Squamous cell carcinoma and basal cell carcinoma of the lips: 25 years of experience in a northeast Brazilian population.

BACKGROUND: The lips are the transition zone between the facial skin and the oral mucosa and are the site of alterations related to a broad spectrum of etiologies. Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) are the most prevalent neoplasms affecting lips. This study evaluated the demographic and clinicopathological features of the SCC and BCC in the lip. MATERIAL AND METHODS: A retrospective cross-sectional descriptive study (1994-2019) was carried out. Demographic and clinicopathologic data were collected from a hospital's dermatological service and an oncologic hospital. The data were submitted to descriptive analysis and Pearson's chi-square and Fisher's exact tests (p ≤ 0.05). RESULTS: 417 medical records were analyzed, of which 323 corresponded to SCC (77.5%) and 94 to BCC (22.5%). SCC showed more frequency in males (58.8%) and BCC in females (54.3%). The lower lip was significantly affected in male patients (p < 0.0001) and by both neoplasms (70.6% and 56.4%, respectively; p = 0.014). SCC and BCC were mainly treated with surgery (88.3% and 93.2%, respectively). Surgical margin was frequently negative in SCC and BCC (87%; 72.3%, respectively), and no recurrence was observed in 79.9% of SCC and 69.1% of BCC cases. CONCLUSIONS: SCC was more frequent in male patients, while BCC showed more frequency in female patients. Both neoplasms mainly affect the lower lip. Understanding the epidemiological profile of these lesions in the lip, as well as their etiology and clinical features, is fundamental for appropriate clinical conduct and the creation and/or amplification of preventive measures.

Swine manure treatment technologies as drivers for circular economy in agribusiness: A techno-economic and life cycle assessment approach.

Anaerobic digestion has been employed as a technology capable of adding value to waste coupled with environmental impact mitigation. However, many issues need to be elucidated to ensure the systems viability based on this technology. In this sense, the present study evaluated technically, environmentally, and economically, four configurations of swine waste treatment systems focused on the promotion of decarbonization and circularity of the swine chain. For this, a reference plant, based on a compact treatment process named SISTRATES® (Portuguese acronym for swine effluent treatment system) was adopted to serve as a model for comparison and validation. The results showed the importance of prioritization of the energy recuperation routes through anaerobic digestion, providing increased economic benefits and minimizing environmental damage. Thus, the SISTRATES® configuration was the one that presented the best designs in a circular context, maximizing the recovery of energy and nutrients, along with the reduction of greenhouse gas emissions, ensuring the sustainability of the pig production chain.

Tres tareas para la exploración de la fluidez verbal: evidencias de su fiabilidad test-retest en adultos argentinos / Three tasks for the exploration of verbal fluency: evidence of test-retest reliability in Argentine adults

Introducción: Las tareas de fluidez fonológica y semántica son de uso frecuente en la evaluación neuropsicológica por su fácil aplicación y buena sensibilidad al deterioro cognitivo. En Argentina es limitado el cuerpo de evidencia psicométrica para dichas tareas, con especial desconocimiento de la estabilidad temporal de sus medidas. La producción psicométrica es aún menor para la variante fluidez de acción (emisión de verbos en infinitivo en un minuto). En efecto, este estudio analiza la fiabilidad test-retest de tres tareas de fluidez en adultos argentinos. Sujetos y métodos: La muestra se compuso de 85 argentinos (medida de edad, 63,7) de población general no clínica, un 75,3% mujeres, de nivel de instrucción medio-alto. Se efectuó un diseño longitudinal-prospectivo administrando tareas de fluidez fonológica, semántica y de acción en dos momentos distintos con un intervalo hasta de cuatro meses. Se analizó el coeficiente de correlación intraclase (CCI), método estadístico sugerido para estudios de fiabilidad test-retest. Para interpretar el CCI se adoptaron los criterios de Fleiss. Resultados: Las tareas de fluidez fonológica y semántica demostraron buena fiabilidad, con un CCI de 0,77 y 0,79. La fluidez de acción obtuvo excelente fiabilidad, con un CCI de 0,9. Conclusión: Las tareas de fluidez relevadas poseen apropiada estabilidad temporal, por lo que se sugiere su uso en investigaciones neuropsicológicas prospectivas (cuando se evalúe el lenguaje en distintos momentos) o cuando se requiera un seguimiento de la evolución de pacientes afásicos en neurorrehabilitación. Basándose en su excelente fiabilidad, se recomienda utilizar con más frecuencia la variante de acción.(AU)

