63 Some of these tests are time-consuming, and therefore not always appropriate for large screening studies, but the throughput of behavioral assessment has been markedly improved in recent years by the use of automated monitoring, computer data processing, and the development of dedicated software for behavioral analysis.64 TABLE I. Table I. Trametinib in vitro models or tests of anxiety in rodents. For a definition of tests vs models, see text. See also refs 95, 96. Adapted from

ref 54: Rodgers RJ. Inhibitors,research,lifescience,medical Animal models of ‘anxiety’: where next? Behav Pharmacol. 1997;8:477-496. Copyright© Lippincott … How can we assess the validity of models? In the mid 1980s, Willner proposed three sets of criteria for assessing animal models of human mental disorders: predictive validity (performance in the

test predicts performance in the condition being modeled), face validity (phenomenological similarity), and construct validity (theoretical rationale).65 , 66 To these “classical” Inhibitors,research,lifescience,medical criteria, we would like to add a new one, recently proposed by Mathias Schmidt in the context of animal models for Inhibitors,research,lifescience,medical depression: the “population validity“ criterion.44 This is a specific extension of the ”face validity“ criterion: the occurrence rate of a disease-like phenotype in an (epi)genetically heterogeneous population should match the human situation (same odds ratio for that risk or predisposition factor). Thus, risk factors such as adverse early life events should only affect a subpopulation of more vulnerable individuals. Application of this criterion poses a number of problems, notably regarding Inhibitors,research,lifescience,medical the number of animals which have to be used. However, the occurrence of anxiety disorders is quite

frequent (lifetime prevalence 15% to 30%) in the general population,67,68 and similar values can be expected in a rat or mice Inhibitors,research,lifescience,medical population, as this has been shown for instance in animal models of PTSD.69 It would seem that application of the population validity criteria is probably essential if we want to develop models of anxiety disorders, and not only models of anxiety within the ”reaction norm“ (ie, in the normal adaptive range), although these models are still useful to delineate the biological and neural mechanisms Bay 11-7085 underlying ”normal“ anxiety, or to evaluate the efficacy of (pharmacological) treatments. Should models be based on clinical symptom classification? In our views, the obvious answer to that question is: no, or at least not exclusively. First, the classifications of psychiatric diseases (either with the DSM-IV or ICD-10 systems) remain essentially syndromic and is constantly being revised.70,71 Second, currently recognized categories of psychiatric disorders include heterogeneous populations of patients, with subpopulations featuring a great diversity in underlying (epi)genetic and other predisposition factors, neurobiological mechanisms, life history, and comorbidities.

Thus, increased overall power in the temporal lobes, if STAT inhibitor reflective of activation of autonomic functioning, is consistent with the hyperarousal theory regarding the underlying mechanism for insomnia. Quieting of high-frequency power in the temporal lobes could be understood as mitigating an underlying driver of insomnia. Limitations The limitations of this study include a small sample size, as well as the use of a wait-list usual care control group rather Inhibitors,research,lifescience,medical than an active control, or sham-placebo group.

Because the study design entailed usual care for the control group, without blinding as to the intervention, it is not possible to rule out placebo or expectation effects as contributors to the improvements Inhibitors,research,lifescience,medical associated with the HIRREM intervention. HIRREM, like other interventions which entail social interaction and relaxation induction, may facilitate improvements not only through auditory tonal mirroring of dominant electroencephalic frequencies but also through nonspecific mechanisms. Placebo biofeedback interventions, for example, have in some cases been shown to offer benefits comparable to Inhibitors,research,lifescience,medical true biofeedback (Nicassio et al. 1982; Hunyor et

al. 1997). Nonetheless other studies have reported that true biofeedback is more efficacious than placebo biofeedback (Henderson et al. 1998; Armagan et al. 2003; Becerra et al. 2006; Rao et al. 2007; Basta et al. 2011). The degree of improvement, and the standard effect size, coupled with persistence of benefit for at least 4 weeks following completion of HIRREM suggests the presence Inhibitors,research,lifescience,medical of a real change. In addition, subjects in both groups continued their usual care throughout the course of the study. It is unclear whether HIRREM alone would achieve the results observed or if combination is necessary. Placebo-controlled studies Inhibitors,research,lifescience,medical of HIRREM are warranted, and future studies should include physiological outcomes and follow-up to evaluate persistence of effect. Conclusion In this pilot clinical trial, the use of HIRREM in subjects with insomnia was feasible and effective

