Whereas more research is needed to

Whereas more research is needed to identify the precise mechanism by which FIN exerts its antidyskinetic effect, the prostanoid receptors that it can negatively modulate dopaminergic transmission is also supported by our previous findings. Indeed, we have previously shown that FIN completely reversed the behavioral alterations induced by exaggerated dopaminergic activation in rodents. Specifically, in Sprague-Dawley rats, systemic FIN injections countered the prepulse inhibition (PPI) deficits and stereotyped behaviors exerted by dopaminergic agonists, but not by the N-methyl-d-aspartate receptor antagonist dizocilpine (Bortolato et al., 2008). Notably, in a subsequent study we demonstrated that these behavioral effects occurred through a negative modulation of dopaminergic receptors in the striatum (Devoto et al., 2012). Furthermore, in both C57BL/6 mice and Long-Evans rats FIN was able to rescue the PPI loss mediated by selective D1 receptor activation (Frau et al., 2013, 2016; Mosher et al., 2016). Importantly, unlike the most used anti-dopaminergic drugs, the behavioral effects of FIN were not accompanied by catalepsy, catatonia or other motor impairments.
5AR is the critical enzyme involved in neurosteroidogenesis as well as in androgens synthesis. Accordingly, the use of FIN and other 5AR inhibitor analogs in the clinical settings is based on the blockade of the conversion of testosterone into dihydrotestosterone (DHT), which has been shown to exert a key role in the pathogenesis of both prostatic hyperplasia and androgenic alopecia (Paba et al., 2011). We recently found that the acute administration of FIN resulted in a significant reduction of the 5AR metabolite allopregnanolone, and increase in its substrates pregnenolone and dehydroepiandrosterone in the rat striatum (Frau et al., 2015). This is of particular importance, as a wide literature suggested that these steroids might modulate dopaminergic function (Di Paolo, 1994; Sánchez et al., 2010). For instance, pregnenolone was recently shown to rescue the altered behavioral outcomes of dopamine transporter knockout mice, which mirror dopamine receptor hyperactivation in the striatum (Wong et al., 2012). Although the neurobiological underpinnings of pregnenolone are not completely understood, it acts as potent agonists of σ1 receptors (Maurice et al., 2006), which have been shown to modulate D1 receptor signaling (Navarro et al., 2010). Similarly, allopregnanolone and dehydroepiandrosterone sulfate modulate the behavioral effects of D1 receptor activation (Frye et al., 2006; Dong et al., 2007), and allopregnanolone has been shown to affect the phosphorylation of DARPP-32 (Mani et al., 2000; Frye and Walf, 2010), a key molecule in D1 receptor signaling cascade and dyskinesia (Svenningsson et al., 2004; Picconi et al., 2003; Santini et al., 2007). Thus, the anti-dopaminergic effect of 5AR inhibitors may derive from a complex modification of the levels of several neurosteroids, which would affect striatal dopamine receptor function.
FIN has been on the market for over twenty years for the treatment of male pattern hair loss and benign prostatic hyperplasia, showing limited side effects in patients. Thus, if this drug will be demonstrated to exert beneficial effects for dyskinesia in Parkinson\’s patients, it may be rapidly introduced in the clinical practice, at least in male subjects. The feasibility of a clinical application is also supported by other clinical findings showing the ability of FIN to produce therapeutic effects in adult male patients affected by Tourette Syndrome (Bortolato et al., 2007; Muroni et al., 2011), a psychiatric disorder characterized by motor fluctuations and phonic tics, which pathophysiology has also been ascribed to striatal dopaminergic dysregulation (Felling and Singer, 2011; Jeffries et al., 2002; Denys et al., 2013). More importantly, FIN was also able to attenuate motor and non-motor side-effects elicited by dopamine replacement therapies in PD patients, such as blepharospasm and pathological gambling (Bortolato et al., 2010, 2012).

This issue of includes the

This issue of includes the second part of our , coordinated by Dr. Edgar Garcia-Rill (University of Arkansas, Little Rock, USA) and Dr. Francisco Urbano (University of Buenos Aires, Argentina). In the previous issue of Sleep Science, the group headed by Dr. Edgar Garcia-Rill published the first two review articles on the theme, focusing on the relation of the pedunculopontine nucleus (PPN) with schizophrenia and insomnia. In this issue, the author addresses the link between the reticular activating system (RAS) and deep brain stimulation and psychostimulant abuse.

