Treatment variability and its relationships to outcomes among patients with Wernicke's encephalopathy: A multicenter retrospective study.

BACKGROUND: Despite guidelines and recommendations, Wernicke's encephalopathy (WE) treatment lacks evidence, leading to clinical practice variability. AIMS: Given the overall lack of information on thiamine use for WE treatment, we analyzed data from a large, well-characterized multicenter sample of patients with WE, examining thiamine dosages; factors associated with the use of different doses, frequencies, and routes; and the influence of differences in thiamine treatment on the outcome. METHODS: This retrospective study was conducted with data from 443 patients from 21 centers obtained from a nationwide registry of the Spanish Society of Internal Medicine (from 2000 to 2012). Discharge codes and Caine criteria were applied for WE diagnosis, and treatment-related (thiamine dosage, frequency, and route of administration) demographic, clinical, and outcome variables were analyzed. RESULTS: We found marked variability in WE treatment and a low rate of high-dose intravenous thiamine administration. Seventy-eight patients out of 373 (20.9%) received > 300mg/day of thiamine as initial dose. Patients fulfilling the Caine criteria or presenting with the classic WE triad more frequently received parenteral treatment. Delayed diagnosis (after 24h hospitalization), the fulfillment of more than two Caine criteria at diagnosis, mental status alterations, and folic acid deficiency were associated significantly with the lack of complete recovery. Malnutrition, reduced consciousness, folic acid deficiency, and the lack of timely thiamine treatment were risk factors for mortality. CONCLUSIONS: Our results clearly show extreme variability in thiamine dosages and routes used in the management of WE. Measures should be implemented to ensure adherence to current guidelines and to correct potential nutritional deficits in patients with alcohol use disorders or other risk factors for WE.

Antifungal and Insecticidal Activities of Selected Plant Species from Cloud Forest of Veracruz, Mexico: A Contribution to the Search of Novel Control Agents against Ambrosia Pest Complexes.

The antifungal and insecticidal activities of 34 extracts from 27 plant species were evaluated against fungal phytopathogens of the genus Fusarium and Xyleborus Scolytine ambrosia beetles involved in Fusarium dieback (FD) and laurel wilt (LW) diseases. Sixteen extracts caused mycelial growth inhibition (MGI) above 23 % at 2 mg mL-1 against F. solani, those from S. nudum and M. argyrophylla exhibited the highest MGI (57 % and 49 %, respectively). Thirteen extracts displayed significant antifungal activity against F. kuroshium, those from C. nocturnum and M. argyrophylla exhibited the highest MGI (100 % and 54.9 %, respectively). Additionally, ten plants extracts caused mortality in at least one of the beetle species tested, mainly from Solanaceae species. In the most active species, 39 phenolics were identified that may have contributed to their biological effects. This study is one of the first to report the potential of plant-derived natural products against the causative agents of FD and LW.

N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo.

N,N-dimethyltryptamine (DMT) is a component of the ayahuasca brew traditionally used for ritual and therapeutic purposes across several South American countries. Here, we have examined, in vitro and vivo, the potential neurogenic effect of DMT. Our results demonstrate that DMT administration activates the main adult neurogenic niche, the subgranular zone of the dentate gyrus of the hippocampus, promoting newly generated neurons in the granular zone. Moreover, these mice performed better, compared to control non-treated animals, in memory tests, which suggest a functional relevance for the DMT-induced new production of neurons in the hippocampus. Interestingly, the neurogenic effect of DMT appears to involve signaling via sigma-1 receptor (S1R) activation since S1R antagonist blocked the neurogenic effect. Taken together, our results demonstrate that DMT treatment activates the subgranular neurogenic niche regulating the proliferation of neural stem cells, the migration of neuroblasts, and promoting the generation of new neurons in the hippocampus, therefore enhancing adult neurogenesis and improving spatial learning and memory tasks.