and was safe and well tolerated. Based on differential change for a subjective clinical insomnia outcome measure, HIRREM improved insomnia compared with continuation of usual care alone. This appeared to be a strong effect based on the standard effect size, and the effect persisted for at least 4 weeks following HIRREM. The CES-D also showed improvement. Exploratory analysis through suggested changes in brain pattern having relevance to the hyperarousal theory of insomnia, with potential implications for understanding the mechanisms of HIRREM for individuals with insomnia. This study suggests a need for additional controlled clinical trials to both confirm the effect and further explore possible mechanisms of action. Acknowledgments We are grateful for the technical expertise and assistance provided by Jenny Steil, Jeremy Fortenberry, and Karin Merk.

4%), while undertriage represents the amount of patients with CPA who were not categorized as A+ (the undertriage rate was 0.8%). A high rate of overtriage will result in an inappropriate high priority dispatch from the limited number of ambulances, while a high rate of undertriage will result in an unnecessary loss of lives. The cut-off value was set as the same value regardless of the type of caller. With the cut-off value, the algorithm for calls

made from nursing home staff achieved high level sensitivity (91.4%), meanwhile the sensitivity of the algorithm for calls made from third party Inhibitors,research,lifescience,medical was relatively low (63.5%). Sensitivity and specificity have a trade-off relationship. An appropriate cut-off value of the algorithms must be reconsidered. We included the obviously Inhibitors,research,lifescience,medical dead patients in our review because these patients were not identifiable at the time of emergency call. Ambulance crews were dispatched to rescue every patient, among whom persons identified as obviously dead at the scene were included. If obvious death is identified at the scene, Inhibitors,research,lifescience,medical patients are not transported to hospitals. When non-transported

cases are excluded from the evaluation study, sensitivity, specificity, predictive values, and likelihood ratios are changed. In this case, the sensitivity, specificity, positive predictive value, Depsipeptide in vivo negative predictive value, positive likelihood ratio,

and negative likelihood ratio of categorizing patients as A+ that resulted Inhibitors,research,lifescience,medical in death or CPA was 78.7% (95%CI: 76.7% – 80.6%), 95.6% (95%CI: 95.4% – 95.8%), 35.1% (95%CI: 33.6% – 36.7%), 99.3% (95%CI: 99.3% – 99.4%), 17.8 (95%CI: 16.7 – 19.0), and 0.22 (95%CI: 0.20 – 0.24), respectively. Several studies on the validity of triage systems have been reported Inhibitors,research,lifescience,medical in the UK [20,21], Canada[23], Finland [24], USA[25] and Australia [26]. Heward et al. reported that 50% of cardiac arrests were identified by the Advanced Medical Priority Dispatch System [20]. Flynn et al. reported that sensitivity and specificity of the Medical Priority Dispatch System for detecting cardiac arrest were 76.7% and 99.2% [26]. Direct comparison on the accuracy of triage systems is difficult because relevant terms for estimating the accuracy have not many been presented in their entirety in the literature. The likelihood ratio incorporates both the sensitivity and specificity of the algorithm and provides a direct estimation of the accuracy of the triage [27,28]. There are several challenges for developing a more improved triage algorithm. The algorithm to assess a patient’s life threat risk can be improved with the data obtained under the new emergency medical services system, in which information obtained during emergency calls is recorded as digital data.

In addition to

cycling at the inner mitochondrial membrane, other types of cycles occur in metabolism. Especially in skeletal muscle cells, the phosphofructokinase (PFK) reaction in conjunction with the fructose-1,6-biphosphatase (FBPase) operating anti-parallel represent a substrate cycle, which may control the pathway of glycolysis (GLY) more Inhibitors,research,lifescience,medical sensitively than would be possible by PFK alone. In this cycle, fructose-1,6-biphosphate (FBP), which is produced by ATP-coupled formation from fructose-6-phosphate (F6P), is cycled back via FBPase to F6P. However, usually both fluxes are not equal. Also to demonstrate the opposite equality of partial conductances Inhibitors,research,lifescience,medical for this kind of cycle, only equal fluxes can be used for this purpose. As a further example, the phosphocreatine shuttle will be considered. The creatine kinase (CK) reaction can also be regarded as a coupled reaction. Here, ATP splitting powers phosphocreatine (PCr) formation from creatine (Cr), which may proceed near equilibrium. As described in detail in reference [1], ATP is shuttled between locations of ATP formation (for

