Phytotoxicity of polymetallic mine wastes from southern Tuscany and Saxony.

Restoration potential of mine wastes or approaches to improve soil conditions and to ameliorate phytotoxicity on these sites may be simulated in standardized greenhouse experiments. Plants can be cultivated side by side on materials from different origins in dilution series with defined admixtures of certain aggregates. Mine wastes used in the present study originated from Fenice Capanne (FC, Tuscany, Italy) and Altenberg (ALT, Saxony, Germany). Tailings of the Italian site contain high concentrations of lead, zinc, arsenic and sulphur while tin, wolfram, molybdenum and lithium are highly elevated in the German mine waste. We tested growth responses of five crop species and analyzed concentrations of various metals and nutrients in the shoot to evaluate the toxicity of the FC mine waste and found oilseed rape being the most and corn the least resistant crop. Interestingly, oilseed rape accumulated seven times higher levels of lead than corn without showing adverse effects on productivity. In a subsequent comparison of FC and ALT mine waste, we cultivated different species of buckwheat (Fagopyrum spec.), a fast growing genus that evolved in mountain areas and that has been shown to be tolerant to low pH and high concentrations of metals. We found that the FC mine waste was more toxic than the ALT substrate in F. tataricum and F. esculentum. However, lower admixtures of FC material (10%) resulted in stronger growth reductions than higher proportions (25%) of the mine waste which was primarily related to the slightly lower pH and higher availability of essential metals due to the admixture of sand. These results confirm the importance of managing the soil chemical and physical characteristics of wastelands and call for the development of assisted reclamation to prepare sites for regular biomass production.

Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma.

This multicentre, open-label phase 1/2 trial determined safety and efficacy of weekly carfilzomib plus cyclophosphamide-dexamethasone (wKCyd) in newly diagnosed multiple myeloma (NDMM) patients aged ⩾65 years or transplant ineligible. Patients received wKCyd for up to nine 28-day cycles, followed by maintenance with carfilzomib until progression/intolerance. The phase 1 portion used a 3+3 dose-escalation scheme to determine the maximum tolerated dose of weekly carfilzomib: 12 patients received wKCyd with carfilzomib doses of 45, 56 and 70 mg/m2. The recommended phase 2 dose was established at 70 mg/m2 and 54 patients (phase 1 and 2) received weekly carfilzomib 70 mg/m2: 85% of them achieved ⩾partial response (PR), 66% ⩾very good PR, 30%⩾near-complete response (CR) and 15% CR. Responses improved in 40 patients who started maintenance: 98% achieved ⩾PR, including 29% CR and 10% stringent CR. After a median follow-up of 18 months, the 2-year progression-free survival and overall survival rates were 53.2% and 81%, respectively. The most frequent grade 3-5 toxicities were neutropenia (22%) and cardiopulmonary adverse events (9%). This is the first study of weekly carfilzomib plus an alkylating agent in elderly patients with NDMM. wKCyd was effective, with an acceptable risk/benefit ratio, and thus can be a valid option in this setting.

A phase 2 study of three low-dose intensity subcutaneous bortezomib regimens in elderly frail patients with untreated multiple myeloma.

This phase 2 trial evaluated three low-dose intensity subcutaneous bortezomib-based treatments in patients ⩾75 years with newly diagnosed multiple myeloma (MM). Patients received subcutaneous bortezomib plus oral prednisone (VP, N=51) or VP plus cyclophosphamide (VCP, N=51) or VP plus melphalan (VMP, N=50), followed by bortezomib maintenance, and half of the patients were frail. Response rate was 64% with VP, 67% with VCP and 86% with VMP, and very good partial response rate or better was 26%, 28.5% and 49%, respectively. Median progression-free survival was 14.0, 15.2 and 17.1 months, and 2-year OS was 60%, 70% and 76% in VP, VCP, VMP, respectively. At least one drug-related grade ⩾3 non-hematologic adverse event (AE) occurred in 22% of VP, 37% of VCP and 33% of VMP patients; the discontinuation rate for AEs was 12%, 14% and 20%, and the 6-month rate of toxicity-related deaths was 4%, 4% and 8%, respectively. The most common grade ⩾3 AEs included infections (8-20%), and constitutional (10-14%) and cardiovascular events (4-12%); peripheral neuropathy was limited (4-6%). Bortezomib maintenance was effective and feasible. VP, VCP and VMP regimens demonstrated no substantial difference. Yet, toxicity was higher with VMP, suggesting that a two-drug combination followed by maintenance should be preferred in frail patients.

