Dopaminergic denervation and associated MRI microstructural changes in the nigrostriatal projection in early Parkinson's disease patients.

Loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and a profound reduction of striatal dopamine are two hallmarks of Parkinson's disease (PD). However, it's unclear whether degeneration starts at the neuronal soma or the striatal presynaptic terminals, and how microstructural degeneration is linked to dopaminergic loss is also uncertain. In this study, thirty de novo PD patients and twenty healthy subjects (HS) underwent 6-[18F]-fluoro-L-dopa (FDOPA) PET and MRI studies no later than 12 months from clinical diagnosis. FDOPA uptake rate (Ki), fractional volume of free-water (FW), and iron-sensitive R2* relaxometry were quantified within nigrostriatal regions. Inter-group differences (PD vs HS) were studied using non-parametric statistics and complemented with Cohen's d effect sizes and Bayesian statistics. Correlation analyses were performed exploring biomarker dependencies and their association with bradykinesia scores. PD patients exhibited a significant decline in nigrostriatal dopaminergic activity, being post-commissural putamen (-67%) and posterolateral SNc (-11.7%) the most affected subregions within striatum and SNc respectively. Microstructural alterations (FW) were restricted to the hemisphere corresponding to the most affected side and followed similar spatial gradients as FDOPA Ki (+20% in posterior putamen and +11% in posterolateral SNc). R2* revealed no relevant significant changes. FDOPA and FW were correlated within the posterolateral SNc, and clinical severity was associated with FDOPA Ki loss. The asymmetry between striatal and SNc changes for both dopaminergic depletion and microstructural degeneration biomarkers is consistent with a neurodegenerative process that begins in the striatal terminals before progressing toward the cell bodies in the SNc.

Dimensions of household food waste focused on family and consumers.

Food waste produced in homes represents the largest fraction of food waste generated along the food chain. Therefore, adequate prevention measures based on the quantitative and qualitative dimensions of the problem need to be put in place to reduce waste. The objective of the review was to identify areas of interest in relation to the food waste in households, considering the family unit as a whole as well as individual family members. Quantifying the problem is an important aspect in order to know its scope and dimension, but prevention also involves knowing the causes in a home. This is a complex issue, which, on a family level, is related to socioeconomic status, educational level, composition and number of members of the household as well as culinary and buying food habits. Individual variables such as age, sex, values, awareness, lifestyle and time spent on food preparation were included to characterize consumers. The focus of the problem is also important because most consumers consider food waste from a social perspective, without being aware of the serious environmental and economic problems. Habits and customs of consumers are considered the leading cause of food waste in homes and knowledge of this issue raises consumer awareness as a preventive tool.

[How far reaches earliness of optical coherence tomography in cognitive impairment]. / Hasta donde llega la precocidad de la tomografia de coherencia optica en el deterioro cognitivo?

INTRODUCTION: Alzheimer's disease (AD) is the leading cause of dementia in the world today. Increasingly greater efforts are being made to be able to detect cognitive impairment in earlier stages, and diagnostic entities such as mild cognitive impairment (MCI) and subjective memory complaints (SMC) are appearing. The number of biomarkers studied with the aim of reaching this goal continues to rise, and include optical coherence tomography. SUBJECTS AND METHODS: The study conducted employed optical coherence tomography to measure the macular thickness and the retinal nerve fibre layer in patients diagnosed with AD (n = 36), in patients with MCI (n = 33), in individuals with SMC (n = 24) and in control subjects (n = 45). RESULTS: Statistically significant differences have been found in terms of the macular thickness among all the groups studied (SMC: 261.8 ± 25.88 µm; MCI: 259.19 ± 22.582 µm; mild AD: 258.53 ± 14.804 µm; moderate AD: 249.32 ± 18.467 µm) and control subjects (271.96 ± 15.57 µm). The same occurs as regards the retinal nerve fibre layer and the difference is statistically significant compared with the control group (94.51 ± 9.203 µm) of all the groups (SMC: 90.44 ± 9.059 µm; MCI: 89.4 ± 10.421 µm; mild AD: 87.12 ± 10.279 µm; moderate AD: 82.25 ± 10.636 µm). CONCLUSION: Optical coherence tomography could be a future biomarker and support tool to facilitate the early diagnosis of cognitive impairment and AD.