Introduction: The phonological and semantic verbal fluency tasks are frequently used in neuropsychological assessment due to their easy application and good sensitivity to dementia. In Argentina, the psychometric evidence for these tasks is limited, with a special lack of knowledge of the temporal stability of its measurements. The psychometric production is even lower for the action fluency variant (emission of verbs in the infinitive in one minute). In effect, this research analyzes the test-retest reliability of three verbal fluency tasks in Argentine adults. Subjects and methods: The sample was made up of 85 Argentine (average age, 63.7 years), 75,3% women and with a medium-high educational level. A prospective longitudinal design was carried out, administering phonological, semantic and action fluency tasks at two different times with an interval of up to four months. The intraclass correlation coefficient (ICC), a statistical method suggested for test-retest reliability studies, was analyzed. For the interpretation of the ICC, the Fleiss criteria were adopted. Results: The phonological and semantic fluency tasks showed good reliability, with ICCs of 0.77 and 0.79. The fluidity of action variant yielded ICC of 0.90, indicating excellent reliability. Conclusions: All fluency tasks have appropriate temporal stability, and their use is recommended when prospective neuropsychological research is planned (with language evaluation at di fferent times) or as a method of monitoring the evolution of aphasic patients undergoing neurorehabilitation. Based on its excellent reliability, it is recommended to use the action variant more frequently.(AU)

[Three tasks for the exploration of verbal fluency: evidence of test-retest reliability in Argentine adults]. / Tres tareas para la exploración de la fluidez verbal: evidencias de su fiabilidad test-retest en adultos argentinos.

INTRODUCTION: The phonological and semantic verbal fluency tasks are frequently used in neuropsychological assessment due to their easy application and good sensitivity to dementia. In Argentina, the psychometric evidence for these tasks is limited, with a special lack of knowledge of the temporal stability of its measurements. The psychometric production is even lower for the action fluency variant (emission of verbs in the infinitive in one minute). In effect, this research analyzes the test-retest reliability of three verbal fluency tasks in Argentine adults. SUBJECTS AND METHODS: The sample was made up of 85 Argentine (average age, 63.7 years), 75,3% women and with a medium-high educational level. A prospective longitudinal design was carried out, administering phonological, semantic and action fluency tasks at two different times with an interval of up to four months. The intraclass correlation coefficient (ICC), a statistical method suggested for test-retest reliability studies, was analyzed. For the interpretation of the ICC, the Fleiss criteria were adopted. RESULTS: The phonological and semantic fluency tasks showed good reliability, with ICCs of 0.77 and 0.79. The fluidity of action variant yielded ICC of 0.90, indicating excellent reliability. CONCLUSIONS: All fluency tasks have appropriate temporal stability, and their use is recommended when prospective neuropsychological research is planned (with language evaluation at different times) or as a method of monitoring the evolution of aphasic patients undergoing neurorehabilitation. Based on its excellent reliability, it is recommended to use the action variant more frequently.

