and put into clinical context.

Nosocomial Herpes Encephalitis: rare but treatable with early MR diagnosis.

Nosocomial/hospital acquired herpes encephalitis is rare and is usually undiagnosed in its early phase because of the non-specific clinical picture and low level of clinical and neuroimaging suspicion. There is a paucity of data in radiology literature for this entity, specifically in the settings of surgery and trauma. We describe two cases of nosocomial herpes simplex encephalitis to demonstrate the imaging clues that might lead to an early diagnosis of this disease.

Bilateral subthalamic nucleus stimulation for Parkinson's disease.

UNLABELLED: High frequency stimulation of the subthalamic nucleus (STN) is known to ameliorate the signs and symptoms of advanced Parkinson's disease. AIM: We studied the effect of high frequency STN stimulation in 23 patients. METHOD: Twenty-three patients suffering from severe Parkinson's disease (Stages III-V on Hoehn and Yahr scale) and, particularly bradykinesia, rigidity, and levodopa-induced dyskinesias underwent bilateral implantation of electrodes in the STN. Preoperative and postoperative assessments of these patients at 1, 3, 6 and 12 months follow-up, in "on" and "off" drug conditions, was carried out using Unified Parkinson's Disease Rating Scale, Hoehn and Yahr staging, England activities of daily living score and video recordings. RESULTS: After one year of electrical stimulation of the STN, the patients' scores for activities of daily living and motor examination scores (Unified Parkinson's Disease Rating Scale parts II and III) off medication improved by 62% and 61% respectively (p<0.0005). The subscores for the akinesia, rigidity, tremor and gait also improved. (p<0.0005). The average levodopa dose decreased from 813 mg to 359 mg. The cognitive functions remained unchanged. Two patients developed device-related complications and two patients experienced abnormal weight gain. CONCLUSION: Bilateral subthalamic nucleus stimulation is an effective treatment for advanced Parkinson's disease. It reduces the severity of "off" phase symptoms, improves the axial symptoms and reduces levodopa requirements. The reduction in the levodopa dose is useful in controlling drug-induced dyskinesias.

The enhanced in vitro hematopoietic activity of leridistim, a chimeric dual G-CSF and IL-3 receptor agonist.

The in vitro activity of leridistim was characterized for cell proliferation, generation of colony-forming units (CFU) and differentiation of CD34+ cells. In AML-193.1.3 cells, leridistim exhibited a significant increase in potency compared to rhG-CSF, SC-65303 (an IL-3 receptor agonist) or an equimolar combination of rhG-CSF and SC-65303. CFU-GM assays demonstrated that at 50% of the maximum response, the relative potency of leridistim was 12-fold greater than the combination of rhG-CSF and rhIL-3 and 44-fold more potent than rhG-CSF alone. In multi-lineage CFU assays, a combination of erythropoietin (rhEPO) and leridistim resulted in greater numbers of BFU-E, CFU-GEMM and CFU-Mk than rhEPO alone. Ex vivo culture of peripheral blood or bone marrow CD34+ cells with leridistim substantially increased total viable cells over cultures stimulated with rhG-CSF, SC-65303, or a combination of rhG-CSF and SC-65303. Culture with leridistim, resulted in a greater increase in myeloid (CD15+/CD11b+), monocytic (CD41-/CD14+) and megakaryocytic (CD41+/CD14-) precursor cells without depleting the progenitor pool (CD34+/CD15-/CD11b-). These results demonstrate that leridistim is a more potent stimulator of hematopoietic proliferation and differentiation than the single receptor agonists (rhG-CSF and SC-65303) either alone or combined. These unique attributes suggest that leridistim may enhance hematopoietic reconstitution following myelosuppressive chemotherapy.

Extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways cooperate in mediating cytokine-induced proliferation of a leukemic cell line.

Granulocyte colony-stimulating factor (G-CSF) and fetal liver tyrosine kinase-3 (Flt3) ligand (FL) act in synergy to induce expansion and mobilization of hematopoietic progenitor cells. Regulation of mitogen activated protein (MAP) kinase pathways and gene transcription, induced by these cytokines were examined using the OCI-AML5 cell line. For this purpose, FL and G-CSF were used either alone, or in combination as the co-addition of FL and G-CSF (FL+G-CSF), or a chimeric molecule, progenipoietin-1 (ProGP-1). Both G-CSF and FL induced phosphorylation of extracellular signal-regulated kinases (ERKs) while p38 mitogen activated protein (MAP) kinase was phosphorylated only in response to G-CSF but not FL. Studies using specific kinase inhibitors suggested that both ERK and p38 MAP kinase pathways were required for the optimal cell proliferation in response to both G-CSF and FL. The magnitude of activation of the ERK pathway and induction of genes involved in cell cycle progression by G-CSF and FL exhibited a strong correlation with the degree of cell proliferation. These data suggest that OCI-AML5 cells proliferate at least in part, due to the activation of both ERK and p38 MAP kinase pathways in response to G-CSF and FL. This study represents the first report of the specific cell cycle genes induced by FL.

