If a child is healthy and free from illness, the entire family benefits…the family then have time to work and save money for other things…” About 97.1% of the caregivers said their MG-132 ic50 children were in good health and this

affords them time to attend to other needs. A twenty eight year old caregiver at Galo-Sota has this to say: “…a healthy child stays-off enough to play. We then have time for daily activities. …the health of the children in the community has improved because they are healthier than they were before the introduction of the project… I don’t know the last time I paid hospital bills for my brother’s daughter who is participating in the project”. Most caregivers expressed the view that their children no more suffer from asra (febrile malaria) and convulsions. Over half, 55 (52.4%)

of the caregivers reported at baseline that they often take their children with fever (asra) to the hospital but at the time of this data collection, only 6.7% said they had often taken their children with fever to the hospital in the past 12 months. Asked why they do not take their children/wards to the hospital often? The responses were almost unanimous that “the children don’t fall sick these days because of the project”. Communities’ relationship with community assistants Opinion leaders interviewed expressed Ulixertinib the view that,

there was harmonious relationship between community members and caregivers on one hand and CAs on the other hand. Also, all the caregivers interviewed reported that CAs took good care of the children and were meeting their expectations, by moving from house to house to administer the drugs. It was also reported that during IPTc rounds, CAs educate caregivers about the health of the children and how to protect them by making them sleep under treated bednets. A twenty two year old mother of two from Salo said: “…as members of this community, any misbehavior on their (CAs) parts already that affect the project negatively also affects them …hence they (CAs) behaved well”. About 82.1% of the caregivers reported that they have very good relationship with the CAs with 14.7% of them saying it was good. The Community assistants were happy and proud to be associated with the project. A 30 year old female CA at Agortoe said, “… we are happy to be serving because the project belongs to the community, …our people entrusted the success or failure of it into our hands… and we don’t want to disappoint them… failure may also affect us personally because some of us have our children, nieces and nephews in the study ….” To a 35 year old male CA at Salo “…we are proud to be contributing towards the health and welfare of the children in our communities…”.

Table I. Summary of ACNP Task Force recommendations. Adapted from ref 6: Rush AJ, Kraemer HC, Sackeim HA, et al. Report by the ACNP Task Force on Response and Remission in Major Depressive Disorder. Neuropsychopharmacology. 2006;31:1841-1853. Copyright© … The ACNP Task Force also reviewed the literature on potential associated factors which may influence the remission, the time of remission and the Inhibitors,research,lifescience,medical stability of the remission.6 These factors include among others the type of treatment, the dose,

the duration of treatment, baseline severity of depressive symptoms, the stage of treatment, resistance (TRD), the compliance, the presence of DSM-IV Axis I, II, or III conditions, environmental stressors, the degree of social support, and the retrospective morbidity of

the illness, as well as neurobiological and genetic vulnerability. There is no general consensus about the length of time the depressed patient in remission should remain in Inhibitors,research,lifescience,medical remission, but, according to most experts, this period of remission is expected to last between 4 and 6 months to be of clinical relevance for the patient.10 The length of the remission period is obviously of great clinical relevance to the patient, and is also Inhibitors,research,lifescience,medical contingent, on the continuation of antidepressant treatment. In a review of 31 randomized trials, Geddes and Colleagues13 have shown that continuing RG-7204 treatment with antidepressants reduced the risk of relapse by 70% compared with treatment discontinuation. The treatment effect, seemed Inhibitors,research,lifescience,medical to persist for between 12 and 36 months. A long-term naturalistic study conducted in Japan by Furukawa and Colleagues in a cohort of 95 unipolar major depressive patients followed up for a 10-year period was recently reported.14 The authors assessed the definition of recovery according to the length of time of remission. Based on the results, they concluded that a period of 2 months of remission was too short to define recover}’, but proposed that a period of 4 to 6 months of remission may be more adequate. ‘This study, however, was not. Inhibitors,research,lifescience,medical controlled and the sample size was too small to draw

definitive 3-mercaptopyruvate sulfurtransferase conclusions. Unfortunately, as previously stated, a significant, number of patients do not. remain symptom-free and continue to present subsyndromal depression or subthreshold depression for some time during their lifetime. These patients have been shown to have a higher risk of early relapse into depression, lower levels of social and psychological functioning, and greater rates of physical morbidity such as cardiovascular disease and stroke, as well as higher rates of mortality.15 Thase has reported that more than one third of depressed patients will reach remission after acute antidepressant treatment.16 Most clinical trials report remission rates of 22% to 40%,“ while effectiveness studies including representative samples of depressed patients closer to clinical practice report lower remission rates – around 11% to 30% .

