Acknowledgments This work was supported in part by NICHD grants R01 HD047242 and HD047242-S1

. The author has no conflicts of interest or necessary disclosures as regards the content of this work.
The goal of this publication is to briefly summarize neuropsychological and neuroimaging findings among adults with traumatic brain injury (TBI) and/or post-traumatic stress disorder (PTSD), and highlight current thinking in the field. Tables have been used to consolidate evidence. The existing data is vast, and complete discussion is outside the purview of this paper. Inhibitors,research,lifescience,medical Readers are encouraged to review publications noted for further discussion of specific areas of interest. Traumatic brain injury (TBI) Diagnostically, to have suffered Inhibitors,research,lifescience,medical a TBI one must have experienced an event (eg, motor vehicle accident, fall) which resulted in a structural injur}’ to the brain or a physiological disruption of brain function (eg, alteration of consciousness [AOC],loss of consciousness [LOC]).TBI Inhibitors,research,lifescience,medical severity is classified according to the extent of injury to the brain or altered consciousness post-injury, not to the severity of sequelae reported or observed. See Table I for

further information regarding classification of TBI severity. Secondary to a cascade of cellular and molecular events, primary 5-HT Receptor inhibitor neurological injury associated with a traumatic event can also cause progressive tissue atrophy and related neurological dysfunction. Ultimately, such processes can result in neuronal cell death (secondary brain damage).1 Cellular mechanisms that modulate pathophysiological and neuroprotective processes Inhibitors,research,lifescience,medical appear to contribute to the nature and extent of

damage postinjury.2 Diffuse axonal injury (DAI), preferential multifocal involvement of myelinated Inhibitors,research,lifescience,medical tracks, often occurs and can be related to the primary injury or secondary brain damage. As the severity of the injury increases, so do findings noted on imaging and neuropsychological measures.3 According to the Centers for Disease Control and Prevention, approximately 1.7 million people per year in the United States sustain a TBI.4 Most injuries incurred by civilians and military personnel are mild in nature.4,5 That is, the associated AOC immediately following the injury is limited CYTH4 (eg, LOC less than 30 minutes). Individuals serving in Iraq and Afghanistan arc sustaining TBIs secondary to blast exposure.5 Reported estimates of TBI vary between 8% and 23%.5,6 Blast exposure can result in TBI via multiple mechanisms including: (i) primary blast – injury caused by the overpressurization wave; (ii) secondary blast – injury secondary to object being thrown by the blast towards the person; and (iii) tertiary blast – when individuals are thrown and strike objects.

These aptamer Scg8-AuAg-nanorods conjugates presented excellent hyperthermia efficiency and selectivity to CEM cells, exceeding the affinity of the original aptamer probes alone. Bimetallic AuAg-nanostructures with a dendrite morphology and hollow interior have also been developed as photothermal absorbers

to destroy A549 lung cancer cells [87]. The photothermal performance of such dendrites required lower NP concentrations and laser power for efficient cancer cell damage when compared to Au-nanorods photothermal therapeutic agents. Likewise, Cheng and coworkers evaluated the photothermal Inhibitors,research,lifescience,medical efficiencies of three Au-based nanomaterials (silica@Au-nanoshells, hollow Au/Ag nanospheres and Au-nanorods) at killing three types of malignant cells (A549 lung cancer cells, HeLa cervix cancer cells, and TCC bladder cancer cells) using a Inhibitors,research,lifescience,medical CW NIR laser [88]. Silica@Au-nanoshells needed the lowest NP concentration for effective photo-ablation, whereas hollow Au/Ag nanospheres and Au-nanorods needed increasingly higher concentrations. Gold has also been used together with magnetic or paramagnetic materials to enhance the photothermal effect and, thus, increase cancer cell death [89, 90]. 2.4.