Accumulation of polycyclic aromatic hydrocarbons by lichen transplants: Comparison with gas-phase passive air samplers.

This study compared the accumulation of 16 polycyclic aromatic hydrocarbons (PAHs) in samples of the lichen Evernia prunastri exposed for 3 months in and around an industrial area of S Italy with that in co-located passive gas-phase air samplers. The results showed a strong linear correlations (R=0.96, P<0.05) between total PAHs in lichens and in passive samplers, clearly indicating that lichen transplants may provide direct quantitative information on the atmospheric load by total PAHs, allowing translation of lichen values into atmospheric concentrations. To the best of our knowledge this is the first study reporting such a correlation with gas-phase passive air samplers.

Analysis of human ß-papillomavirus and Merkel cell polyomavirus infection in skin lesions and eyebrow hair bulbs from a cohort of patients with chronic lymphocytic leukaemia.

BACKGROUND: Research demonstrates an increased incidence of skin cancer in immunocompromised hosts, including patients with chronic lymphocytic leukaemia (CLL) and organ transplant recipients (OTRs). Active human ß-papillomavirus (ß-HPV) infection has been found in OTR skin lesions, suggesting its possible involvement in skin carcinogenesis. Merkel cell polyomavirus (MCPyV) has also been reported in cases of skin cancer. OBJECTIVES: To investigate the potential correlations between patient clinical features and skin cancer development, and the presence of ß-HPV and MCPyV DNA and protein markers in skin lesions and hair bulbs from patients with CLL. METHODS: The clinical features of 293 patients with CLL were analysed according to the presence or absence of skin lesions. ß-HPV and MCPyV infection was investigated in skin lesions and hair bulbs from the study cohort by both polymerase chain reaction (PCR) analysis and immunohistochemical screening. RESULTS: No significant correlations were observed between any of the analysed haematological parameters and the development of skin cancer. PCR analysis revealed the presence of ß-HPV and MCPyV DNA in skin lesions, and 83% of positivity for MCPyV DNA in hair bulbs, while systematic immunohistochemical analysis of all the lesions failed to detect any expression of the viral proteins ß-HPV E4, L1 or MCPyV LTAg. CONCLUSIONS: Overall, the data indicate that carriage of ß-HPV and MCPyV in the lesional skin and hair bulbs from patients with CLL without any evident reactivation at skin tumour sites most likely represents coincidental rather than causal infection. This contrasts with previous findings in relation to OTR-derived skin lesions.

Uptake and acute toxicity of cerium in the lichen Xanthoria parietina.

Environmental cerium (Ce) levels are likely to increase in the near future and monitoring of its biological effects will therefore be necessary. The aim of this study was to test if treatment of the lichen Xanthoria parietina with Ce-containing solutions (0.1mM, 1mM, 10mM and 100mM) causes Ce bioaccumulation (both extra- and intra-cellularly) as well as physiological (sample viability, membrane lipids peroxidation, photosynthetic performance, water-soluble proteins content) and ultrastructural alterations. The results showed that treatment with Ce solutions induces Ce bioaccumulation, both extra-cellularly and intra-cellularly, which in turn causes an acute toxicity, evident as decreased sample viability, marked decrease in the photosynthetic performance and important changes in the ultrastructure.

Biological effects of ammonia released from a composting plant assessed with lichens.