e., left caudate = 1.36 ± 0.47, right caudate = 1.45 ± 0.62, left putamen = 1.12 ± 0.43, right putamen = 1.26 ± 0.59). In contrast, there was no main effect of the hemisphere (i.e., left, right) (F = 1.1; P = 0.30), nor any region by hemisphere interaction (i.e., caudate, putamen DAT-BPND values × left, right hemisphere) (F = 0.5; P = 0.47). Of note, PD duration was #OSI-906 solubility dmso randurls[1|1|,|CHEM1|]# negatively correlated with DAT-BPND values in the left striatum (left caudate: R = −0.65, P < 0.03; left putamen: R = −0.66, Inhibitors,research,lifescience,medical P < 0.02) (i.e., patients with longer disease duration displayed significantly lower left striatal DAT-BPND values) while a borderline effect was found in the right striatum (right caudate: R = −0.50, P = 0.09; right putamen:

R = −0.55, P = 0.06) (Fig. 1). Figure 1 Correlation analyses between the average dopamine-transporter (DAT)-binding Inhibitors,research,lifescience,medical values for the bilateral striatum (caudate and putamen), and

the duration (in months) of Parkinson’s disease (PD). Please note that due to the extremely close DAT values in the … Overall, these DAT-imaging results revealed Inhibitors,research,lifescience,medical the typical pattern of dopaminergic degeneration in PD (i.e., greater dopaminergic loss in putamen compared to the caudate) and confirmed previous findings showing that disease duration correlates with the level of dopamine loss in the striatum (Antonini et al. 1995). No main effect of the hemisphere, or a region by hemisphere interaction, was found but this obviously depended on the presence of a

similar number of PD patients with a prevalently left-sided (n = 5) and right-sided (n = 7) disease. fMRI results The ANOVA investigating the main effect of task revealed Inhibitors,research,lifescience,medical several regions within and outside ROIs that showed progressively increased activations as a function of the working-memory load (F’sdf(66) > 15, P’s < 0.05, FWE, whole-brain Inhibitors,research,lifescience,medical correction) (Fig. 2). Figure 2 Main effect of task. The brain regions shown are those where the BOLD activity progressively increases as a function of higher working-memory loads. The color bar represents F statistics. Maps are thresholded at P < 0.05, family-wise error (FWE), ... The ANOVA exploring the main effect of group (PD-Off, HCs) showed greater activations in the left middle occipital cortex (left: x, −16; y, isothipendyl −100; z, 0; F = 18.23, P < 0.001) and right cuneus (x, 22; y, −90; z, 28; F = 13.72, P < 0.001, uncorrected) in PD patients versus controls. A significant group by task interaction was also detected in the right precuneus (x, 22; y, −82; z, 34; F = 14.63, P < 0.001, uncorrected) and left thalamus (x, −14; y, −28; z, 14; F = 9.05, P < 0.001, uncorrected). These latter findings were driven by increased BOLD response in PD-Off patients versus HCs only during high-load working-memory trials. A significant treatment effect (PD-Off, PD-On) was found in the left superior frontal gyrus (SFG) and left putamen (P’s < 0.05, FWE, svc) (Fig. 3A and B).

Our previous studies

revealed that the kc and Kc values in the SBE4-β-CyD system were 0.145 ± 0.012h−1 and 144 #PF 01367338 randurls[1|1|,|CHEM1|]# ± 18M−1, respectively [19]. Therefore, it is evident that the inhibitory effect of SBE7-β-CyD on enzymatic degradation of insulin glargine is more potent than that of SBE4-β-CyD. Figure 6 Effects of Sul-β-CyD and SBE7-β-CyD (5 to 20mM) on tryptic cleavage (2IU) of insulin glargine (0.1mM) in phosphate buffer (pH 9.5, I = 0.2) at 37°C. Each point represents Inhibitors,research,lifescience,medical the mean ± S.E.M. of … Recently, it has been reported that the aspartic acid residue existing in the catalytic pocket of trypsin is responsible for attracting and stabilizing positively charged lysine and/or arginine on the substrate Inhibitors,research,lifescience,medical peptide [29]. Therefore, the insulin glargine/Sul-β-CyD interaction or insulin glargine/SBE7-β-CyD complex is speculated to ameliorate the interaction between the negatively charged aspartic acid in the catalytic pocket of trypsin and positively charged lysine and/or arginines mentioned earlier, since Sul-β-CyD and SBE7-β-CyD have negative charge originating from the sulfate and sulfonate Inhibitors,research,lifescience,medical groups, respectively.