Drug Delivery The vast Inhibitors,research,lifescience,medical majority of clinically used drugs for cancer are low molecular-weight compounds that diffuse rapidly into healthy tissues being evenly distributed within the body, Inhibitors,research,lifescience,medical exhibit a short half-life in the blood stream and a high overall clearance rate. As a consequence, relatively small amounts of the drug reach the target site, and distribution into healthy tissues leads to severe side effects. Poor drug delivery and residence at the target site leads to significant complications, such as multidrug resistance [91]. As seen above, nanoparticles can be used as vectors for targeting cancer tissue/cells so as to optimize biodistribution of drugs. The Inhibitors,research,lifescience,medical NPs’ performance as drug vectors depends on the size and surface functionalities

of the particles, drug release rate, and particle disintegration. These systems show evidence of enhanced delivery of unstable drugs, more enough targeted distribution and capability to evade/bypass biological Sunitinib supplier barriers. AuNPs have already been used as vehicles for the delivery of anticancer drugs, such as paclitaxel- [92] or Platinum- (Pt-) based drugs (e.g., cisplatin, oxaliplatin, etc.) [93, 94]. Gibson et al. described the first example of 2 nm AuNPs covalently functionalized with the chemotherapeutic drug paclitaxel [92]. The administrations of hydrophobic drugs require molecular encapsulation, and it is found that nanosized particles are particularly efficient in evading the reticuloendothelial system [95]. Gold-gold sulfide nanoshells covered by a thermosensitive hydrogel matrix have been developed as a photothermal modulated drug-delivery system [96].

0 years, age range = 8.2–15.6 years). Controls were originally recruited through community and hospital postings or were biological children of a participating adoptive or foster parent. None had a documented history of prenatal exposure to alcohol or other teratogenic substances, a learning disability, or other neurological or psychiatric condition. Demographics Inhibitors,research,lifescience,medical Parents or caregivers completed a child history form that included comprehensive information of the child’s prenatal, birth, developmental, and familial history. Socioeconomic

status (SES) was computed using the Hollingshead Four-Factor Index (Hollingshead 1975) based on the education and occupation of biological or foster parents. All participants were assessed for intelligence with the Wechsler Abbreviated Scale of Intelligence (WASI; Inhibitors,research,lifescience,medical Wechsler 1999), which provides a full-scale IQ score. Image acquisition and processing High-resolution T1-weighted MRI scans were obtained in the axial plane (repetition time = 10.06 msec, echo time = 4.2 msec, inversion time = 400 msec, flip angle = 20°, field of view = 180 mm, acquisition matrix = 256 × 192,

slice thickness = 1.5 mm) Inhibitors,research,lifescience,medical using a 1.5 Tesla GE signal excite scanner (General Electric Medical Systems, Milwaukee, WI). All scans were processed using the automated CIVET pipeline (version 1.1.10; Montreal Neurological Institute at McGill University, Montreal, Quebec, Canada). First, they were registered to the symmetric ICBM 152 template (Collins et al. 1994) and then corrected for radiofrequency inhomogeneity (Sled et al. 1998). Next,

skulls were stripped from the brain tissue (Smith Inhibitors,research,lifescience,medical 2002), which was then classified into grey matter, white matter, and cerebrospinal fluid (CSF) Inhibitors,research,lifescience,medical components (Zijdenbos et al. 2002; Tohka et al. 2004). Deformable models were used to construct the inner white matter surface and grey matter–CSF interface or pial surface in both hemispheres (Kim et al. 2005). These this website yielded four surfaces of 40,962 vertex points per surface. CT was measured from each vertex point on the white matter surface to the corresponding pial-surface point (Lerch and Evans 2005). CT data were blurred with a 20-mm surface-based diffusion-blurring kernel (Chung and Taylor 2004) and nonlinearly aligned using surface-based registration (Lyttelton et al. 2007). SA MTMR9 was computed at each vertex point of the pial surface by estimating the two dimensional area of a triangle formed by three vertices on the surface mesh and attributing a third of this area to each of the three vertices (Lyttelton et al. 2009). In addition to the vertex-wise analysis, each cortical hemisphere was segmented into sub-regions using the ANIMAL algorithm (Collins et al. 1995). From these data, measures of total cortical grey matter volume, total SA, and average CT were derived for each of the four hemispheric lobes (frontal, parietal, temporal, occipital), thus eight in total.