Sleep is a vital physiological function and is known to be crucial to physical and mental health in children. Sleep Disorders (SlD) are among the most common complaints in childhood, often undervalued by clinicians. Large epidemiological studies have found that about 30% of children suffer from sleep problems [1–4].
Extrinsic and intrinsic factors influence sleep, particularly socio-cultural environment and some medical conditions such as breathing disorders [5,6]. Sleep disordered breathing (SDB) is increasingly recognized in children with primary snoring, upper airway resistance syndrome and obstructive sleep neurokinin receptor (OSA). A combination of anatomic factors such as adenotonsillar hypertrophy and decreased oropharyngeal dimensions is involved in the development of SDB, as well as overweight and obesity in children [7]. Snoring is more common in adults than in children, although it is estimated that approximately 6–12% of children snore frequently and that between 1% and 3% of children suffer from obstructive sleep apnea hypoventilation syndrome [8,9]. SDB includes potentially severe complications for children such as neurobehavioural and cognitive, as well as the consequences in adulthood with an increased prevalence of metabolic syndrome with hypertension, obesity and insulin resistance [10,11].
It is recognized that poor sleep habits have physical, educational and social consequences [12]. As a result, it often interferes with daily life activities and family functioning. Family systems are dynamic, with reciprocal interactions that could have impact in child sleep, as well as child sleep problems can lead to family conflicts [13]. Not least important is the role of children׳s sleeping disorders in their mental health in adulthood [14].
The high prevalence of sleep problems, their negative implications for children and family and the success of educational interventions emphasize the need for early screening of Sleep Disorders [15]. Questionnaires are applied in clinical practice as recognized screening methods to evaluate sleep [16].

Material and methods

A total of 128 children were considered eligible (Fig. 1).

The prevalence of SlD found (59.4%) was higher than reported in the medical literature [1–4]. A possible explanation may be related with low parents’ education. Subscales associated with behavioral SlD were the most relevant in this sample, fact explained by the capability of CSHQ-PT on the evaluation of this kind of disturbances.
The higher scores in bedtime resistance and parasomnias, obtained by the CSHQ-PT subscales of this study, when compared to those of CSHQ-PT validation study, are probably due to the type of families involved. In fact, children living in a single parent family had more sleep disturbances (p=0.048), especially parasomnias (p=0.019). The fact of co-sleeping being more practiced in monoparental families brings more awareness of parents for perceiving sleep disturbances.
In what concerns to SDB, children had more daytime sleepiness (p=0.034). According to the literature, SDB should also influence school performance [18]; however this was not found in this study. This lack of association was probably due to the sample size. The low rate of school retention (3.2%) may have led to an underestimation of the association between children׳s school performance and Sleep Disorders in general, and SBD in particular. The same happened regarding overweight (8.0%).

br Introducci n En tal sentido

En tal sentido, la pregunta central del trabajo que motivó emprender esta investigación es la siguiente: ¿La globalización es una variable exegética fundamental o existen otros elementos sustantivos para comprender el grado de desarrollo social y económico experimentado en Latinoamérica? De acuerdo selective estrogen receptor modulators lo anterior, la hipótesis central de esta investigación es que si bien la globalización podría explicar en cierta medida las desventajas económicas y sociales de América Latina, gran parte de los apuros del subcontinente obedecen a una serie de presencias y ausencias. Presencias generalizadas de Estados, aparatos de gobierno y administraciones públicas ineficientes, con insuficiente grado de profesionalismo y, lo que es más grave, deshonestos. Ausencias de, entre otras cosas, arreglos institucionales más racionales que permitan generar mejores políticas públicas.

Los retos del Estado contemporáneo en América Latina

Diversas posturas teóricas respecto a la globalización



La caída de los precios
Entre junio de 2014 y febrero de 2015 los precios internacionales del petróleo experimentaron un descenso de 60%, no del todo sorpresivo en virtud de que la economía europea casi entró en una triple recesión en 2014; se desaceleró la economía china; se profundizó la así llamada revolución del gas y petróleo shale (de lutitas o pizarra) en eu, y se exacerbaron las pujas de los tres productores más grandes del mundo −Arabia Saudita, eu y Rusia− por aumentar su autosuficiencia energética y/o acrecentar su participación de mercado, cercana en conjunto a 40%. De esta manera, el precio de la mezcla mexicana bajó de 98.79 dólares por barril (d/b) en junio de 2014 (intradía llegó a ubicarse en hasta 135 d/b) a 39.26 d/b promedio en enero de 2015, como muestra la gráfica 1.
Es evidente que el precio del petróleo es excesivamente volátil; por ejemplo, en los 20 años previos a 2015 se movió de un promedio anual piso de 10.17 d/b en 1998 a un techo de 101.97 d/b en 2012, para caer de nuevo a 39.26 d/b en 2015 (véanse valores de las barras de la gráfica 2, a pleural cavity leerse en el eje izquierdo). En términos de variaciones porcentuales, las cuales se asocian lo mismo a choques de demanda –principalmente caída del consumo, la inversión y/o las exportaciones−, que de oferta (conflictos bélicos de los países productores, caída de reservas probadas, desastres naturales, etc.), las recesiones de 1997 del Sureste Asiático y de 1998 de Rusia provocaron que la mezcla mexicana se redujera en dos años 46%; la “burbuja tecnológica” de 2001 condujo a una caída de 25%; la así llamada Gran Recesión de 2009 llevó a un descenso de 31.9%, y los acontecimientos de 2014 propiciaron una disminución de 54.9%, como muestra la línea continua de la gráfica 2, a leerse en el eje derecho.
Lo que cuesta mucho trabajo a los seguidores del mercado petrolero internacional reconocer, particularmente los responsables de las finanzas públicas, es que la caída de los precios siempre ha estado precedida de períodos de crecimiento estable de la economía mundial, como la década de los noventa, los siete años posteriores a 2001, y el lapso de recuperación de 2010-2013, posterior a la Gran Recesión. Además, haber actuado sobre el gasto público parecía contradictorio con la realidad: la reacción de los precios del petróleo después de una caída pronunciada tiende a ser muy fuerte, como evidencia la gráfica 2 (años de 1999, 2002 y 2010-2011); a fines de enero de 2015 los mercados empezaron a marcar el piso a la caída más reciente de precios (los 39.26 d/b de la gráfica 1 parecen ser una cota inferior); el gobierno contaba con recursos adicionales crecientes gracias a la puesta en operación de la reforma hacendaria (1.3 puntos porcentuales más de ingresos tributarios respecto al PIB captados en 2014), y por primera vez desde 2009 recibiría recursos, seguramente considerables, por concepto de las coberturas petroleras que había contratado. Además, sus importaciones de gasolinas y diesel se abaratarían, sin que por ello tuviera que modificar los precios al menudeo de dichos carburantes.