TITLE: Tres tareas para la exploración de la fluidez verbal: evidencias de su fiabilidad test-retest en adultos argentinos.Introducción. Las tareas de fluidez fonológica y semántica son de uso frecuente en la evaluación neuropsicológica por su fácil aplicación y buena sensibilidad al deterioro cognitivo. En Argentina es limitado el cuerpo de evidencia psicométrica para dichas tareas, con especial desconocimiento de la estabilidad temporal de sus medidas. La producción psicométrica es aún menor para la variante fluidez de acción (emisión de verbos en infinitivo en un minuto). En efecto, este estudio analiza la fiabilidad test-retest de tres tareas de fluidez en adultos argentinos. Sujetos y métodos. La muestra se compuso de 85 argentinos (medida de edad, 63,7) de población general no clínica, un 75,3% mujeres, de nivel de instrucción medio-alto. Se efectuó un diseño longitudinal-prospectivo administrando tareas de fluidez fonológica, semántica y de acción en dos momentos distintos con un intervalo hasta de cuatro meses. Se analizó el coeficiente de correlación intraclase (CCI), método estadístico sugerido para estudios de fiabilidad test-retest. Para interpretar el CCI se adoptaron los criterios de Fleiss. Resultados. Las tareas de fluidez fonológica y semántica demostraron buena fiabilidad, con un CCI de 0,77 y 0,79. La fluidez de acción obtuvo excelente fiabilidad, con un CCI de 0,9. Conclusión. Las tareas de fluidez relevadas poseen apropiada estabilidad temporal, por lo que se sugiere su uso en investigaciones neuropsicológicas prospectivas (cuando se evalúe el lenguaje en distintos momentos) o cuando se requiera un seguimiento de la evolución de pacientes afásicos en neurorrehabilitación. Basándose en su excelente fiabilidad, se recomienda utilizar con más frecuencia la variante de acción.

Cuestionario de reserva cognitiva: análisis psicométrico desde la teoría de respuesta al ítem / Cognitive Reserve Questionnaire: psychometric analysis from the item response theory

Introducción: La reserva cognitiva es la capacidad para tolerar mejor el daño cerebral mediante recursos cognitivos preexistentes y compensatorios. Un método de evaluación es el cuestionario de reserva cognitiva (CRC) de Rami. El objetivo fue realizar un análisis de la calidad informativa del CRC desde la teoría de respuesta al ítem (TRI), con el fin de aportar datos más precisos sobre la fiabilidad de consistencia interna. Se probó, además, la validez convergente con medidas de atención, memoria de trabajo y fluidez. Sujetos y métodos: Participaron 210 argentinos de población general (media edad, 66,8 años). El CRC se administró junto con el test de dígitos y tres tareas de fluidez. Se ajustó un modelo de respuesta graduada desde la TRI con estimación de parámetros de discriminación (a) y dificultad (b), y se elaboró una curva de información del CRC. Se efectuaron correlaciones bivariadas y parciales. Resultados: La TRI indicó una alta discriminación para los ítems del CRC ‘Escolaridad’ y ‘Nivel de ocupación’ (tanto para la versión de ocho ítems como para la versión de seis ítems). En el CRC de ocho ítems se obtuvo una baja discriminación para ‘Formación musical’ y ‘Juegos intelectuales’. En ambas versiones del CRC, la curva indica mayor valor informacional a bajo nivel del constructo. Hubo correlación con el test de dígitos y con las tareas de fluidez, incluso al controlar por edad. Conclusiones: El presente estudio es el primer análisis del CRC desde la TRI, que concluye que el instrumento resulta más confiable cuando se aplica a sujetos con menor reserva. El CRC posee aceptable validez convergente.(AU)

INTRODUCTION: Cognitive reserve is the ability to better tolerate brain damage through pre-existing and compensatory cognitive resources. One assessment method is the Rami CRQ-Cognitive Reserve Questionnaire. The objective was to carry out an analysis of the informative quality of the CRQ from the item response theory (IRT), in order to provide more precise data on the reliability of internal consistency. Convergent validity was also tested with measures of attention, working memory, and fluency. SUBJECTS AND METHODS: 210 Argentines from the general population (mean age, 66.8 years) participated. The CRQ was administered together with the digits test and three fluency tasks. A graded response model was fitted from IRT with estimation of discrimination parameters (a) and difficulty (b), and a CRQ information curve was created. Bivariate and partial correlations were made. RESULTS: The IRT indicated high discrimination for the CRQ items ‘Education’ and ‘Occupation level’ (both for the 8-item version and the 6-item version). In the CRQ of 8 items, low discrimination was obtained for ‘Musical training’ and ‘Intellectual games’. In both versions of the CRQ, the curve indicates greater informational value at a low level of the construct. There was a correlation with the digits test and with fluency tasks, even when controlling for age. CONCLUSIONS: This study is the first analysis of CRQ from IRT, concluding that the instrument is more reliable when applied to subjects with less reserve. The CRQ has acceptable convergent validity.(AU)

[Cognitive Reserve Questionnaire: psychometric analysis from the item response theory]. / Cuestionario de reserva cognitiva: análisis psicométrico desde la teoría de respuesta al ítem.

