(Or to be more precise, FK866 cost quercetin supplementation showed no greater beneficial effects than placebo.) All three groups improved their test scores,

showing, perhaps, the effects of training and expectation. Nothing in this appropriately powered, well conducted study suggests any role for quercetin as a cognitive enhancer. Cortisol plays a major part in the development of depression, to the extent that it is probable that Inhibitors,research,lifescience,medical all depression results from some degree altered cortisol responsiveness. The best and most cited example of the potency of cortisol in this respect is that where cortisol levels are pathologically high in Cushing Syndrome, depression affects almost everyone. When cortisol Inhibitors,research,lifescience,medical levels are normalised, the depression abates (Kelly et al., 1996). Extrapolating from these observations, psychiatrists wondered whether reducing cortisol levels in non-Cushing’s subjects might treat depression. Paul David Singalas and co-workers review the role of metyrapone in this issue. Metyrapone inhibits cortisol synthesis and so reduces cortisol plasma levels. Most of the studies of metyrapone have been limited in size, scope and scientific rigour but all have been broadly positive. The best conducted study showed an effect size of 0.6 when metyrapone was added to standard antidepressants. Clearly more studies are required but metyrapone

shows considerable promise – only its Inhibitors,research,lifescience,medical lack of patent protection Inhibitors,research,lifescience,medical militates against its more widespread testing and use. In the second review article in this issue, Praharaj and Sharma report on the use of amantadine for olanzapine-induced weight gain. Amantadine is a dopamine releaser and re-uptake inhibitor that started out as an antiviral agent used Inhibitors,research,lifescience,medical for influenza. It also reduces appetite and is associated with weight loss. As such it seemed an excellent candidate to prevent or reverse the often profound weight gain seen with olanzapine. Praharaj and

Sharma uncovered six studies examining the use of amantadine with olanzapine but only two met their inclusion criteria. These two studies combined showed a statistically significant and clinically worthwhile advantage over placebo in terms of weight reduction and frequency of weight loss. until Amantadine thus is a suitable treatment for olanzapine-associated weight gain but is perhaps a second-line treatment after the better established metformin which has additional antidiabetic properties. Two further letters-to-the-editor demonstrate the need to expect the unexpected even when prescribing commonly used drugs. Hayward and Luft describe a peculiar presentation of delirium caused by a combination of lithium clomipramine and Channing and colleagues demonstrate the dangers of using successive doses of long- acting drugs (clonazepam in this case) in acute situations – the danger of accumulation should not be underestimated.

64 Many patients whose symptoms do not disappear completely are considered resistant to treatment, although, strictly

speaking, this is a pseudoresistance that can be caused by insufficient dosage, insufficient treatment time, poor adherence, or clinical evolution.65 Depression is an illness that is difficult to treat due to its inherent characteristics, factors that affect the prescription of medication and proper treatment (such as poor adherence and low dosage), comorbidity, and ineffective treatment.66 Inhibitors,research,lifescience,medical A great deal of the enormous personal, social, and economic cost brought on by depression is due to poor social functioning, which has generally been underestimated. While there are differences among the various treatments available to achieve better social functioning, it must be recognized than an improvement in symptoms docs not necessarily Inhibitors,research,lifescience,medical ensure better functioning in society67 or at work.68 Factors affecting adherence The arsenal of antidepressants available is much larger today, and the new medications are as efficient as the old tricyclics and monoamine oxidase inhibitors (MAOIs), but with fewer side effects. Although information on the diagnosis and treatment Inhibitors,research,lifescience,medical of

depression has been publicized in the media, nonadherence to therapy continues to be a major problem. Little research has been done into the factors associated with noncompliance in treatment for affective disorders, and nonadherence in unipolar and bipolar disorders has been estimated to range from 10% to 60%.69,70 Adherence studies using patients’ self-reports show that patients tend to overestimate their compliance, especially older subjects.71 A patient’s beliefs Inhibitors,research,lifescience,medical about the illness, unpleasant side effects, ineffective treatment, and cultural factors arc all variables in noncompliance.72 Among teenagers prescribed imipramine, it was find protocol determined that the oppositional defiant

disorder and family dysfunction Inhibitors,research,lifescience,medical affected adherence to the medication, rather than the side effects.73 The latency period in the early stages of medication and poor tolerance crotamiton for antidepressants have an effect on compliance.74 In addition, the physician’s initial communication style significantly influences a patient’s attitude toward the usefulness of antidepressants.75 Patients’ attitudes and beliefs about the illness and treatment have proven to be as effective in predicting adherence as the unpleasant side effects of the drugs.69,70 Treatment with selective serotonin reuptake inhibitors (SSRIs) is abandoned less frequently than therapy with conventional and modern tricyclics, but the difference is small and is based on short-term, controlled, randomized trials. Therefore, in clinical practice, generalizations cannot be made about a greater adherence to SSRIs.