This hypothesis in which the insulin glargine/Sul-β-CyD interaction and insulin glargine/SBE7-β-CyD complex ameliorate the interaction between the aspartic acid and lysine and/or arginines is supported by the finding that the aromatic amino acid residues in insulin glargine which are capable of

interacting with β-CyDs (at B24-, B25-phenylalanines, B26-tyrosine, Inhibitors,research,lifescience,medical and B28-proline) locate near the three digestive sites by trypsin (B22-B23, B29-B30, and B31-B32) [17]. These results suggest that Sul-β-CyD and SBE7-β-CyD act as stabilizers of insulin glargine against Inhibitors,research,lifescience,medical enzymatic degradation by their respective interactions with insulin glargine. 3.7. Subcutaneous Administration of Insulin Glargine/β-CyDs Solutions to Rats To confirm whether Sul-β-CyD and SBE7-β-CyD are useful excipients for insulin glargine in vivo, we evaluated the effects of the β-CyDs on pharmacokinetics and pharmacodynamics of insulin glargine after subcutaneous injection to rats. In our preliminary studies, we found Phosphoprotein phosphatase that neither Sul-β-CyD (100mM) nor SBE7-β-CyD (100mM) changed the serum glucose level-time profiles remarkably in comparison with that of insulin glargine alone (2IU/kg) after subcutaneous injection to rats (data not shown). Taking the positive results of SBE7-β-CyD in ultrafiltration (Figure 2) and dissolution (Figure 3) studies by contrast to those of Sul-β-CyD into account, further in vivo investigation was performed with a higher concentration of SBE7-β-CyD.

The articles in German and French were assembled in a four-volume book entitled “Moritz Schiff’s Gesammelte Beiträge Zur Physiologie” (Lausanne, 1894–1898). In volume 1, Schiff himself rearranged some of his articles on centers in the nervous system that are related to respiration. Immediately after his death, the British Medical Journal published a highly praising obituary but, Inhibitors,research,lifescience,medical in the last century, there were only a few attempts

1,5,13,18,20–22 to recognize Schiff’s contributions to nearly all fields of physiology, at a period when experimental physiology was still taking its formative steps. Schiff should also be regarded as a person who paid dearly for his adherence to the ideas of freedom and liberalism and to genuine physiological research. His Inhibitors,research,lifescience,medical personality, contributions, and impact deserve a thorough biography. Footnotes Conflict of interest: No potential conflict of interest relevant to this article was reported.
In 1988, Brenner, Anderson, and Garcia suggested that a low nephron number, acquired in

utero, may be a common denominator in populations with high susceptibility to hypertension and renal disease.1 Such a kidney with fewer nephrons, and hence a low filtration surface area, would Inhibitors,research,lifescience,medical have a reduced capacity to excrete sodium, inducing a hypervolemic state, thereby contributing to the development of hypertension (Figure 1). Animal experiments and epidemiological data have accumulated in support of this “nephron Inhibitors,research,lifescience,medical number” hypothesis.2–8 Nephron number varies surprisingly widely among individuals, more, for example, than height or weight, with a variability of up to 10-fold within select populations.5,6,9–17 An individual’s nephron number is the result of a complex interplay between genetics and environment that plays out through their Inhibitors,research,lifescience,medical lifetime, carrying the imprint of their past, being reflected in their present renal function, and impacting their future risk of hypertension and kidney disease. Figure

1 Known causes of low nephron number. no DETERMINANTS OF NEPHRON NUMBER Prenatal Life and Birth Weight Kidney development in humans begins in the 9th week and ends around the 36th week of gestation.5 There is no evidence for postnatal nephrogenesis in humans, except in extremely preterm infants in whom abnormal nephrogenesis was observed until day 40 after birth.16,18 Similarly, in preterm baboons followed for 21 days after birth, nephrogenesis did continue, but the proportion of immature, poorly vascularized and abnormal glomeruli was increased compared to gestational controls.19 In young adult rats exposed to a low protein diet in utero, glomerulogenesis was retarded with a higher proportion of Dabrafenib ic50 immature nephrons, associated with abnormalities in the glomerular basement membrane and podocyte structure.