Kearney and Levine present a detailed survey of teenage childbearing

Kearney and Levine (2012) present a detailed survey of teenage childbearing in the US. The main conclusion is that both actual and perceived lack of economic opportunities influence early motherhood. After these factors have been taken into account, teenage motherhood does not appear to cause additional difficulties later in their lives. The authors discuss their main BTL-105 that the combination of being poor and living in an unequal and less mobile society contributes to a low expectation of success, thus leading to choices that favour short-term satisfaction such as the decision to have a baby when young. They conclude that teenagers in very unequal states are 5 percentage points more likely to give birth than teenagers in the least unequal states. The authors included other variables, such as poverty concentration and absolute levels of deprivation; none of these additional factors altered the estimated relationship between inequality and teen fertility among women with low socioeconomic status. In another study, Kearney and Levine (2014) analyzed both theoretically and empirically the role of income inequality in teenage nonmarital childbearing among poor women. They also found a positive relationship.
Berquó et al. (2012) reached similar conclusions using Brazilian data, although the authors also claim that lack of knowledge about contraception and contraceptive failure are important factors associated with teenage pregnancy, independently of educational and economic status. They argue that pregnancy is often the result of an absence of a life plan: access to better education, better living conditions, and greater enhance options during youth. In absence of good options for the future, pregnancy is a contingent decision made by the teenager today.
The arguments presented by Kearney and Levine (2012, 2014) and Berquó et al. (2012) strengthen the role of low future expectations of teenagers as a trigger mechanism for actions that result in teenage pregnancy.
Another factor that may influence early fertility is birth control. The increased availability of contraception after the 60s, with the introduction of innovative methods such as pills, IUDs, and improvement in sterilization, may have reduced the costs as well as improved the efficiency of contraceptive methods (Schultz, 1997). Hotz and Miller (1988) found a significant variation in the impact of the cost of children on female labor supply when considering different contraceptive behaviors.
According to Caetano (2004), the starting point of official family planning policies in Brazil was 1985, when the government implemented the Programa de Assistencia Integral a Saude da Mulher (PAISM). This program stimulated the public debate on women\’s health, including fertility. It was also at this point that the Demographic Health Survey (DHS) in Brazil began; it has been carried out in 1986, 1996, and 2006.
Table 1 shows data on the contraception trends both among all teenagers (15–19) and among all women of reproductive age (15–44 in 1986, and 15–49 in 1996 and 2006), by region. For the country as a whole we observe an increase in the prevalence rate from 43.7 to 81.5% among all women and from 7.7 to 75.8% for teenagers. This rate varied across regions, with the Northeast having the lowest rate in 1986 (34.8%), but the highest increase (48.2 percentage points) over the 1986–2006 period. By contrast, the South presented the highest prevalence in 1986 (50.3%) but a small variation over the same period (31.9 percentage points). Among all women using any method of contraception, sterilization was the most practiced method in 1986, followed by the pill and condoms, with little relevance. The trends show increased use of condoms (from 2.4% in 1986 to 21.5% in 2006) as well as increased use of female sterilization from 1986 (39.4%) to 1996 (49.4%) followed by a strong decrease in 2006 (32.2%). The use of pills decreased from 38.9% in 1986 to 29% in 2006. The trend in contraceptive methods used by teenagers was completely different: sterilization was virtually nonexistent in this group during the whole period, while the pill was the most used method in 1986 (80% of prevalence), but has since declined (to 39,5% in 2006). On the other hand, the prevalence of condoms increased dramatically, from 2.5% in 1986 to 48.6% in 2006. It is interesting to note the contrast: while the prevalence of contraception rates grew enormously in the period, the percentage of teenagers (15–19 years) who were or have ever been pregnant increased from 13.1% in 1986 to 17.9% in 1996, and then to 23.1% in 2006.