In contrast, haloperidol showed a smaller overall impairment, on the first day, which had increased dramatically by the fourth day and was still marked on many measures after 48 hours of washout. This study predicted a clear difference between the two compounds in cognitive toxicity with repeated dosing in patients, which has been largely borne out, by subsequent clinical trials. Interestingly, despite being markedly impaired with haloperidol after 48 hours of washout, the volunteers reported no lowering of self-rated alertness compared with predosing, which is the opposite pattern to that described in the previous trial.

Inhibitors,research,lifescience,medical Despite this clear impairment with haloperidol 3 mg in the elderly, another trial in this population, which used a 2-mg dose in an attempt to avoid this see more extreme cognitive toxicity, found Inhibitors,research,lifescience,medical relatively little overall impairment.27 On two measures, haloperidol 2 mg was shown to be inferior to amisulpride 50 and 200 mg, the latter drug showing no impairment and some occasional Inhibitors,research,lifescience,medical signs of enhancement. In another trial in elderly volunteers, acute doses of moclobemide 100 and 300 mg were shown to produce little overall impairment and some

enhancement of memory processes compared with trazodone 150 mg, which produced widespread and marked impairment.28 Remacemide, a noncompetitive Af-methyl-D-aspartate (NMDA) antagonist under development for the treatment of epilepsy, was found to lead to dose-dependent cognitive impairment in acute doses up to 400 mg in a 5-way, placebo-controlled, crossover design in 16 young volunteers.29 Diazepam 10 mg was used as an internal control, and produced a similar Inhibitors,research,lifescience,medical range of impairments as remacemide 400 mg, though the profile of these impairments in terms of the magnitudes of actions on various aspects of function

was quite distinct. However, in subsequent repeated dosing trials, no Inhibitors,research,lifescience,medical effects of remacemide have been discovered, despite the doses being equivalent to therapeutically relevant equivalents in enzyme-activated patients.30 This suggests that, for some compounds, such as olanzapine mentioned previously, tachyphylaxis for cognitive impairment can occur with repeated dosing. The benzodiazepine antagonist flumazenil has been shown to reverse the effects of midazolam 17-DMAG (Alvespimycin) HCl on cognitive function in healthy volunteers.31 Interestingly, despite this effect, when given alone in three infusions of 0.5, 2.5, and 5 mg, flumazenil produced a wide range of cognitive impairment, in a placebo-controlled, double -blind, crossover trial.32 Similar effects when flumazenil is administered to patients with Alzheimer’s disease (AD) will be reported in a later section.33 There is obvious interest in the cognitive effects of the opioids when used to treat cancer pain.

86–0.88 for RT using the first 10 trials. The stop signal task was even higher, (α = 0.98) for RT and (α = 0.96) for Accuracy based on first 100 trials. Table 3 Correlations between tasks shows the relationship between performance on the spatial working memory task and the stop signal task for both parents and children Figure 3 Behavioral performance shows box plots depicting the performance of the participants over the different load conditions

is as expected: with increasing load the accuracy decreases and the reaction time increases. Left Y-axis shows Accuracy (acc) and right … Cognitive control symptoms and behavior We also examined summary statistics and correlations between symptoms and cognitive Inhibitors,research,lifescience,medical measures (Table ​(Table2),2), showing that the best measures are based on the criterion that they are associated to the predicted amount with attention symptoms and the RT across all four load conditions Inhibitors,research,lifescience,medical and percent inhibition, based on previous