Vitamin D Modifies the Incidence of Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation Depending on the Vitamin D Receptor (VDR) Polymorphisms.

PURPOSE: The biologically active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (vit D), has immunoregulatory properties via binding vitamin D receptor (VDR). In a prospective trial, we previously reported a reduction in the incidence of chronic GvHD (cGvHD) among patients who received vit D after allogeneic stem cell transplantation (allo-HSCT; Clinical Trials.gov: NCT02600988). Here we analyze the role of patients and donors' VDR SNPs on the immunomodulatory effect of vit D. PATIENTS AND METHODS: Patients undergoing allo-HSCT were included in a prospective phase I/II clinical trial (Alovita) in three consecutive cohorts: control (without vit D), low-dose (1,000 IU/day), and high-dose (5,000 IU/day) groups. Vit D was given from day -5 until +100 after transplant. Genotyping of four SNPs of the VDR gene, FokI, BsmI, ApaI, and TaqI, were performed using TaqMan SNP genotyping assays. RESULTS: We observed a decrease in the incidence of overall cGvHD at 1 year after allo-HSCT depending on the use or not of vit D among patients with FokI CT genotype (22.5% vs 80%, P = 0.0004) and among those patients without BsmI/ApaI/TaqI ATC haplotype (22.2% vs 68.8%, P = 0.0005). In a multivariate analysis, FokI CT genotype significantly influenced the risk of cGvHD in patients treated with vit D as compared with the control group (HR 0.143, P interaction < 0.001). CONCLUSIONS: Our results show that the immunomodulatory effect of vit D depends on the VDR SNPs, and patients carrying the FokI CT genotype display the highest benefit from receiving vit D after allo-HSCT.

Long-term Video Tracking of Cohoused Aquatic Animals: A Case Study of the Daily Locomotor Activity of the Norway Lobster (Nephrops norvegicus).

We present a protocol related to a video-tracking technique based on the background subtraction and image thresholding that makes it possible to individually track cohoused animals. We tested the tracking routine with four cohoused Norway lobsters (Nephrops norvegicus) under light-darkness conditions for 5 days. The lobsters had been individually tagged. The experimental setup and the tracking techniques used are entirely based on the open source software. The comparison of the tracking output with a manual detection indicates that the lobsters were correctly detected 69% of the times. Among the correctly detected lobsters, their individual tags were correctly identified 89.5% of the times. Considering the frame rate used in the protocol and the movement rate of lobsters, the performance of the video tracking has a good quality, and the representative results support the validity of the protocol in producing valuable data for research needs (individual space occupancy or locomotor activity patterns). The protocol presented here can be easily customized and is, hence, transferable to other species where the individual tracking of specimens in a group can be valuable for answering research questions.

Subtly Modulating Glycogen Synthase Kinase 3 ß: Allosteric Inhibitor Development and Their Potential for the Treatment of Chronic Diseases.

Glycogen synthase kinase 3 ß (GSK-3ß) is a central target in several unmet diseases. To increase the specificity of GSK-3ß inhibitors in chronic treatments, we developed small molecules allowing subtle modulation of GSK-3ß activity. Design synthesis, structure-activity relationships, and binding mode of quinoline-3-carbohydrazide derivatives as allosteric modulators of GSK-3ß are presented here. Furthermore, we show how allosteric binders may overcome the ß-catenin side effects associated with strong GSK-3ß inhibition. The therapeutic potential of some of these modulators has been tested in human samples from patients with congenital myotonic dystrophy type 1 (CDM1) and spinal muscular atrophy (SMA) patients. We found that compound 53 improves delayed myogenesis in CDM1 myoblasts, while compounds 1 and 53 have neuroprotective properties in SMA-derived cells. These findings suggest that the allosteric modulators of GSK-3ß may be used for future development of drugs for DM1, SMA, and other chronic diseases where GSK-3ß inhibition exhibits therapeutic effects.