INTRODUCTION: Cognitive reserve is the ability to better tolerate brain damage through pre-existing and compensatory cognitive resources. One assessment method is the Rami CRQ-Cognitive Reserve Questionnaire. The objective was to carry out an analysis of the informative quality of the CRQ from the item response theory (IRT), in order to provide more precise data on the reliability of internal consistency. Convergent validity was also tested with measures of attention, working memory, and fluency. SUBJECTS AND METHODS: 210 Argentines from the general population (mean age, 66.8 years) participated. The CRQ was administered together with the digits test and three fluency tasks. A graded response model was fitted from IRT with estimation of discrimination parameters (a) and difficulty (b), and a CRQ information curve was created. Bivariate and partial correlations were made. RESULTS: The IRT indicated high discrimination for the CRQ items 'Education' and 'Occupation level' (both for the 8-item version and the 6-item version). In the CRQ of 8 items, low discrimination was obtained for 'Musical training' and 'Intellectual games'. In both versions of the CRQ, the curve indicates greater informational value at a low level of the construct. There was a correlation with the digits test and with fluency tasks, even when controlling for age. CONCLUSIONS: This study is the first analysis of CRQ from IRT, concluding that the instrument is more reliable when applied to subjects with less reserve. The CRQ has acceptable convergent validity.

TITLE: Cuestionario de reserva cognitiva: análisis psicométrico desde la teoría de respuesta al ítem.Introducción. La reserva cognitiva es la capacidad para tolerar mejor el daño cerebral mediante recursos cognitivos preexistentes y compensatorios. Un método de evaluación es el cuestionario de reserva cognitiva (CRC) de Rami. El objetivo fue realizar un análisis de la calidad informativa del CRC desde la teoría de respuesta al ítem (TRI), con el fin de aportar datos más precisos sobre la fiabilidad de consistencia interna. Se probó, además, la validez convergente con medidas de atención, memoria de trabajo y fluidez. Sujetos y métodos. Participaron 210 argentinos de población general (media edad, 66,8 años). El CRC se administró junto con el test de dígitos y tres tareas de fluidez. Se ajustó un modelo de respuesta graduada desde la TRI con estimación de parámetros de discriminación (a) y dificultad (b), y se elaboró una curva de información del CRC. Se efectuaron correlaciones bivariadas y parciales. Resultados. La TRI indicó una alta discriminación para los ítems del CRC 'Escolaridad' y 'Nivel de ocupación' (tanto para la versión de ocho ítems como para la versión de seis ítems). En el CRC de ocho ítems se obtuvo una baja discriminación para 'Formación musical' y 'Juegos intelectuales'. En ambas versiones del CRC, la curva indica mayor valor informacional a bajo nivel del constructo. Hubo correlación con el test de dígitos y con las tareas de fluidez, incluso al controlar por edad. Conclusiones. El presente estudio es el primer análisis del CRC desde la TRI, que concluye que el instrumento resulta más confiable cuando se aplica a sujetos con menor reserva. El CRC posee aceptable validez convergente.

New-onset lupus nephritis after male-to-female sex reassignment surgery.

We report an original case of a 27-year-old transgender woman who developed lupus nephritis after male-to-female sex reassignment surgery. The patient had been taking hormones to induce feminization since the age of 18. She was admitted with malar "butterfly" rash, anasarca and hypertension, associated with an increase in serum creatinine (1.7 mg/dl). Renal involvement was characterized by nephritic and nephrotic syndrome. Autoantibody tests were positive for antinuclear antibodies and anti-double-stranded DNA, and complement levels were markedly reduced. Renal biopsy demonstrated diffuse proliferative glomerulonephritis and granular immune complexes deposits with a "full-house" pattern at the immunofluorescence level. The induction treatment was realized with corticosteroid and cyclophosphamide and maintenance immunosuppression phase with mycophenolate, obtaining complete remission. We speculated that lupus nephritis was induced by estrogens and antiandrogen therapy and gonadectomy. In the present case, we discuss the role of sex hormones in systemic lupus erythematosus onset and review the cases linked to transgender patients.

