A case of natural infection with Dirofilaria immitis in a coati (Nasua narica) from Mexico.

This paper aims to describe the natural infection with Dirofilaria immitis in Nasua narica (white-nosed coati) from Yucatán, Mexico. Two carcasses of N. narica were collected on a highway that crosses through a dense forest with patches used for agriculture and livestock activities. We performed necropsies, and two female adult nematode parasites from the heart of one specimen were collected and preserved for their molecular identification using a conventional PCR directed at a fragment of the small subunit (18S) ribosomal RNA (18S-rRNA) gene. Bioinformatic analysis showed a similarity of 99 % with three sequences from D. immitis (two from Japan). Additionally, we performed a phylogenetic tree with the recovered sequence. All these analyses showed that D. immitis is present in N. narica from Mexico. The transmission of D. immitis toward populations of Nasua sp. may be due to indirect and accidental contact with domestic dogs or wild canids that share the same environment.

Molecular detection of the reptile-associated Borrelia group in Amblyomma dissimile, Mexico.

Recently, the first record of Borrelia associated with reptiles in Mexico was published; however, no studies have been done to assess the role of Mexican ticks as potential vectors of this Borrelia group. Amblyomma dissimile is a hard tick mainly associated with amphibians and reptiles in this country. The aim of this study was to evaluate the presence of Borrelia in A. dissimile from Mexico. We collected 60 A. dissimile individuals attached to 16 Rhinella horribilis. DNA was extracted and all specimens were screened individually for Borrelia by amplification of a fragment of the 16S rDNA and an additional fragment of the flagellin gene. Five ticks were positive for Borrelia, DNA sequences corresponded to Borrelia sp. and group with sequences of the reptile-associated Borrelia group. This is the first report of Borrelia in A. dissimile and the second report of the reptile-associated Borrelia group in Mexico. This study also highlights the importance of this tick species as potential vector of this group.

Detection of Candidatus Bartonella odocoilei n. sp. in Lipoptena mazamae associated with white-tailed deer in Campeche, Mexico.

The deer ked Lipoptena mazamae (Diptera: Hippoboscidae) (Róndani), is a blood-feeding obligate ectoparasite of several species of deer and brocket. However, at present little information is available about its role as a vector of hemoparasites. Nonetheless, it is considered a competent vector for the transmission of Bartonella species. The aim of this study was performing the morphological and molecular identification of ked flies and to carry out the detection of Bartonella. We collected specimens from Chiná, Campeche, Mexico associated with white-tailed deer. Using polymerase chain reaction (PCR), of COI, gltA and rpoB genes, we were able to obtain the first barcode for L. mazamae from Mexico and identified a new species of Bartonella which was found with a prevalence of 73%. The data obtained in this study confirmed the presence of L. mazamae associated with white-tailed deer and its possible role as vector of Candidatus Bartonella odocoilei n. sp. in Mexico and we considered that it may also be present in white-tailed deer populations in the U.S.A. Additional investigations into Bartonella species associated with deer ked could provide further insight into their pathogenicity and its role as a zoonotic agent.

Advanced-stage mycosis fungoides: role of the signal transducer and activator of transcription 3, nuclear factor-κB and nuclear factor of activated T cells pathways.

