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Abstract Background Tackling social impacts derived from gender disparities is a pathway to universal health coverage (UHC). Gender intersects with other factors behind social and health inequalities, exacerbates them and influences health systems’ performance. However, there is scarcity of gender-based studies that assess the social and economic impacts of non-communicable diseases (NCDs). This study aims to identify economic and social impacts of NCDs by gender and its correlates. Methods Following the guidelines proposed in the Cochrane Manual for Systematic Reviews of Interventions and the PRISMA Statement, we conducted a narrative and structured literature review to identify the economic (direct medical and non-medical, and indirect costs) and social (right to health, employment, poverty, social exclusion, and others) impacts of NCDs by gender, and its structural, sociodemographic, health conditions, political and health systems correlates, for the period 2002–2022, in English and Spanish. Reviewed studies were described according to country and research context, temporal evolution, gender, impacts of NCDs and correlates. Findings Five thousand five hundred fifty-one publications by title and abstract were reviewed, and 185 articles were selected. There is limited evidence with gender perspective addressing the social and economic impacts of NCDs (around 10% of publications) that helps to better understand the difference in the burden of these conditions between men and women. We identified that the social burden primarily affects women in their quality of life, where gender inequities are observed in aspects such as: health care, employment status and living conditions. In addition, a greater responsibility falls on them as caregivers. On the other hand, the economic burden affects more to men, both in terms of direct medical costs and indirect costs. Among the factors that most influenced the identified impacts, we found gender, age, and socioeconomic level. We also identified that access to health insurance that offers financial protection against these conditions is essential to reduce these impacts. Conclusions NCDs pose a significant social and economic burden due to their impact on the health of the population, healthcare systems, and the economies of households and nations, which will likely increase over time. This impact is closely related to gender, although it has been scarcely documented. Public policies aimed at enhancing access and achieving UHC are essential to guarantee effective financial protection in health, especially for the most vulnerable sectors of the population.

Wildfires are recognized as major contributors to forest loss and soil degradation on a global scale. Understanding the cumulative effects of fire regimes on forest ecosystems and soil dynamics necessitates a deeper exploration of wildfire-vegetation-soil interactions over the long term. This study delves into the wildfire-landscape dynamics within the “Baixa Limia Serra do Xurés” Natural Park, a region prone to fires in Galicia, Spain. By analyzing available statistical and remote sensing data, we identified significant shifts in fire regimes and landscape dynamics between the periods of 2000–2010 and 2010–2020. Our findings indicate a potential extension of the fire season, reflecting the impacts of climate change. Despite improvements in firefighting capabilities, the occurrence of large fires is on the rise in the Natural Park, underscoring the need for proactive management strategies in such areas. Notably, significant fire events in 2011, 2016, 2017, and 2020 extensively affected wooded areas, constituting the majority of the burned area. Shrubs and forests emerged as particularly vulnerable, with varying degrees of burn severity influencing post-fire vegetation recovery rates. While shrublands expanded their coverage between 2000 and 2010, rocky areas with sparse vegetation showed an increase over the subsequent decade (2010–2020), indicating soil degradation and potential desertification in areas affected by recurrent and severe fires, especially within zones designated for the highest levels of protection (with fire rotation periods of less than 1 year). In conclusion, this study provides valuable insights into the impacts of wildfires, changes in land cover, and post-fire soil-vegetation dynamics, which can inform management and conservation efforts in fire-prone mountainous regions. Leveraging advanced remote sensing techniques enables the monitoring of cumulative soil degradation resulting from repeated wildfires over extended periods.

Hydrogels have shown promise in improving soil quality and alleviating plant drought stress. This study investigated the effectiveness of four hydrogel composites composed of polyvinyl alcohol, sodium alginate, and pine or olive tree biochar in improving bean (Phaseolus vulgaris) plant growth and soil microbial activities. The experiment was conducted in natural soil, where biochar–hydrogel composites were applied at a concentration of 0.75% hydrogel per soil weight (w/w) for 35 days under two different moisture conditions: adequate moisture (70% of water holding capacity (WHC)) and drought stress (40% WHC). The results showed variation between hydrogel composites and, more importantly, between water regimes. Under water deficit conditions, biochar–hydrogel composites consistently caused a decrease in plant weight and in chlorophyll (CHL) CHLa/CHLb ratio. Furthermore, antioxidant enzyme activities and malondialdehyde and protein levels generally increased in contrast to the observations at 70% WHC. Regarding microbial activities, the composites reduced soil respiration (12–38%) while promoting phosphatase activity (42–65%) under both moisture regimes. Overall, the introduction of hydrogel composites did not show consistently positive effects on either plants or soil microorganisms. To thoroughly evaluate the efficacy of these hydrogels as soil amendments, further studies are needed, considering different soil types, plant species, and hydrogel application rates.

Following spinal cord injury (SCI), the regenerative capacity of the central nervous system (CNS) is severely limited by the failure of axonal regeneration. The regeneration of CNS axons has been shown to occur by grafting predegenerated peripheral nerves (PPNs) and to be promoted by the transplantation of neural precursor cells (NPCs). The introduction of a combinatorial treatment of PPNs and NPCs after SCI has to address the additional problem of glial scar formation, which prevents regenerating axons from leaving the implant and making functional connections. Previously, we discovered that the synthetic sulfoglycolipid Tol-51 inhibits astrogliosis. The objective was to evaluate axonal regeneration and locomotor function improvement after SCI in rats treated with a combination of PPN, NPC, and Tol-51. One month after SCI, the scar tissue was removed and replaced with segments of PPN or PPN+Tol-51; PPN+NPC+Tol-51. The transplantation of a PPN segment favors regenerative axonal growth; in combination with Tol-51 and NPC, 30% of the labeled descending corticospinal axons were able to grow through the PPN and penetrate the caudal spinal cord. The animals treated with PPN showed significantly better motor function. Our data demonstrate that PPN implants plus NPC and Tol-51 allow successful axonal regeneration in the CNS.