The clinic-based nature of the programs, which mix stable patients and newly maintained patients, along with inadequate staffing, and minimal incentives for patient change, can lead to a culture of continued illicit drug use and chronic unemployment.94 In spite of many decades of improving and saving lives, methadone maintenance is often viewed

as perpetuating addiction or being immoral. The traditional method of withdrawal Inhibitors,research,lifescience,medical is decreasing the methadone dose rapidly until 30 mg is reached, and then slowly tapering from that, eg 5 mg/week or switching to clonidine.102,103 A more recent approach involves transferring the patient to buprenorphine/naloxone and then tapering as described in the section on discontinuing buprenorphine.103 Partial agonist maintenance Buprenorphine Buprenorphine, a Schedule III controlled substance, Inhibitors,research,lifescience,medical is a high affinity partial n-opioid agonist, k antagonist, and ORL-1 receptor agonist.104 Studies from 1980 on found it useful for treating opioid withdrawal and dependence.105-109 Office-based buprenorphine maintenance has Pexidartinib clinical trial already increased treatment availability for opioid-dependent individuals and brought into treatment populations Inhibitors,research,lifescience,medical that had been unable or

unwilling to attend methadone maintenance clinics, eg, prescription opioid addicts. Prescription opioid addicts seeking office-based buprenorphine are likely to present different issues than heroin addicts applying for methadone maintenance.110 Primary-care physicians who have not treated opioid dependence will also present new challenges to the field. Anecdotal Inhibitors,research,lifescience,medical reports describe patients on buprenorphine

as feeling Inhibitors,research,lifescience,medical more clear-headed, more energetic, and more aware of emotions than on methadone maintenance.111 To diminish possible diversion to parenteral use, the recommended form of buprenorphine is a 4:1 combination with naloxone (Suboxone). The mono form (Subutex) is used for pregnant women and, at times, for induction. Federal regulations In 2002, the FDA approved buprenorphine for the treatment of opioid dependence in office-based practice. It was already being used for such treatment in other L-NAME HCl countries. Physicians need to receive 8 hours of specialized training in person or online, and then apply for a waiver from the Department of Health and Human Services. They are limited to 30 patients on buprenorphine for the first year, and can then apply to increase the number to 100. Pharmacology Buprenorphine binds to the n receptor and activates it, but as the dose increases, there is a ceiling on some opioid agonist effects, such as respiratory depression, making it safer than a full agonist as far as overdose.

More importantly, the research indicates that the etiology and pathophysiology of “look-alike” conditions may be quite different, and the these heterogeneities must be identified before treatments are developed for the larger class of patients with ASD and related disorders.14 Despite the rapid advances in genetics, most clinical research has not considered genetic and individual differences by conducting “genotype-up” research studies. Instead, the studies have been “phenotype-down” research in which a broad,

Inhibitors,research,lifescience,medical behaviorally defined group of individuals are considered to establish a research sample. In many studies, all individuals with “autism spectrum Inhibitors,research,lifescience,medical disorders” are eligible for participation, and BYL719 solubility dmso neuroimaging, neuropsychological tests, or other modalities are used to examine differences

between subjects with ASD and those with typical development. While this has certainly been a feasible approach, phenotypic or genotypic hetereogeneity may have washed out important clues to the pathophysiology of autism, as well as rendering it impossible to find meaningful biomarkers of autism. To Inhibitors,research,lifescience,medical address this, researchers are beginning to perform “deep phenotyping” of biological and clinical variables, as well as behavioral manifestations of ASD, in order to identify subgroups of individuals with ASD that have unique and specific biological abnormalities. Finding abnormalities in basic biologic