findings in the literature of relatively modest but significant correlations between inattention symptoms and working memory (e.g., Rogers et al. 2011), and consistent with neurocognitive profiles for ADHD (Walshaw et al. 2010). The correlations between the child and the parent measures on working memory and selleck inhibitor response inhibition variables are high Inhibitors,research,lifescience,medical (e.g., r = 0.73; Percent inhibition), suggesting our tasks may have significant heritability (e.g., similar to the heritability for Intelligence = 0.75, Nessier et al. 1996), and thus Inhibitors,research,lifescience,medical would be appropriate for use in genetic association studies or useful as endophenotypes in psychiatric research (Gottesman and Gould 2003). Examining correlations and narrow-sense heritability (double

the slope of the regression) between parent and offspring can reveal the ceiling of potential heritability, but does not properly control for epistasis or environment effects (Lynch and Walsh 1998). In order to address the confound of potential shared variance between parent and child due to shared computing equipment and testing environment Inhibitors,research,lifescience,medical we conducted a leverage analysis (see Table ​Table5).5). We determined how much of the parents and child’s RT would have to be explained by shared computing equipment and other testing environmental factors by assuming that it is possible to decompose the observed covariance between parent and child into two components: One due to the familial connection between parent Farnesyltransferase and child, and one that is due to shared testing environment. In this model it is possible to determine how large a proportion of the observed covariance would have to be due to the shared environment to make the rest of the covariance – assumed to be due to actual association between parent and child not significantly different from zero. The estimates for the variability in parent and child scores due to this shared environment component range from a standard deviation of 33 msec (Go Trial RT) to a standard deviation of 154 msec (WM Load 5 RT).

Therefore it could be particular important to study rare gene variants and their impact on cardiac remodeling, since genome-wide approach, generally accepted now for searching new disease-causing and disease-modifying genes, usually does not cover rare polymorphisms with a frequency 5% and less. In conclusion, we have shown that the A213V substitution represents a rare polymorphism

with a population frequency of approximately 1%, that is overrepresented in patients with heart dilation of various origins (4,6%). This makes it most likely Inhibitors,research,lifescience,medical that the A213V shift constitutes a conditional mutation predisposing to malign cardiac remodeling under other stressful conditions. More studies A213V desmin biomechanical properties can shed light on the detailed mechanisms, Inhibitors,research,lifescience,medical involved in cardiac maladaptation in A213V patients. Acknowledgements This work was supported by the Swedish Heart-Lung foundation, Stiftelsen Frimurare Barnhuset, King Gustav V and Queen Victoria foundation, Sällskapet Barnavård, Stiftelsen Samariten, Ronald MacDonald

Child Fund, Sunnerdahls Handikappfond, Swedish Research Council and United Mitochondrial Inhibitors,research,lifescience,medical Disease Foundation as well as Russian Federal program “Scientific and Educational recourses of in Russian Innovation”.
The human immunodeficiency virus (HIV) causes diverse disorders of the brain, spinal cord and peripheral nerves. Rarely, polymyositis and myoglobinuria are seen. Two other neuromuscular syndromes in people with HIV antibodies are nemaline myopathy and bibrachial amyotrophic diplegia, a form of motor neuron Inhibitors,research,lifescience,medical disease. These associations have not been proven epidemiologically and it is uncertain whether HIV infection is a risk factor for either amyotrophic lateral sclerosis (ALS) itself or

Inhibitors,research,lifescience,medical other motor neuron diseases. However, CHIR-258 manifestations of ALS in people with HIV infection can be treated effectively with Highly Active Antiretroviral Therapy (HAART), which would therefore be expected to lower the rate at which new cases appear. Nemaline Myopathy History: Drs. Engel and Askanas have been leaders in the study of nemaline myopathy and other conditions in which abnormal inclusions are found in muscle. Nemaline found myopathy is defined by the clinical and histologic manifestations. It was named by G. Milton Shy, W. King Engel and their associates in 1963 (1). “Nemaline” was applied because muscle biopsies showed deposits of thread-like structures; the word came from the Greek “nema”. The threads were dark red with the Gomori stain and contain actin. The clinical syndromes are seen most often in infants and children (2, 3). One form, however, occurs in adults, warranting the name “sporadic late onset nemaline myopathy” (SLONM) (4). In infants and children, the disease is often familial in a pattern consistent with autosomal recessive inheritance. In adults, the disease is almost always sporadic and is seen in association with other conditions (2).