Abstract Glycolysis is the metabolic pathway that converts glucose into pyruvate. Central nervous system (CNS) pathologies, such as spinal cord injury (SCI) and ischemia, are accompanied by an increase of the glycolytic pathway in the damaged areas as part of the inflammatory response. Pyruvate kinase is a key glycolytic enzyme that converts phosphoenolpyruvate and ADP to pyruvate and ATP. The protein has two isoforms, PKM1 and PKM2, originated from the same gene. As a homodimer, PKM2 loses the pyruvate kinase activity and acts as a transcription factor that regulates the expression of target genes involved in glycolysis and inflammation. After SCI, resident microglia and hematogenous macrophages are key inducers of the inflammatory response with deleterious effects. Activation of the bile acid receptor TGR5 inhibits the pro-inflammatory NFκB pathway in microglia and macrophages. In the present study we have investigated whether bile acids affect the expression of glycolytic enzymes and their regulation by PKM2. Bacterial lipopolysaccharide (LPS) induced the expression of PKM1, PKM2 and its target genes in primary cultures of microglial and Raw264.7 macrophage cells. SCI caused an increase of PKM2 immunoreactivity in macrophages after SCI. Pretreatment with tauroursodeoxycholic acid (TUDCA) or taurolithocholic acid (TLCA) reduced the expression of PKM2 and its target genes in cell cultures. Similarly, after SCI, TUDCA treatment reduced the expression of PKM2 in the lesion center. These results confirm the importance of PKM2 in the inflammatory response in CNS pathologies and indicate a new mechanism of bile acids as regulators of PKM2 pathway.

Hypoglycemia unawereness is a complication of type 1 diabetes treatment and of type 2 diabetes treatment treated with insulin or sulfonylureas, characterized by a reduced ability to perceive the onset of episodes of hypoglycemia. In general, it coexists with an insufficient counterregulatory hormonal response to hypoglycemia called: hypoglycemia associated autonomic failure (HAAF). The development of hypoglycemia unawereness and counterregulatory failure to hypoglycemia significantly increase the risk of severe hypoglycemia. Scoring scales have been developed to identify this group of people at high risk of severe hypoglycemia in the clinic. The cornerstone of treatment is to avoid hypoglycemia through a multifactorial intervention of clinical care and structured education.

The use of zinc oxide nanoparticles (ZnO NPs), applied as a possible micronutrient source, in conjunction with organic pesticides in agricultural soils has the potential to alter the environmental behavior and toxicity of these chemicals to soil biota. This research examines the joint effects of ZnO NPs and the herbicide metribuzin (MTZ) on phytotoxicity to plants, toxicity to soil microorganisms, and the accumulation of Zn and MTZ in plants. After 23 days, effects on growth, photosynthetic pigment content, and oxidative stress biomarkers in bean plants (Phaseolus vulgaris) and soil enzymatic activities were evaluated. Additionally, the amounts of Zn and MTZ (and the latter’s main metabolites) in soil and plant tissues were quantified. ZnO NPs reduced ammonium oxidase activity and growth among MTZ-stressed plants while reducing photosynthetic pigment levels and enhancing antioxidant enzymatic activities. MTZ had a marginal impact on the availability and accumulation of Zn in plant tissues, although significant effects were observed in some specific cases. In turn, ZnO NPs drastically affected MTZ degradation in soil and influenced MTZ accumulation/metabolization in the bean plants. Our findings indicate that the indirect effects of ZnO NPs, through their interaction with commonly used organic pesticides, may be relevant and should be taken into account in agricultural soils.

Introduction: several studies have suggested that low and high birth weight are associated with obesity (OB) and overweight (OW) during childhood and adulthood. Objectives: to determine the association between birth weight and OB in 9-year-old schoolchildren from three areas of Argentina. Materials an methods: anthropometric measurements and blood pressure (BP) were taken in 1.131 schoolchildren (505 males) of an average age of 8.8±2.1 years in three areas of Argentina during 2019. Mothers were asked about their children’s birth weight and lifestyle. Results: 21.1% (239) of the children had OW (BMI>85 95 percentile). The prevalence of low birth weight (4.000 g) was 7.3% (n=82). The 9-year-old z-BMI score increased significantly with increasing birth weight: low birth weight (z-BMI=0.33), normal (z-BMI=0.72) and high (z-BMI=1.12). In multiple logistic regression models, it was found that low birth weight was inversely associated with OB (OR, 0.41 [95% CI: 0.19-0.92]), while high birth weight was directly associated with OB adjusted for age and sex (OR, 2.48 [95% CI 1.53-4.02]). Conclusions: our data indicate that high birth weight, but not low birth weight, is associated with OB in 9-year-old schoolchildren, while low birth weight is inversely associated with OB.

Objetivo. Estimar las prevalencias municipales de mala nutrición en población preescolar en México, y describir su variabilidad y su relación con la cobertura del Programa Nacional México Sin Hambre. Material y métodos. A partir de datos de la Encuesta Nacional de Salud y Nutrición de 2012, la desigualdad del ingreso y marginación municipal se aplicó un modelo normal generalizado para obtener las distribuciones municipales de los indicadores de nutrición y estimar las prevalencias de mala nutrición. Resultados. Las prevalencias de talla baja variaron de 7.8% (IC95%: 5.9-8.9) a 64.2% (49.2-72.5), las de bajo peso de 0.6% (0.005-1.7) a 22.2% (13.5-34.9) y de sobrepeso u obesidad de 2.6% (0.2- 3.9) a 14.4% (11.9-27.7). De los 554 municipios con prevalencias de talla baja mayor que 25%, 275 fueron cubiertos por el programa México Sin Hambre. Conclusiones. La estimación de prevalencias municipales de mala nutrición evidenció grandes diferencias al interior del país, mismas que podrían asistir la política pública.

A pot experiment was conducted to determine the influence of commercial nanoparticles (ZnO-NPs) at different doses for use as nanofertilizer on nutrient uptake and its distribution in cherry tomato (Solanum lycopersicum L var. cerasiforme) plants in an acidic (soil pH 5.5) and calcareous soil (soil pH 8.5) from the Mediterranean area. We determined crop yield; macro- (N, P, K, Mg, S and Ca) and micro-nutrient (B, Cu, Fe, Mn, Na and Zn) concentrations in the different parts of the crop (root, stem, leaves and tomato fruits) and the extent of nutrient translocation to the aerial part of the plant. The concentrations of macronutrients N, P, K and Mg in tomato fruits grown in both soils can be considered adequate in terms of nutritional requirements. However, the Ca concentration in tomato fruits grown in the calcareous soil did not reach the required concentration to be considered sufficient. This effect was related to the characteristics of this calcareous soil. Although different concentrations of ZnO-NPs did not affect Fe and Na concentrations in tomato fruit, B concentration in tomato fruits increased with the application of ZnO-NPs. In addition, Cu concentration decreased with the application of ZnO-NPs compared to treatments without any Zn application (Nil-ZnO NP) in the calcareous soil. Manganese concentrations decreased with ZnO-NPs application in both soils. The effect of the application of ZnO-NPs depends on soil characteristics. Zinc applied as a nanofertilizer in the form of ZnO-NPs can be used to increase the crop yield and to obtain an adequate Zn biofortification in cherry tomato crop. The Zn concentrations in tomato fruits reached ranges of 4.5–4.8 mg Zn kg−1 in the acidic soil and 2.5–3,5 mg Zn kg−1 in the calcareous soil. Nutrient concentrations in these fruits following biofortification are adequate for human consumption.