TITLE: Hasta donde llega la precocidad de la tomografia de coherencia optica en el deterioro cognitivo?Introduccion. La enfermedad de Alzheimer (EA) es la primera causa de demencia mundial. Cada vez son mas los esfuerzos para lograr una deteccion temprana del deterioro cognitivo y surgen en el panorama cientifico entidades diagnosticas como el deterioro cognitivo leve (DCL) y las quejas subjetivas de memoria (QSM). Debido a ello, aparecen numerosos biomarcadores estudiados para conseguir dicho objetivo, entre ellos la tomografia de coherencia optica. Sujetos y metodos. Se ha realizado un estudio que utiliza la tomografia de coherencia optica para medir el grosor macular y la capa de fibras nerviosas de la retina en pacientes diagnosticados de EA (n = 36), pacientes con DCL (n = 33), en individuos con QSM (n = 24) y en sujetos control (n = 45). Resultados. Se han encontrado diferencias estadisticamente significativas en cuanto al grosor macular entre todos los grupos estudiados (QSM: 261,8 ± 25,88 µm; DCL: 259,19 ± 22,582 µm; EA leve: 258,53 ± 14,804 µm; EA moderada: 249,32 ± 18,467 µm) y sujetos control (271,96 ± 15,57 µm). Respecto a la capa de fibras nerviosas de la retina, ocurre de igual manera, y la diferencia es estadisticamente significativa frente al grupo control (94,51 ± 9,203 µm) de todos los grupos (QSM: 90,44 ± 9,059 µm; DCL: 89,4 ± 10,421 µm; EA leve: 87,12 ± 10,279 µm; EA moderada: 82,25 ± 10,636 µm). Conclusion. La tomografia de coherencia optica podria situarse como un futuro biomarcador y una herramienta de apoyo para facilitar el diagnostico precoz del deterioro cognitivo y de la EA.

Hemoconcentration induced by exercise: Revisiting the Dill and Costill equation.

The Dill and Costill equation is used to estimate the exercise-induced hemoconcentration. However, this calculation requires drawing an extra whole-blood sample, which cannot be frozen and has to be analyzed with dedicate instrumentation in a relative short time. The aim of the present study was to explore the usefulness of some serum biochemical parameters to estimate hemoconcentration induced by exhaustive exercise. Fourteen healthy male subjects (19-34 years) performed a15-min running test at 110% of anaerobic threshold speed. Hemoglobin, hematocrit, brain natriuretic peptide (BNP), creatinine, gamma-glutamyltransferase (GGT), total-proteins, albumin, total calcium (Ca), K(+), Na(+), and Cl(-) were determined in blood samples taken before, after exercise, and after a 30-min recovery period. Plasma volume loss (ΔPV) was calculated by Dill and Costill equation. At post-exercise and after recovery, the percentage increments of total-proteins, albumin, GGT and Ca correlated significantly with ΔPV. Bland-Altman analyses showed that correcting BNP, creatinine, and K(+) concentration by Ca percentage increments yield biases and limits of agreement that are acceptable when compared with Dill and Costill equation correction. Ca concentration may be used as a hemoconcentration biomarker in high-intensity exercise, which would allow scientists and physicians avoid extra costs, facilitate in-field research, and delayed estimation of hemoconcentration using stored serum samples.

Exercise effects on erythrocyte deformability in exercise-induced arterial hypoxemia.

Exercise-induced arterial hypoxemia (EIAH) is often found in endurance-trained subjects at high exercise intensity. The role of erythrocyte deformability (ED) in EIAH has been scarcely explored. We aimed to explore the role of erythrocyte properties and lactate accumulation in the response of ED in EIAH. ED was determined in 10 sedentary and in 16 trained subjects, both before and after a maximal incremental test, and after recovery, along with mean corpuscular volume (MCV) and red blood cell lactate concentrations. EIAH was found in 6 trained subjects (∆SaO2=-8.25±4.03%). Sedentary and non-EIAH trained subjects showed reduced ED after exercise, while no effect on ED was found in EIAH trained subjects. After exercise, lactate concentrations rose and MCV increased equally in all groups. ED is strongly driven by cell volume, but the different ED response to exercise in EIAH shows that other cellular mechanisms may be implicated. Interactions between membrane and cytoskeleton, which have been found to be O2-regulated, play a role in ED. The drop in SaO2 in EIAH subjects can improve ED response to exercise. This can be an adaptive mechanism that enhances muscular and pulmonary perfusion, and allows the achievement of high exercise intensity in EIAH despite lower O2 arterial transport.