Modulation of cAMP-specific PDE without emetogenic activity: new sulfide-like PDE7 inhibitors.

A forward chemical genetic approach was followed to discover new targets and lead compounds for Parkinson's disease (PD) treatment. By analysis of the cell protection produced by some small molecules, a diphenyl sulfide compound was revealed to be a new phosphodiesterase 7 (PDE7) inhibitor and identified as a new hit. This result allows us to confirm the utility of PDE7 inhibitors as a potential pharmacological treatment of PD. On the basis of these data, a diverse family of diphenyl sulfides has been developed and pharmacologically evaluated in the present work. Moreover, to gain insight into the safety of PDE7 inhibitors for human chronic treatment, we evaluated the new compounds in a surrogate emesis model, showing nonemetic effects.

Phosphodiesterase 7 inhibition preserves dopaminergic neurons in cellular and rodent models of Parkinson disease.

BACKGROUND: Phosphodiesterase 7 plays a major role in down-regulation of protein kinase A activity by hydrolyzing cAMP in many cell types. This cyclic nucleotide plays a key role in signal transduction in a wide variety of cellular responses. In the brain, cAMP has been implicated in learning, memory processes and other brain functions. METHODOLOGY/PRINCIPAL FINDINGS: Here we show a novel function of phosphodiesterase 7 inhibition on nigrostriatal dopaminergic neuronal death. We found that S14, a heterocyclic small molecule inhibitor of phosphodiesterase 7, conferred significant neuronal protection against different insults both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures. S14 treatment also reduced microglial activation, protected dopaminergic neurons and improved motor function in the lipopolysaccharide rat model of Parkinson disease. Finally, S14 neuroprotective effects were reversed by blocking the cAMP signaling pathways that operate through cAMP-dependent protein kinase A. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that phosphodiesterase 7 inhibition can protect dopaminergic neurons against different insults, and they provide support for the therapeutic potential of phosphodiesterase 7 inhibitors in the treatment of neurodegenerative disorders, particularly Parkinson disease.

A new tracking system for the measurement of diel locomotor rhythms in the Norway lobster, Nephrops norvegicus (L.).

The Norway lobster, Nephrops norvegicus (L.), is a deep-water burrowing decapod of high commercial value. Diel variations in trawl captures are produced by population rhythms of burrow emergences related to day-night cycles. Rhythms seem to be different in males and females since catches show variations in sex ratios depending on the season. Our hypothesis is that the diel rhythm of activity in this species can be distinguished in three different behavioural sets, the durations of which show gender-related modulation: door-keeping, proximal-, and distal-emergence from the burrow. Our aim is to detail the functioning of a new tracking system allowing the durations of these three behavioural components to be determined. Movement of animals was detected by subdividing aquaria into different zones by means of three rows of infrared-emitting and -receiving photodiodes in which blue light emitters were also integrated for the generation of light cycles. We recorded movement patterns in adult males and females (n=20) exposed to a standard photoperiod regime (i.e., 12 h; monochromatic at 480 nm of 5 lx) over 12 days. Marked diel nocturnal rhythms were reported at all barriers, with activity peaks diffused over the night at the burrow entrance and located at the day-night transition at other barriers (i.e., crepuscular peaks that decreased in the next few hours of darkness). Mean total activity was significantly higher for females than males at the burrow entrance (i.e., door-keeping behaviour). Males had significantly higher activity at other locations (proximal- and distal-emergence behaviours).

Improved mitochondrial function and increased life span after chronic melatonin treatment in senescent prone mice.