Objective. To provide an overview of morbidity and mor­tality due to acute diarrheal disease in Mexico in order to understand its magnitude, distribution, and evolution from 2000 to 2016. Materials and methods. We carried out a longitudinal ecological study with secondary sources of information. We used data from epidemiological surveillance, health services, and vital statistics. We calculated and mapped measures of utilization of health services rates and mortal­ity due to diarrheal diseases. Results. Diarrhea morbidity decreased by 42.1% across the period. However, emergency department attendances increased by 50.7% in the Ministry of Health. The hospitalization rate and mortality among the gen­eral population decreased by 37.6 and 39.7%, respectively, and the infant mortality rate decreased by 72.3% among children under five years of age. Chiapas and Oaxaca had the highest mortality among the states of Mexico. Conclusions. Cases of diarrhea, including rotavirus, have decreased in Mexico. However, in 2016, 3.4 per 100 000 people died due to diar­rhea, which could have been avoided with health promotion.

Abstract Background The importance of submicroscopic malaria infections in high-transmission areas could contribute to maintain the parasite cycle. Regarding non-endemic areas, its importance remains barely understood because parasitaemia in these afebrile patients is usually below the detection limits for microscopy, hence molecular techniques are often needed for its diagnosis. In addition to this, the lack of standardized protocols for the screening of submicroscopic malaria in immigrants from endemic areas may underestimate the infection with Plasmodium spp. The aim of this study was to assess the prevalence of submicroscopic malaria in afebrile immigrants living in a non-endemic area. Methods A prospective, observational, multicentre study was conducted. Afebrile immigrants were included, microscopic observation of Giemsa-stained thin and thick blood smears, and two different molecular techniques detecting Plasmodium spp. were performed. Patients with submicroscopic malaria were defined as patients with negative blood smears and detection of DNA of Plasmodium spp. with one or both molecular techniques. Demographic, clinical, analytical and microbiological features were recorded and univariate analysis by subgroups was carried out with STATA v15. Results A total of 244 afebrile immigrants were included in the study. Of them, 14 had a submicroscopic malaria infection, yielding a prevalence of 5.7% (95% confidence interval 3.45–9.40). In 71.4% of the positive PCR/negative microscopy cases, Plasmodium falciparum alone was the main detected species (10 out of the 14 patients) and in 4 cases (28.6%) Plasmodium vivax or Plasmodium ovale were detected. One patient had a mixed infection including three different species. Conclusions The prevalence of submicroscopic malaria in afebrile immigrants was similar to that previously described in Spain. Plasmodium vivax and P. ovale were detected in almost a third of the submicroscopic infections. Screening protocols for afebrile immigrants with molecular techniques could be useful for a proper management of these patients.

Metribuzin is a pre- and post-emergence triazinone herbicide used in a variety of crops. This herbicide is degraded in the environment into three major metabolites that have high water solubility, high to very high soil mobility, and low to moderate persistence in soil. This paper describes the development of an analytical method based on ultrasound-assisted extraction and GC-MS/MS determination for the determination metribuzin and its main metabolites in soil and plants. The developed method provided good recoveries for all compounds in soil and plants (from 73 to 121%). The quantitation limits obtained from plants (2.6 to 18 µg/kg) allow determining the presence of these compounds at trace levels. To evaluate the applicability of the developed methods, bean plants were grown in plastic pots with soil treated with metribuzin and collected after 23 days. At the end of the assay, only 11% of the initial concentration of metribuzin remained in soil. Metribuzin and its three metabolites were detected in plants, desamino-diketo-metribuzin is the most abundant metabolite. It is expected that the application of these methods can provide more data to monitor metribuzin residues due to herbicide treatments.

ZnO nanoparticles (ZnO-NPs) can reach soil in both deliberate and non-deliberate ways, which leads to contamination. Notwithstanding knowledge about ZnO-NPs impacts on earthworms inhabiting these soils is limited and gaps appear in the recovery of damaged functions after their migration to unpolluted environments. To estimate these impacts, earthworms (Eisenia andrei) were exposed to different concentrations of coated ZnO-NPs (20, 250, 500, 1000 mgZnkg−1) in an acidic agricultural soil (pH 5.4) for 28 days. Subsequently, earthworms were placed in the same unpolluted soil to study the depletion of Zn accumulated and the recovery potential of the affected functions for another 28-day period.In the exposure phase, ecotoxicological responses were dose-dependent. Mortality and growth were affected at 500 and 1000 mg kg− 1, and the reproduction was impaired from 250 mgZnkg− 1 compared to control (54% fecundity and 80% fertility reduction). Zn uptake increased with coated ZnO-NPs in soil but it did not exceed 163 mgZnkg− 1 earthworm. During the recovery period, the Zn in earthworms were similar to the control regardless of the initially Zn accumulated. Reproduction parameters returned to the control values in the animals pre-exposed to 250 mgZnkg− 1 as coated ZnO-NP. In the earthworms preexposed to the two highest doses, growth and fertility were stimulated compared to the control when placed in clean soil, but not fecundity. However, the total hatchlings number did not reach the control figures after 28 days, but probably would for in longer times, which would be key for maintaining earthworm populations.

The bile acid tauroursodeoxycholic acid (TUDCA) reduces cell death under oxidative stress and inflammation. Implants of bone marrow-derived stromal cells (bmSC) are currently under investigation in clinical trials of spinal cord injury (SCI). Since cell death of injected bmSC limits the efficacy of this treatment, the cytoprotective effect of TUDCA may enhance its benefit. We therefore studied the therapeutic effect of TUDCA and its use as a combinatorial treatment with human bmSC in a rat model of SCI. A spinal cord contusion injury was induced at thoracic level T9. Treatment consisted of i.p. injections of TUDCA alone or in combination with one injection of human bmSC into the cisterna magna. The recovery of motor functions was assessed during a surveillance period of six weeks. Biochemical and histological analysis of spinal cord tissue confirmed the anti-inflammatory activity of TUDCA. Treatment improved the recovery of autonomic bladder control and had a positive effect on motor functions in the subacute phase, however, benefits were only transient, such that no significant differences between vehicle and TUDCA-treated animals were observed 1–6 weeks after the lesion. Combinatorial treatment with TUDCA and bmSC failed to have an additional effect compared to treatment with bmSC only. Our data do not support the use of TUDCA as a treatment of SCI.