The LRRK2 inhibitor GSK2578215A induces protective autophagy in SH-SY5Y cells: involvement of Drp-1-mediated mitochondrial fission and mitochondrial-derived ROS signaling.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been associated with Parkinson's disease, and its inhibition opens potential new therapeutic options. Among the drug inhibitors of both wild-type and mutant LRRK2 forms is the 2-arylmethyloxy-5-subtitutent-N-arylbenzamide GSK257815A. Using the well-established dopaminergic cell culture model SH-SY5Y, we have investigated the effects of GSK2578215A on crucial neurodegenerative features such as mitochondrial dynamics and autophagy. GSK2578215A induces mitochondrial fragmentation of an early step preceding autophagy. This increase in autophagosome results from inhibition of fusion rather than increases in synthesis. The observed effects were shared with LRRK2-IN-1, a well-described, structurally distinct kinase inhibitor compound or when knocking down LRRK2 expression using siRNA. Studies using the drug mitochondrial division inhibitor 1 indicated that translocation of the dynamin-related protein-1 has a relevant role in this process. In addition, autophagic inhibitors revealed the participation of autophagy as a cytoprotective response by removing damaged mitochondria. GSK2578215A induced oxidative stress as evidenced by the accumulation of 4-hydroxy-2-nonenal in SH-SY5Y cells. The mitochondrial-targeted reactive oxygen species scavenger MitoQ positioned these species as second messengers between mitochondrial morphologic alterations and autophagy. Altogether, our results demonstrated the relevance of LRRK2 in mitochondrial-activated pathways mediating in autophagy and cell fate, crucial features in neurodegenerative diseases.

Evaluation of enniatins A, A1, B, B1 and beauvericin in Portuguese cereal-based foods.

Sixty-one samples of Portuguese cereal-based foods were analysed for the occurrence of emerging mycotoxins called enniatins (A, A1, B and B1) and beauvericin. Samples were extracted with a mixture of acetonitrile/water (85/15, v/v) using an Ultra-Turrax homogeniser, and mycotoxins were detected with liquid chromatography coupled to a mass spectrometer. This method was validated and adequate values of recovery (70-103%) and relative standard deviation (<15%) were obtained. Signal suppression/enhancement was studied and matrix-matched calibration used to minimise this effect, but no additional clean-up step was necessary. The mass spectrometer was operated in selected reaction monitoring (SRM) mode and with selected transitions for each compound to quantify and to qualify them. Fifty-nine per cent of samples were contaminated. The percentages of enniatins were 53%, 49%, 44% and 16% for A1, B, B1, and A, respectively, and for beauvericin it was 1.6%. For the total samples, the mean contamination was 30, 24, 15, 2.1 and 0.1 ng g⁻¹ for enniatins A1, B, B1 and A, and beauvericin, respectively. The wheat-based samples showed higher levels and greater prevalence than any other cereals monitored. These results were used to estimate the daily intake of ENs from wheat-based cereal by the Portuguese population. At the same time, the usefulness of this method in the analysis of other important mycotoxins (aflatoxin B1, ochratoxin A, deoxynivalenol, T-2 toxin, fumonisin B1 and zearalenone) was evaluated.

The nigrostriatal system in the presymptomatic and symptomatic stages in the MPTP monkey model: a PET, histological and biochemical study.

Parkinson's disease (PD) is diagnosed when striatal dopamine (DA) loss exceeds a certain threshold and the cardinal motor features become apparent. The presymptomatic compensatory mechanisms underlying the lack of motor manifestations despite progressive striatal depletion are not well understood. Most animal models of PD involve the induction of a severe dopaminergic deficit in an acute manner, which departs from the typical, chronic evolution of PD in humans. We have used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administered to monkeys via a slow intoxication protocol to produce a more gradual development of nigral lesion. Twelve control and 38 MPTP-intoxicated monkeys were divided into four groups. The latter included monkeys who were always asymptomatic, monkeys who recovered after showing mild parkinsonian signs, and monkeys with stable, moderate and severe parkinsonism. We found a close correlation between cell loss in the substantia nigra pars compacta (SNc) and striatal dopaminergic depletion and the four motor states. There was an overall negative correlation between the degree of parkinsonism (Kurlan scale) and in vivo PET ((18)F-DOPA K(i) and (11)C-DTBZ binding potential), as well as with TH-immunoreactive cell counts in SNc, striatal dopaminergic markers (TH, DAT and VMAT2) and striatal DA concentration. This intoxication protocol permits to establish a critical threshold of SNc cell loss and dopaminergic innervation distinguishing between the asymptomatic and symptomatic parkinsonian stages. Compensatory changes in nigrostriatal dopaminergic activity occurred in the recovered and parkinsonian monkeys when DA depletion was at least 88% of control, and accordingly may be considered too late to explain compensatory mechanisms in the early asymptomatic period. Our findings suggest the need for further exploration of the role of non-striatal mechanisms in PD prior to the development of motor features.