instance in the inter-selleck chemicals membrane space in mitochondria) and locations of high ATP demand like Inhibitors,research,lifescience,medical myofibrils. By analogy to an electric circuit built by two in series batteries with an outer Inhibitors,research,lifescience,medical circuit

conductance (see Appendix (A4)), the output affinity of PCr formation in the inter-membrane space of mitochondria corresponds to A1I with associated LIc1, whereas the affinity of the reverse reaction in myofibrils corresponds to A1II(with LIIc2). To ensure diffusional flow of PCr and Cr between both locations, an additional driving force (corresponding to Ue; see (A4)) with associated conductance must be present. Under such conditions partial conductances do not match. Only when the additional Inhibitors,research,lifescience,medical conductance corresponding to the diffusional process (Le) is added to LIc1 does this sum become opposite and equal to LIIc2, as is shown in (A4). Le depends others greatly on structural features. So, to achieve a high diffusional conductance, diffusional paths must be as short as possible, which in turn requires a high grade of structural organization [26,27,28]. It seems worth mentioning that coupled systems like pump and leak cycles are often not in a steady state. For instance, steady state cycling through sarco/endoplasmatic reticulum Ca2+ ATPases (SERCA) and Ca2+ release channels of the sarcoplasmatic reticulum (SR) breaks off during activation of contraction. There is an enormous Ca2+ efflux through release channels; meanwhile the pumping rate of SERCAs may be low.

A significant interaction effect was observed between time and the group (repeated measure ANOVA) in the WOMAC total score and the WOMAC subscales scores of pain, stiffness, and function. In the placebo group, maximum improvement occurred at the 4th week and there was no significant improvement during the remaining time. In the HCQ group, maximum improvement occurred at the 8th week and lasted over the entire remaining follow-up period. There were significant Inhibitors,research,lifescience,medical differences between the two groups as CX-5461 in vitro regards the degree of reduction in the WOMAC total score and the WOMAC

subscales scores of pain, stiffness, and function at weeks 4, 8, 12, 16, 20, and 24 (figures 2-​-55). Table Inhibitors,research,lifescience,medical 2 Mean WOMAC scores over time in the studied patients Figure 2 This graph illustrates the mean changes

from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score over 24 weeks of treatment in the studied patients Figure 5 This is a represntation of the mean changes from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function score over 24 weeks of treatment in the study population Inhibitors,research,lifescience,medical Figure 3 This graph illustrates the mean changes from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score over 24 weeks of treatment in the studied patients Figure Inhibitors,research,lifescience,medical 4 This is an illustration of the mean changes from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) stiffness score over 24 weeks of treatment in the study population There was a statistically significant difference between the two groups vis-à-vis the average number of painkiller pills consumed during the trial (0.74 pill per day in the HCQ group and 0.96 pill in the placebo group; P=0.035). Inhibitors,research,lifescience,medical Three patients in the HCQ group discontinued the treatment due to drug side effects (skin rash in 2 and vertigo in one), whereas there were no drug side effects in the placebo group. The difference between the two groups with respect to the frequency of drug side effects

was statistically significant (P=0.001). Discussion The knee joint is commonly afflicted by osteoarthritis. As much as knee osteoarthritis is a disease of high prevalence in world Dichloromethane dehalogenase populations and is associated with high morbidity, the treatment has shown little progress in the last decades.10,11 Pharmacologic treatment categories for osteoarthritis are typically set up to designate whether drugs are symptom-relieving or disease-modifying. Nonetheless, the evidence has thus far proved insufficient as to which drugs have optimal disease-modifying properties in osteoarthritis.2 Antimalarial agents have immunomodulatory and anti-inflammatory properties, and the effectiveness of these drugs in the therapy of some rheumatic diseases has been well known in the medical literature for many years.