The antioxidant and CB2 receptor agonist properties of Δ9-tetrahydrocannabivarin (Δ9-THCV) afforded neuroprotection in experimental Parkinson's disease (PD), whereas its CB1 receptor antagonist profile at doses lower than 5 mg/kg caused anti-hypokinetic effects. In the present study, we investigated the anti-dyskinetic potential of Δ9-THCV (administered i.p. at 2 mg/kg for two weeks), which had not been investigated before. This objective was investigated after inducing dyskinesia by repeated administration of L-DOPA (i.p. at 10 mg/kg) in a genetic model of dopaminergic deficiency, Pitx3ak mutant mice, which serves as a useful model for testing anti-dyskinetic agents. The daily treatment of these mice with L-DOPA for two weeks progressively increased the time spent in abnormal involuntary movements (AIMs) and elevated their horizontal and vertical activities (as measured in a computer-aided actimeter), signs that reflected the dyskinetic state of these mice. Interestingly, when combined with L-DOPA from the first injection, Δ9-THCV delayed the appearance of all these signs and decreased their intensity, with a reduction in the levels of FosB protein and the histone pAcH3 (measured by immunohistochemistry), which had previously been found to be elevated in the basal ganglia in L-DOPA-induced dyskinesia. In addition to the anti-dyskinetic effects of Δ9-THCV when administered at the onset of L-DOPA treatment, Δ9-THCV was also effective in attenuating the intensity of dyskinesia when administered for three consecutive days once these signs were already present (two weeks after the onset of L-DOPA treatment). In summary, our data support the anti-dyskinetic potential of Δ9-THCV, both to delay the occurrence and to attenuate the magnitude of dyskinetic signs. Although further studies are clearly required to determine the clinical significance of these data in humans, the results nevertheless situate Δ9-THCV in a promising position for developing a cannabinoid-based therapy for patients with PD.

Blood culture negative endocarditis (BCNE) is frequent in infective endocarditis (IE). One of the causes of BCNE is fastidious microorganisms, such as Bartonella spp. The aim of this study was to describe the epidemiologic, clinical characteristics, management and outcomes of patients with Bartonella IE from the “Spanish Collaboration on Endocarditis-Grupo de Apoyo al Manejo de la Endocarditis infecciosa en España (GAMES)”cohort. Here we presented 21 cases of Bartonella IE. This represents 0.3% of a total of 5590 cases and 2% of the BCNE from the GAMES cohort. 62% were due to Bartonella henselae and 38% to Bartonella quintana. Cardiac failure was the main presenting form (61.5% in B. hensalae, 87.5% in B. quintana IE) and the aortic valve was affected in 85% of the cases (76% in B. henselae, 100% in B. quintana IE). Typical signs such as fever were recorded in less than 40% of patients. Echocardiography showed vegetations in 92% and 100% of the patients with B. henselae and B. quintana, respectively. Culture was positive only in one patient and the remaining were diagnosed by serology and PCR. PCR was the most useful tool allowing for diagnosis in 16 patients (100% of the studied valves). Serology, at titers recommended by guidelines, only coincided with PCR in 52.4%. Antimicrobial therapy, in different combinations, was used in all cases. Surgery was performed in 76% of the patients. No in-hospital mortality was observed. One-year mortality was 9.4%. This article remarks the importance for investigating the presence of Bartonella infection as causative agent in all BCNE since the diagnosis needs specific microbiological tools and patients could benefit of a specific treatment.

During recent decades, a tick-borne rickettsial syndrome, characterized by eschar and painful lymphadenopathy after Dermacentor marginatus-bite, has been described as an emerging rickettsiosis in Europe. Our group named it DEBONEL (Dermacentor-borne-necrosis-erythema-lymphadenopathy), regarding the vector and the main infection signs. Other groups called it TIBOLA (tick-borne-lymphadenophathy) and, later, SENLAT (scalp-eschar-and-neck-lymphadenopathy-after-tick-bite), expanding, in the latter, the etiological spectrum to other pathogens. Objective: To investigate the etiology of DEBONEL agents in our area, and to compare their epidemiological/clinical/microbiological characteristics. During 2001–2020, 216 patients clinically diagnosed of DEBONEL (the largest series from one center) in La Rioja (northern Spain) were examined. Rickettsia spp. were amplified in 14/104 (13.46%) blood samples, 69/142 (48.59%) eschar swabs, 7/7 (100%) biopsies, and 71/71 (100%) D. marginatus from patients. For samples in which Rickettsia was undetected, no other microorganisms were found. ‘Candidatus Rickettsia rioja’, Rickettsia slovaca, Rickettsia raoultii, and Rickettsia DmS1 genotype were detected in 91, 66, 4, and 3 patients, respectively. DEBONEL should be considered in patients with clinical manifestations herein described in areas associated to Dermacentor. The most frequently involved agent in our environment is ‘Ca. R. rioja’. The finding of Rickettsia sp. DmS1 in ticks attached to DEBONEL patients suggests the implication of other rickettsia genotypes.

Chronic neuropathy is the most prevalent of the diabetic complications. Distal and symmetric sensitive polyneuropathy, and autonomic compromise, particularly cardiac autonomic neuropathy,are the most studied; occasionally they are asymptomatic. Like diabetic patients, prediabetics can also develop neuropathy. Prevention is a key component in these complications. Autonomic neuropathy affects several body´s organs and systems. Our goal is to describe those less known clinical manifestations, and because of this, less considered complications that affect cardiovascular, gastrointestinal system and bladder functioning.