No vaccines and antiviral drugs are currently available

No vaccines and antiviral drugs are currently available to prevent and treat ZIKV infection. Animal models are essential for the development of such countermeasures. Young A129 mice (lacking interferon α/β receptor) and AG129 (lacking interferon α/β and γ receptors) were recently reported to succumb to ZIKV infection and to develop neurological signs (Aliota et al., 2016; Lazear et al., 2016; Malone et al., 2016). Since these mouse models are deficient in innate immune response, an immune competent animal model is needed. Non-human primates have been well documented as a more relevant animal model for flavivirus infections (Sariol and White, 2014; Zompi and Harris, 2012), and have been widely used for DENV and WNV pathogenesis studies and vaccine efficacy tests (Sariol and White, 2014). ZIKV was first isolated from a febrile rhesus macaques (Dick et al., 1952). Multiple monkey species in forests were found to be seropositive for ZIKV (McCrae and Kirya, 1982), suggesting that non-human primates can be infected and support viral replication.
Initial experiments performed in 1950s showed that rhesus monkeys inoculated subcutaneously (s.c.) or intracerebrally (i.c.) with the African ZIKV strain MR766 developed no signs of pyrexia, but generated antibodies within 2 to 3weeks after infection (Dick, 1952). However, bioinformatics analysis suggests that the ongoing epidemic strains in the Americas have accumulated some amino GSK503 changes that might contribute to the explosive epidemics (Faria et al., 2016; Wang et al., 2016). Here, we have established a non-human primate model using a contemporary ZIKV strain GZ01/2016 (GenBank accession no: KU820898) that was isolated from a patient returned from Venezuela to China in 2016 (Zhang et al., 2016). ZIKV infection upon subcutaneous in rhesus macaques resulted in fever, viremia, and robust viral shedding in multiple body fluids including saliva, urine, and lacrimal fluids. The major target organs of ZIKV and specific immune response in non-human primates were also characterized in detail. Our study establishes the non-human primate model of ZIKV infection with contemporary clinical isolate that will be valuable for evaluating candidate vaccines and therapeutics as well as understanding ZIKV pathogenesis, dissemination and transmission.

Materials & Methods


The mechanism of ZIKV pathogenesis remains largely unclear. This is partly due to the lack of a robust animal model that recapitulates the clinical manifestations and disease kinetics as seen in ZIKV patients. Our results showed that rhesus macaques could be infected by the contemporary ZIKV strain that is circulating in south Americas. This non-human primate model described here partly recapitulates some clinical features and viral kinetics in ZIKV-infected patients, and therefore may serve as a model to study ZIKV disease and pathogenesis. Very recently, a rhesus macaque model of ZIKV infection was reported with a clinical strain isolated in French Polynesian in 2013 (Dudley et al., 2016). The 2013 ZIKV strain caused viremia and viral RNA shedding in urine and saliva, while viral shedding in lacrimal fluids was not determined. Specially, inappetence was seen in most ZIKV-infected animals (Dudley et al., 2016), and no other abnormal clinical sighs were noted in their study. In our study, four of five rhesus macaques developed fever upon ZIKV infection, that is directly associated with disease. The challenge dose used in Dudley\’s experiments was 100-fold lower than that in our study, which may account for the difference in clinical symptoms.
The viral shedding features in various body fluids in ZIKV-infected macaques correlated with the clinical findings from patients. The presence of high loads of viral RNA in these body fluids supports that besides blood, urine and saliva are now used for clinical diagnosis of ZIKV. Especially, our results demonstrate that viral RNA was abundant in lacrimal fluids in ZIKV-infected adult macaques, supporting the use of tears or lacrimal fluids for clinical diagnosis. ZIKV-associated damages have been documented in babies with microcephaly (de Paula Freitas et al., 2016; Ventura et al., 2016a; Ventura et al., 2016b), and conjunctivitis is also a common symptom in adult ZIKV patients (Dasgupta et al., 2016; Deng et al., 2016; Duffy et al., 2009). Whether the level of viral RNA in body fluids associated with disease severity remains unknown.

