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PubMed2004

Synaptic targeting by Alzheimer's-related amyloid beta oligomers.

The cognitive hallmark of early Alzheimer's disease (AD) is an extraordinary inability to form new memories. For many years, this dementia was attributed to nerve-cell death induced by deposits of fibrillar amyloid beta (Abeta). A newer hypothesis has emerged, however, in which early memory loss is considered a synapse failure caused by soluble Abeta oligomers. Such oligomers rapidly block long-term potentiation, a classic experimental paradigm for synaptic plasticity, and they are strikingly elevated in AD brain tissue and transgenic-mouse AD models. The current work characterizes the manner in which Abeta oligomers attack neurons. Antibodies raised against synthetic oligomers applied to AD brain sections were found to give diffuse stain around neuronal cell bodies, suggestive of a dendritic pattern, whereas soluble brain extracts showed robust AD-dependent reactivity in dot immunoblots. Antigens in unfractionated AD extracts attached with specificity to cultured rat hippocampal neurons, binding within dendritic arbors at discrete puncta. Crude fractionation showed ligand size to be between 10 and 100 kDa. Synthetic Abeta oligomers of the same size gave identical punctate binding, which was highly selective for particular neurons. Image analysis by confocal double-label immunofluorescence established that >90% of the punctate oligomer binding sites colocalized with the synaptic marker PSD-95 (postsynaptic density protein 95). Synaptic binding was accompanied by ectopic induction of Arc, a synaptic immediate-early gene, the overexpression of which has been linked to dysfunctional learning. Results suggest the hypothesis that targeting and functional disruption of particular synapses by Abeta oligomers may provide a molecular basis for the specific loss of memory function in early AD.

Aged↗

PubMed2002

A multicenter, double-blind, randomized comparison study of the efficacy and tolerability of once-daily tazarotene 0.1% gel and adapalene 0.1% gel for the treatment of facial acne vulgaris.

The efficacy and tolerability of tazarotene 0.1% gel and adapalene 0.1% gel were compared in a multicenter, double-blind, randomized, parallel-group study in 145 patients with mild-to-moderate facial acne vulgaris. Both treatments were applied once daily in the evenings for up to 12 weeks. Compared with adapalene, treatment with tazarotene was associated with a significantly greater incidence of treatment success (> or = 50% global improvement) (78% vs 52%; P=.002) and significantly greater reductions in overall disease severity (P<.0001), noninflammatory lesion count (P<.0001), and inflammatory lesion count (P=.0002). In the early weeks of treatment, tazarotene was associated with transiently greater levels of burning, pruritus, erythema, and peeling compared with adapalene (P<.01). However, mean levels of these parameters were consistently less than mild in both treatment groups and, at the end of treatment, patients considered both treatments to be comparably well tolerated (the proportion of patients in each group who rated the comfort of their treated skin as comfortable or very comfortable was 76% with tazarotene and 69% with adapalene). Mean usage of study medication was 0.32 g per application of tazarotene and 0.42 g per application of adapalene, which resulted in cost-effectiveness ratios of $79.95 per treatment success for tazarotene and $107.88 per treatment success for adapalene. Sensitivity analyses suggest that these cost-effectiveness results are robust across a range of cost and efficacy assumptions. In conclusion, tazarotene 0.1% gel was more effective than adapalene 0.1% gel and was also a more cost-effective treatment option.

Acne Vulgaris↗

PubMed2026

An acute dose of glyphosate alters novel object exploration and hippocampal cFos expression in a sex-dependent manner in wildtype mice.

Glyphosate (GLY) is the active ingredient in most herbicides, including off-the-shelf weed killers such as Roundup®. GLY crosses the blood-brain barrier, increases oxidative stress and genotoxicity, and impacts reproduction, but the extent of its effects remains unclear. Previous research reports conflicting evidence on sex-specific susceptibility to GLY's effects, and very few investigate the effects of a single, acute dose on learning, memory, and neuronal activation. In vitro studies have found GLY interferes with gene expression and is uniquely capable of inducing DNA double strand breaks (DSBs) compared to other herbicides. DSBs can induce expression of immediate early genes (IEGs), which are important for synaptic plasticity, learning, and memory. However, a clear connection between GLY, IEGs, and learning and memory has yet to be made. To explore this, we tested male and female wildtype mice in novel object recognition after they received an acute, oral dose of 0, 250, or 500 mg/kg of GLY and assessed hippocampal DSB and IEG levels. We hypothesized that a single dose of GLY would impair memory by disrupting IEG expression and would affect males more than females. We did not find robust evidence that GLY impaired memory, though females that received 500 mg/kg did not explore the novel object more than the familiar. Hippocampal DSBs were decreased following 500 mg/kg in both sexes, yet hippocampal IEG immunoreactivity was decreased in GLY-exposed males only, revealing a complex sex-dependent relationship. These data add to the literature that GLY is potentially detrimental, highlighting the need for further investigations.