Data extraction The primary sources of data included the Mental Health Act office registers, source legal CTO documents, prescription charts and electronic patient records including medication details, ZSTK474 contemporary clinical notes and summaries. A baseline data pro forma was completed by clinical research staff. Analysis Statistical analyses with SPSS software included baseline descriptive analyses. Age at CTO initiation was calculated and categorized according to ‘Count me in’ census categories [Care Quality Commission,

2009]. Conditions stated on CTO were coded according to commonly occurring themes (as Inhibitors,research,lifescience,medical outlined in Table 3). Current antipsychotic medication was categorized according to class and formulation and antipsychotic polypharmacy was noted. Doses for antipsychotics were converted into percentage of maximum dose licensed according the British National Formulary (%BNF) [Royal Pharmaceutical Society of Great Britain, 2008]. Completion of SOAD certification was categorized according to time of completion and reason for lack Inhibitors,research,lifescience,medical of completion Inhibitors,research,lifescience,medical within 6 months (as outlined in Table 3). Table 3. CTO statutory reasons, conditions and medication. Results Sample characteristics There were 195 patients initiated on a CTO in the first year of legislation: 65% were male,

52% were of black ethnic origin, 5.6% were legally married, and 3.1% were employed or were students (see Table 1). The mean age at CTO initiation was 40.6 years (SD 14.1, range 17.0–89.1 years). The most common Inhibitors,research,lifescience,medical diagnosis was schizophrenia (70.8%). Five potential cases were lost as the patients were

entered into the nationwide RCT and randomized to the non-CTO arm of the trial (four cases were randomized to the CTO arm of the trial and are included here) [OCTET team, personal communication]. Table 1. Sample characteristics. CTO use and ethnicity For the 195 patients, 30 (15.4%) CTOs were conversions from former supervised discharge orders (section 25a), and 7 (3.6%) patients were previously Inhibitors,research,lifescience,medical on a criminal court appointed treatment order (section 37). CTOs were started more frequently in the first phase of the study (first cohort quartile (Q1): 64 (32.8%, including 10 section 25a conversions); Q2: 62 (31.8%, including 20 section 25a conversions); Q3: 39 (20.0%); Q4: 30 (15.4%)). Variation in CTO use was identified for secondary care patients across the four local medroxyprogesterone boroughs in the Trust (N = 165, χ2 = 11.3, df = 3, p = 0.012; see Table 2). For each individual borough, the proportion of patients of black ethnic origin in the sample was significantly greater than expected, based on population data [Office for National Statistics, 2001]. However, based on Trust Mental Health Act data (April 2007-March 2008) for section 3 (6-month hospital treatment order) patients, the proportion of patients of black ethnic origin in our sample was not significantly greater than expected (observed 52.3%, expected 50.2%, N = 195, χ2 = 0.

De Haas et al., reported fewer overall complications with simultaneous colorectal resection and liver metastasectomy (11% vs. 24%, respectively); but mortality rates were similar when compared to CP-868596 ic50 staged resections (45). Other studies have reported similar rates for both morbidity and mortality with simultaneous resection compared to staged resections (46-48). Despite these results, some centers still support a staged resection, with initial colorectal resection followed by future interval/delayed hepatic resection (35,49,50). Inhibitors,research,lifescience,medical The management

of metachronous CRLM disease is generally straightforward and involves initial colorectal resection and later resection Inhibitors,research,lifescience,medical of CRLM. Treatment algorithms for patients with CRLM have evolved

because of improved response rates with the addition of targeted agents to treatment regimens. Multiple trials have been shown to significantly increase response rates when adding bevacizumab or cetuximab to irinotecan or oxaliplatin backbone regimens (51-54). For example, cetuximab was evaluated in the phase II multi-center CELIM trial. Patients with unresectable CRLM were Inhibitors,research,lifescience,medical randomized to receive cetuximab with either FOLFOX6 or FOLFIRI (52). The ORR was 68% in the FOLFOX6 arm and 57% in the FOLFIRI arm (52). R0 liver resection was subsequently performed in 20 of 53 (38%) patients in the cetuximab/FOLFOX6 group and in 16 of 53 (30%) patients in the cetuximab/FOLFIRI group. The increases in ORRs have ranged between 10-30% with corresponding increased rates of hepatic resection