Glucocorticoids also exert non genomic actions that

Glucocorticoids also exert non-genomic actions that can occur rapidly within a period of several minutes. This is thought to occur through the activation of signal transduction pathways, or through the interactions of glucocorticoids with cellular membranes (Strehl and Buttgereit, 2013; Kadmiel and Cidlowski, 2013). Through these genomic and non-genomic mechanisms of action, glucocorticoids exert a number of different effects in almost every tissue of the human body. Furthermore, through the above-mentioned interactions and pathways, the HPA axis and glucocorticoids interact with and regulate a number of fundamental physiological systems, including the nervous, cardiovascular, immune, musculoskeletal, visual, reproductive, and integumentary systems, and also play a role in regulating glucose and liver metabolism, mood and cognition, metabolic processes, and maintaining circadian rhythm (Smith and Vale, 2006; Kadmiel and Cidlowski, 2013; Kalsbeek et al., 2012). Not surprisingly, then, the HPA axis has received increasing attention over the past decade due to its critical role in regulating stress and its ability to influence a variety of health outcomes (Moisiadis and Matthews, 2014; Kalsbeek et al., 2012; Turecki, 2014; Eades et al., 2014; Cameron, 2006; Conradt et al., 2013; Edelman et al., 2012; Lee et al., 2014; Wan et al., 2014).
Studies aimed at exploring epigenetic regulation of the buy FG-4592 that code for the hormones, proteins, and receptors within the HPA axis may further our understanding of the pathways through which glucocorticoid dysregulation might increase risk for a number of diseases. Although several studies and reviews have examined the impact of adverse childhood experiences, socioeconomic adversity, and other environmental stressors on epigenetic regulation (most commonly DNA methylation) of individual HPA axis genes, such as NR3C1, AVP, or FKBP5 (Palma-Gudiel et al., 2015; Daskalakis and Yehuda, 2014; Zannas et al., 2016; Needham et al., 2015), no comprehensive review exists that has examined the epigenetic regulation of all HPA axis genes within the entire glucocorticoid regulatory pathway. More importantly, no extant reviews systematically discuss the full range of clinical associations found in relation to epigenetic regulation of these genes. While one recent review has outlined the role of glucocorticoid sensitivity in various diseases (Quax et al., 2013), there also exists no comprehensive review that enumerates the full range of epigenetic pathways that might lead to glucocorticoid dysregulation, and ultimately, disease.
The purpose of this systematic review, therefore, is to critically examine the extant literature on DNA methylation of CRH, CRH-R1/2, CRH-BP, AVP, POMC, ACTH, ACTH-R, NR3C1, FKBP5, and HSD11β1/2 in relation to clinical outcomes in adults. In doing so, our aim is to also highlight current challenges in the field that will need to be addressed in order to develop clinically meaningful prognostic biomarkers, and to outline future research directions needed to create an evidence base that can inform public policy practice.

This systematic review was conducted according to Cochrane PRISMA (Preferred Reporting Items for Systematic Reviews buy FG-4592 and Meta-Analyses) guidelines (Liberati et al., 2009), and the software used to store information was RevMan 5.3.

Thirty-two articles were identified as meeting our review inclusion and exclusion criteria. Full details of all studies retrieved in our review are given in Tables 1–5; however, we have limited our more detailed discussions in these sections to the high-quality and promising extant research that emerged from our review. Given the exceptional complexity of the HPA axis and its far-reaching interactions with a number of physiological systems, the plausible mechanisms and pathways through which epigenetic regulation of the HPA axis might contribute to disease are understandably varied. We will therefore also provide a critical discussion of the pathways implicated in the results reported across studies, where evidence exists, in order to contextualize the results reported for the many divergent conditions included in this review.

Since Tnmd KO mice harbor very mild developmental changes

Since Tnmd KO mice harbor very mild developmental changes, including interesting ultrastructural phenotype characterized by irregular and thicker collagen I fibrils when examined by electron microscopy (Docheva et al., 2005), we hypothesized possible structural and biomechanical alterations of the tendon tissue on nano-level. To pinpoint such we implicated AFM topography and force indentation analyses, a technology that has been largely used in cartilage research, demonstrating solid data on nano-structural and -biomechanical assessment of cartilage pathologies (Gronau et al., 2017; Prein et al., 2016; Stolz et al., 2009). AFM of collagen I fibers in sedentary and trained Achilles tendons confirmed these previous observations and additionally revealed that the fibers are significantly stiffer in the KO than in WT tendons. Moreover, while fiber size increased and stiffness decreased with training in control mice, the KO tendons were non-responsive. The ability of tendons to stretch and recoil is important to save energy during locomotion for economic force generation (Alexander, 1991). However, at the same time they must not undergo irreversible deformation. Physiological stretching of tendons in vivo decreases crimp numbers close to 50% in order to reduce the degree of fibril undulation (Franchi et al., 2007). This is more important for tendons than muscle, since muscle can elongate by almost 10% while in purchase Pyridoxal isonicotinoyl hydrazone the whole tendon unit can only lengthen by 3–4% (Elsalanty et al., 2007). Vilarta et al., observed more aligned and intensely packed fibrils in Achilles tendons of rats after exercise (Vilarta and Vidal Bde, 1989). Stiffening of human tendons was observed in aging or diabetic individuals due to increased pathological cross-linking of collagen fibrils (Shadwick, 1990; Couppe et purchase Pyridoxal isonicotinoyl hydrazone al. 2016). Stiffness of tendons varies with age, sex, physical activity and fatigue (Kubo et al., 2001b; Kubo et al., 2001a; Kubo et al., 2001c; Reeves, 2006). Interestingly, different types of tendons modulate their stiffness to each other, for example in endurance running, tendons in the knee joints become stiffer and in planter joints softer to guarantee optimal running performance (Kubo et al., 2015). Supplementary Fig. 7 depicts the explanation of this phenomenon. When subjected to the same amount of mechanical load, stiffer tendons extend less and in turn store less energy. In contrast, tendons that are more elastic extend further, store more energy and can therefore prevent premature rupturing. In endurance training the tendon spring softens; the softer the spring, the more elastic potential energy can be stored and less restoring force is needed resulting in more economic running.
A rise in blood-flow (Langberg et al., 1998), collagen-turnover (Langberg et al., 2000), glucose uptake (Hannukainen et al., 2005) and altered regulation of matrix metalloproteases (Koskinen et al., 2004) are detected in tendons during exercise. Tendons also adapt differently depending on the nature of the exercise. For example, Svensson et al. (2016) used resistance training protocol (building up strength, anaerobic endurance and size of skeletal muscles; involving fast-twitch muscle fibers) that resulted in tendon stiffening. In contrast, Wood and Brooks (2016) reported endurance running (involving slow-twitch fibers) led to more elastic tendon tissues in tendons of old mice, which is in line with our results. Endurance running in humans leads to softening of Achilles tendons (Ooi et al., 2015) and tendons of young mice adjusted to treadmill running by alterations in collagen fiber diameter, distribution, cross-sectional area and number (Michna, 1984; Michna and Hartmann, 1989; Majima et al., 2003). It will be of great importance in subsequent studies to investigate more precisely the structural-functional relationship between tendon tissue and both muscle fiber types by applying different exercise protocols as well as to couple AFM data with whole tendon biomechanical tests.