Animals↗

PubMed1993

Effect of cervical spinal adjustments on lumbar paraspinal muscle tone: evidence for facilitation of intersegmental tonic neck reflexes.

OBJECTIVES: To determine whether spinal adjustments, delivered to the upper vs. lower cervical spine, might result in tonic neck reflex-induced alterations in the activity of the lumbar paraspinal musculature. DESIGN: Randomized, double-blind, before/after treatment comparisons. SETTING: Cervical Ergonomics Laboratory, Palmer College of Chiropractic-West, Sunnyvale, CA. SUBJECTS: Healthy, nonsymptomatic chiropractic college students, about evenly divided with respect to gender and ranging from 23-38 yr of age. INTERVENTION: Modified "diversified" spinal adjustments, delivered bilaterally to either the upper (C2) or lower (C7) cervical region. MAIN OUTCOME MEASURE: Tissue compliance measures using a tissue compliance meter, obtained from each subject at sites 2 cm on either side of the spinous processes of L1, L2, L3, L4 and L5 both prior to and within 15 min following treatments. RESULTS: Upper cervical adjustments produced changes in lumbar tissue compliance which were only slight (p < .05) and not significantly different from that which occurred following upper cervical sham manipulation (p > .1). However, lower cervical adjustments induced increases in tissue compliance (decreases in tone) which were highly significant (p < .001) and relatively robust compared to those found following upper cervical adjustments (p < .01). Furthermore, the greatest effects were observed on either side of the L4 and L5 spinous processes, suggesting influences on the gluteal musculature in particular. CONCLUSIONS: Results indicate that cervical spinal manipulation can have significant effects on the tone of the lumbopelvic musculature, presumably by facilitating tonic neck reflexes involving intersegmental spinal pathways.

Adult↗

PubMed2005

Functional magnetic resonance imaging with intermolecular double-quantum coherences at 3 T.

Functional magnetic resonance imaging (fMRI) based on the selection of intermolecular double-quantum coherences (iDQC) was performed with a standard birdcage coil at 3 T in a group of normal human volunteers. Suppression of spurious signal contributions from unwanted coherence-transfer pathways was achieved by combining a two-step phase cycle and a long repetition time of 5 s. A gradient-recalled echo iDQC sequence (echo time, T(E) = 80 ms) yielded robust activation with a visual paradigm. Maximum z-scores were about half of those observed with conventional blood-oxygen level dependent fMRI, whereas the functional signal change increased by more than a factor of 5. No activation was obtained with a spin-echo iDQC sequence (T(E) = 160 ms), in which dephasing accumulated during the evolution period was fully rephased by an appropriate delay time. It is hypothesized that substantial inherent diffusion weighting of the iDQC technique efficiently suppresses intravascular contributions to the functional contrast. A consistent quantitative explanation of the observed amount of signal change currently remains speculative.

Adult↗

PubMed1999

Comparability testing of a humanized monoclonal antibody (Synagis) to support cell line stability, process validation, and scale-up for manufacturing.