[Pharmacoeconomic aspects of oral cytostatic agents]. / Aspectos farmacoeconómicos de los citostáticos orales.

When validating oral chemotherapy, pharmacists should confirm the suitability and correctness of the prescription, applying the same safety standards as those used for parenteral cytostatic drugs. There are an increasing number of cancers for which orally administered drugs are available, which increases patient satisfaction as these drugs can be taken at home without the need to visit a hospital. As oral cytostatic treatments increase, so does the importance of ensuring optimal treatment compliance. The new oral cytostatic agents are less toxic, reduce indirect costs and imply less loss of time for patients and their families. However, the cost of these agents should be below a threshold acceptable for society. As an aid to decision making, pharmacoeconomic tools should be used.

One year of complete clinical response in a metastatic breast cancer patient treated with a combination of lapatinib and gemcitabine.

The treatment of metastatic breast cancer is challenging. We recently assisted in the development of targeted therapies (in combination with chemotherapy or as monotherapy) that have improved results for selected groups of patients. Lapatinib is a dual tyrosine kinase inhibitor that has shown efficacy in breast cancer. Consequently, its use has been approved, in combination with capecitabine, for the treatment of disease positive for the human epidermal growth factor receptor. Here, we present a case of complete clinical response to a combination of lapatinib and gemcitabine that was maintained for 1 year.

Use of the modified quick easy cheap effective rugged and safe sample preparation approach for the simultaneous analysis of type A- and B-trichothecenes in wheat flour.

A suitable extraction and purification method for the simultaneous liquid chromatography-mass spectrometry (LC-MS) determination of five mycotoxins, three type A, diacetoxyscirpenol (DAS), T-2 toxin (T-2) and HT-2 toxin (HT-2), and two type B-trichothecenes, deoxynivalenol (DON) and nivalenol (NIV), has been optimised using a modified "Quick Easy Cheap Effective Rugged and Safe" (QuEChERS) method. Different solvents were studied in the extraction procedure to obtain better recoveries, which ranged from 86 to 108%, using a 85/15 (v/v) mixture of methanol/acetonitrile. The values obtained for recovery, repeatability and reproducibility of the optimized method are in agreement with Commission Directive 2005/26/EC for methods of analysis of Fusarium toxins. Finally, this optimized procedure was applied in wheat flour samples commercialized in Spain.

Glucose influence on the production of T-2 toxin by Fusarium sporotrichioides.

Toxigenic isolate of Fusarium sporotrichioides was tested for the T-2 toxin production on PDA plates during 10 days under various glucose concentrations. T-2 toxin was determined by LC-MS and confirmed with LC-MS/MS. This analytical method has been applied, for the first time, to an extensive study of T-2 accumulation. Results showed that the production of this mycotoxin is directly correlated to the concentration of glucose present in the medium. Concentrations of T-2 toxin produced by the strain of F. sporotrichioides ranged from 0 to 1.45 mg/kg. The better T-2 production was evidenced in the fermentation operated with 20% of glucose.

Isolated colorectal liver metastases locally progressing after stereotactic body radiotherapy rescued with surgery.

Treatment of patients with metastatic colorectal cancer has changed in recent years, with many patients now being offered intent-to-treat regimens. In this context, a multidisciplinary approach to the metastatic disease may lead to individualized treatment for any patient. Stereotactic body radiotherapy (SBRT) is not the most common treatment. Here, we present the clinical case of a patient with a solitary liver metastasis initially treated with SBRT that was rescued with surgery when a local recurrence was detected.

New MRI, 18F-DOPA and 11C-(+)-alpha-dihydrotetrabenazine templates for Macaca fascicularis neuroimaging: advantages to improve PET quantification.