One of the limitations of this study is the differences

One of the limitations of this study is the differences in the patient populations between the two CRC patient cohorts. As shown in Table 1 and 2, there were differences in the number of patients with stage IV CRC between cohort 1 and cohort 2. At first, we validated the clinical significance of SNORA21 cesium chloride in cohort 1 to determine the cut-off value of SNORA21 expression based on the comparison of cancerous and matched adjacent normal tissues. Since cohort 1 had a smaller population of patients with stage IV disease, we also validated the SNORA21 expression levels in cohort 2 by including 47 patients with stage IV CRC. In spite of the differences in the populations of two independent cohorts, SNORA21 expression consistently increased according to tumor invasion, distant metastasis and vascular invasion, indicating that SNORA21 may be involved in tumor progression.


Gastric cancer (GC) is the fourth most common human malignant disease and the second leading cause of cancer-related deaths worldwide. (Torre et al., 2015) In recent years, significantly improved outcomes have been reported for patients with GC, largely thanks to improved drug therapy. (Noh et al., 2014) According to new guidelines, 5-fluorouracil/oxaliplatin chemotherapy is recommended as the standard postoperative chemotherapy regimen for advanced GC. (Noh et al., 2014) Significant survival benefits of 5-fluorouracil/oxaliplatin chemotherapy have been reported in patients with metastatic gastric cancer as well as those who have undergone surgery. (Longley et al., 2003; McLean and El-Omar, 2014; Noh et al., 2014; Razzak, 2014) However, the efficacy of 5-fluorouracil/oxaliplatin chemotherapy greatly differs among individuals, with local recurrence or distant metastasis occurring in approxiamately 40% of GC patients during the course of the disease. (McLean and El-Omar, 2014; Razzak, 2014) Therefore, the accurate prediction of chemotherapy efficacy is clinically important to guide individualized regimens and improve treatment outcomes.(Jiang et al., 2016; McLean and El-Omar, 2014) Several potential molecular predictors (e.g., p53, cyclooxygenase 2 (COX2), p21, Ki-67, excision repair cross-complementing gene 1 (ERCC1), thymidylate synthase (TS), and thymidine phosphorylase (TP)) of chemosensitivity have been investigated in colon cancer, breast cancer and GC,(Kwon et al., 2007; Metzger et al., 1998; Sulzyc-Bielicka et al., 2011; Xu et al., 2016) but these biomarkers still require validation and are not a part of the standard clinical practice in GC evaluations. Therefore, prognostic and predictive tools are urgently required to identify those patients likely to benefit from 5-fluorouracil/oxaliplatin chemotherapy.(Longley et al., 2003).
The PAKs (p21-activated kinases) belong to a highly conserved family of serine/threonine protein kinases that are important mediators of Rac and Cdc42 function.(Radu et al., 2014) PAKs have been implicated in the regulation of multiple cellular functions, including cell motility, actin reorganization, gene transcription, cell transformation, and apoptotic signaling, and more recently in radiotherapy and chemotherapy resistance signaling.(Radu et al., 2014; Zhang et al., 2010) PAK6 is the most recently identified and the least well known member of the PAK family. Recent studies have reported that PAK6 expression is increased and indicated poor prognosis in hepatocellular carcinoma (HCC), colorectal cancer (CRC) and prostate cancer (PCa).(Chen et al., 2015; Wen et al., 2009) Furthermore, PAK6 may be a good predictor of 5-FU response in colon cancer.(Chen et al., 2015) Knockdown of PAK6 expression inhibits PCa growth and enhances chemosensitivity to docetaxel (Wen et al., 2009). When combined with irradiation, inhibition of PAK6 leads to significantly decreased PCa cell survival.(Zhang et al., 2010) Another study reported that PAK6 expression was reduced and associated with good prognosis in clear cell renal cell carcinoma (ccRCC).(Liu et al., 2014) However, the molecular and prediction (prognosis and chemosensitivity) functions of PAK6 in GC are not yet well known.