According to this view, drugs with an anti-cytokine Proteasome inhibition assay action, such as those contrasting TNFα, have

been proven independently by our and Grounds’ group to protect mdx muscle against early necrosis. TNFα is a key proinflammatory cytokine that stimulates the inflammatory response, and pharmacological blockade of TNFα activity with the neutralising Inhibitors,research,lifescience,medical antibody infliximab (Remicade) or with a chimera compound bearing its soluble receptor, such as etanercept (Enbrel) is clinically effective at reducing symptoms of chronic inflammatory diseases. In mdx mice, infliximab delays and reduces the necrosis of dystrophic muscle in young mdx mice (16). A protective effect of TNFα blockade is reinforced by further studies using etanercept or the specific Inhibitors,research,lifescience,medical antibody against murine TNFα; in exercised adult mdx mice additional physiological benefits on mouse strength, chloride channel function (a cellular biomarker muscle state) and CK levels have been observed (17-19). The profile of the anti-TNFα drugs in mdx mice overlap that observed with cyclosporine, suggesting the importance to modulate immune response (20). The controversial outcome and/or

impact of these drugs Inhibitors,research,lifescience,medical in clinical settings on DMD may derive from their toxicity (enhanced risks of serious infections) and/ or difficulty in finding proper human doses in young patients; Inhibitors,research,lifescience,medical however these drugs may also be adjuvant for future gene/cell therapies. Other compounds, acting as inhibitors of NF-kB or as wide anti-inflammatories, such as flavocoxid, have been found beneficial in mdx mice, with a wide modulation in function and in expression of various pro-inflammatory pathways (21, 22). Some of these actions also overlap a possible antioxidant effect, due to the expected cross-talk between the two pathways (see below) (21). Similarly, classical non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen Inhibitors,research,lifescience,medical and flurbiporfen have been found to ameliorate function and disease

course in mdx, especially if combined with or linked to a nitric Idoxuridine oxide (NO)-donating moiety which is claimed to enhance satellite cells activation and myogenic program (23, 24). By contrast, we could not confirm in the exercised mdx mouse model, a similar efficacy of meloxicam, a NSAID with higher affinity for the inducible-form of cyclo-oxygenase 2 (COX-2). This could be related to the role of COX-2 derived eicosanoids in promoting muscle regeneration (18, 25). Clinical trials in DMD boys with various anti-inflammatories are under considerations. However, the choice of the best drug is still unclear and must carefully consider the risk/benefit ratio also in relation to patient’s age, the drug-specific toxicological profile and the delicate role of inflammation in muscle repair.

40 As for CREB, numerous target genes for ΔFosB have been identified in NAc by use of candidate gene and genome-wide approaches.10,32 While CREB induces dynorphin, ΔFosB suppresses it, which contributes to ΔFosB’s pro-reward effects.38 Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively

induced in the chronic drug-treated state.41 Many other ΔFosB targets have been shown to mediate the Inhibitors,research,lifescience,medical ability of certain drugs of abuse to induce synaptic plasticity in the NAc and associated changes in the dendritic arborization of NAc medium spiny neurons, as will be discussed below. The functional consequences of ΔFosB induction in other brain regions is less well understood,

although its induction in orbitofrontal cortex (OFC) has been studied in some detail. Here, ΔFosB mediates tolerance that occurs to the cognitive-disrupting SCR7 ic50 effects of cocaine during a course of chronic exposure, and this adaptation is associated Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical with increased cocaine self-administration.42,43 Genome-wide assays have suggested several potential target genes that mediate these effects.42 Despite ΔFosB’s unique temporal properties, and the knowledge that it is induced in traditional memory circuits (eg, hippocampus), there has not yet been an exploration of the role of ΔFosB in behavioral memory, an interesting subject for future research. Epigenetic mechanisms In more recent years, studies of transcription have been pushed one step further Inhibitors,research,lifescience,medical to epigenetics44 (see Figure 1), which can be broadly defined as a change in gene expression that occurs in the absence of a change in DNA sequence. Epigenetic mechanisms control the packaging of DNA within a cell nucleus via its interactions with histones and many other types of nuclear proteins, which together comprise chromatin. Gene Inhibitors,research,lifescience,medical expression is controlled by the state of this packaging through the covalent modification of histones, other proteins, and DNA itself.