functions such as sleep15 and default neural networks16 among subgroups of individuals might represent new treatment targets for those individuals. Those novel therapies then could be tested in the larger Inhibitors,research,lifescience,medical ASD population for replication and generalization (or not!) In the future, clinical studies Inhibitors,research,lifescience,medical of ASD should include not only carefully characterized, homogeneous samples of ASD subjects, but also should strive to determine the specificity of the findings to autism. Comparisons against other subjects with other neurodevelopmental disorders, intellectual disabilities, communication deficits, and other symptoms will ensure that the findings are uniquely relevant to ASD. The studies could then search for genetic and nongenetic etiologies, disease modifiers, and factors conferring risk or projection. Medical treatment of ASD has been notoriously unsuccessful, PAK6 with limited impact on the core symptoms of deficits in social reciprocity and communication and the presence of excessive restrictions of interest or behaviors. As with research into the etiology of ASD, it is possible that treatment trials have failed because they have studied heterogeneous subject groups. It is possible that greater success might result from smaller trials of more homogeneous subject groups (such as Fragile X patients or individuals with a history ol acute regression).

The obsessions interfere with attention and concentration, thus interfering with cognitive tasks and often social interactions. The obsessions and compulsions can be very

time-consuming: they interfere with functioning because of the time they occupy, and because patients with OCD often develop patterns of avoidance of situations or things that provoke their obsessions or compulsions. OCD typically begins in late adolescence or early adulthood with an earlier age of onset for males than females.8-10 In adult clinical samples, OCD is equally common in females as in males,“ but, due to a higher incidence of childhood-onset OCD in males, younger samples have more males than females.12 Compared with clinical samples, epidemiological #JNK inhibitor mw keyword# studies tend to show a later age of onset and a higher proportion of females than males.12 The lifetime prevalence of OCD is estimated to be between 1.9% and 3.3%. 12 Most studies show a chronic course that extends across the lifetime with waxing and waning of symptoms, although in about 10% of cases

there is a malignant deteriorating Inhibitors,research,lifescience,medical course.9,13 Neurobiological evidence shows clearly that the serotonin system is important in OCD. This evidence has come from treatment response to serotonin reuptake inhibitors (SRIs), including studies of SRIs versus desipramine, which demonstrated the selective efficacy of SRIs,14,15 as well as from pharmacological challenge studies and cerebrospinal fluid Inhibitors,research,lifescience,medical neurotransmitter metabolite studies.16 There is also evidence, Inhibitors,research,lifescience,medical however, of a role for the dopamine system in OCD on the basis of both theory (derived from basic human and animal research) and the efficacy of dopaminergic augmentation in refractory OCD.16,17 Neuroimaging in OCD has revealed much about the disorder and about the effects of treatment. Structural imaging supports the hypothesis that the OC spectrum disorders involve corticostriatal dysfunction6; specifically, magnetic resonance imaging (MRI) studies have shown volumetric abnormalities in the caudate and Inhibitors,research,lifescience,medical a rightward shift in caudate volume. Functional imaging in OCD has shown increased activity in the corticostriatal pathway involving the orbitofrontal

cortex and the caudate nucleus.6,18 Importantly, successful treatment of OCD with cither SRI or cognitive behavioral therapy (CBT) results in normalization of orbitofrontal activity.6,19,20 There are now a number of pharmacotherapies available Urease for treating OCD. The first medication discovered to be effective in OCD was clomipramine, a serotonin and norepinephrine reuptake inhibitor (SNRI).21 The development of selective serotonin reuptake inhibitors (SSRIs) greatly expanded the options for treatment of OCD. The SSRIs have more favorable side-effect profiles than clomipramine, and have become the first-line treatments for OCD. They include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. Venlafaxine, a newer SNRI, is also used to treat OCD.

This fact can lead to reduced specificity, as many neurological diseases or disease

stages can be characterized by similar changes in the concentrations of the metabolites that can be measured accurately. Secondly, MRS measurements performed in vivo can never become more repeatable than measurements performed in phantoms; for most metabolites, measurement repeatability in vitro is limited to 2% to 3%. Consequently, assuming that this limit is reached in vivo, changes on the order of -5% in metabolite concentrations will be needed on an individual patient basis, in order for this change to be attributed to changes due to disease or treatment. Unfortunately, Inhibitors,research,lifescience,medical natural variability of baseline states of different persons is within this range, preventing diagnosis of the disease using this approach. Moreover, such small changes from the baseline state Inhibitors,research,lifescience,medical of one BEZ235 mw person might require more than few weeks of drug treatment, if trying to decide whether a treatment works or not. On the upside, however, MRS measurements are short, noninvasive, and can easily yield quantitative results with commercially available data analysis programs.63 Such MRS-based approaches for monitoring disease response to treatment