Biochemical and functional testing of a humanized monoclonal antibody directed against Respiratory Syncytial Virus (Synagis) has been performed to evaluate cell line stability, support process validation, and to demonstrate "comparability" during the course of process development. Using a variety of analytical methods, product manufactured at different sites and in bioreactors from 20 litres to 10,000 litres was shown to be biochemically and functionally equivalent. The biochemical testing for microheterogeneity found on Synagis included evaluation of changes in post-translational modifications such as deamidation, truncation, and carbohydrate structure. Studies were also performed to support cell line stability assessment and cell culture process validation. Cell culture conditions were deliberately varied in an attempt to determine if this would have an impact on the microheterogeneity of the product. In these studies Synagis was produced from cells cultured beyond the population doublings achieved at the maximum manufacturing scale, under conditions of low glucose, and using harvest times outside of the historical manufacturing operating range. Results showed that there was a different pattern of glycosylation during the early stages of bioreactor culture. No other changes in microheterogeneity were apparent for the other culture conditions studied. In summary, comparability assessment demonstrated that the Synagis manufacturing process is robust and consistent resulting in a predictable and reproducible monoclonal antibody product.

Antibodies, Monoclonal↗

PubMed2003

Sequence-universal recognition of duplex DNA by oligonucleotides via pseudocomplementarity and helix invasion.

The well-known Watson-Crick complementarity rules, which were discovered 50 years ago, elegantly direct the specific pairing of two DNA single strands. On the contrary, once formed, the double-stranded (ds) DNA lacks such a simple and sequence-universal recognition principle, since most of the characteristic chemical groups of nucleobases are now buried deep inside the double helix, the major DNA form. We report a promising versatile approach for highly selective recognition of designated sites within dsDNA featuring considerable practical potential for a variety of molecular-biological, biotechnological, gene-therapeutic, and diagnostic applications. It may also have implications for prebiotic evolution of genetic machinery at the primordial stages of the origin of life. Our design synergistically employs the robust helix-invasion ability of recently developed DNA mimics and analogs, pseudocomplementary peptide nucleic acids and pseudocomplementary oligonucleotides, thus enabling the sequence-unrestricted recognition of chosen DNA duplexes by nucleobase oligomers. Using this basically general approach, we selectively tagged a unique mixed-base site on the target dsDNA fragment with streptavidin and/or multiply labeled this site with fluorophores via the primer-extension reaction.

DNA↗

PubMed2006

Selective NMR measurements of homonuclear scalar couplings in isotopically enriched solids.

Scalar (J) couplings in solid-state NMR spectroscopy are sensitive to covalent through-bond interactions that make them informative structural probes for a wide range of complex materials. Until now, however, they have been generally unsuitable for use in isotopically enriched solids, such as proteins or many inorganic solids, because of the complications presented by multiple coupled but nonisolated spins. Such difficulties are overcome by incorporating a z-filter that results in a robust method for measuring pure J-coupling modulations between selected pairs of nuclei in an isotopically enriched spin system. The reliability of the new experimental approach is established by using numerical simulations and tested on fully (13)C-labeled polycrystalline L-alanine. It is furthermore shown to be applicable to partially enriched systems, when used in combination with a selective double-quantum (DQ) filter, as demonstrated for the measurement of (2)J((29)Si-O-(29)Si) couplings in a 50% (29)Si-enriched surfactant-templated layered silicate lacking long-range 3D crystallinity. J-coupling constants are obtained with sufficient accuracy to distinguish between different (29)Si-O-(29)Si pairs, shedding insight on the local structure of the silicate framework. The new experiment is appropriate for fully or partially enriched liquid or solid samples.

Journal Article↗

PubMed2005

Critical comparison of various connected quadruple excitation approximations in the coupled-cluster treatment of bond breaking.

To assess the limits of single-reference coupled-cluster (CC) methods for potential-energy surfaces, several methods have been considered for the inclusion of connected quadruple excitations. Most are based upon the factorized inclusion of the connected quadruple contribution (Qf) [J. Chem. Phys. 108, 9221 (1998)]. We compare the methods for the treatment of potential-energy curves for small molecules. These include CCSD(TQf), where the initial contributions of triple (T) and factorized quadruple excitations are added to coupled-cluster singles (S) and doubles (D), its generalization to CCSD(TQf), where instead of measuring their first contribution from orders in H, it is measured from orders in H=e(-(T1+T2))He(T1+T2); renormalized approximations of both, and CCSD2 defined in [J. Chem. Phys. 115, 2014 (2001)]. We also consider CCSDT, CCSDT(Qf), CCSDTQ, and CCSDTQP for comparison, where T, Q, and P indicate full triple, quadruple, and pentuple excitations, respectively. Illustrations for F2, the double bond breaking in water, and N2 are shown, including effects of quadruples on equilibrium geometries and vibrational frequencies. Despite the fact that no perturbative approximation, as opposed to an iterative approximation, should be able to separate a molecule correctly for a restricted-Hartree-Fock reference function, some of these higher-order approximations have a role to play in developing new, more robust procedures.