Promegapoietin, a family of chimeric growth factors, supports megakaryocyte development through activation of IL-3 and c-Mpl ligand signaling pathways.

OBJECTIVE: The signaling pathways induced by promegapoietin (PMP), a family of chimeric growth factors that activate the human IL-3 and c-Mpl receptors, were investigated. METHODS: The biological activity of PMP was examined by receptor binding, cell proliferation, ex vivo expansion of hematopoietic progenitor cells, and in vivo production of platelets. The activation of signaling pathways was examined by Western blot and Northern blot analyses. RESULTS: Two PMP molecules, PMP-1 and PMP-1a, induced proliferation of cells expressing the IL-3 receptor, c-Mpl, or both receptors and bound to the IL-3 receptor and c-Mpl with high affinity. Ex vivo expansion assays using human bone marrow CD34(+) cells suggested that PMP-1 induced greater total cellular expansion as well as expansion of CD41(+) megakaryocytic precursor cells than IL-3 or c-Mpl ligand alone. Subcutaneous administration of 50 microg/kg of PMP-1 for 10 days to rhesus monkeys resulted in increased platelet production in vivo from a baseline of 357 +/- 45 x 10(3) cells/mL to 1376 +/- 151 x 10(3) cell/mL. PMP-1 induced phosphorylation of the beta(c) subunit of IL-3 receptor and c-Mpl, JAK2, and STAT5b, but not STAT3. PMP-1 induced greater expression of Pim-1, c-Myc, and cyclin D2 than did either an IL-3 receptor agonist or c-Mpl receptor agonist alone. The magnitude of induction of early response genes was similar for PMP and the coaddition of IL-3 receptor agonist and c-Mpl receptor agonist. CONCLUSION: PMP combines the biological activities of IL-3 and c-Mpl ligand in a single molecule that can simultaneously activate signaling pathways induced by both these ligands.

Enhanced ability of daniplestim and myelopoietin-1 to suppress apoptosis in human hematopoietic cells.

Modified and chimeric cytokines have been developed to aid in the recovery of hematopoietic precursor cells after myeloablative chemotherapy. The interleukin-3 (IL-3) receptor agonist, daniplestim, binds to the IL-3 receptor-alpha subunit with 60-fold greater affinity and induces cell proliferation and colony-forming unit formation 10- to 22-fold better than native IL-3. A chimeric cytokine, myelopoietin-1, composed of daniplestim and a G-CSF receptor agonist binds both the IL-3 and G-CSF receptors. While the in vivo effects of daniplestim and myelopoietin-1 are well described, the mechanisms by which they stimulate growth are not well understood. We have investigated the effects of daniplestim and myelopoietin-1 on the prevention of apoptosis in two human hematopoietic cell lines, OCI-AML.5 and AML 193. Daniplestim and myelopoietin-1 prevented apoptosis to a greater degree than native recombinant IL-3 or G-CSF as determined by annexin V/propidium iodide binding and TUNEL assays. Daniplestim and myelopoietin-1 promoted the maintenance of the mitochondrial membrane potential better than native IL-3 or G-CSF. These cytokines promoted a lower redox potential as higher levels of free radicals were detected after cytokine treatment than in cytokine-deprived cells implying increased respiration. These results indicate that daniplestim and myelopoietin-1 are able to prevent apoptosis in hematopoietic cells more effectively than native IL-3 and G-CSF. These effects of daniplestim and myelopoietin-1 may contribute to their effective ability to repopulate hematopoietic precursor cells after chemotherapy.

Cavernous haemangioma in the interpeduncular cistern: case report and review of literature.

A rare case of a cavernous haemangioma in the interpeduncular cistern is reported. The patient, forty-five year old male presented with excruciating left sided trigeminal neuralgia and diplopia for the past one year. Examination revealed left third and fifth nerve paresis. Magnetic resonance imaging showed a well-defined, lobulated tumour in the interpeduncular cistern. The tumour was totally excised through a subtemporal route. Histology of the tumour revealed a cavernous haemangioma. Extracerebral location for a cavernous haemangioma is rare. An interpeduncular cavernous haemangioma has never been reported earlier in literature. The clinical and radiological features are discussed and relevant literature is briefly reviewed.