Inhibitors,research,lifescience,medical can prove invaluable for phase II clinical trials, by allowing a significant reduction of the number of enrôlées.51,64 Positron emission tomography Positron emission tomography (PET) using 18fluorodeoxyglucose (18FDG) is used to study cortical metabolism. In AD patients, 18FDG-PET shows Inhibitors,research,lifescience,medical a typical

pattern of reduced cortical uptake in the region of the temporal and parietal association cortex, particularly in the region of the posterior cingulum; in mild-to-moderate stages of AD, prefrontal association areas are affected as well.65 MCI subjects already show – to a lesser extent – a similar distribution of metabolic deficits which can predict conversion from MCI to AD with an accuracy of over Inhibitors,research,lifescience,medical 80%. 66,67 Many researchers regard 18FDG-PET as the gold standard in the in vivo diagnosis of early stages of AD, although this method is not widely available and is relatively expensive. The benefit of 18FDG-PET for differential diagnosis in AD patients is less well validated. Established automated analysis algorithms are alreadyavailable for PET investigations, providing clinicians with z-score maps for metabolic Dichloromethane dehalogenase deviation (for example see ref 68). PET has not yet been used in multicenter treatment trials; however, several monocenter studies have been conducted with PET demonstrating the effect of cholinergic treatment, in particular, on the metabolic pattern in AD patients. A problematic aspect of the majority of the studies is that the analyses are usually based on unblinded treatment arms and that treated responders (according to clinical criteria) were compared with untreated and treated nonresponders.

In particular, prefrontal and temporal callosal fiber bundle integrity predicted psychomotor speed in a working memory task but not the ability to balance on one foot with eyes closed, and parietal fiber bundle integrity selectively predicted balance performance but not psychomotor speed.69 Chanraud et al67 used DTI to investigate the effects of chronic alcoholism on mesencephalic fibers connecting the midbrain to the Inhibitors,research,lifescience,medical thalamus and the

midbrain to the pons in 20 alcoholic and 24 control men. Alcoholics had fewer fibers than controls for midbrain-pons bundles but not for midbrain-thalamus bundles. The midbrainpons fiber deficit in alcoholics was predictive of poorer cognitive flexibility. This relation is consistent with the idea that cognitive functions Inhibitors,research,lifescience,medical and abilities are both mediated and constrained by the anatomical characteristics of the underlying white matter tracts interconnecting gray matter nodes of complex cortico-subcortical circuits,73 and that disruption of selective (eg, mesencephalic) fiber bundles impairs cognition, such as Capmatinib manufacturer mental flexibility. Among the fiber tracts showing Inhibitors,research,lifescience,medical alcoholism-related microstructural compromise are the fornix and the cingulum,27 two major

fiber tracts of the limbic system. The fornix connects the hippocampus with hypothalamic regions including the mammillary bodies, and is involved in memory Inhibitors,research,lifescience,medical formation.74-76 The

cingulate bundle of the limbic system has long and short fibers that surround the corpus callosum and course along cingulate cortex and parahippocampal gyrus. The cingulate bundle connects orbitofrontal, dorsolateral prefrontal, and medial frontal cortices with parietal, temporal association, and medial temporal cortices including hippocampus and amygdala. The cingulum has been associated with several brain functions including pain and emotion,77 Inhibitors,research,lifescience,medical cognitive and motor control,25 memory,78 and spatial orientation.79,80 Whether the degradation of fornix and cingulate fibers connecting cortico-limbic-striatal nodes of emotion and reward circuits is directly and selectively related to deficits in component processes of emotional regulation, cognitive control, reward learning, and the urge to drink in alcoholism remains only to be investigated. Neuroimaging studies in alcoholism are beginning to link craving and binge drinking to cortico-limbic structural and functional integrity.81-85 Conclusion recent advance of neuroimaging techniques such as DTI and fMRI have provided the opportunity to study structural and functional compromise of brain networks in chronic alcoholism. These studies provide clear evidence for brain-behavior relationships that support the role of alcoholism-related white matter fiber degradation as a substrate of cognitive and motor impairment.