BACKGROUND: The malignant mechanisms that control the development of cutaneous T-cell lymphoma (CTCL) are beginning to be identified. Recent evidence suggests that disturbances in specific intracellular signalling pathways, such as RAS-mitogen-activated protein kinase, T-cell receptor (TCR)-phospholipase C gamma 1 (PLCG1)-nuclear factor of activated T cells (NFAT) and Janus kinase (JAK)-signal transducer and activator of transcription (STAT), may play an essential role in the pathogenesis of CTCL. OBJECTIVES: To investigate the mechanisms controlling disease development and progression in mycosis fungoides (MF), the most common form of CTCL. METHODS: We collected 100 samples that were submitted for diagnosis of, or a second opinion regarding, MF between 2001 and 2018, 80% of which were in the early clinical stages of the disease. Formalin-fixed paraffin-embedded tissues were used for histological review and to measure the expression by immunohistochemistry of surrogate markers of activation of the TCR-PLCG1-NFAT, JAK-STAT and NF-κB pathways. Folliculotropism and large-cell transformation were also examined. RESULTS: NFAT and nuclear factor kappa B (NF-κB) markers showed a comparable activation status in early and advanced stages, while STAT3 activation was more frequent in advanced stages and was associated with large-cell transformation. Consistently with this observation, STAT3 activation occurred in parallel with MF progression in two initially MF-negative cases. A significant association of NFAT with NF-κB markers was also found, reflecting a common mechanism of activation in the two pathways. Genomic studies identified nine mutations in seven genes known to play a potential role in tumorigenesis in T-cell leukaemia/lymphoma, including PLCG1, JAK3 and STAT3, which underlies the activation of these key cell-survival pathways. A higher mutational allele frequency was detected in advanced stages. CONCLUSIONS: Our results show that STAT3 is activated in advanced cases and is associated with large-cell transformation, while the activation of NFAT and NF-κB is maintained throughout the disease. These findings could have important diagnostic and therapeutic implications. What's already known about this topic? Mycosis fungoides is characterized by a clonal expansion of T cells in the skin. The mechanisms controlling disease development and progression are not fully understood. What does this study add? An association of the nuclear factor of activated T cells and nuclear factor kappa B pathways was found, which could reflect a common mechanism of activation. These pathways were activated in early and advanced stages at the same level. Signal transducer and activator of transcription 3 activation was associated with large-cell transformation and was more frequent in advanced stages. A genomic analysis of cutaneous T-cell lymphoma-associated genes was performed. Nine mutations were detected. What is the translational message? These results could have important implications for the treatment of MF in the near future.

Molecular detection of Mycoplasma ovis in an outbreak of hemolytic anemia in sheep from Veracruz, Mexico.

Mycoplasma ovis is a small, pleiotropic bacterium, which parasitizes the external surface of erythrocytes of several species of artiodactyl mammals, especially sheep and goats. We here report an outbreak of ovine mycoplasmosis in a sheep flock of a private ranch (Universidad Veracruzana) in Veracruz, Mexico. For the identification of Mycoplasma and other hemoparasitic bacterial agents, we stained blood smears with the DiffQuick® technique and additionally amplified several fragments of 16S rDNA gene. We detected the presence of morulas in erythrocytes from 30 sick female adult sheep, and found Mycoplasma ovis DNA in all of them. Furthermore, three of these animals also tested positive for Anaplasma ovis. Our findings represent the first record of M. ovis and A. ovis in an outbreak of hemolytic anemia in a sheep flock, leading to severe livestock loss in a ranch of Mexico. This study highlights the importance of establishing an active surveillance of both pathogens in the country.

Posttransplant monomorphic Burkitt's lymphoma: clinical characteristics and outcome of a multicenter series.

Burkitt's monomorphic posttransplant lymphoproliferative disorder (B-PTLD) is an uncommon subtype of PTLD. Owing to the paucity of this complication, clinical characteristics and outcome has not been fully described. Clinical characteristics and outcomes of 20 patients diagnosed with B-PTLD from 10 transplant centers belonging to the GEL/TAMO group were reviewed. Median time from transplant to B-PTLD was 7.2 years. All the cases fulfill the morphologic and genetic criteria of B-PTLD, whereas Epstein-Barr virus (EBV) was detected in 70% of cases. Patients were treated with different chemotherapy combinations, and three patients received upfront rituximab monotherapy. The great majority of patients receiving CHOP-like regimens attained a complete response (CR) (73%), similar to that obtained with dose-intensive chemotherapy (83% CR). In contrast, patients receiving upfront rituximab monotherapy required subsequent chemotherapy. Two patients (10%) died during treatment due to infection. The median progression-free survival and overall survival (OS) were 16 months and 139 months, respectively. When analyzing variables predicting for OS, we found that patients with bone marrow involvement had an adverse prognosis, with a median OS of 6 months (p = 0.008). In conclusion, B-PTLD is an uncommon complication usually associated with EBV infection and with an aggressive clinical course, particularly in patients with bone marrow involvement. High-dose chemoimmunotherapy obtained similar responses to R-CHOP, suggesting that R-CHOP could be an adequate alternative for these patients. In contrast, rituximab monotherapy does not seem to be effective enough to control the disease.