Journal Article↗

PubMed1998

Predictors of differential response to clozapine and haloperidol. Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia.

BACKGROUND: We sought to identify baseline predictors of response to clozapine. METHODS: Data were from a 15-site randomized clinical trial comparing clozapine and haloperidol in hospitalized patients with refractory schizophrenia (n = 423). Three-month outcomes were analyzed with the full sample (n = 368 due to attrition). Because of crossovers, analyses of 12-month outcomes were conducted with crossovers excluded (n = 291). Clinical predictors included age, race, diagnosis (current substance abuse, paranoid subtype of schizophrenia, or depressive syndrome), severity of symptoms, quality of life, age at onset of schizophrenia, extrapyramidal symptoms, and VA compensation payment. Multiple regression analysis was used to examine the interaction of treatment condition and each of these variables in predicting outcomes for symptoms, quality of life, side effects, and days hospitalized. RESULTS: Patients with higher quality of life at baseline (p = .04) and higher symptoms (p = .02) had relatively smaller declines in hospital days at 6 months. In the 12-month sample patients with higher levels of symptoms had greater symptom reductions at 12 months (p = .03) and greater improvement in quality of life (p = .004). CONCLUSIONS: Although high levels of symptoms were associated with greater improvement on clozapine, these findings are not robust enough to suggest that any specific, clinically defined subgroup of refractory patients should be preferentially targeted for clozapine treatment.

Adult↗

PubMed2000

Selective serotonin re-uptake inhibitors for children and adolescents.

OBJECTIVES: 1) To briefly review the scientific basis for the use of selective serotonin re-uptake inhibitors (SSRIs) in children and adolescents. 2) To review the current data on the efficacy, safety and tolerability in children and adolescents. METHOD: A Medline search back to 1990 was conducted. Review articles and double blind, placebo controlled trials were critically reviewed. Additional hand searches were performed with key journals and in specific areas of interest for this paper. RESULTS: Most of the published papers are from North America. There is an increasing use of SSRIs in child and adolescent psychiatry. The main disorders studied are mood and anxiety disorders. The data supporting efficacy is still limited. The most robust data is in the treatment of OCD and depression. CONCLUSION: Taking the limited data together with clinical experience and with adult studies, there is a valuable role for SSRIs as a component of treatment for various child and adolescent psychiatric disorders.

Adolescent↗

PubMed1990

Benzodiazepine-induced impairment of matching-to-sample performance in humans.

The effects of benzodiazepines on a visual pattern matching-to-sample (MTS) task were examined in nine healthy male volunteers. The MTS task employed randomly generated checkerboard-like stimuli presented on a video display. The sample and two comparison stimuli were simultaneously presented. Nonmatching comparison stimuli were randomly generated to be 3.125, 6.25, 12.5, 25.0, 37.5, or 50.0 percent different from the sample. Subjects responded on left or right button manipulanda to identify the matching comparison stimulus. The nonmatching stimulus condition was maintained constant for a 60-sec component and the percentage difference of the nonmatching stimuli was systematically varied across multiple components. The effects of triazolam (2.25-9.0 micrograms/kg) and lorazepam (7.5-45 micrograms/kg) were examined in a within-subjects, double-blind, placebo-controlled study. Under placebo conditions, response rates and accuracy were a positive function of the nonmatching stimulus discriminability. Triazolam produced dose-related decreases in response rate at nonmatching stimulus conditions greater than or equal to 25%. Only the 9.0 micrograms/kg dose of triazolam decreased accuracy and this occurred across all nonmatching stimulus conditions. Lorazepam effects were qualitatively similar but less robust than those of triazolam.

Adult↗

PubMed2006

Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial.