[Cerebral vasoreactivity: Concordance of breath holding test and acetazolamide injection in current practice: 20 cases of asymptomatic carotid artery stenosis]. / Étude de la vasoréactivité cérébrale en Doppler transcrânien : évaluation du test d'apnée comparé à l'injection d'acetazolamide en soins courants. Exploration de 20 sténoses carotidiennes asymptomatiques.

INTRODUCTION: Cerebral vasoreactivity (CVR) is the ability of the brain's vascular system to keep cerebral blood inflow stable. Impaired CVR is a risk marker of stroke in patients with asymptomatic carotid stenosis. The gold standard to assess CVR with transcranial ultrasound is acetazolamide (ACTZ) injection. The breath holding test (BHT) might be easier to perform. CVR proved to be efficient in laboratory conditions but not in routine practice. OBJECTIVES: To study the validity of BHT versus ACTZ in routine practice in a vascular exploration unit in patients with asymptomatic carotid stenosis. METHODS: Study of concordance of BHT and ACTZ, to assess CVR in patients consecutively explored on the same day. RESULTS: Eighteen patients with 20 carotid stenosis were included. The temporal window was missing in 20% of cases. Only 11 out of the 20 procedures were analyzed. Concordance was low between BHT and ACTZ to assess CVR (k=0.3714). CONCLUSION: BHT cannot replace ACTZ injection. It might be a first-step test so that ACTZ injection might be avoided if CVR is normal. Our present results must be confirmed by further study enrolling many more patients.

Hepcidin and ferritin blood level as noninvasive tools for predicting breast cancer.

BACKGROUND: Currently used CA15-3 and CEA have found their clinical application particularly in the follow-up of patients with advanced disease. Novel biomarkers are urgent, especially for improving early diagnosis as well as for discriminating between benign and malignant disease. PATIENTS AND METHODS: In the present study, we used a proteomic approach based on surface-enhanced laser desorption/ionization-time of flight-mass spectrometry screening with the aim of identifying differentially expressed 2-30 kDa proteins in plasma of patients with malignant (65 cases) and benign (88 cases) breast lesions with respect to 121 healthy controls. RESULTS: We found that the most promising SELDI peaks were those corresponding to hepcidin-25 and ferritin light chain. We evaluated the capability of these peaks in predicting malignant and benign breast lesions using the area under the receiver operating characteristic curve (AUC). The results showed a good capacity to predict malignant breast lesions for hepcidin-25 [AUC: 0.82; 95% confidence interval (CI) 0.75-0.90] and ferritin light chain (AUC: 0.86; 95% CI 0.79-0.92). Conversely, a weak and satisfactory capability to predict benign breast lesion was observed for hepcidin-25 (AUC: 0.63; 95% CI 0.41-0.85) and ferritin light chain (AUC: 0.73; 95% CI 0.49-0.97). A significant association between HER2 status and hepcidin-25 was observed and the distribution of transferrin and ferritin were found significantly different in patients with breast cancer when compared with that of controls. CONCLUSIONS: This study provides evidence that hepcidin and ferritin light chain level in plasma may be of clinical usefulness to predict malignant and benign disease with respect to healthy controls.

Sandwich ELISA assay for the quantitation of palytoxin and its analogs in natural samples.

Palytoxins are potent marine biotoxins that have recently become endemic to the Mediterranean Sea, and are becoming more frequently associated with seafood. Due to their high toxicity, suitable methods to quantify palytoxins are needed. Thus, we developed an indirect sandwich ELISA for palytoxin and 42-hydroxy-palytoxin. An intralaboratory study demonstrated sensitivity (limit of detection, LOD = 1.1 ng/mL; limit of quantitation, LOQ = 2.2 ng/mL), accuracy (bias of 2.1%), repeatability (RSDr = 6% and 9% for intra- and interassay variability, respectively) and specificity: other common marine toxins (okadaic acid, domoic acid, saxitoxin, brevetoxin-3, and yessotoxin) do not cross-react in this assay. It performed well in three different matrices: observed LOQs were 11.0, 9.6, and 2.4 ng/mL for mussel extracts, algal net samples and seawater, respectively, with good accuracy and precision. The LOQ in seafood is 11 µg palytoxin/kg mussel meat, lower than that of the most common detection technique, LC-MS/MS.