of 5-20% when cetuximab was combined with chemotherapy across most studies (29,52,55). Improvements in ORRs and subsequent rates of surgical Inhibitors,research,lifescience,medical resection have also been observed with bevacizumab. In the First Bevacizumab Expanded Access Trial (First Inhibitors,research,lifescience,medical BEAT), bevacizumab was added to the investigator’s choice of fluoropyrimidine-based chemotherapy for patients with CRLM (54). Of 1,914 patients, 225 were able to undergo surgery with curative intent (11.8%). Resection rates were higher in patients receiving oxaliplatin-based chemotherapy (16.1%) than in those receiving irinotecan-based chemotherapy (9.7%). 4-Aminobutyrate aminotransferase Finally, Falcone et al. reported a 66% ORR with FOLFOXIRI alone, whereas response rates with single backbone chemotherapy regimens in most trials were much lower and ORRs have generally increased with the addition of bevacizumab or cetuximab (20,21,51). Despite great improvements in response rates and resectability with standard and targeted agents, chemotherapy has the potential for liver damage and toxic side-effects that can affect surgical outcomes. Significant decreases in liver function have been described with 5-FU, oxaliplatin, and irinotecan and can contribute to increased perioperative morbidity (43,56).

It should be noted that mutations in the EGFR which have been shown to predict sensitivity to tyrosine kinase inhibitors in lung cancer, are very rarely seen in colorectal cancer (32). A search for other biomarkers have revealed mixed results with some studies showing BRAF mutations to predict lack of response (33) while others link BRAF mutations to prognosis but not response to EGFR inhibitor therapy (25). EGFR expression was initially thought Inhibitors,research,lifescience,medical to be necessary for the efficacy of EGFR inhibitor therapy. The initial trials with EGFR inhibitors were selleck screening library therefore restricted to patients with tumors expressing EGFR.

A retrospective review and a phase II trial found responses to therapy present in patients with tumors with low or no EGFR expression and therefore suggested that expression of EGFR should not be used to select patients who would be eligible for targeted blockade (34,35). EGFR gene copy number Inhibitors,research,lifescience,medical affects clinical outcomes in EGFR inhibitor treated patients in some but not all studies and remains controversial. A recent meta-analysis did show increased EGFR copy number to be associated with increased OS in patients receiving EGFR inhibitors as second-line therapy (HR 0.60, 95% CI, 0.47-0.75) but not as first-line therapy so this matter is still under investigation (36). However, given that increased copy number usually correlates with higher EGFR expression by immunohistochemistry, it Inhibitors,research,lifescience,medical is possible that EGFR copy number will not have a significant

impact on outcome related to EGFR blockade. A large number of patients with mCRC whose tumors show absence of KRAS mutations are non-responders. A systematic Inhibitors,research,lifescience,medical review of 8 studies published in 2008 calculated the sensitivity and specificity of KRAS testing and found KRAS mutations to have a specificity of 0.93 but a sensitivity of 0.47, demonstrating the need for further predictive biomarkers for patients with KRAS wild-type Inhibitors,research,lifescience,medical tumors (37). The EGAPP Working Group recently published recommendations for use of KRAS testing to determine likelihood

of benefit with EGFR inhibitor therapy. They concluded that while sufficient evidence is available to support the predictability of KRAS mutations in codon 12 and 13, evidence is inadequate for less frequent KRAS mutations (such as in codon 61). There is also some controversy about codon 13 that will be discussed later in this review. Furthermore, they recommend against Endonuclease testing for BRAF, NRAS, PIK3CA and loss of expression of PTEN or AKT proteins as insufficient evidence exists to use these to guide EGFR inhibitor treatment decisions (38). The concordance of KRAS mutational testing between the primary tumor and metastatic sites was recently reviewed in a meta-analysis looking at 19 publications with 986 paired primary and distant metastases. The study found a high concordance rate of 94.1% (95% CI, 88.3-95.0%) between primary tumor and metastatic sites while the concordance between primary tumor and lymph node metastasis was lower at 81.