Risk indicators only indicate that there is an association between the variable and the onset, while no causal association is assumed. In principle, these risk indicators can be used to identify target groups for preventive interventions. In the next part of this paper, we will show that several groups of interventions actually have focused

on such high-risk groups. Although many risk indicators are known to be associated with the onset of mental disorders, most of them have a low specificity. This low specificity implies that most subjects who are exposed to the risk factor do not develop the disorder, and that one such risk factor by itself is not sufficient to bring the disorder into Inhibitors,research,lifescience,medical being.50,51 Furthermore, most risk indicators are related to lifetime risk, while target populations for preventive interventions must have an increased risk at the shorter term. Suppose, for example, that the risk of developing a major depressive disorder in the general Wnt inhibitor population is

2.5% in 1 year.52,53 If a high-risk group has a relative Inhibitors,research,lifescience,medical risk of developing a depressive disorder of 4.00, this will be highly significant (if the research Inhibitors,research,lifescience,medical population is large enough). However, this means that still only about 10% of the high-risk group will actually develop a depressive disorder, and about 90% will not. Many epidemiological researchers are satisfied after finding a highly significant relative risk of 4.00, but from the point of view of prevention this is clearly not enough. A high-risk group will probably be difficult Inhibitors,research,lifescience,medical to motivate for participation in a preventive program if only 10% eventually will develop the disorder, apart from the question of whether it is ethically acceptable to identify such a population as being “at risk” when most are in fact not at risk, or to intervene in such a population when for the vast Inhibitors,research,lifescience,medical majority of participants the intervention is not needed, and thus the time they spend on it is, in a sense, wasted. Furthermore, such an intervention is probably not very efficient or cost-effective, because the majority will never develop a disorder and the intervention has no preventive effect in this majority. From the perspective of preventive

intervention research, this low specificity is also problematic because very large numbers of subjects are needed to provide all sufficient statistical power for these intervention studies.51 Suppose, for example, that we would be able to motivate people from the high-risk group (10% of whom will develop a mental disorder in the following year) to participate in a preventive intervention. In order to show that such an intervention is capable of reducing the incidence from 10% to 5% (a risk reduction of 50%), we would need about 950 persons in a controlled trial (assuming a statistical power of 0.80; alpha level 0.05; calculations in STATA/SE 8.2). Trials of this size are logistically complex, expensive, and have a high risk of failure.

As the regional time series are obtained by averaging all voxels within a region, an inaccuracy of up to a voxel size was tolerated in this work without having a significant impact on the final results. Analysis of the fMRI data in subjects’ native space has a very high level of spatial correspondence accuracy in comparison with approaches that use spatial normalization into common space, but it

is forced into a set of predefined regions motivated by the neuroanatomy of the #BIO GSK-3 manufacturer keyword# human brain. Nonetheless, the method is extendable to any different set of brain regions. For this study, we used FreeSurfers’ predefined cortical and subcortical regions. Localization accuracy of native space method directly depends on the accuracy of the underlying T1 image Inhibitors,research,lifescience,medical segmentation. Thus, any inaccuracy in the underlying T1 image segmentation will directly affect the localization accuracy in the native space. Even though FreeSurfer Inhibitors,research,lifescience,medical segmentation was reported to be comparable to manual segmentation (which is the silver standard in the field),

an extra effort was made to check the accuracy of the underlying segmentation. We manually double-checked the FreeSurfer’s results for any possible error, and corrections were made when needed. By analyzing the resting-state BOLD fMRI data in subjects’ native space, we achieved a higher between-subject localization accuracy which increased our statistical power to detect alterations in DMN connectivity in each hemisphere independently. Such advantages made the detection of significant unilateral Inhibitors,research,lifescience,medical disruption in the connectivity Inhibitors,research,lifescience,medical of DMN possible. The prevailing method of spatial normalization and smoothing failed to find such effect under the same

conditions. In addition, the commonly accepted practice of interhemispheric averaging not only prevents analysis of two hemispheres independently, isothipendyl it also appeared to be a separate source of inaccuracy and seems to be problematic in practice. Our unilateral significant finding between supramarginal gyrus and superior-frontal cortex survived Bonferroni correction, had a large effect size, and correlated with cognitive performance. These observations support the hypothesis of unilateral disruption of DMN; however, replication of these findings with a larger number of samples is needed to further validate this hypothesis. Acknowledgments This work was supported by NIA R01 AG026158, K01 AG044467, and T32 AG000261. We thank Nikhil Chandra and Deirdre O’Shea for their help in data collection, MRI data reconstruction, and correction. Conflict of Interest None declared.