Normalization of neuroimaging studies to a stereotaxic space allows the utilization of standard volumes of interest (VOIs) and voxel-based analysis (SPM). Such spatial normalization of PET and MRI studies requires a high quality template image. The aim of this study was to create new MRI and PET templates of (18)F-DOPA and (11)C-(+)-alpha-dihydrotetrabenazine ((11)C-DTBZ) of the Macaca fascicularis brain, an important animal model of Parkinson's disease. MRI template was constructed as a smoothed average of the scans of 15 healthy animals, previously transformed into the space of one representative MRI. In order to create the PET templates, (18)F-DOPA and (11)C-DTBZ PET of the same subjects were acquired in a dedicated small animal PET scanner and transformed to the created MRI template space. To validate these templates for PET quantification, parametric values obtained with a standard VOI-map applied after spatial normalization to each template were statistically compared to results computed using individual VOIs drawn for each animal. The high correlation between both procedures validated the utilization of all the templates, improving the reproducibility of PET analysis. To prove the utility of the templates for voxel-based quantification, dopamine striatal depletion in a representative monkey treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was assessed by SPM analysis of (11)C-DTBZ PET. A symmetric reduction in striatal (11)C-DTBZ uptake was detected in accordance with the induced lesion. In conclusion, templates of M. fascicularis brain have been constructed and validated for reproducible and automated PET quantification. All templates are electronically available via the internet.

Management of platinum-resistant ovarian cancer with the combination of pemetrexed and gemcitabine.

INTRODUCTION: Platinum resistant ovarian cancer is a current challenge in Oncology. Current approved therapies offer no more of a 20% of response. New therapeutic options are urgently needed. PATIENTS AND METHODS: Patients were treated with the combination of Pemetrexed 500 mg/m(2) d1 and Gemcitabine 1000 mg/m(2) d1,8 in a 21 days basis. RESULTS: 10 platinum-resistant ovarian cancer patients were treated under compassionate use. Mean previous chemotherapy lines were 3.3. Mean administered cycles were 4. Mean CA 125 decrease was on average of 47%, with one patient experiencing a 95% decrease in her CA 125 level. 1 patient had a complete clinical remission, and 2, had partial radiological responses. Mean Progression free survival was 16.5 weeks, and Overall Survival was 21.2 weeks. Treatment was well tolerated. CONCLUSIONS: Deemd to the observed activity, the combination of Pemetrexed and Gemcitabine deserves deeper investigation in platinum-resistant ovarian cancer patients.

Circulating tumor cells in breast cancer: methodology and clinical repercussions.

Breast cancer is the most common type of cancer among women, and clinicians have long recognized its heterogeneity. Its detection and treatment in early stages allow for reduction of mortality. Despite the advances and new strategies for combining surgical, radiotherapy, and chemotherapy options, however, the percentage of patients developing metastases and advanced stages remains high. Even though serum tumor markers have been used for the early diagnosis of metastases, their systematic determination has not had an effect on survival. Methods that are more reliable are needed to detect metastases earlier than with the common clinical methods and thus start treatment before overt relapse. Early indicators of response or resistance to treatment are also an issue in clinical practice. Imaging techniques are time consuming, and it is difficult to detect changes that indicate response limited to therapy, and approaches to defining changes in tumor mass are time and resource consuming. In contrast, detection of circulating tumor cells (CTC) could be a useful tool in early detection of relapse and response to systemic chemotherapy. Extremely sensitive techniques are available that are easily applied to peripheral blood samples, which might provide enormous research possibilities in this area.

Clinical case report and literature review: metachronous colorectal splenic metastases.

A 52-year-old woman with a rising carcinoembryonic antigen CEA, no clinical or radiological findings, a negative colonoscopy, and a positron emission tomography (PET) scan that revealed an isolated hypermetabolic lesion in the spleen. The patient underwent splenectomy by laparoscopic surgery. The pathological study confirmed the presence of an isolated metastasis to the spleen. This case reveals the rare occurrence of isolated splenic metastases in the context of colorectal cancer and illustrates the role of PET when a patient shows a rising CEA with negative clinicoradiological studies.

Screening and chemoprevention in lung cancer.

Lung cancer is a major health problem due to its incidence and mortality. The risk factors, the existence of a preclinical phase, and the relationship between stage at diagnosis and survival are known. A number of strategies that aim to diagnose lung cancer in its earliest stages, based principally on imaging studies, are therefore being tested. Several drugs aimed at reducing the probability of developing lung cancer in the at-risk population are also under study. At the present time, the results obtained have not been encouraging and we do not have a clear strategy either for early diagnosis or for the use of chemopreventive agents.