In this study, we investigated whether ammonia emissions from industrial composting of organic waste may influence the surrounding environment, using lichens as bioindicators. To this purpose, samples of N-tolerant and N-sensitive lichens, namely Xanthoria parietina and Evernia prunastri, were transplanted for 1-3 months along transects at increasing distance (0-400 m) from a composting facility in Tuscany, Italy. Atmospheric concentrations of ammonia were measured using passive samplers. The physiological response of lichen transplants was investigated by means of the photosynthetic efficiency (measured as chlorophyll a fluorescence emission), the integrity of cell membranes (measured as electrolyte leakage), and sample viability (measured as enzymatic activity of dehydrogenase). Epiphytic lichen communities were investigated using biodiversity indices. The results showed decreasing concentrations of ammonia, from 48.7 µg/m(3) at the composting facility to 2.7 µg/m(3) at 400 m. The N-tolerant X. parietina was not affected and some physiological parameters even showed a higher performance, while the N-sensitive E. prunastri showed a reduced performance with increasing atmospheric concentrations approaching the source. A shift from lichen communities composed by meso-acidophilous species (actual condition) to more nitrophilous communities in the near future, approaching the composting facility is suggested. It is concluded that lichens can provide useful data for decision-makers to establish correct science-based environmentally sustainable waste management policies.

Hipotiroidismo congénito, reporte de un caso / Congenital hypothyroidism, a case report

El hipotiroidismo congénito (HC) es la endocrinopatía más frecuente en el recién nacido, presenta una frecuencia de 1:3163 nacimientos. En Chile el tamizaje neonatal se realiza mediante un test de determinación de la tirotrofina (TSH)en papel filtro. CASO CLÍNICO: recién nacido de parto eutócico de3180 gr. y Apgar 9-10 a los 5 minutos; que ingresó al servicio de Neonatología al sexto día de vida por cuadro de ictericia asociado a hipoactividad y dificultad para alimentarse. Se diagnosticó hiperbilirrubinemia neonatal con sospecha de un cuadro infeccioso. Se trató con antibióticos y fototerapia intensiva disminuyendo la bilirrubinemia total de 28,57 a 14 mg/dl. Posterior al tratamiento recae en hipoactividad y con dificultad para alimentarse. Se solicitan exámenes de control, encontrándose bilirrubinemia mantenida de 18 mg/dl y hematocrito 35,7 por ciento, planteándose la posibilidad de una enfermedad metabólica, por lo que se realizaron exámenes que son enviados a Santiago para confirmación de patología metabólica; desde Santiago confirman una TSH venosa alterada de762 uIU/ml y una T4 total de 0.53 ug/dl, diagnosticando un hipotiroidismo congénito, por lo que se inició tratamiento con Levotiroxina15 ug/Kg/día. DISCUSIÓN: el hipotiroidismo congénito es una patología poco común de difícil diagnóstico, pero fácilmente detectable tamizaje neonatal midiendo TSH. En Chile, la estrategia de toma de este examen en los tiempos especificados según la categoría del recién nacido, facilita la prevención de complicaciones. En cambio cuando el tamizaje es retrasado, sólo queda la sospecha de esta entidad patológica...

Congenital hypothyroidism (CH) is the most common endocrinopathy newborn, and occurs in approximately1:3163 births. In Chile the newborn screening test is performed by a determination of thyrotropin (TSH) on filter paper. CASE REPORT: Newborn by eutocic delivery of 3180 gr. and 9-10 Apgar at 5 minutes; was admitted to the neonatology unit at six day of life because of jaundice associated with hypoactivity and poor feeding. Neonatal hyperbilirubinemia with suspected infectious condition was diagnosed and treated with antibiotics and intensive phototherapy decreasing total bilirubin 28.57 to14 mg/dl. Although treatment, the patient remains hypoactive and with poor feeding. Screening tests showed a persistent billirubin of 18mg/dl and hematocrit 35.7 percent, raising the possibility of a metabolic disease. Test were performed and sent to Santiago for confirmation, and congenital hypothyroidism was confirmed with and elevated serum TSH 762 uIU/ml and low T40.53 ug/dl, treatment with levothyroxine 15 ug/kg/day was started. DISCUSSION: Congenital hypothyroidism is a rare disease difficult to diagnose, but easily detected by neonatal screening of TSH measurement. In Chile the strategy of taking this exam at specific times according newborn categorization, facilitates the prevention of complications. However, when the screening is delayed, we can only suspect this pathological entity...