In patients with advanced, incurable cancer, anticancer treatment may alleviate patients’ cancer-related symptoms and cancer-associated complications [1]. These beneficial effects may occur even in the absence of a tumor response [2]. In contrast, reduction of tumor size does not necessarily imply a benefit to patients [3]. Chemotherapy may cause physical and psychosocial side effects [4]. An important focus of treatment is therefore to have a beneficial impact on health-related quality of life (HRQL) [5]. HRQL was reported by health care professionals [6] and medical

oncologists [7] to be the most important outcome in assessing the effect of palliative chemotherapy. Inhibitors,research,lifescience,medical However, HRQL considerations rated by physicians after consultation were poorly associated with decisions regarding modification Inhibitors,research,lifescience,medical of palliative chemotherapy [8]. While both monitoring of tumor response and toxicity are defined by gold standards (i.e., RECIST, CTCAE v3.0), symptoms and syndromes, also conceptualized as patient-reported outcomes Inhibitors,research,lifescience,medical (PROs), are yet only partially incorporated in routine oncology care [9,10]. Symptoms, which are subjective perceptions of patients, cannot be measured by currently used toxicity scales [11]. Syndromes are mainly clinically described patterns, a combination of symptoms and clinical signs. Cachexia for instance is Inhibitors,research,lifescience,medical the combination of

the sign weight loss and the symptom anorexia [12]. It is often assumed that an oncologist can estimate the symptoms of the patient accurately using a regular history. However, oncologists’ perceptions may differ from patients’ reported physical and psychosocial experiences. In patients with advanced cancer, the assessment of relevant psychological domains, but also of pain, Inhibitors,research,lifescience,medical asthenia/fatigue,

or nutritional problems are often underestimated [13,14]. They may not be detected (lack of screening), not be quantified by the patient or by a professional (lack of measuring individuals’ symptom distress) [15,16] or their impact on patients’ everyday functioning is not taken into account (lack of estimation of the magnitude of the problem). Physicians’ concerns about time constraints arising from dealing whatever with unexpected or complex symptoms may contribute to underestimation of symptoms, [17]. In Switzerland, an average of 15minutes of consultation time is general find protocol practice [18]. For the monitoring of anticancer treatment, the palliative effect of chemotherapy on disease-related symptoms and syndromes [15] has been operationalized by defining a clinical benefit criterion. In pancreatic cancer, the endpoint of clinical benefit response (a composite assessment of pain, performance status and weight) was created to provide a way in which the impact of therapy on tumor-related symptoms could be assessed [19] and has become a well-accepted outcome parameter.

Finally, the neuropathophysiology of TBI may be complicated by secondary neurological and systemic medical problems. Some develop as a consequence of TBI (eg, post-traumatic seizures, cerebral edema, subfalcinc or transtentorial herniation, vasconstrictive ischemic infarctions), some arise as concurrent, consequences of biomechanical craniocerebral trauma (eg, epidural or subdural hematoma, subarachnoid hemorrhage, intracranial infection), and others are the selleck inhibitor result, of concurrent physical injuries or medical

interventions (eg, hypovolemia, Inhibitors,research,lifescience,medical hypotension, hypoxia-ischemia, systemic infection/sepsis, iatrogenic sedation). Although these arc most, Inhibitors,research,lifescience,medical commonly problems among persons hospitalized as a result, of TBI, their development is not, limited to hospitalized patients and they require consideration in all cases as potential contributors to neuropsychiatric disturbances and targets of medical and neurorehabilitative interventions. Post-traumatic encephalopathy; a framework for addressing neuropsychiatric disturbances during TBI rehabilitation Evaluation and treatment approaches follow logically from Inhibitors,research,lifescience,medical the philosophy within which clinical phenomena are observed and interpreted and diagnoses formulated.66 This is particularly so when facing the diagnostic and therapeutic challenges presented by post- traumatic

cognitive, emotional, behavioral, and sensorimotor (ie, neuropsychiatric) disturbances: an understanding of such problems borne of traditional guild-like perspectives of neurosurgery, neurology, psychiatry, or rehabilitation Inhibitors,research,lifescience,medical medicine (and related disciplines) increases these challenges by focusing narrowly or emphasizing disproportionately Inhibitors,research,lifescience,medical one or another elements of the patient’s presentation germane to (ie, within the more limited scope of practice of) each of these disciplines. The information

presented in the preceding sections of this article highlights the need for a transdisciplinary understanding of traumatic brain injury and its consequences, and calls for a neuropsychiatrically-informed, neurobiologically-anchored clinical approach. Our group suggested previously6,22 17-DMAG (Alvespimycin) HCl that the pattern and course of clinical phenomena typical of the early post-injury period are usefully conceptualized as a post-traumatic encephalopathy. In the following section, it is suggested that this concept serves usefully as a foundation upon which to develop such an transdisciplinary clinical approach. Definition of post-traumatic encephalopathy Post-traumatic encephalopathy (PTE) denotes the clinical manifestations of brain dysfunction that develop immediately following application of an external physical force (including acceleration/deceleration and/or blast-related forces) to the brain.