ABSTRACT Background: non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developed countries. Lifestyle changes are the pillar of the treatment, although a pharmacological approach is sometimes required in the case of a failure to respond/adhere to the diet. Objective: the aim of this study was to evaluate the effect of silymarin and the influence of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) variant on the response to treatment in patients with NAFLD in a pilot study. Methods: a total of 54 patients with a NAFLD proven biopsy were enrolled in an open prospective study and were treated with Eurosil 85(r) (silymarin + vitamin E) for six months. Biochemical parameters and cardiovascular risk factors (diabetes mellitus, dyslipidemia, hypertriglyceridemia, arterial hypertension and HOMA-IR > 2.5) were recorded before and after six months of treatment. Non-invasive indexes (fatty liver index, lipid accumulation product and NAFLD-fibrosis score) were also calculated. The rs738409 PNPLA3 gene polymorphism status was also determined. Results: significant statistical changes from baseline values after six months of treatment were observed in transaminases levels but not in non-invasive index markers. Twenty patients (37.1%) were G allele carriers and had a higher percentage of lobular inflammation and ballooning on the basal liver biopsy. Patients with the G allele had a smaller decrease in transaminases levels after treatment with silymarin + vitamin E than non-G-allele carriers. Conclusions: treatment with silymarin + vitamin E produced a decrease in transaminases after six months of treatment without an accompanying weight loss. PNPLA3 G-allele carriers responded poorly to the treatment.

Cannabinoids act as pleiotropic compounds exerting, among others, a broad-spectrum of neuroprotective effects. These effects have been investigated in the last years in different preclinical models of neurodegeneration, with the cannabinoid type-1 (CB1) and type-2 (CB2) receptors concentrating an important part of this research. However, the issue has also been extended to additional targets that are also active for cannabinoids, such as the orphan G-protein receptor 55 (GPR55). In the present study, we investigated the neuroprotective potential of VCE-006.1, a chromenopyrazole derivative with biased orthosteric and positive allosteric modulator activity at GPR55, in murine models of two neurodegenerative diseases. First, we proved that VCE-006.1 alone could induce ERK1/2 activation and calcium mobilization, as well as increase cAMP response but only in the presence of lysophosphatidyl inositol. Next, we investigated this compound administered chronically in two neurotoxin-based models of Parkinson’s disease (PD), as well as in some cell-based models. VCE-006.1 was active in reversing the motor defects caused by 6-hydroxydopamine (6-OHDA) in the pole and the cylinder rearing tests, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity detected in the substantia nigra. Similar cytoprotective effects were found in vitro in SH-SY5Y cells exposed to 6-OHDA. We also investigated VCE-006.1 in LPS-lesioned mice with similar beneficial effects, except against glial reactivity and associated inflammatory events, which remained unaltered, a fact confirmed in BV2 cells treated with LPS and VCE-006.1. We also analyzed GPR55 in these in vivo models with no changes in its gene expression, although GPR55 was down-regulated in BV2 cells treated with LPS, which may explain the lack of efficacy of VCE-006.1 in such an assay. Furthermore, we investigated VCE-006.1 in two genetic models of amyotrophic lateral sclerosis (ALS), mutant SOD1, or TDP-43 transgenic mice. Neither the neurological decline nor the deteriorated rotarod performance were prevented with this compound, and the same happened with the elevated microglial and astroglial reactivities, albeit modest spinal motor neuron preservation was achieved in both models. We also analyzed GPR55 in these in vivo models and found no changes in both TDP-43 transgenic and mSOD1 mice. Therefore, our findings support the view that targeting the GPR55 may afford neuroprotection in experimental PD, but not in ALS, thus stressing the specificities for the development of cannabinoid-based therapies in the different neurodegenerative disorders.

Infective endocarditis (IE) is a severe and life-threatening disease. Identification of infectious etiology is essential for establishing the appropriate antimicrobial treatment and decreasing mortality. The aim of this study was to explore the potential utility of metataxonomics for improving microbiological diagnosis of IE. Here, next-generation sequencing (NGS) of the V3–V4 region of the 16S rRNA gene was performed in 27 heart valve tissues (18 natives, 5 intravascular devices, and 4 prosthetics) from 27 patients diagnosed with IE (4 of them with negative blood cultures). Metataxonomics matched with conventional diagnostic techniques in 24/27 cases (88.9%). The same bacterial family was assigned to 24 cases; the same genus, to 23 cases; and the same species, to 13 cases. In 22 of them, the etiological agent was represented by percentages > 99% of the reads and in two cases, by ~70%. Staphylococcus aureus was detected in a previously microbiological undiagnosed patient. Thus, microbiological diagnosis with 16S rRNA gene targeted-NGS was possible in one more sample than using traditional techniques. The remaining two patients showed no coincidence between traditional and 16S rRNA gene-targeted NGS microbiological diagnoses. In addition, 16S rRNA gene-targeted NGS allowed us to suggest coinfections that were supported by clinical data in one patient, and minority records also verified mixed infections in three cases. In our series, metataxonomics was valid for the identification of the causative agents, although more studies are needed before implementation of 16S rRNA gene-targeted NGS for the diagnosis of IE.

Abstract Background Neuroprotection with cannabinoids in Parkinson’s disease (PD) has been afforded predominantly with antioxidant or anti-inflammatory cannabinoids. In the present study, we investigated the anti-inflammatory and neuroprotective properties of VCE-003.2, a quinone derivative of the non-psychotrophic phytocannabinoid cannabigerol (CBG), which may derive its activity at the peroxisome proliferator-activated receptor-γ (PPARγ). The compound is also an antioxidant. Methods We evaluated VCE-003.2 in an in vivo [mice subjected to unilateral intrastriatal injections of lipopolysaccharide (LPS)] model of PD, as well as in in vitro (LPS-exposed BV2 cells and M-213 cells treated with conditioned media generated from LPS-exposed BV2 cells) cellular models. The type of interaction of VCE-003.2 at the PPARγ receptor was furtherly investigated in bone marrow-derived human mesenchymal stem cells (MSCs) and sustained with transcriptional assays and in silico docking studies. Results VCE-003.2 has no activity at the cannabinoid receptors, a fact that we confirmed in this study using competition studies. The administration of VCE-003.2 to LPS-lesioned mice attenuated the loss of tyrosine hydroxylase (TH)-containing nigrostriatal neurons and, in particular, the intense microgliosis provoked by LPS in the substantia nigra, measured by Iba-1/Cd68 immunostaining. The analysis by qPCR of proinflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and inducible nitric oxide synthase (iNOS) in the striatum showed they were markedly elevated by the LPS lesion and strongly reduced by the treatment with VCE-003.2. The effects of VCE-003.2 in LPS-lesioned mice implied the activation of PPARγ receptors, as they were attenuated when VCE-003.2 was co-administered with the PPARγ inhibitor T0070907. We then moved to some in vitro approaches, first to confirm the anti-inflammatory profile of VCE-003.2 in cultured BV2 cells exposed to LPS. VCE-003.2 was able to attenuate the synthesis and release of TNF-α and IL-1β, as well as the induction of iNOS and cyclooxygenase-2 (COX-2) elicited by LPS in these cells. However, we found such effects were not reversed by GW9662, another classic PPARγ antagonist. Next, we investigated the neuroprotective effects of VCE-003.2 in cultured M-213 neuronal cells exposed to conditioned media generated from LPS-exposed cultured BV2 cells. VCE-003.2 reduced M-213 cell death, but again, such effects were not reversed by T0070907. Using docking analysis, we detected that VCE-003.2 binds both the canonical and the alternative binding sites in the PPARγ ligand-binding pocket (LBP). Functional assays further showed that T0070907 almost abolished PPARγ transcriptional activity induced by rosiglitazone (RGZ), but it did not affect the activity of VCE-003.2 in a Gal4-Luc system. However, T0070907 inhibited the effects of RGZ and VCE-003.2 on the expression of PPARγ-dependent genes upregulated in MSCs. Conclusions We have demonstrated that VCE-003.2 is neuroprotective against inflammation-driven neuronal damage in an in vivo model of PD and in in vitro cellular models of neuroinflammation. Such effects might involve PPARγ receptors, although in silico and in vitro experiments strongly suggest that VCE-003.2 targets PPARγ by acting through two binding sites at the LBP, one that is sensitive to T0070907 (canonical binding site) and other that is not affected by this PPARγ antagonist (alternative binding site).