Dentro de este rubro destaca el estado

Dentro de este rubro destaca el estado civil de las mujeres contribuyentes, generalmente viudas que acudían Erlotinib Hydrochloride la justicia federal para obtener el reintegro de ciertas contribuciones pagadas en demasía, para obtener algunas prebendas impositivas en los juicios hereditarios de los que eran parte, o bien para evitar el pago de multas. Una vez más, es posible comprobar que no sólo mujeres con actividades comerciales como María Goríbar de Zaldívar, cuyo caso hemos expuesto en otros trabajos (Becerril 2015, p. 212), acudían al juicio de amparo, sino que otras mujeres de la élite social del momento también vieron en este recurso un remedio en contra del cobro de ciertos impuestos. En este último supuesto se encontraba Elena Mariscal de Limantour, viuda de Julio M. Limantour (1863-1909) –quien fue hermano del famoso secretario de Hacienda del gobierno encabezado por Porfirio Díaz, Jose Yves Limantour (1854-1935)– que en 1921 acudió, junto a otros coagraviados, a impugnar una tasación de impuestos.
Como puede observarse, nuevamente nos encontramos frente a una gran variedad de sujetos sociales, personas físicas y morales; mujeres y hombres, que acudieron al amparo en materia fiscal para buscar solucionar algunos de los conflictos derivados del pago de sus contribuciones. Las sentencias de amparo recopiladas nos permiten ordenar en 82 grupos diferentes los impuestos y rubros tributarios impugnados (véase Tabla 2).
Del análisis del sistema tributario contenido en las sentencias de amparo en materia fiscal interpuesto en los años de 1917-1935, nuevamente es posible obtener una radiografía tributaria del momento. Como puede observarse, destaca la presencia de contribuciones que ya no deberían estar vigentes, como las alcabalas, junto a otras más que comenzaban su vigencia bajo la constante impugnación de los contribuyentes, como fue el caso del impuesto sobre la renta. Por otro lado, también queda de manifiesto el enfrentamiento entre la potestad fiscal federal y la estatal; sin embargo, a este conflicto iba a unirse la municipal, la cual, junto a las dos primeras, también tendría impacto en los gastos públicos. Impuestos al petróleo, a la industria textil, juntas calificadoras, instituciones de crédito, facultad económico-coactiva, impuestos a los ferrocarriles, sobre profesiones, prediales, etc., (véase Tabla 2) constituían la masa de tributaria que realmente se cobraba y cuya impugnación por vía de amparo demuestra su aplicación real más allá de la mera enunciación contenida en la ley de ingresos del erario federal. En adelante, la verdadera batalla a librarse en los tribunales de la federación sería el determinar quién y en qué rubros estaba legalmente

Consideraciones finales
El estudio de las sentencias de amparo que resguarda la Suprema Corte de Justicia de la Nación pone de manifiesto la interacción entre el ente público y los contribuyentes. Dichos documentos nos permiten observar cómo el Estado, la ley, la doctrina jurídica y la teoría económica, los contribuyentes, el desempeño económico y el discurso político se mezclan y experimentan un constante reacomodo en sus postulados, pero cuyo fin último siempre será la obtención de ingresos a target cell través de las contribuciones y su legitimación por medio de los tribunales federales. De esta forma, es posible encontrar diversos sujetos sociales que acudieron al juicio de amparo para reclamar justicia fiscal. No obstante que en este ensayo no entramos al estudio del sentido de las sentencias de amparo, es decir si se concedió o negó, pues es materia de otro estudio mucho más amplio, las características generales de los causantes, género y ocupación, nos permiten caracterizar el papel cada uno desempeñó en la dinámica económica del momento.
Por ejemplo, en cuanto hace a la personalidad jurídica de los contribuyentes, destaca el aumento de personas morales, si bien el grueso de los quejosos son personas físicas, el beneficio de hacer negocios por medio de una persona jurídica colectiva es patente en las tres primeras décadas del siglo xx por encima de las última tres del siglo xix. Esto último pone de manifiesto la diversificación en la forma de hacer negocios en el México posrevolucionario. Al mismo tiempo, ponen en evidencia a ciertos sectores privilegiados por el Porfiriato que parecían haberse diluido una vez derrotado dicho régimen pero que, sin embargo, hacen acto de presencia en los tribunales federales cuando ven afectados sus intereses fiscales. En este sentido, destaca también el aumento drástico de la participación de otros sujetos sociales no esperados pero presentes, con capacidad de decisión dentro de la estructura jurídica mexicana: las mujeres. En materia fiscal, poco importa el género de los contribuyentes pues, al final de cuentas, se trata de un tipo específico de ciudadano que se requiere cumpla obligaciones tributarias, sea hombre o mujer. Por otro lado, los impuestos impugnados por vía de amparo ponen de manifiesto el quehacer diario en la vida fiscal mexicana. De poco servía que en la norma algunos de ellos se hubiesen abolido, muchos se seguían cobrando con otros nombres, pero con las mismas funciones, tan sólo véase el caso de los impuestos tachados de alcabalatorios, las mercedes de aguas, el arrendamiento de contribuciones y un largo etcétera.