The study was conducted according to the Declaration of Helsinki and approved by the Institution’s Ethical Committee. A written informed consent was obtained from the patients before implant, as requested by the Study protocol (8). Patients were discharged 2 days post-implantation after confirming the electrical lead parameters. If required, a reprogramming was done to adjust atrial sensitivity and to optimize AV synchronous pacing. The conditions of the wound at the site of PM implantation were verified 7 days after. Patients were randomized – 1month post stabilization – to AT/AF prevention

pacing Inhibitors,research,lifescience,medical features programmed OFF or ON. Patients crossed over to the opposite pacing program, six months later and remained in the same pacing program till the end of the study. Pharmacological

therapy was not changed. Patients were reexamined at 1, 6, 12, 18 and 24 months thereafter, by Inhibitors,research,lifescience,medical clinical assessment, standard 12-lead electrocardiogram, 24h-Holter monitoring and echocardiogram. The device performance was assessed at every visit. Device characteristics All patients with DM1 underwent dual-chamber PM system implantation (Medtronic Inhibitors,research,lifescience,medical Adapta ADDR01, Medtronic Inc., Minneapolis, MN, USA). The right ventricular lead (Medtronic 4074 CapSure Sense) was positioned in the apex, under fluoroscopic guidance; the bipolar atrial screw-in lead (Medtronic 5076 CapSureFix) was positioned in the right atrial appendage (RAA) or on the right side of the interatrial septum (Bachmann’s bundle – BB – region), according to optimal site, defined as the location with lowest pacing and highest sensing thresholds. Inhibitors,research,lifescience,medical To reduce atrial lead over-sensing, the sensitivity configuration was Inhibitors,research,lifescience,medical bipolar. To minimize confounding variables with different electrode materials and interelectrode spacing, the identical model lead was used in all the patients. Similarly, PMs

with identical behaviour and telemetric capabilities were used to assure accuracy in comparing measurements between the two groups of patients. All the devices were programmed in AAI-DDD mode; the lower rate was set to 60 b.p.m. Mode switches were programmed to occur for atrial rates > 200 b.p.m. persisting for > 12 ventricular beats. Managed Ventricular Pacing algorithm (MVP, Medtronic Inc.) was enabled to promote Org 27569 the intrinsic conduction and to reduce the possible influence of high-percentage ventricular pacing on AF incidence. Atrial Preference Pacing (APP, Medtronic Inc.) was enabled according to the prospective programming compliance criteria. The devices used in this study were programmed to detect the episodes of atrial Selleckchem Dinaciclib tachycardia and to record summary and detailed data, including atrial and ventricular electrograms (EGMs).

Overall, the treatment groups were well matched with respect to baseline characteristics (table 1). All the patients were in the Global Initiative for Obstructive Lung Disease (GOLD) class of severe or very severe at baseline. Table 1 Demographic and hemodynamic characteristics at baseline The mean http://www.selleckchem.com/products/Bosutinib.html 6-minute walk distance increased by 41 meters in the Pentoxifylline group (351.9±65 at baseline to 393±67 meters

at week 12; P<0.001), and increased by 25 meters in the placebo group (328±79 at baseline to 353±66 meters at week 12; P<0.001). Despite the significant Inhibitors,research,lifescience,medical increase in the 6-minute walk distance in both groups, there was no statistically significant difference between the groups (P=0.142). After the administration of Pentoxifylline for 12 weeks, there was no increase (compared to the placebo) in the mean resting arterial oxygen saturation and heart rate, or nor was there a decrease in dyspnea score (table 2). The individual 6-minute walk distance of both patient groups is plotted against time in figures 2 and ​and33. Table 2