Proteomic profile in familial breast cancer patients.

OBJECTIVES: Breast cancer is the most common form of cancer affecting women, and the strongest risk factor remains family history. Although screening in asymptomatic women seems able to reduce breast-cancer related mortality, it is of limited usefulness in young women and patients with familial breast cancer syndrome. New diagnostic tools useful for breast cancer management are urgently needed. The aim of the present paper is to look for new candidate tumor markers useful for diagnosis in these patients. DESIGN AND METHODS: In this prospective study 292 serum samples (100 from healthy people, 100 from sporadic breast cancer patients and 92 from familial breast cancer patients) were analyzed by SELDI-TOF-MS. All samples both from cancer patients and healthy subjects were run in duplicate and randomly spotted on CM10 and IMAC30 protein chip array. Data were analyzed using the expression differential mapping (EDM) tool, decisional tree and multivariate analysis. A further in silico investigation was performed in order to hypothesize the identity of evidenced peptides. RESULTS: EDM highlighted thirteen and sixteen significant differentially expressed peaks by CM10 and IMAC30 protein chip respectively. Subsequent analysis showed that two peaks at m/z 11730 and 5066 were differentially expressed in sporadic and familial breast cancer patients respectively, while a peak at m/z 8127 was overexpressed only in familial breast cancer patients. The diagnostic power of protein peaks was tested by decisional tree; sensitivity and specificity ranged from 17% to 91.67%. CONCLUSIONS: We show that the serum profile of familial breast cancer patients was different when compared with that of sporadic breast cancer patients. We hypothesized the identity of the most significant peaks, and further studies are now planned in order to definitively establish the identity.

Targeting of the adaptor protein Tab2 as a novel approach to revert tamoxifen resistance in breast cancer cells.

Pharmacological resistance is a serious threat to the clinical success of hormone therapy for breast cancer. The antiproliferative response to antagonistic drugs such as tamoxifen (Tam) critically depends on the recruitment of NCoR/SMRT corepressors to estrogen receptor alpha (ERα) bound to estrogen target genes. Under certain circumstances, as demonstrated in the case of interleukin-1ß (IL-1ß) treatment, the protein Tab2 interacts with ERα/NCoR and causes dismissal of NCoR from these genes, leading to loss of the antiproliferative response. In Tam-resistant (TamR) ER-positive breast cancer cells, we observed that Tab2 presents a shift in mobility on sodium dodecyl sulfate--PAGE (SDS-PAGE) similar to that seen in MCF7 wt upon stimulation with IL-1ß, suggesting constitutive activation. Accordingly, TamR treatment with Tab2-specific short interfering RNA, restored the antiproliferative response to Tam in these cells. As Tab2 is known to directly interact with the N-terminal domain of ERα, we synthesized a peptide composed of a 14-aa motif of this domain, which effectively competes with ERα/Tab2 interaction in pull-down and co-immunoprecipitation experiments, fused to the carrier TAT peptide to allow internalization. Treatment of TamR cells with this peptide resulted in partial recovery of the antiproliferative response to Tam, suggesting a strategy to revert pharmacological resistance in breast cancer. Silencing of Tab2 in TamR cells by siRNA caused modulation of a gene set related to the control of cell cycle and extensively connected to BRCA1 in a functional network. These genes were able to discern two groups of patients, from a published data set of Tam-treated breast cancer profiles, with significantly different disease-free survival. Altogether, our data implicate Tab2 as a mediator of resistance to endocrine therapy and as a potential new target to reverse pharmacological resistance and potentiate antiestrogen action.

Characterization of a serum protein pattern from NSCLC patients treated with Gefitinib.