Therefore, the use of the CVS task or the normative data in unhealthy populations is not supported by the findings of this study alone. Conclusion In this study, we quantitatively analyzed the functional brain properties of a CVS task. The task was found to provide robust activation of the occipital lobe, as well as regions in the middle frontal gyrus associated with coordinating eye movements and in regions of the insula associated with task-level control and focal attention. As expected, the task demonstrated deactivation patterns commonly implicated in the default-mode network. Further deactivation was noted in the posterior region of the cerebellum, most likely associated

Inhibitors,research,lifescience,medical with the formation of optimal search strategy. We believe the task will be useful in studies of visual attention in the neuroscience community as well as in mapping visual click here function in

clinical fMRI. Acknowledgments We would like to thank Raymond Poelstra, MD, and Marilyn Reed, BSN, for their helpful discussions and input in the design and implementation Inhibitors,research,lifescience,medical of the CVS for presurgical treatment planning. We thank Lynn Caldwell, PhD, Regina Schmidt, PhD, Laurie Quill, MS, Nicole Arbuckle, MS, and Kristie Nemeth, MS, for helpful discussions and input in the design and implementation of the CVS Inhibitors,research,lifescience,medical with regard to the study of human performance. We acknowledge funding support from the US Air Force during the development of the CVS. Conflict of Interest None declared. Funding Information We acknowledge funding support from the US Air Force during the development of the CVS.
Please note that an editorial related to this article, “The role of FGF2 in spinal cord trauma and regeneration research,” doi: 10.1002/brb3.207, can be Inhibitors,research,lifescience,medical found here, also published

in Brain and Behavior. Introduction In mammals, a major barrier for axonal regeneration Inhibitors,research,lifescience,medical after spinal cord injury (SCI) is the formation of the glial scar at the lesion. The glial scar is composed of astrocytes, which are triggered in response to extrinsic signals to activate and proliferate to generate a dense network of hypertrophic stellate cells that form an impenetrable barrier to the regrowth of damaged axons. Thus, one therapeutic strategy could be to improve the environmental conditions at the lesion site post-SCI to better support neuronal survival and axonal regrowth. Neurotrophic factors are good candidates to be examined due to their supportive Ribonucleotide reductase role during developmental neurogenesis. In addition to improving environmental signals, therapies need to target the cells that are already present at the injury site as these can play crucial roles in either supporting or blocking regeneration. For example, induction of radial glia-like and neuronal progenitor cells, which during development serve as scaffolds to support neuronal migration and give rise to neurons, may improve regeneration.

In a study of 13 153 individuals, between 48 and 67 years of age, who regularly utilized NSAIDs or asprin, no associations between NSAID use and any of the cognitive tests were observed, although a modest, association was observed between aspirin use and better performance on delayed recall and verbal fluency tests.201 Yet others observed no positive impact of prescription NSAID use on cognitive function in community-dwelling older adults.202

However, as emphasized by Pasinetti,76 daily doses of up to 1200 mg of NSAIDs such as ibuprofen are analgesic but not, anti-inflammatory, and it, typically Wnt inhibitor requires daily doses Inhibitors,research,lifescience,medical of 2400 mg for a systemic anti-inflammatory effect. It is interesting to note that in an investigation of the impact of chronic NSAID use on cognitive decline in older adults, Rozzini et al203 found a positive association Inhibitors,research,lifescience,medical between chronic NSAID use and reduction in cognitive decline over 3 years, as measured

by the Short. Portable Mental Status Questionnaire. As Karplus and Saag204 point out, large-scale, randomized, Inhibitors,research,lifescience,medical controlled trials using NSAIDs in this population are needed before it, is clear whether the known risks of NSAIDs are outweighed by their potential long-term benefits on cognition. There have been several investigations of the impact, of G biloba on cognitive function in adults asymptomatic for dementia. Several of these studies found that G biloba appeared to improve speed of processing and memoryfunction, particularly on measures of working memory.205-207 However, these studies were typically Inhibitors,research,lifescience,medical short, in duration, ranging from 6 hours to 12 weeks, and included middleaged rather than older adults. Several, large-scale, multisite, randomized clinical trials of G biloba in older adults arc ongoing and their results should further clarify the relationship between this agent, and cognitive performance in this population. The influence of estrogen on cognition and memory in normal aging has also received

Inhibitors,research,lifescience,medical considerable recent, attention.208-214 One of the most, consistent findings to emerge from the above literature links estrogen to the maintenance of memory function in aging women. Several Electron transport chain studies found that estrogen significantly improved performance on tasks of both the immediate and delayed recall of verbal and nonverbal material.213-217 While several observational studies have shown that estrogen administration has a positive effect, on attention span, concentration, and memory function, others have not observed an association between ERT and cognitive function.218-220 Methodological differences among these investigations, including variation in the age of subjects and the cognitive tests employed, may account for the mixed results.