Sensitive and label-free biosensing of RNA with predicted secondary structures by a triplex affinity capture method.

A novel biosensing approach for the label-free detection of nucleic acid sequences of short and large lengths has been implemented, with special emphasis on targeting RNA sequences with secondary structures. The approach is based on selecting 8-aminoadenine-modified parallel-stranded DNA tail-clamps as affinity bioreceptors. These receptors have the ability of creating a stable triplex-stranded helix at neutral pH upon hybridization with the nucleic acid target. A surface plasmon resonance biosensor has been used for the detection. With this strategy, we have detected short DNA sequences (32-mer) and purified RNA (103-mer) at the femtomol level in a few minutes in an easy and level-free way. This approach is particularly suitable for the detection of RNA molecules with predicted secondary structures, reaching a limit of detection of 50 fmol without any label or amplification steps. Our methodology has shown a marked enhancement for the detection (18% for short DNA and 54% for RNA), when compared with the conventional duplex approach, highlighting the large difficulty of the duplex approach to detect nucleic acid sequences, especially those exhibiting stable secondary structures. We believe that our strategy could be of great interest to the RNA field.

Effect of environmental manganese exposure on verbal learning and memory in Mexican children.

Manganese (Mn) is an essential metal, but in excess it becomes neurotoxic. Children's developing nervous system may be especially vulnerable to the neurotoxic effects of overexposure to this metal. The aim of this study was to assess the effect of Mn exposure on verbal memory and learning in 7- to 11-year-old children. We tested 79 children living in the Molango Mn-mining district and 95 children from a non-exposed community in the same State of Mexico. The Children's Auditory Verbal Learning Test (CAVLT) was administered. Blood and hair samples were obtained to determine Mn concentrations using atomic absorption spectrophotometry. CAVLT performance was compared between the two groups and multilevel regression models were constructed to estimate the association between biomarkers of Mn exposure and the CAVLT scores. The exposed group presented higher hair and blood Mn (p<0.001) than the non-exposed group (median 12.6 vs. 0.6µg/g, 9.5vs. 8.0µg/L respectively), as well as lower scores (p<0.001) for all the CAVLT subscales. Hair Mn was inversely associated with most CAVLT subscales, mainly those evaluating long-term memory and learning (ß=-0.47, 95% CI -0.84, -0.09). Blood Mn levels showed a negative but non-significant association with the CAVLT scores. These results suggest that Mn exposure has a negative effect on children's memory and learning abilities.

Comparative study of intact specimen extraction in laparoscopic nephrectomy by Pfannenstiel incision.

OBJECTIVES: The aim of our study is to demonstrate that the Pfannenstiel incision is a reliable option in terms of postoperative complications compared to other types of incisions usually performed for kidney extraction after laparoscopic nephrectomy. MATERIALS AND METHODS: Retrospective and comparative study of 256 patients who underwent laparoscopic nephrectomy or nephroureterectomy. Patients were divided into two groups: specimen extraction by Pfannenstiel incision (group 1) and specimen extraction by way of other incisions (group 2). Incisional hernia, surgical site infection, pain score, seroma, haematoma/bleeding, wound dehiscence and muscle paralysis were analyzed in each patient. RESULTS: Patients in Pfannenstiel group presented a rate of wound complications of 11.72% vs. 27.34% with other incisions, p=0.002, it was significantly inferior the rate of wound dehiscence (5.5% vs. 12.5%, p=0.047) and seroma (3.1% vs. 7.8%, p=0.022). Using multivariate logistic regression, Pfannenstiel incision was a significant protective predictor factor for wound complications (OR=0.34, p=0.005). CONCLUSIONS: The Pfannenstiel incision allowed the extraction of bigger kidney masses with less incidence of dehiscence, seroma and in general wound complications. The hospital stay was lower in Pfannenstiel extraction group. These results present this incision as a reliable and safe option in the decision of which incision to select.