Antimony toxicity in the lichen Xanthoria parietina (L.) Th. Fr.

In this paper we tested if treating the lichen Xanthoria parietina with Sb-containing solutions causes Sb bioaccumulation as well as physiological and ultrastructural changes. Total and intracellular antimony content in Sb-treated samples increased progressively with increasing concentration in the treatment solutions. Incubation of X. parietina thalli with Sb at concentrations as low as 0.1mM caused a decrease in sample viability, measured as intensity of respiratory activity, and damage to cell membranes, expressed in terms of membrane lipid peroxidation, as well as ultrastructural changes such as plasmolysis, impairment of the thylakoid system of the alga and cytoplasmic lipid droplets. The photosynthetic system hardly responded, at least under the tested experimental conditions.

Lenalidomide-prednisone induction followed by lenalidomide-melphalan-prednisone consolidation and lenalidomide-prednisone maintenance in newly diagnosed elderly unfit myeloma patients.

This multicenter phase II trial evaluated the safety and efficacy of lenalidomide-prednisone (RP) induction, followed by lenalidomide-melphalan-prednisone (MPR) consolidation and RP maintenance in elderly unfit newly diagnosed myeloma patients. Patients received four 28-day RP induction courses (lenalidomide 25 mg/day on days 1-21 and prednisone 50 mg three times/week), followed by six 28-day MPR consolidation cycles (melphalan 2 mg, prednisone 50 mg three times/week and lenalidomide 10-15 mg/day on days 1-21), and maintenance with lenalidomide (10 mg/day on days 1-21 every 28 days) plus prednisone (25 mg three times/week). Forty-six patients were enrolled. Median age was 75 years, 59% of patients had at least one comorbidity and 35% at least two. Partial response rate was 80%, including 29% very good partial response. Median time to progression was 19.6 months, median progression-free survival was 18.4 months and 2-year overall survival was 80%. At the tolerated consolidation dose (melphalan 25 mg/month and lenalidomide 10 mg/day), the most frequent grade 3 adverse events were neutropenia (36.4%), anemia (12.1%), cutaneous reactions (18.2%) and infections (12.1%). Grade 4 neutropenia occurred in 12.1% of patients. In conclusion, RP induction followed by MPR consolidation and RP maintenance showed a manageable safety profile, and reduced the risk of severe hematological toxicity in unfit elderly myeloma patients.

Physiological response of the epiphytic lichen Evernia prunastri (L.) Ach. to ecologically relevant nitrogen concentrations.

This study investigated the physiological response of the epiphytic lichen Evernia prunastri to ecologically relevant concentrations of nitrogen compounds. Lichen samples were sprayed for 4 weeks either with water or 50, 150 and 500 µM NH(4)Cl. The integrity of cell membranes and chlorophyll a fluorescence emission (F(V)/F(M) and PI(ABS)) were analyzed. No membrane damage occurred after the exposure period. F(V)/F(M), a classical fluorescence indicator, decreased during the second week of treatment with 500 µM NH(4)Cl and the third week with 50 and 150 µM NH(4)Cl. PI(ABS), an overall index of the photosynthetic performance, was more sensitive and decreased already during the first week with 500 µM NH(4)Cl and the second week with 150 µM NH(4)Cl. Since E. prunastri has been exposed to ammonium loads corresponding to real environmental conditions, these findings open the way to an effective use of this species as early indicators of environmental nitrogen excess.

Bioacumulation and ultrastructural effects of Cd, Cu, Pb and Zn in the moss Scorpiurum circinatum (Brid.) Fleisch. & Loeske.