Quantitative model for Gal4p-mediated expression of the galactose/melibiose regulon in Saccharomyces cerevisiae.

A mathematical model based on equilibrium binding between Gal4p and its specific DNA binding site has been developed. A model for GAL gene expression solely due to cooperativity, as a function of Gal4p concentration, has been developed for a gal80 mutant. The above model was extended to include other known regulatory molecules, namely Gal80p and Gal3p. Parameters determined from the above simulation were then used to represent a physiological status of gene expression in response to glucose (in terms of Gal4p concentration) and galactose in a wild-type strain. We demonstrate that in a wild-type strain glucose repression is more stringent due to cooperativity and autogenous regulation, while the induction response to galactose is only through autogenous regulation. The biological significance of autogenous regulation in Saccharomyces cerevisiae is discussed vis-a-vis the lactose operon of Escherichia coli.

Characterization and optimization of absorbing plasma-enhanced chemical vapor deposited antireflection coatings for silicon photovoltaics.

We have optimized plasma-enhanced chemical vapor deposition (PECVD) of SiN-based antireflection (AR) coatings with special consideration for the short-wavelength (<600 nm) parasitic absorption in SiN. Spectroscopic ellipsometry was used to measure the dispersion relation for both the refractive index n and the extinction coefficient k, allowing a precise analysis of the trade-off between reflection and absorption in SiN-based AR coatings. Although we focus on photovoltaic applications, this study may be useful for photodetectors, IR optics, and any device for which it is essential to maximize the transmission of light into silicon. We designed and optimized various AR coatings for minimal average (spectrally) weighted reflectance (? R(w) ?) and average weighted absorptance (? A (w) ?), using the air mass 1.5 global solar spectrum. In most situations ? R (w) ? decreased with higher n, but ? A (w) ? increased because k increased with n. For the practical case of a single-layer AR coating for silicon under glass, an optimum refractive index of ~2.23 (at 632.8 nm) was determined. Further simulations revealed that a double-layer SiN stack with an n = 2.42 film underneath an n = 2.03 film gives the minimum total photocurrent loss. Similar optimization of double-layer SiN/SiO(2) coatings for silicon in air revealed an optimum of n = 2.28 for SiN. To determine the allowable tolerance in index and film thickness, we generated isotransmittance plots, which revealed more leeway for n values below the optimum than above because absorption begins to reduce photocurrent for high n values.

An optimal strategy to model microbial growth in a multiple substrate environment.

A comprehensive model is developed based on an optimal strategy describing varied microbial growth phenomenon involving sequential and simultaneous utilization of substrate. The model mimics the complex regulatory process of a cell which results in diverse growth process with the help of simple multi-variable constrained optimization, which aims at maximizing the specific cell growth. The metabolic processes of a cell are represented by simple flux balance equations. The different growth phenomenon exhibited by a microorganism are attributed to different levels of control present inside the cell. Provision is made in the model for these controls, in the form of constraints in the optimization formulation. The model prediction matches well with the experimental data of simultaneous growth of E. coli K12 on a mixture of glucose and organic acids like lactate, pyruvate, and acetate. Moreover, the model predictions are well in agreement with earlier published experimental data for the growth of E. coli K12 on other organic acids like fumarate, alpha-ketoglutarate, and succinate. (c) 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 56: 635-644, 1997.

Radiofrequency field surveys in hospitals.

The authors surveyed levels of radiofrequency (RF) fields in the frequency range 0.1-1,000 MHz in four hospitals in the Philadelphia area, to obtain background information related to the possible interference of radiofrequency fields with medical equipment. Two large center-city hospitals, a regional county hospital, and two suburban hospitals were surveyed. Measurements were made at six to 12 sites in each hospital, in each of the three frequency bands. More limited additional measurements were conducted in a fifth hospital as well. Sites were selected to include areas where strong RF signals from transmitting antennas might be expected to be present (e.g., locations close to windows in upper stories of buildings near paging antennas) as well as other representative sites in the hospital. The median RF field strengths were quite low (0.1-0.5 V/m), but at specific locations the RF signals from broadcast sources exceeded 1 V/m. Much stronger fields were recorded close to electrosurgical units and hand-held transmitters (cellular telephones and UHF transceivers).

Mutational analysis of the alpha subunit of the human interleukin-3 receptor.