This paper summarizes a mathematical model for the industrial heating and cooling processes of a steel workpiece corresponding to the steering rack of an automobile. The general purpose of the heat treatment process is to create the necessary hardness on critical parts of the workpiece. Hardening consists of heating the workpiece up to a threshold temperature followed by a rapid cooling such as aquaquenching. The high hardness is due to the steel phase transformation accompanying the rapid cooling resulting in non-equilibrium phases, one of which is the hard microconstituent of steel, namely martensite. The mathematical model describes both processes, heating and cooling. During the first one, heat is produced by Joule’s effect from a very high alternating current passing through the rack. This situation is governed by a set of coupled PDEs/ODEs involving the electric potential, the magnetic vector potential, the temperature, the austenite transformation, the stresses and the displacement field. Once the workpiece has reached the desired temperature, the current is switched off an the cooling stage starts by aquaquenching. In this case, the governing equations involve the temperature, the austenite and martensite phase fractions, the stresses and the displacement field. This mathematical model has been solved by the FEM and 2D numerical simulations are discussed along the paper.

The 3-hydroxyquinone derivative of the non-psychotrophic phytocannabinoid cannabigerol, so-called VCE-003.2, and some other derivatives have been recently investigated for neuroprotective properties in experimental models of Parkinson’s disease (PD) in mice. The pharmacological effects in those models were related to the activity on the peroxisome proliferator-activated receptor-γ (PPAR-γ) and possibly other pathways. In the present study, we investigated VCE-004.8 (formulated as EHP-101 for oral administration), the 3-hydroxyquinone derivative of cannabidiol (CBD), with agonist activity at the cannabinoid receptor type-2 (CB2) receptor in addition to its activity at the PPAR-γ receptor. Studies were conducted in both in vivo (lesioned-mice) and in vitro (SH-SY5Y cells) models using the classic parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). Our data confirmed that the treatment with VCE-004.8 partially reduced the loss of tyrosine hydroxylase (TH)-positive neurons measured in the substantia nigra of 6-OHDA-lesioned mice, in parallel with an almost complete reversal of the astroglial (GFAP) and microglial (CD68) reactivity occurring in this structure. Such neuroprotective effects attenuated the motor deficiencies shown by 6-OHDA-lesioned mice in the cylinder rearing test, but not in the pole test. Next, we explored the mechanism involved in the beneficial effect of VCE-004.8 in vivo, by analyzing cell survival in cultured SH-SY5Y cells exposed to 6-OHDA. We found an important cytoprotective effect of VCE-004.8 at a concentration of 10 µM, which was completely reversed by the addition of antagonists, T0070907 and SR144528, aimed at blocking PPAR-γ and CB2 receptors, respectively. The treatment with T0070907 alone only caused a partial reversal, whereas SR144528 alone had no effect, indicating a major contribution of PPAR-γ receptors in the cytoprotective effect of VCE-004.8 at 10 µM. In summary, our data confirmed the neuroprotective potential of VCE-004.8 in 6-OHDA-lesioned mice, and in vitro studies confirmed a greater relevance for PPAR-γ receptors rather than CB2 receptors in these effects.

Background: Testosterone deficiency (hypogonadism) is common among men undergoing haemodialysis, but its clinical implications are not well characterized. Testosterone is an anabolic hormone that induces erythrocytosis and muscle synthesis. We hypothesized that testosterone deficiency would be associated with low muscle mass, physical inactivity and higher dosages of erythropoietin-stimulating agents (ESA). Methods: Single-center cross-sectional study of 57 male haemodialysis patients. None of the patients was undergoing testosterone replacement therapy. Total testosterone was measured in serum. Body composition (by bioelectrical impedance analysis) and physical activity (by the use of pedometers) were assessed. Patients with testosterone levels below the normal range were considered hypogonadal. Results: Mean testosterone level was 321 ± 146 ng/dL; 20 patients (35%) were hypogonadal. Hypogonadal patients were older and had lower mean arterial blood pressure, higher interleukin-6 levels, lower lean body mass and higher fat body mass. A negative association between testosterone and normalized ESA dose was found in uni- and multivariate regression analyses. Testosterone levels directly correlated with lean body mass regardless of confounders. Hypogonadal patients had lower physical activity than their counterparts [2753 ± 1784 vs. 4291 ± 3225 steps/day (p = 0.04)]. The relationship between testosterone and physical activity was independent of age, comorbidities and inflammatory markers, but dependent on the proportion of muscle mass. Conclusion: Hypogonadism is common in our male haemodialysis population and is associated with higher ESA doses, reduced muscle mass and lower physical activity. The link between low testosterone levels and physical inactivity may conceivably relate to reduced muscle mass due to inadequate muscle protein synthesis.