OBJECTIVES: The purpose of this study was to evaluate the efficacy of a protein-based pattern in serum previously determined by MALDI-TOF-MS (Matrix Assisted Laser Desorption Ionization-Time of Flight) and considered potentially useful for prediction of clinical outcome of EGFR (epidermal growth factor receptor) TKIs (tyrosine kinase inhibitors) treated patients. DESIGN AND METHODS: We generated SELDI-TOF (Surface Enhanced Laser Desorption Ionization-Time of Flight) spectra in sera of 11 advanced NSCLC treated with Gefitinib. We detected the clusters with m/z 5843, 11445, 11529, 11685, 11759 and 11903 which were previously reported to be potential predictors of response to Gefitinib treatment. RESULTS: Four cluster peaks with m/z 5843, 11445, 11529, 11685 corresponded to SAA (serum amyloid A) protein on the basis on their calculated molecular weight, peptide fingerprinting and antibodies recognition. CONCLUSIONS: We confirm that several proteins already reported were isoforms of SAA but further studies are in development in order to evaluate the predictive value of such algorithm.

Acute oral toxicity in mice of a new palytoxin analog: 42-hydroxy-palytoxin.

The acute oral toxicity of a new palytoxin congener, 42-hydroxy-palytoxin (42-OH-PLTX), was investigated in female CD-1 mice. The toxin (300-1697 µg/kg), administered by gavage, induced scratching, jumping, respiratory distress, cyanosis, paralysis and death of mice, with an LD50 of 651 µg/kg (95% confidence limits: 384-1018 µg/kg) within 24 h. Hematoclinical analyses showed increased plasma levels of lactate dehydrogenase and aspartate-aminotransferase at doses of 600 µg/kg and above, as well as of alanine-aminotransferase, creatine phosphokinase and potassium ions at ≥ 848 µg/kg. Histology revealed inflammatory lesions in the non-glandular area of the stomach of mice that survived up to 24 h after gavage (424-1200 µg/kg). Although no histological alterations were seen in skeletal and cardiac muscles, changes in some plasma biomarkers (creatine phosphokinase, lactate dehydrogenase) suggested involvement of these tissues in 42-OH-PLTX oral toxicity, in agreement with epidemiological data on seafood poisonings ascribed to palytoxins. Complete recovery of the tissue and hematological changes was observed two weeks post-exposure. Furthermore, 42-OH-PLTX induced in vitro delayed erythrocyte hemolysis at concentrations similar to those of PLTX (EC50 = 7.6 and 13.2 x 10⁻¹² M, respectively). This hemolysis could be completely neutralized by a monoclonal anti-PLTX antibody. The in vivo data, together with the in vitro data recorded for 42-OH-PLTX, seem to indicate Na+/K+-ATPase as one of the key cellular targets of this toxin.

Effects of the marine toxin palytoxin on human skin keratinocytes: role of ionic imbalance.

Palytoxin (PLTX), a marine toxin identified in Palythoa zoanthid corals and Ostreopsis dinoflagellates, represents an increasing hazard for human health. Recently, dermatological problems have been associated to cutaneous exposure to PLTX during Ostreopsis blooms arising the need for experimental data characterizing PLTX effects on the skin. This study highlights in vitro the cytotoxic effects of PLTX on human keratinocytes (HaCaT cell line). A short time exposure (4h) to PLTX reduced mitochondrial activity (MTT assay), cell mass (SRB assay) and plasma membrane integrity (LDH leakage) with different potencies: EC50 values of 6.1 ± 1.3×10⁻¹¹, 4.7 ± 0.9 × 10⁻¹° M and 1.8 ± 0.1 × 10⁻8 M, respectively. PLTX effect on mitochondrial activity was ouabain- and Na+-sensitive, but only partially sensitive to removal of Ca²+ ions. One hour exposure to the toxin also induced a Na+-dependent and Ca²+-independent superoxide anion production. These results indicate that among the chain of intracellular events following the interaction of PLTX with the Na+/K+-ATPase the first and crucial step is the increased intracellular Na+ concentration that triggers a sequence of cell dysfunction involving mitochondrial affection and oxidative stress, leading to an irreversible cell death. The PLTX concentrations inducing cytotoxicty seem to be lower than those of potential cutaneous human exposure during Ostreopsis ovata blooms, indicating the harmful potential of the toxin.

Valproic acid restores ER alpha and antiestrogen sensitivity to ER alpha-negative breast cancer cells.