As just some examples, acetylation of histones tends to promote gene activation, methylation of histones can either promote gene activation Adenosine or repression depending on the Lys residue undergoing this modification, and methylation of DNA is generally associated with gene repression although certain variant forms of methylation (eg, 5-hydroxymethylation) may be associated with gene activation. Epigenetics is an appealing mechanism because, in other systems, for example, developmental and cancer biology, certain epigenetic modifications can be permanent. For this reason, epigenetics has been pursued both in learning and memory models (eg, refs 45-48) as well as in addiction;44,49 in both systems profound changes have been reported in histone acetylation and methylation and in DNA methylation. As just one example, the histone methyltransferase, G9a, is implicated in both memory50 and addiction.

44 The gene for catecholamine O-methyltransferase (COMT) codes for one of the major enzymes catalyzing the metabolism of dopamine. It has been mapped to chromosomal region 22q11, and contains a functional polymorphism (Val158Met) that results in two common variants of the enzyme

(Val and Met) corresponding to high and low dopamine catabolism, respectively The COMT gene has been examined several times for an association with schizophrenia. Although not conclusive, family-based association studies and case-control studies do support the claim that variability Inhibitors,research,lifescience,medical of this gene could constitute a risk factor for schizophrenia, specifically the Val allele.45 Studies of healthy individuals, and schizophrenia patients have further demonstrated that the Inhibitors,research,lifescience,medical COMT genotype is related in an allele dosage fashion to performance on tests of working memory and executive functions, with more Met alleles associated with better performance.46-48 Egan et al46 also examined the effect of COMT genotype on prefrontal physiology during a working memory task using functional magnetic resonance imaging (MRI) . Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Thus, according to these results, the high levels of dopamine

Inhibitors,research,lifescience,medical in individuals with the Met/Met genotype enhance prefrontal function and Inhibitors,research,lifescience,medical therefore cognitive performance, and are also associated with lower risk for psychosis (Figure 2). Figure 2. Schematic representation of the putative

effect of a schizophrenia ZVADFMK susceptibility gene (COMT) on neurotransmission and the relationship with cognition and psychosis. COMT polymorphisms effect dopamine regulation in the frontal lobes, through which Inhibitors,research,lifescience,medical cognitive … Conclusion The evidence reviewed in this paper strongly supports the view that cognitive deficits are a risk factor for schizophrenia and other psychotic disorders. Cognitive deficit is a stable, “trait-like” condition, independent of psychotic symptoms and mostly unaffected by antipsychotic treatments. In some patients, it is evident many years before psychotic symptoms are expressed and, after the onset of psychotic symptoms, cognitive deficits are present in the large majority of patients. Future studies of the genetic basis of specific cognitive functions and the association between old genes, cognition, and brain processes will undoubtedly help better understand the role of cognition in the development of psychotic illness.
Historically, pioneers of the concept of schizophrenia were more convinced of the evidence for hereditary than environmental causes for the disorder. In considering disease causation, Bleuler wrote “Schizophrenia appears to be independent of external conditions and circumstances.”1 Kraepelin also emphasized the importance of inheritance, but did consider that “…

PIK3CA mutations and/or PTEN loss have been shown to predict response in some (70-73) but not all studies (74,75). These studies are all limited by small numbers and often a lack of validation for correlative LBH589 supplier testing. The largest study to date with 1,022 tumor

samples showed only PIK3CA mutations in exon 20 (constituting the kinase domain) to be predictive of response but not mutations Inhibitors,research,lifescience,medical in exon 9 (the helical domain). About 20% of PI3KCA mutations were located in exon 20 while 68.5% were located in exon 9. The investigators did not look at PTEN expression (76). These results suggest that alterations in the PIK3/Akt/mTor pathway may be responsible for some of the patients who do not respond to EGFR inhibitors initially. Inhibitors,research,lifescience,medical A few groups have specifically looked at mechanisms of resistance in patients who have progressed on an EGFR inhibitor. Montagut et al. found two out of 10 patients who had progressed on cetuximab to have a mutation in the EGFR ectodomain (S492R) which prohibits binding of cetuximab but not panitumumab (77). Misale et al. performed KRAS gene deep sequencing on tumors from patients who had progressed on an EGFR inhibitor and found secondary KRAS mutations in 6 out of 10 cases suggesting that this could either be acquired mutations on therapy or the selection of pre-existent KRAS mutant clones (78). Inhibitors,research,lifescience,medical IGF-1R is upregulated in 50-90% of mCRC and has been