Holmium laser enucleation of the prostate (HoLEP) as same-day surgery: A safe and feasible option.

OBJECTIVE: To study the feasibility of holmium laser enucleation (HoLEP) performed as a same-day surgery. MATERIAL AND METHODS: Prospective observational study including 25 patients submitted to HoLEP. Patients were discharged the same day if they met the established criteria. RESULTS: The mean age of the patients was 65.1 years and prostate volume was 45.8cc. All patients were discharged the same day of surgery. The overall complication rate at 30 days was 12% (Clavien I 100%). The rate of re-hospitalization was 0%. Patient satisfaction rate with the day surgery pathway was 95%. CONCLUSIONS: The initial analysis of our results suggests that outpatient HoLEP is a safe and effective alternative with low rate of complications. According to satisfaction rates, patients prefer the day surgery pathway for the performance of HoLEP.

Hypothyroidism reduces glutamate-synaptic release by ouabain depolarization in rat CA3-hippocampal region.

Thyroid hormones modulate the physiology of the hippocampus in humans, where glutamate plays an important role as neurotransmitter. The aim of this work was to study the effect of hypothyroidism on hippocampal glutamate extracellular levels, release, uptake, and synthesis. The effects of PDC (a glutamate transporter inhibitor) and ouabain (a Na(+) /K(+) -ATPase inhibitor) infusion on microdialysate glutamate and aspartate levels of CA3 hippocampal region were evaluated. Animals were assigned to one of the following groups: hypothyroid group (Hyp), receiving methimazole (anantithyroid drug); replacement group (Hyp + T(4) ), receiving antithyroid treatment plus thyroxine; and euthyroid control group (Eut). Dialysate fractions were collected every 15 min to determine basal glutamate levels for 1 hr. Then, PDC (10 mM) or ouabain (100 µM) was infused for 30 min. Results showed lower glutamate and aspartate basal levels in Hyp than in Eut groups. PDC infusion increased amino acids levels in all groups, whereas ouabain infusion increased glutamate and aspartate levels only in the Eut group. The infusion of tetrodotoxin (TTX; a voltage-gated sodium channel inhibitor) prevented the glutamate increase in euthyroid rats. The Hyp + T(4) group showed glutamate levels similar to those found in the Eut group. Additionally, glutaminase activity in hippocampus was lower in the Hyp group than in the Eut or Hyp + T(4) group. Results suggest that high-affinity glutamate transporters are not altered by hypothyroidism; however, decreased hypotyroidism reduced vesicular glutamate release in the CA3-hippocampal region as a consequence of diminished glutamate synthesis.

Effect of 17ß-estradiol on zinc content of hippocampal mossy fibers in ovariectomized adult rats.

Sex hormones such as estrogen (17ß-estradiol) may modulate the zinc content of the hippocampus during the female estrous cycle. The mossy fiber system is highly plastic in the adult brain and is influenced by multiple factors including learning, memory, and stress. However, whether 17ß-estradiol is able to modulate the morphological plasticity of the mossy fibers throughout the estrous cycle remains unknown. Ovariectomized (Ovx) female 70- to 90-day-old Sprague-Dawley rats without or with estrogen supplement (OvxE) were compared with control rats in three stages of the estrous cycle: diestrus, proestrus, and estrus. The brain tissue from each of the five groups was processed with Timm's silver sulfide technique using the Image J program to measure the mossy fiber area in the stratum lucidum of CA3. Total zinc in the hippocampus was measured using Graphite Furnace Atomic Absorption Spectrophotometry. Two additional (Ovx and OvxE) groups were examined in spatial learning and memory tasks using the Morris water maze. Similar increases in total zinc content and mossy fiber area were observed. The mossy fiber area decreased by 26 ± 2 % (difference ± SEM percentages) in Ovx and 23 ± 4 % in estrus as compared to the proestrus group and by 18 ± 2 % in Ovx compared to OvxE. Additionally, only the OvxE group learned and remembered the task. These results suggest that estradiol has a significant effect on zinc content in hippocampal CA3 during the proestrus stage of the estrous cycle and is associated with correct performance in learning and memory.