This paper tested if culturing the moss Scorpiurum circinatum (Brid.) Fleisch. & Loeske with metal solutions (Cd, Cu, Pb and Zn) for 30 days causes metal bioaccumulation and ultrastructural changes. The results showed that despite the high heavy metal concentrations in treatment solutions, treated samples did not show severe ultrastructural changes and cells were still alive and generally well preserved. Bioaccumulation highlighted that moss cells survived to heavy metal toxicity by immobilizing most toxic ions extracellularly, likely in binding sites of the cell wall, which is the main site of metal detoxification.

Long-term biological monitoring of environmental quality around a solid waste landfill assessed with lichens.

The diversity of epiphytic lichens and the accumulation of selected trace elements in the lichen Flavoparmelia caperata L. (Hale) were used as indicators of pollution around a landfill in central Italy along 14 years of waste management. Lichens revealed an increased deposition for some elements (i.e., Cd, Cr, Fe and Ni) and a decrease of the lichen diversity at sites facing the landfill after an enlargement of the dumping area. However, the results allowed to exclude a significant increase in heavy metal depositions in the surrounding area and suggested that successful waste management may be associated with environmental quality. It is concluded that lichen monitoring might provide essential information to enhance the implementation of ecological impact assessment, supporting industrial regulatory procedures, also when waste management is concerned.

Hematologic improvement and response in elderly AML/RAEB patients treated with valproic acid and low-dose Ara-C.

The histone deacetylase inhibitor (HDACi) valproic acid (VPA) has been shown to be active on acute myeloid leukemia (AML) and refractory anemia with excess of blasts (RAEB). Thirty-one elderly AML/RAEB patients (AML n=25; RAEB n=6) with a high rate of comorbidity were entered in a phase II study with low-dose cytarabine (Ara-C) and VPA. Fitness was evaluated by means of the Comprehensive Geriatric Assessment (CGA), including the Cumulative Illness Rating Scale (CIRS) score, the self-sufficiency scores of Activity of Daily Living (ADL) and Instrumental Activity of Daily Living (IADL). Eight patients obtained a lasting complete remission and 3 other patients obtained hematologic improvement for a total response rate of 35%. Five of 11 responding patients were relapsed or resistant after a previous treatment with Ara-C. Seven of 11 responding patients were assessed as frail at enrollment and/or had IADL impairment. Grades 3 and 4 toxicities were mainly hematological. Low-dose Ara-C and VPA is a relatively non-toxic combination with good therapeutic activity in elderly patients with AML/RAEB. This therapeutic approach represents an alternative treatment for patients who cannot undergo standard induction therapy.

Progressive multifocal leucoencephalopathy after autologous bone marrow transplantation: a treatment option.

A patient with multiple myeloma was treated with high-dose chemotherapy followed by two autologous bone marrow transplantations (ABMTs). Nine months after the second ABMT the patient complained of severe left hemiparesis, paraesthesias, left homonymous visual field defects and gait ataxia. She was diagnosed with progressive multifocal leucoencephalopathy (PML) confirmed by detection of JC virus (JCV) DNA and prescribed cidofovir every other week and mirtazapine daily. Her symptoms and signs remained stable and after 6 months the JCV DNA was undetectable in the cerebrospinal fluid. Repeated MRI scans demonstrated the stabilisation of demyelinating lesion volume; after more than 2 years of follow-up the patient's neurological examination does not show significant variations. Combination of cidofovir and mirtazapine may be helpful in the treatment of PML in HIV-negative patients.

Analysis of the host pharmacogenetic background for prediction of outcome and toxicity in diffuse large B-cell lymphoma treated with R-CHOP21.