This article is about the tone of voice (acoustic perception) in patients with restrictive anorexia nervosa (AN-R). Our goal was to study whether or not there is an alteration of the tone in restrictive anorexia nervosa when the disease has started in the puberty. The total sample consisted of 148 subjects divided in two groups: control (n=102) and AN-R (n=46). The voice´s fundamental frequencies (F0) were determined based on the repetition of two phonemes ("a" and "i") and measured by a microphone Plantonic 300 and a digital recorder. We analyzed the voice´s F0 using Praat software. We present the first data for the normal range of the F0 in Spanish healthy women from 9 to 17 years old who were Spanish native speakers. Finally, we show a comparison of data between AN-R patients and control group.

Diabetes is a chronic and progressive disease associated with potentially disabling complications. Among them, diabetic neuropathy is probably the most frequent symptomatic manifestation, having an important social and economic impact. Painful somatic neuropathy and autonomic neuropathy treatment have been a challenge for years. New medical approaches that relief pain are now available and give hope to diabetic patients.

Diabetic neuropathy (DN) is the most common and early microvascular alteration associated to diabetes mellitus (DM); however, this event is most missed and less diagnosed. At the same time, it is widely known that metabolic syndrome (MS) is highly prevalent and the relationship between this status and macrovascular commitment is documented. The Diabetic Neuropathy Committee is focused in analyzing the neuropathic effect within the framework of MS and in one of its components such as non-diabetic disglycemia. The under diagnosis and increase of morbidity and mortality risk of these patients alert the medical community of the existence of this microvascular alteration exceeding the DM framework and is also present in MS and disglycemia either at fasting and postprandial.

Several studies have involved antiretroviral therapy in the pathogenesis of low bone mineral density (BMD), while others have not confirmed this association. In this study we analyze the impact of HIV status, traditional risk factors and antiretroviral therapy in BMD in an HIV-infected population living in Madrid.We performed a cross-sectional analysis of 107 individuals infected with HIV and exposed to antiretroviral treatment to estimate the prevalence of decreased BMD. Bone mineral density of lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry. In a multivariate analysis variables related with HIV status, antiretroviral drugs and traditional risk factors were included.Low BMD was diagnosed in 63 participants (58.9%), including osteoporosis in 11 (10%). At least one cause of osteoporosis was identified in 43 patients (40%), with a deficiency of vitamin D in 86 (89%) and secondary hyperparathyroidism in 30 (28%). In multivariate analysis, increasing age, a treatment based on boosted PI and tenofovir DF, and previous exposure to tenofovir were identified as independent risk factors for a decreased BMD in both lumbar spine and femoral neck.We have confirmed a high prevalence of reduced BMD, which is favoured by ritonavir-boosted PI and TDF. Bone safety should continue to be evaluated in clinical trials and cohort studies in order to demonstrate that the new drugs offer additional advantages regarding the impact on BMD.

In a recent study, we described the neuroprotective properties of VCE-003.2—an aminoquinone derivative of the non-psychotropic phytocannabinoid cannabigerol (CBG)—administered intraperitoneally (i.p.) in an inflammatory model of Parkinson’s disease (PD). We also demonstrated that these properties derive from its activity on the peroxisome proliferator-activated receptor-γ, in particular at a regulatory site within this receptor type. In the present study, we wanted to further confirm this neuroprotective potential using an oral lipid formulation of VCE-003.2, developed to facilitate the clinical development of this phytocannabinoid derivative. To this end, we evaluated VCE-003.2, administered orally at two doses (10 and 20 mg/kg), to mice subjected to unilateral intrastriatal injections of lipopolysaccharide (LPS), a classic model of inflammation-driven neuronal deterioration that recapitulates characteristics of PD. The administration of VCE-003.2 to these mice showed, as expected, poor activity in the different motor tests (rotarod, computer-aided actimeter) used in experimental parkinsonism, in general due to the lack of evident changes in these behaviors by LPS lesion. However, VCE-003.2, at 20 mg/kg, was highly active in improving the changes detected in LPS-lesioned mice in the cylinder rearing test. In addition, the histopathological analysis of the basal ganglia revealed a trend towards recovery at 20 mg/kg VCE-003.2 in the loss of tyrosine hydroxylase-containing nigrostriatal neurons, as well as a complete reduction in the elevated LAMP-1 immunolabeling (reflecting autophagy impairment) caused by LPS lesion. These effects were not seen at 10 mg/kg. This was associated with a partial reduction in the intense glial reactivity provoked by LPS in the substantia nigra, in particular the astroglial reactivity labeled with glial fibrillary acidic protein. The analysis using qPCR in the striatum of proinflammatory mediators, such as tumor necrosis factor-α, interleukin-1β, inducible nitric oxide synthase, and cyclooxygenase-2, showed that the marked elevations provoked by the LPS lesion tended to be, in general, attenuated by VCE-003.2 treatment, with the greatest effects normally found with the highest dose of 20 mg/kg. In summary, our data confirm the neuroprotective potential of an oral formulation of VCE-003.2 against neuronal injury in an in vivo model of PD based on neuroinflammation, and this study opens the possibility to further the development of oral VCE-003.2 in the clinic.

Human giardiosis and cryptosporidiosis are caused by the enteric protozoan parasites Giardia duodenalis and Cryptosporidium spp. Both pathogens are major contributors to the global burden of diarrhoeal disease, affecting primarily children and immunodebilitated individuals in resource-poor settings. Giardiosis and cryptosporidiosis also represent an important, often underestimate, public health threat in developed countries. In Spain only limited information is currently available on the epidemiology of these infections. Molecular data on the diversity, frequency, geographical distribution, and seasonality of G. duodenalis assemblages/sub-assemblages and Cryptosporidium species/sub-genotypes are particularly scarce.A longitudinal molecular epidemiological survey was conducted between July 2015 to September 2016 in patients referred to or attended at the Hospital San Pedro (La Rioja, Northern Spain) that tested positive for G. duodenalis (N = 106) or Cryptosporidium spp. (N = 103) by direct microscopy and/or a rapid lateral flow immunochromatographic assay. G. duodenalis infections were subsequently confirmed by real-time PCR and positive isolates assessed by multi-locus sequence genotyping of the glutamate dehydrogenase and β-giardin genes of the parasite. Cryptosporidium species and sub-genotypes were investigated at the 60 kDa glycoprotein or the small subunit ribosomal RNA genes of the parasite. Sociodemographic and clinical parameters of infected patients were also gathered and analysed.Out of 90 G. duodenalis-positive isolates by real-time PCR a total of 16 isolates were successfully typed. AII (44%, 7/16) was the most prevalent sub-assemblage found, followed by BIV (31%, 5/16) and BIII (19%, 3/16). A discordant genotype result AII/AIII was identified in an additional (6%, 1/16) isolate. No mixed infections A+B were detected. Similarly, a total of 81 Cryptosporidium spp. isolates were successfully typed, revealing the presence of C. hominis (81%, 66/81) and C. parvum (19%, 15/81). Obtained GP60 sequences were assigned to sub-type families Ib (73%, 59/81) within C. hominis, and IIa (7%, 6/81) and IId (2%, 2/81) within C. parvum. A marked inter-annual variation in Cryptosporidium cases was observed.Human giardiasis and cryptosporidiosis are commonly identified in patients seeking medical care in Northern Spain and represent a more important health concern than initially thought. Assemblage A within G. duodenalis and sub-genotype IbA10G2 within C. hominis were the genetic variants of these parasite species more frequently found circulating in the population under study. Molecular data presented here seem to suggest that G. duodenalis and Cryptosporidium infections arise through anthroponotic rather than zoonotic transmission in this Spanish region.