A phase 2, double-blind, placebo-controlled trial of a valproate/lithium combination in ALS patients.

BACKGROUND: Few treatments are currently available for amyotrophic lateral sclerosis (ALS). A combination of lithium carbonate and valproic acid (VPA-Li) was shown to inhibit motor neuron death and delay disease progression. METHODS: Outpatients with a typical ALS presentation were enrolled in a randomized, placebo-controlled trial to assess the efficacy of orally administered VPA-Li. Changes in a functional scale score (ALSFRS-R) and survival rate were chosen as primary outcome variables. Secondary outcome variables included BMI, respiratory monitoring, quality of life, and a global impression of the treatment. RESULTS: Out of 42 patients enrolled, 20 individuals receiving VPA-Li and 18 on placebo treatment were included in the final analysis. Forty-five percent of patients receiving VPA-Li completed the trial, whereas only 22.22% of patients in the placebo group attended the final visit 18 months later (P = 0.09). Major changes in the ALSFRS-R score were observed, including a decrease of 1.195 points/month in the placebo group (95% CI: 0.7869-1.6031) and of 0.5085 under VPA-Li treatment (95% CI: 0.2288-0.7882) between months 6 and 14. Adverse events included bad mouth taste, constipation, and anorexia. Survival rate, body weight, and quality of life were positive outcomes by the end of the trial despite a high sample reduction, especially in the placebo group. The inclusion of 212 subjects in each group would confirm these differences. CONCLUSIONS: Combined VPA-Li treatment associated with slower ALS progression and better secondary outcomes. This dual treatment overcame the futility threshold and merits further investigation in ALS.

Neurocognitive function in adult residents of a mining district in Mexico after reducing manganese exposure: Follow-up after 11 years.

BACKGROUND: Little is known about the neurotoxic effects of chronic exposure to airborne Mn once exposure has been reduced. The environmentally exposed and the reference adult populations evaluated in 2002 were followed, after an environmental management program (EMP) was implemented to reduce the exposure in a mining district in Mexico. OBJECTIVE: The aim of this study was to compare the association between exposure to Mn and neurocognitive performance in environmentally exposed and reference groups of adults before and after EMP implementation. METHODS: In 2013, the same battery of neurocognitive tests used in the initial study (2002) was applied to 58 adults exposed to airborne Mn and 30 adults from the reference community. A cumulative exposure index (CEI) was estimated for the study population before and after the EMP. Categorical outcomes were analyzed using logistic regression, and the resulting ORs were compared between studies. Continuous outcomes were analyzed using linear regression. All models were adjusted for age, years of education, socioeconomic status and blood lead levels. RESULTS: Exposed adults from the post-EMP study showed an improvement in fine motor and verbal regulation of motor skills (OR < 1) compared to the exposed adults from the pre-EMP study (OR > 1). In both pre- and post-studies, the exposed adults showed a deterioration in their dynamic organization of motor activity compared to the reference group (p < 0.05); however, they showed no significant change in attention and working-memory performance. DISCUSSION: After four years of a significant reduction in airborne Mn levels resulting from EMP implementation, chronically exposed adults showed an improvement in fine motor and verbal regulation of motor skills; however, the remaining areas of their motor and cognitive functions remained impaired.

Serum prolactin rises in Mexican school children exposed to airborne manganese.