Knowledge on the impact of pharmacogenetics in predicting outcome and toxicity in diffuse large B-cell lymphoma (DLBCL) is scant. We tested 106 consecutive DLBCL treated with R-CHOP21 for 19 single nucleotide polymorphisms (SNPs) from 15 genes potentially relevant to rituximab-CHOP (R-CHOP) pharmacogenetics. Associations of SNPs with event-free survival (EFS) and toxicity were controlled for multiple testing. Genotypic variants of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase p22phox (CYBA rs4673) and alpha1 class glutathione S-transferase (GSTA1 rs3957357) were independent predictors of EFS (CYBA rs4673 TT genotype: HR 2.06, P=0.038; GSTA1 rs3957357 CT/TT genotypes: HR 0.38, P=0.003), after adjusting for International Prognostic Index (IPI). CYBA rs4673 and GSTA1 rs3957357 also predicted outcome in DLBCL subgroups by IPI. Impact of SNPs on toxicity was evaluated in 658 R-CHOP21 courses utilizing generalized estimating equations. NCF4 rs1883112 was an independent predictor against hematologic (odds ratios (OR): 0.45; P=0.018), infectious (OR: 0.46; P=0.003) and cardiac toxicity (OR: 0.37; P=0.023). Overall, host SNPs affecting doxorubicin pharmacodynamics (CYBA rs4673) and alkylator detoxification (GSTA1 rs3957357) may predict outcome in R-CHOP21-treated DLBCL. Also, NCF4 rs1883112, a SNP of NAD(P)H oxidase p40phox, may have a function in protecting against hematologic and nonhematologic toxicity. These results highlight the need to improve characterization of the host genetic background for a better prognostication of DLBCL.

Telomere length is an independent predictor of survival, treatment requirement and Richter's syndrome transformation in chronic lymphocytic leukemia.

Telomere length (TL) has been associated with outcome in chronic lymphocytic leukemia (CLL). The aim of this extensive analysis carried out on 401 CLL patients was to assess TL conclusively as a prognostic biomarker. Our study included two cohorts used as learning (191 patients) and blinded validation series (210 patients). A TL cutoff of 5000 bp was chosen by receiver operating characteristic (ROC) analysis and Youden's index in the learning series. In this series, TL< or =5000 bp was independently associated to a worse outcome for both overall survival (OS; 105.5 vs 281 months, P<0.001) and treatment-free survival (TFS; 24.6 vs 73 months, P<0.001). In the blinded validation series, TL< or =5000 bp was confirmed as an independent outcome predictor for OS (79.8 vs not reached, P<0.001) and TFS (15.2 vs 130.8 months, P<0.001). Moreover, TL< or =5000 bp independently predicted the risk of Richter's syndrome (5-year risk: 18.9 vs 6.4%, P=0.016). Within CLL subsets defined by biological predictors, TL consistently identified patient subgroups harboring unfavorable prognosis. These results demonstrate that TL is a powerful independent predictor of multiple outcomes in CLL, and contributes to refine the prognostic assessment of this disease when utilized in combination with other prognostic markers. We thus believe that this prognostic biomarker has the potential for a more widespread use in CLL.

Integrated biomonitoring of air quality with plants and lichens: a case study on ambient ozone from central Italy.

A biennial integrated survey, based on the use of vascular plants for the bioindication of the effects of tropospheric ozone together with the use of automatic analysers of ozone, as well as the mapping of lichen biodiversity was performed in the area of Castelfiorentino (Tuscany, central Italy). Photochemically produced ozone proved to be a fundamental presence during the warm season, with maximum hourly means reaching 114 ppb, exceeding the information threshold as fixed by EU: the use of supersensitive tobacco Bel-W3 confirmed the opportunity of carrying out detailed cost-effective monitoring surveys. The potential for didactical and educational implications of this methodology are appealing. Critical levels set up for the protection of vegetation have exceeded considerably. The comparison of biomass productivity in sensitive and resistant individuals (NC-S and NC-R white clover clones, in the framework of an European network) provided evidence that ambient ozone levels are associated with relevant reduction (up to 30%) in the performance of sensitive material; effects on flowering were also pronounced. The economic assessment of such an impact deserves attention. Mapping of epiphytic lichen biodiversity--which has been used to monitor air quality worldwide--was not related to ozone geographical distribution as depicted by tobacco response.