Changes Inhibitors,research,lifescience,medical in 6-Minute Walk Test, dyspnea score, and oxygenation before and after Pentoxifylline administration Figure 2 Individual 6-minute walk distance (MWD) in the Pentoxifylline Inhibitors,research,lifescience,medical group is plotted against time in weeks. Figure 3 Individual 6-minute walk distance (MWD) in the placebo group is plotted against time in weeks. Discussion COPD is characterized by dyspnea-induced impairment and as such can significantly Inhibitors,research,lifescience,medical limit the performance of everyday tasks. Hence, a primary goal in the management of COPD is to improve dyspnea with a view to facilitating physical activities irrespective of the severity of the disease if the patient’s health-related quality of life is to be enhanced.20 Pentoxifylline is a xanthine-derived agent, which possesses several properties that could have beneficial effects for the patient with Inhibitors,research,lifescience,medical COPD. It improves the flow properties of blood by decreasing blood viscosity and reducing RBCs and platelet aggregation.21 It also increases

cardiac output and O2 consumption and attenuates systemic vasoconstriction.22 The drug is currently used in patients with peripheral vascular disease to increase blood perfusion and improve oxygen delivery. In addition, Pentoxifylline has been reported to increase the cardiac index and there is preliminary evidence that it can reduce hypoxia-induced Levetiracetam pulmonary vasoconstriction.6 In the current study, the hypothesis that the net effect of this constellation of pharmacologic properties would improve gas exchange in COPD patients was tested in a group of patients with severe and very severe COPD in conjunction with pulmonary hypertension immediately after exercise. Haas et al.3 demonstrated that Pentoxifylline improved treadmill walk time, arterial saturation, and pulmonary gas exchange in patients with moderate to severe COPD. Why did we obtain such disparate results relative to that study? There are a number of possible explanations.

It is important to recognize some of the limitations of these strategies at the outset. Although most common putatively functional SNPs are known, rarer SNPs may have large phenotypic effects, and there are many such variants yet to be discovered. Not all functional SNPs are easily recognized as such. SNPs vary by population, and populations differ in the extent to which common genetic variation has been identified. The same population variation is reflected in differences in haplotype structure. Finally, haplotype reconstruction is almost always accomplished via computer algorithms,

and the results are estimated. Inhibitors,research,lifescience,medical With these limitations in mind, we discuss several examples of genetic associations with DD phenotypes, focusing on interesting physiological candidates and on replicated findings. Association of variants that map

at or near the D2 dopamine receptor (DRD2 locus) with drug or alcohol dependence was proposed many years ago Inhibitors,research,lifescience,medical and has been widely debated. We identified a “suggestive” linkage peak for ND at the region of chromosome 11 that includes the NCAM1-TTC12-ANKK1-DRD2 gene cluster.23 The inconsistent results with Inhibitors,research,lifescience,medical DRD2 may be attributable to an indirect effect – observed association could actually be mediated through variation at a nearby locus in linkage disequilibrium with DRD2. To test this hypothesis, we genotyped 43 SNP markers in a region including DRD2 and the three adjacent genes, in an SD linkage sample of >1600 subjects. We found Inhibitors,research,lifescience,medical very strong evidence of association of multiple SNPs at TTC12 and ANKK1 in two different populations, EAs and AAs (minimal P=0.0007 in AAs and minimal P=0.00009 in EAs), and highly significant association of a single haplotype (set of markers) spanning TTC12 and ANKK1 to ND in the pooled sample (P=0. 0000001). Thus, a risk locus for ND maps to a region that spans TTC12

and ANKK1 . The exact localization of the risk haplotype depends on the disease definition, and whether and which co-occurring diagnoses are present in the study Inhibitors,research,lifescience,medical sample.24 These results support the hypothesis that the DRD2 findings could be attributable to variants in nearby loci. Such variants could reflect either functional variation that affect and those loci (and not DRD2), or relatively distant regulatory regions important for DRD2 function. The ANKK1 finding in ND has been replicated.25 Another set of risk loci that are of interest in learn more relation to the risk of drug dependence are those encoding proteins that regulate or mediate opioidergic function. All of the opioid receptor genes have been reported to be associated with substance dependence liability. A functional polymorphism in OPRM1 (Asn40 Asp), which encodes the mu-opioid receptor, has been the most extensively studied in this regard, though the association is controversial.