Histone deacetylase inhibitors (HDIs) are valuable drugs in breast cancer where estrogen receptor alpha (ER alpha) can be silenced by epigenetic modifications. We report the effect of the clinically available HDI, valproic acid (VPA), on ER alpha expression and function in ER-negative breast cancer cells, MDA-MB-231. VPA induced ER alpha mRNA and protein, while did not modify ER beta. In VPA-treated cells, we also observed: (1) a correct transcriptional response to estradiol after transfection with the luciferase gene under the control of an estrogen-responsive minimal promoter (ERE-TKluc); (2) increased expression of the ER-related transcription factor FoxA1; (3) estradiol-induced up-regulation of several estrogen-regulated genes (e.g. pS2, progesterone receptor); (4) inhibitory effect of tamoxifen on cell growth. In conclusion, the HDI VPA, inducing ER alpha and FoxA1, confers to MDA-MB 231 cells an estrogen-sensitive "phenotype", restoring their sensitivity to antiestrogen therapy.

Palytoxin toxicity after acute oral administration in mice.

The acute oral toxicity of palytoxin (PLTX), a highly toxic compound associated with seafood intoxication in tropical and subtropical areas, was investigated in mice. After gavage administration (300-1697 microg/kg) to groups of five female CD-1 mice, signs of toxicity and lethality were recorded for 24 h. The LD(50) was 767 microg/kg (95% confidence limits: 549-1039 microg/kg) and the main symptoms observed were scratching, jumping, respiratory distress and paralysis. Hematoclinical analyses showed increased levels of creatine phosphokinase and lactate dehydrogenase at doses of 600 microg/kg and above, and aspartate transaminase at 848 microg/kg and above. Histological analysis revealed acute inflammation of the forestomach in mice surviving up to 24h after administration (424-1200 microg/kg). Other histological alterations were observed in the liver and pancreas, while cardiac and skeletal muscle cells revealed only ultrastructural alterations visible by transmission electron microscopy. Ultrastructural and hematoclinical findings suggest an involvement of skeletal and/or cardiac muscle as targets of PLTX, according to the observed human symptoms. A NOEL of 300 microg/kg can be estimated from this acute oral toxicity study.

Plasma exchange for polyradiculoneuropathy following kidney transplantation: a case report.

We describe a case of polyradiculoneuropathy (PRN) following living donor kidney transplantation, without clinical evidence of preexisting infection. In this study plasma exchange treatment resulted 6 days later in improvement in extremity weakness and paresthesias in the upper and lower extremities. Total neurological recovery was obtained 3 months after the onset of symptoms.

The use of extracorporeal photopheresis for allograft rejection in liver transplant recipients.

BACKGROUND: Originally introduced for cutaneous T-cell lymphomas and autoimmune diseases, extracorporeal photopheresis (ECP) has been proven effective to reverse allograft rejection. The aim of the present work was to show the results of a single-center experience with ECP for the treatment of biopsy-proven rejection in selected liver transplant (LT) recipients. PATIENTS AND METHODS: A retrospective review of five LT patients (M:F=4:1; median age 51 years) undergoing ECP for biopsy-proven allograft rejection between January 1996 and December 2003. In this period 476 LT were performed on 441 patients. RESULTS: The indications for LT were three cases of HCV-related cirrhosis, complicated by hepatocellular carcinoma in two; one HBV-HDV-alcoholic cirrhosis; and one fulminant HBV hepatitis. All patients received calcineurin-inhibitor (CNI)-based immunosuppression with induction using anti-IL2R monoclonal antibodies. Indications for ECP were: ductopenic rejection in one patient with HCV recurrence; steroid-resistant acute rejection in two; acute rejection in a major ABO-mismatched liver graft; and one acute rejection in a patient with a proven allergy to steroids. The median interval from LT to inception of ECP was 43 days. The median number of ECP sessions per patient was 20. During the course of ECP, two patients tested positive for CMV antigenemia, associated in one case with bacterial pneumonia. All patients tolerated ECP and there were no procedure-related complications. At a median follow-up of 7.9 months after start of ECP, neither rejection relapses nor HCV/HBV recurrences have been observed. Three patients are off ECP with complete reversal and low-dose immunosuppression. Two patients are still receiving ECP with full-dose immunosuppression: one has achieved normal liver function but ECP is indicated due to a major ABO-incompatible liver graft, while the other patient's liver functions have not yet returned to baseline values.