CONTEXT: Oral naltrexone can completely antagonize the effects produced by opioid agonists. However, poor compliance with naltrexone has been a major obstacle to the effective treatment of opioid dependence. OBJECTIVE: To evaluate the safety and efficacy of a sustained-release depot formulation of naltrexone in treating opioid dependence. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled, 8-week trial conducted at 2 medical centers. PARTICIPANTS: Sixty heroin-dependent adults. INTERVENTIONS: Participants were stratified by sex and years of heroin use (> or = 5 vs < 5) and then were randomized to receive placebo or 192 or 384 mg of depot naltrexone. Doses were administered at the beginning of weeks 1 and 5. All participants received twice-weekly relapse prevention therapy, provided observed urine samples, and completed other assessments at each visit. MAIN OUTCOME MEASURES: Retention in treatment and percentage of opioid-negative urine samples. RESULTS: Retention in treatment was dose related, with 39%, 60%, and 68% of patients in the placebo, 192 mg of naltrexone, and 384 mg of naltrexone groups, respectively, remaining in treatment at the end of 2 months. Time to dropout had a significant main effect of dose, with mean time to dropout of 27, 36, and 48 days for the placebo, 192 mg of naltrexone, and 384 mg of naltrexone groups, respectively. The percentage of urine samples negative for opioids, methadone, cocaine, benzodiazepines, and amphetamine varied significantly as a function of dose. When the data were recalculated without the assumption that missing urine samples were positive, a main effect of group was not found for any drugs tested except cocaine, where the percentage of cocaine-negative urine samples was lower in the placebo group. Adverse events were minimal and generally mild. This formulation of naltrexone was well tolerated and produced a robust, dose-related increase in treatment retention. CONCLUSION: These data provide new evidence of the feasibility, efficacy, and tolerability of long-lasting antagonist treatments for opioid dependence.

Adolescent↗

PubMed2000

A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression.

BACKGROUND: Multiple groups have reported on the use of repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant major depression. The purpose of this study is to assess the efficacy of rTMS in unmedicated, treatment-resistant patients who meet criteria for major depression. METHODS: Depressed subjects, who had failed to respond to a median of four treatment trials, were assigned in a randomized double-blind manner to receive either active (n = 10; 20 2-sec trains of 20 Hz stimulation with 58-sec intervals; delivered at 80% motor threshold with the figure-of-eight coil positioned over the left dorsolateral prefrontal cortex) or sham (n = 10; similar conditions with the coil elevated and angled 45 degrees tangentially to the scalp) rTMS. These sequences were applied during 10 consecutive weekdays. Continuous electroencephalogram sampling and daily motor threshold determinations were also obtained. RESULTS: The group mean 25-item Hamilton Depression Rating Scale (HDRS) score was 37.2 (+/- 2.0 SEM) points. Adjusted mean decreases in HDRS scores were 14.0 (+/- 3.7) and 0.2 (+/- 4.1) points for the active and control groups, respectively (p <.05). One of 10 subjects receiving active treatment demonstrated a robust response (i.e., HDRS decreased from 47 to 7 points); three other patients demonstrated 40-45% decreases in HDRS scores. No patients receiving sham treatment demonstrated partial or full responses. CONCLUSIONS: A 2-week course of active rTMS resulted in statistically significant but clinically modest reductions of depressive symptoms, as compared to sham rTMS in a population characterized by treatment resistance.

Adolescent↗

PubMed1999

A pilot controlled clinical trial of ABT-418, a cholinergic agonist, in the treatment of adults with attention deficit hyperactivity disorder.

OBJECTIVE: Despite the increasing recognition of attention deficit hyperactivity disorder (ADHD) in adults, there is a paucity of controlled pharmacological trials. Recent reports have suggested the potential usefulness of cholinergic agents for ADHD. To this end, the authors completed a controlled study of ABT-418, a novel cholinergic activating agent, for the treatment of adults with ADHD. METHOD: This was a double-blind, placebo-controlled, randomized, crossover trial that compared a transdermal patch of ABT-418 (75 mg/day) to placebo in adults who met DSM-IV criteria for ADHD. There were two 3-week treatment periods separated by 1 week of washout. RESULTS: Of the 32 subjects enrolled in the study (88% were men; mean age = 40 years, SD = 9), 29 completed the study. At the endpoint of each active arm (last observation carried forward), a significantly higher proportion of subjects was considered improved while receiving ABT-418 than while receiving placebo (40% versus 13%). Similarly, at endpoint there was a significantly greater reduction in ADHD symptom checklist scores (28% versus 15%). Symptoms reflective of attention, and subjects with less severe ADHD, responded more robustly to ABT-418. Treatment with ABT-418 was relatively well tolerated; dizziness and nausea were the most frequently reported adverse effects. CONCLUSIONS: The results of this investigation indicate that ABT-418, a nicotinic analog, may be a potentially useful agent for the treatment of ADHD.