We investigated whether chronic melatonin administration influences mitochondrial oxidative stress and life span in mice. Diaphragmatic mitochondria from female senescent prone (SAMP8) and senescent resistant (SAMR1) mice at 5 and 10 months of age were studied. Mitochondrial oxidative stress was determined by measuring the levels of lipid peroxidation, glutathione and glutathione disulfide, and glutathione peroxidase and reductase activities. Mitochondrial function was assessed by measuring the activity of the respiratory chain complexes and the ATP content. The results suggest that the age-dependent mitochondrial oxidative damage in the diaphragm of SAMP8 mice was accompanied by a reduction in the electron transport chain complex activities and in ATP levels. Furthermore, melatonin administration between 1 and 10 months of age normalized the redox and the bioenergetic status of the mitochondria and increased the ATP levels. Melatonin also increased both half-life and longevity, mainly in SAMP8 group. These results suggest an age-related increase in mitochondria vulnerability to oxidation in SAM mice at 10 months of age that was counteracted by melatonin therapy. The effects of melatonin on mitochondrial physiology probably underline the ability of the indoleamine to increase maximal life span in these animals.

Valoración multimétodo de la composición corporal en karatecas / Multimethod valuation of the body composition in karatecas

La imporatncia que la constitución física, tanto la composición corporal como el somatotipo, presenta con relación al rendimiento deportivo ha sido ampliamente estudiada en múltiples disciplinas atléticas dado que existen patrones de referencia construidos a partir de los individuos que configuran la élite de cada deporte. En el caso del kárate, la escasez de trabajos con deportistas de nuestro país nos animó a realizar un estudio de un grupo de karatecas utilizando técnicas de Cineantropometría Bioimpedanciometría y Densiometría Pletismográfica. Hemos estudiado un amplio grupo de karatecas de sexo masculino, de edades comprendidas entre los 20 y los 30 años, con un nivel mínimo de cinturón verde, que entrena un mínimo de 4 horas semanales y que participa en competiciones regionales, nacionales y/o internacionales. Nuestro interés se centró en calcular su Prototipo Morfológico y su Composición Corporal, así como en estudiar el grado de similitud existente entre los diversos métodos que evalúan dicha composición corporal. Nuestro grupo tiene un somatotipo medio (3.4-5.7-1.6), que puede ser definido como Endo-Mesomórfico. Además, no encontramos la suficiente homogeneidad biotipológica en nuestra muestra ya que el Indice de Dispersión del Somatotipo es de 3.05. En cuanto a la composición corporal, el porcentaje de grasa calculado por los diferentes métodos, superó claramente el 10% y el Indice de Masa Corporal (IMC) se situó en 25.1. Por último, observamos unos resultados muy similares en los distintos parámetros hallados mediante Impedanciometría y Densiometría, y más dispares si comparamos cualquiera de estos métodos con los antropométricos clásicos, especialmente en lo referente al compartimento graso y al método de Carter

The importance that the physical constitution, both the corporal composition and somatotype, it presents with relation to the sport performance has been widely studied in multiple athletic disciplines provided that there exit patterns of reference constructed from the individuals who form the elite of each sport. In case of karate, the shortage of works with sportsmen of our country animated to us to realize a study of a group of karatecas using technologies of Kinanthropometry, Bioelectrical-Impedance and Plethysmographic Densitometry. We have studied a wide group of karatecas of masculine sex, of ages includes between 20 and 30 years, with a minimal level of green belt, which they dedicate to the training at least 4 weekly hours and which they take part in competitions regionals, nationals and /or internationals. Our interest centred on calculating its Morphologic Protoype and its Corporal Composition, as well as on studing the degree of existing similarity between the diverse methods that evaluate the above mentioned corporal composition. Our group proved an average somatotype had (3.4-5.7-1.6), which it can be defined as Endo-Mesomorfic. In addition, we did not find sufficient biotipologycal homogeneity in our sample since the Somatotype Dispersion Index was of 3.05. As for the corporal composition, the percentage of fat calculated by the different methods, overcame clearly 10% and the Body Mass Index (BMI) placed in 25.1. Finally, we observed very similar results in the different parameters found by means of Impedance and Densiometry, and more unlike if we compared anyone of these method with the classic anthropometrics, specially in what concerns to the greasy compartment and the method of Carter