The alpha subunit of the human interleukin-3 receptor (IL-3R alpha) is a 70-kD glycoprotein member of the hematopoietin receptor superfamily. This protein associates with a beta subunit common to the receptors for IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) to form a high-affinity receptor for IL-3. To identify regions of IL-3R alpha critical for ligand binding and receptor function, cDNAs encoding mutant receptors were generated and expressed in COS cells along with the beta subunit. Mutant receptors lacking almost the entire cytoplasmic domain of IL-3R alpha [IL-3R alpha(CD)] or carrying a substitution of trp for leu in the membrane proximal leu-ser-x-trp-ser (LSXWS) box bound 125I-IL-3 with nearly the same affinity as wild-type IL-3R alpha. In contrast, a mutant lacking the entire "LSXWS" motif failed to bind 125I-IL-3 with high affinity despite showing surface expression. In addition, hybrid receptors composed of the first 104 amino acids (aa) of IL-3R alpha joined to aa 118 through 400 of the alpha subunit of the GM-CSF receptor (GM-R alpha) [IL-3R alpha/GM-R alpha] or the first 118 aa of GM-R alpha joined to aa 104 through 378 of IL-3R alpha [GM-R alpha/IL-3R alpha] failed to bind 125I-IL-3 in the presence of the beta subunit. A third hybrid receptor composed of the first 281 residues of IL-3R alpha fused to residues 306 through 379 of GM-R alpha [IL-3R alpha/GM-R alpha-DS] also failed to bind 125I-IL-3 in the presence of the beta subunit but, in contrast to the IL-3R alpha/GM-R alpha hybrid, demonstrated weak surface expression. Mutant receptors lacking the N-terminal 30 aa and the N-terminal 9 aa also did not bind 125I-IL-3 with high affinity, although both were expressed on the cell surface. These data suggest that although the cytoplasmic domain and the leucine residue of the "LSXWS" box are not critical for ligand binding or beta-subunit association, the "LSXWS" motif and amino-terminal sequences are important for these functions.

Craniotomy guidance using a stereo-video-based tracking system.

In open intracranial neurosurgery, it is desirable to minimize exposure and to approach the target in the most accurate way possible. The VISLAN system described here employs a completely passive hand-held locator which is tracked by a video system and does not require a mechanical linkage nor cables. The system also tracks easily recognizable, constant, anatomical landmarks of the patient. By this means the initial registration of pre-operative imaging and the detection of, and correction for, patient movement can be accomplished. High-resolution MRI segmented interactively is used to define external surface and brain anatomy. Thus, a pre-operative patient representation (POPR) is planned. During the surgical procedure the patient's head is illuminated by structured light and stereo-video pictures obtained from two television cameras mounted above the head. The system is calibrated and registered with the POPR using a chamfered matching algorithm. The locator is also tracked in space by the video system, and its tip position shown in relation to the POPR on the video monitor.

Frameless stereotaxy and interactive neurosurgery with the ISG viewing wand.

Preliminary experience with the ISG wand for frameless stereotaxy is presented. The wand is a multijointed mechanical arm with a range of 25 inch radius sphere. The arm has a analog/digital hybrid transducers to locate the spatial position of the probe tip. The real time displays of triplanar 2D images with an optional 2D/3D image helps in surgical planning and interactive surgery. Seventeen patients underwent neurosurgical procedures with the help of wand. The wand was used to place minimal craniotomies, localise the brain-tumour interface and excise the lesions. The wand had an accuracy of 1.8 mm (SEM +/- 0.36 mm) in localising the lesions. Thus, the use of frameless stereotaxy has made easier and more precise surgical planning in several applications.

Evidence for hypoxia-induced, programmed cell death of cultured neurons.

Apoptosis, a form of cell death ("programmed" cell death) in which the nucleus and cytoplasm shrink and often fragment, serves to eliminate excessive or unwanted cells during remodeling of embryonic tissues, during organ involution, and in tumor regression. In acute pathological states, such as ischemia, the cells tend to swell and lyse--a process called necrosis. We hypothesize that the delayed neural death clinically associated with hypoxia may, in part, represent apoptosis. A tissue culture model of 24 hours of hypoxia was employed using sympathetic neurons. Pretreatment with an endonuclease inhibitor (aurintricarboxylic acid) decreased cell death by 53%, depolarizing conditions (55 mM potassium chloride) decreased cell death by 33%, and an RNA synthesis inhibitor (actinomycin D) by 26% (all have been shown to prevent apoptosis). Pretreatment with antisense c-myc had no effect. Fluorescent staining with propidium iodide (a DNA marker) demonstrated chromatin condensation and agarose gel electrophoresis demonstrated a DNA "ladder." These data suggest that apoptosis may play a role in hypoxic cell death and that in this paradigm, expression of c-myc is unnecessary. This would suggest a new approach to our understanding of hypoxia and open new strategies to lessen neuronal damage secondary to this process.