Inhibitors,research,lifescience,medical associated with poor prognosis. Cells with an altered IGF-1R pathway seem to escape EGFR inhibitor mediated cell death by activation of the PI3K pathway by heterodimerization of IGF-1R with EGFR. Overexpression of IGF-1 has been associated with resistance to cetuximab in KRAS wild-type tumors (79). HER3 is overexpressed in 30-80% of metastatic CRC and has been associated with Inhibitors,research,lifescience,medical EGFR

inhibitor resistance (80). Its effects are mediated through the PI3K/Akt pathway. MET overexpression is found in most mCRC, both in KRAS wild-type and KRAS mutant tumors and interacts with the EGFR pathway to promote growth of CRC cells (81). Preclinical evidence suggests that coupling of MET with HER3 may lead to sustained activation of PI3K/Akt pathway in lung cancer cell lines, thereby bypassing the inhibited EGFR (82). Furthermore, it is possible that resistance to EGFR inhibitors could result from a selection of clones already resistant to the drugs. It is therefore all clear that several different mechanisms may signal resistance through the PI3K/Akt pathway and extend survival of the cancer cell. This is currently an active area of ongoing research. Summary EGFR inhibitors are an important addition to the growing armamentarium in metastatic colorectal cancer. In an era of emphasis on refining therapy, the presence of KRAS mutation will predict for resistance and limit exposure to patients who are more likely to benefit.

16,15 Hypnotic medication offers only short-term efficacy and, in the long term, may itself disrupt sleep.44,45 Hypnotic use may also lead to exacerbation

of sleep apnea and daytime carryover effects, such as sedation, delirium, falls, fractures, cognitive impairment, and anterograde amnesia46 and has been associated with increased morbidity and mortality.35,37-42 The 1991 National Institutes Inhibitors,research,lifescience,medical of Health (NIH) Consensus Conference on the Treatment of Sleep Disorders of Older People concluded that “nonsedative hypnotic RGFP966 research buy approaches to improve sleep quality in the elderly population are sorely needed.”19 Pulsatile GH secretion continues with aging, but with a pattern of diminished GH pulse amplitude.4 In particular, nighttime GH secretion declines, so that there is often no longer a clear night-day GH rhythm. SWS also declines with aging, although it is unclear whether the GH decline is due to the reduction in SWS, whether SWS deteriorates because Inhibitors,research,lifescience,medical of the decline in GH, or whether both arc decreased because of a common reduction at a higher level of regulation

(eg, GHRH). Recent studies have shown that sleep is influenced by clinical extremes of GH status47,48 and that sleep can be improved in response to acute GH administration49 Inhibitors,research,lifescience,medical or Inhibitors,research,lifescience,medical stimulation of the GH-IGF-I axis using GHRH.50 Acute GHRH administration increases SWS51 and acute decreases in GH status by a GH-releasing factor antagonist decrease slow-wave amplitude and SWS duration52 in animals. Among hormones, GHRH displays the bestdocumented sleep-promoting activity and is clearly implicated in the regulation of sleep, specifically non REM sleep. GHRH hypothalamic neurons projecting

to the basal forebrain, specifically Inhibitors,research,lifescience,medical the medial preoptic area, likely act directly to increase non-REM/SWS.53 Three independent laboratories have recently reported that GHRH promotes sleep in healthy young subjects,54-58 although two older studies reported no such effect59,60 and there is some evidence to suggest that the impact of GHRH on the sleep of the elderly may be weaker.61,62 Aging, cognition, Carnitine dehydrogenase and somatotrophic hormones While it has been extensively documented that significant changes in several major areas of cognitive function develop with advancing age, such declines do not develop uniformly. For example, some components of memory remain relatively intact with advancing age (eg, primary or shortterm memory) , while others do not (eg, secondary or longterm memory). A major distinction that is useful for describing those functions that are preserved versus impaired by advancing age was proposed by Cattell, ie, the concepts of crystallized versus fluid intelligence.