Este artículo expone los resultados sobre las técnicas más utilizadas en la medición de la movilidad educativa intergeneracional y la evidencia empírica encontrada hasta el año 2012 para América Latina y Colombia. Los métodos empleados para el proceso de pesquisa de la bibliografía científica fueron la consulta en revistas de sociología, economía y educación, en bases de datos (Jstor, EBSCOhost, Redalyc, Scielo) y reservorios de información. Los resultados señalan que no hay un consenso en la medición; sin embargo, los métodos más utilizados son las matrices de transición, modelos Markov e índices sintéticos. La evidencia muestra que la movilidad absoluta ha aumentado en América Latina. No obstante, la movilidad relativa es baja en comparación con los países desarrollados. Los vínculos entre el nivel educativo de padres e hijos continúan siendo muy fuertes, tanto en América Latina como en Colombia.

La biblioteca universitaria se encuentra en un proceso de transformación ante el Espacio Europeo de Educación Superior (EEES). Este nuevo marco implica básicamente un cambio en el modelo de enseñanza, centrado en el aprendizaje y basado en una serie de competencias que convierten al estudiante en protagonista de su propio aprendizaje. Este cambio en el paradigma docente integra las Tecnologías de la Información y Comunicación (TICs), así como los planteamientos e-learning y la alfabetización digital, en los futuros modelos educativos. Para apoyar este cambio las bibliotecas universitarias deben adaptar sus espacios y servicios a las nuevas necesidades docentes, evolucionando a un Centro de Recursos para el Aprendizaje e Investigación (CRAI). En este trabajo se analizan los procesos de conversión de la biblioteca universitaria, y el nuevo papel de los bibliotecarios, ante las necesidades informativas que demanda la comunidad universitaria.The university library is found in a process of transformation before the European Higher Education Area. This new environment implies basically a change in the model of teaching, centered in the learning and based on a series of competences that convert the student in protagonist of their own learning. This change in the educational paradigm integrates the Information Technologies and Communication, as well as the e-learning and the information literacy approaches, in the future educational models. To support this change the university libraries should adapt their spaces and services to the new educational needs for their transformation in a Learning Resources Centre (LCR). In this work the challenges of the university library, and the new role of the librarians, are analyzed before the informative needs that demands the university community.

En esta investigación se evaluaron los efectos del grado de apertura comercial en los diferentes períodos presidenciales, en el crecimiento económico de Colombia (1970-2009). Tomando como referencia las principales reformas institucionales y acuerdos comerciales, relacionados con el manejo de la apertura comercial y la dinámica de las exportaciones e importaciones desagregadas de Colombia. Mediante la elaboración de un modelo ANOVA se comparó e identificó el grado de apertura comercial en los diferentes períodos presidenciales, considerando períodos aperturistas a aquellos gobiernos en los cuales el grado de apertura fue estadísticamente similar al período presidencial de Cesar Gaviria Trujillo (categoría base y/o de comparación) y proteccionistas a los períodos que fueron estadísticamente inferiores. Posteriormente, se elaboró un modelo ANCOVA, donde el crecimiento económico dependía del grado de apertura comercial y de una variable Dummy que indica la presencia o ausencia de períodos presidenciales aperturistas. Los resultados de la investigación demuestran que en administraciones como la de Alfonso López Michelsen y Virgilio Barco se había obtenido un grado de apertura similar al del gobierno de Cesar Gaviria. Además, se evidencia que solo en tres de los diez períodos presidenciales estudiados se obtuvo en promedio un superávit en la balanza comercial colombiana. Concluyendo, que la relación entre el grado de apertura comercial y el crecimiento económico de Colombia es inversa y no existe diferencia alguna en el efecto que causa la presencia de períodos presidenciales aperturistas y proteccionistas en el crecimiento económico del país.

The transcription factor Nrf2 (NF-E2-related factor 2) and its target gene products, including heme oxygenase-1 (HO-1), elicit an antioxidant response that may have therapeutic value for Parkinson's disease (PD). However, HO-1 protein levels are increased in dopaminergic neurons of Parkinson's disease (PD) patients, suggesting its participation in free-iron deposition, oxidative stress and neurotoxicity. Before targeting Nrf2 for PD therapy it is imperative to determine if HO-1 is neurotoxic or neuroprotective in the basal ganglia.We addressed this question by comparing neuronal damage and gliosis in Nrf2- or HO-1-knockout mice submitted to intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for five consecutive days. Nrf2-knockout mice showed exacerbated gliosis and dopaminergic nigrostriatal degeneration, as determined by immunohistochemical staining of tyrosine hydroxylase in striatum (STR) and substantia nigra (SN) and by HPLC determination of striatal dopamine and 3,4- dihydroxyphenylacetic acid (DOPAC). On the other hand, the severity of gliosis and dopaminergic degeneration in HO-1-null mice was neither increased nor reduced. Regarding free-iron deposition, both Nrf2- and HO-1-deficient mice exhibited similar number of deposits as determined by Perl's staining, therefore indicating that these proteins do not contribute significantly to iron accumulation or clearance in MPTP-induced Parkinsonism.These results suggest that HO-1 does not protect or enhance the sensitivity to neuronal death in Parkinson's disease and that pharmacological or genetic intervention on Nrf2 may provide a neuroprotective benefit as add on therapy with current symptomatic protocols.