Early studies on manganese (Mn) exposure have shown that this transition metal affects dopamine neurotransmission. Dopamine serves as a tonic inhibitor of prolactin release in the anterior hypophysis, thus the serum prolactin levels in occupationally Mn exposed workers has been found increased. However, little is known about environmental Mn exposure effect on this hormone. In the present study we assessed serum prolactin in environmentally (mainly through air) exposed children living in the proximity of a rich Mn zone in Mexico and a control group with similar socioeconomic and ethnic characteristics. We also determined Mn levels in blood and hair, hemoglobin and anthropometric variables. Children between 7 and 11 years old were included (77 from Mn exposed and 93 from control communities). Blood Mn was higher in exposed children (median 9.5 µg/L, rank [5.5, 18]) as compared to the control group (median 8 µg/L, rank [5, 14]) (p<0.05, Mann-Whitney). Hair Mn was also increased in the exposed group (median 13.2 µg/g, rank [4.2, 48]) in comparison to the control group (median 0.6 µg/g rank [0.06, 3.6]). Prolactin was found increased in the exposed children (median 12.35 ng/ml, rank [2.90, 33.70]) versus controls (median 7.77 ng/ml, rank [2.7, 23.6]). Positive correlations were found between prolactin and both blood Mn and hair Mn (Rho=0.217 and 0.250, respectively, p<0.05). A linear regression, with prolactin as the dependent variable, showed hair Mn as the determinant variable after adjusting by age, hemoglobin and sex. After a stratification of hair and blood Mn into low, medium and high content, significant associations were also found, confirming the relationship between prolactin and hair Mn. Results suggest that children from these Mn environmentally exposed communities could be at risk of endocrine alterations.

Total and bioavailable arsenic concentration in arid soils and its uptake by native plants from the pre-Andean zones in Chile.

Arsenic is the most important contaminant of the environment in northern Chile. Soil samples and plant organs from three native plant species, Pluchea absinthioides, Atriplex atacamensis and Lupinus microcarpus, were collected from arid zones in order to determine the total and bioavailable arsenic concentrations in soils and to assess the bioconcentration factor (BCF) and transport index (Ti) of arsenic in the plants. Total arsenic concentrations in soils (pH 8.3-8.5) where A. atacamensis and P. absinthioides were collected, reached levels considered to be contaminated (54.3 ± 15.4 and 52.9 ± 9.9 mg kg⁻¹, respectively), and these values were approximately ten times higher than in soils (pH 7.6) where L. microcarpus was collected. Bioavailable arsenic ranged from 0.18 to 0.42% of total arsenic concentration. In the three plant species, arsenic concentration in leaves were significantly (p ≤ 0.05) higher than in roots. L. microcarpus showed the highest arsenic concentration in its leaves (9.7 ± 1.6 mg kg⁻¹) and higher values of BCF (1.8) and Ti (6.1), indicating that this species has a greater capacity to accumulate and translocate the metalloid to the leaf than do the other species.

Imbalance between nitric oxide and dopamine may underly aggression in acute neurological patients.

The neurochemical basis of aggressive behavior in humans is not fully understood. In this study we explored the relationship between aggressiveness (as measured by the Overt Aggression Scale), cognitive performance (as measured by the Mini Mental State Examination), and biochemical markers of dopamine neurotransmission (homovanillic acid, HVA) and nitric oxide synthesis (nitrite plus nitrate, NO(x)) in cerebrospinal fluid from 70 patients with acute brain disorders, mainly brain infections. Aggressive behavior and cognitive performance showed an inverse correlation. NO(x)/HVA ratio was inversely correlated to aggressive behavior, and positively correlated to cognitive performance. A subanalysis with antipsychotic-naïve patients confirmed those results. The balance between nitric oxide and dopamine could be related to the cognitive control of aggressive impulse.

Glutamine and citrulline concentrations reflect nitric oxide synthesis in the human nervous system. / Las concentraciones de glutamina y citrulina reflejan la síntesis del óxido nítrico en el sistema nervioso humano.