br Conclusions br Conflict of interest br Acknowledgements This


Conflict of interest

This work was supported by the National Institute on Drug Abuse under Grant R01DA017843 awarded to M. Luciana, by the National Institute on Alcohol Abuse and Alcoholism under Grant R01AA020033 awarded to M. Luciana, and by BTRCP41 EB015894 and P30 NS076408 grants awarded to the University of Minnesota\’s Center for Magnetic Resonance Research. Support from the University of Minnesota\’s Center for Neurobehavioral Development and the Minnesota Supercomputing Institute is also gratefully acknowledged.

Among adolescents in treatment for a substance use disorder (SUD), cannabis use disorders (CUDs) are the most prevalent SUDs (SAMHSA, 2010; Wisselink et al., 2014). Adolescent compared to adult onset of cannabis use is associated with greater cognitive deficits, poorer socio-economic status, poorer educational achievement and more chronic CUD trajectories (Meier et al., 2012; Perkonigg et al., 2008; Stinson et al., 2006; Swift et al., 2001). Unfortunately, only a minority of individuals with a CUD enter treatment (Agosti and Levin, 2004) and post-treatment relapse rates remain high (52–70%; Budney et al., 2008; Chauchard et al., 2013; Zumdick et al., 2006). These high relapse rates and the significant personal and societal harms associated with adolescent CUDs warrant the development of new treatment strategies. Knowledge of the neuropsychological processes associated with adolescent CUDs may help to identify new treatment targets, however, little is known about these mechanisms in adolescents.
The imbalance between strong drug-oriented motivational processes and compromised control processes is thought to play a significant role in the development and maintenance of SUDs (Everitt and Robbins, 2005; Koob and Volkow, 2010; Wiers et al., 2007). Strong motivational processes may develop over the course of repeated substance use through processes such as sensitization and conditioning. Encounters with cues (e.g., certain emotional states, objects, contexts) that buy dhpg have previously been associated with substance use may bias behaviour towards substance use in a relatively automatic way. More specifically, substance-related cues can grab attention (attentional bias), activate approach action tendencies (approach bias) and increase craving (Wiers et al., 2007). Cognitive control appears to be compromised in individuals with a SUD and has been found to moderate the relation between biased motivational processes and substance use (Grenard et al., 2008; Houben and Wiers, 2009; Peeters et al., 2012; Sharbanee et al., 2013; Thush et al., 2008). A relatively poor capacity to regulate motivational processes (pre-existent or compromised by substance use) may thereby further support continued substance use and relapse.
In line with previous findings on other SUDs, evidence is emerging albinism biased motivational processes are present in adult heavy cannabis users and individuals with a CUD. For example, cannabis cues can induce craving in adults with a CUD (Lundahl and Johanson, 2011). Moreover, an attentional bias towards cannabis cues has repeatedly been established in heavy cannabis users (Cousijn et al., 2013a; Field, 2005; Field et al., 2004, 2006) and individuals with a CUD (Asmaro et al., 2014; Cousijn et al., 2013a). Furthermore, dependent cannabis users showed a stronger attentional bias than non-dependent cannabis users (Cousijn et al., 2013a). The approach bias towards cannabis cues has been observed in heavy cannabis users (Cousijn et al., 2011; Field et al., 2006) and was found to be predictive of an increase in cannabis use six months later (Cousijn et al., 2011). Regarding cognitive control, the current literature provides preliminary evidence for a bidirectional relationship with CUDs: Long-term cannabis use may (temporarily) compromise cognitive control (Crean et al., 2011), whereas individuals with relative poor levels of cognitive control may have an increased risk of developing cannabis dependence (Cousijn et al., 2013b, 2014a,b). Cognitive control may only moderate the relationship between motivational processes and cannabis use in more severe and chronic cannabis users, not in all heavy users (Cousijn et al., 2013a,c). Despite these limited data on neuropsychological mechanisms underlying CUDs, the available studies in adult cannabis users suggest an important role for both cognitive control and motivational processes, such as attentional bias, approach bias, and craving in the development and maintenance of CUDs.