INTRODUCTION: Although citrulline is produced by nitric oxide (NO) synthase upon activation of the NMDA glutamate receptor, nitrite and nitrate (NOx) concentration is considered the best marker of NO synthesis, as citrulline is also metabolised by other enzymes. This study analyses the correlation between human cerebrospinal fluid NOx and citrulline concentrations in order to determine the extent to which citrulline reflects NO synthesis and glutamatergic neurotransmission. METHODS: Participants were patients with acute neurological diseases undergoing lumbar puncture (n=240). NOx and amino acid concentrations were determined by HPLC. RESULTS: NOx concentrations did not vary significantly where infection (p=0,110) or inflammation (p=0,349) were present. Multiple regression analysis showed that NOx concentration was correlated with glutamine (r=-0,319, p<0,001) and citrulline concentrations (r=0,293, p=0,005) but not with the citrulline/arginine ratio (r=-0,160, p=0,173). ANCOVA confirmed that NOx concentration was correlated with citrulline concentration (F=7,6, p=0,007) but not with the citrulline/arginine ratio (F=2,2, p=0,136), or presence of infection (F=1,8, p=0,173) or inflammation (F=1,4, p=0,227). No association was found between NOx and arginine or glutamate concentrations. CONCLUSION: The results suggest that CSF citrulline concentration reflects NOx synthesis to some extent, despite the contribution of other metabolic pathways. In addition, this study shows that glutamine is an important modulator of NO synthase activity, and that arginine and glutamate are not correlated with NOx.

Psoralen plus ultraviolet A +/- interferon-alpha treatment resistance in mycosis fungoides: the role of tumour microenvironment, nuclear transcription factor-kappaB and T-cell receptor pathways.

BACKGROUND: Interferon (IFN)-alpha is widely used in the treatment of mycosis fungoides (MF) and when used in combination with photochemotherapy (psoralen plus ultraviolet A, PUVA) both improved response and duration of complete remission have been reported. However, in spite of encouraging results of the initial studies, currently there is no information available on specific prognostic factors enabling prediction of patients' resistance to PUVA +/- IFN-alpha treatment. OBJECTIVES: To identify factors responsible for resistance to PUVA +/- IFN-alpha treatment in MF patients. PATIENTS/METHODS: The gene expression profiling of pretreatment samples from 29 patients diagnosed as IA, IB or IIA stage of MF enrolled in a randomized PUVA vs. PUVA + IFN-alpha clinical trial was analysed using cDNA microarrays. A Cox model (SAM) and gene set enrichment analysis (GSEA) were used for identification of genes and biologically significant pathways related to resistance to treatment. RESULTS: Genes involved in NF-kappaB signalling, T-cell receptor (TCR) signalling, cytokine signalling and proliferation were differentially expressed between responders and nonresponders. Interestingly, expression of markers representative of those pathways was found not only in the tumoral cells, but also in specific subpopulations of macrophages, dendritic cells and other non-neoplastic cell types constituting the tumour microenvironment, likely involved in the promotion of survival and proliferation of cutaneous T-cell lymphoma. CONCLUSIONS: Gene expression changes in both the tumour and the tumour microenvironment are an important determinant of treatment outcome in early-stage MF patients. Some proinflammatory factors such as NF-kappaB, inflammatory cytokines and their receptors in addition to TCR-associated molecules could be promising targets for MF treatment.

Verbal Memory and Learning in Schoolchildren Exposed to Manganese in Mexico.

Manganese (Mn) is an essential nutrient for cellular function, but in high concentrations, it is neurotoxic. Environmental exposure to Mn has been associated with cognitive effects in children. This study aimed to assess the effect of environmental exposure to Mn on verbal memory and learning in schoolchildren residents from two municipalities in the state of Hidalgo, Mexico. Cross-sectional studies were conducted in 2006 and 2013 with a total of 265 schoolchildren of 7 to 11 years old. Children's Auditory Verbal Learning Test-2 (CAVLT-2) was used to assess verbal memory and learning. Mn exposure tertiles were defined according to hair manganese (MnH) levels determined by atomic absorption spectrophotometry. Linear regression models were used to estimate the association between MnH levels and CAVLT-2 scores. The models were adjusted by potential confounders. The lowest and highest exposure tertiles were defined below and above MnH levels of ≤ 0.72 and ≥ 3.96 µg/g, respectively. Mn exposure was significantly associated with an average of 5- to 9-point decrease in learning curves and summary CAVLT-2 scores in the highest tertile. This study adds to the evidence of decreased verbal memory and learning in schoolchildren environmentally exposed to manganese.