Administration, Cutaneous↗

PubMed1987

Correlates of antimanic response to carbamazepine.

Nineteen acutely manic patients were studied in a double-blind trial of carbamazepine in doses averaging 1240 mg/day, achieving blood levels of 10.4 +/- 2.2 micrograms/ml. Clinical improvement in mood and psychomotor components of the manic syndrome was rapid in onset, generally parallel to that observed in previous patients treated with neuroleptics, and was associated with increases in the total hours of nighttime sleep. Compared to the seven nonresponders, the 12 patients who improved were significantly more manic during the baseline placebo period, tended to be more dysphoric, and were significantly more rapid cyclers over their entire course of illness as assessed by episodes in the year before NIMH admission (7.0 +/- 5.6 vs. 2.7 +/- 2.4 in the nonresponders). While improvement was robust in responders, it was not always complete, and some of these patients remained mildly to moderately symptomatic. All seven patients with a negative family history of affective illness in first degree relatives were responders, while those with a positive family history were equally divided. These preliminary data suggest that several predictors of poor response to lithium carbonate (manic severity, anxiety and dysphoria, rapid cycling, and negative family history) may be associated with good antimanic response to carbamazepine.

Antipsychotic Agents↗

PubMed2003

A FlashPlate assay for the identification of PARP-1 inhibitors.

A novel FlashPlate scintillation proximity assay has been developed for the high-throughput screening (HTS) of large compound libraries to identify inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1), an important enzyme involved in DNA repair. The assay was originally developed for the 96-well FlashPlate but is easily transferred to a 384-well format. Moreover, the authors demonstrate that the assay is sufficiently sensitive to determine accurate IC(50) values and adaptable for kinetic evaluation of lead molecules. The mechanism of action of the assay requires the binding of PARP-1 to a double-stranded DNA oligonucleotide leading to the active enzyme. Using NAD(+) and (3)H-NAD(+) as substrate, activated PARP-1 synthesizes labeled poly(ADP-ribose) chains. Once the reaction is stopped, ADP-ribose polymers are brought into proximity with the pretreated FlashPlate walls, resulting in signal amplification. This signal is then detected by a TopCount scintillation plate reader. The developed assay is a robust and reproducible method of screening for PARP-1 inhibitors that is low maintenance and cost-effective and can easily be automated.

Adenosine Diphosphate Ribose↗

PubMed2005

Impact of selenium on mood and quality of life: a randomized, controlled trial.

BACKGROUND: Selenium is known to be important to the brain. Three small, published studies have suggested an effect of selenium supplementation or deprivation on mood in healthy volunteers. We investigated these findings on a much larger scale. METHODS: In this double-blind, placebo-controlled intervention, 501 UK participants aged 60-74 were randomly allocated to receive 100, 200 or 300 microg selenium/d as high-selenium yeast or placebo yeast. Mood (Profile of Moods States - Bipolar Form [POMS-BI] questionnaire), "quality of life" (Short Form 36 [SF-36] questionnaire) and plasma selenium were measured at baseline and six months. RESULTS: Supplementation significantly increased plasma selenium above baseline values: from an overall mean (SD) of 90(19) ng/g to 91(26), 144(27), 191(41) and 227(53) ng/g in the placebo, 100, 200, 300 microg selenium groups respectively (p < .001). Four hundred forty-eight participants completed the POMS-BI questionnaires at both time points, with no significant differences in total mood or mood-subscale scores seen between doses. After six months of supplementation, mean (SD) total mood scores for the four doses were 163(36), 161(37), 162(33), 162(34), F(3,443) = .25, p = .86. Quality of life was similarly unaffected. CONCLUSIONS: There was no evidence that selenium supplementation benefited mood or quality of life in these elderly volunteers. Though this is at odds with some previous results, our robust study design, much larger sample size and longer supplementation period, together with the evidence that the brain is a privileged site for selenium retention, suggest that this is a reliable finding.

Affect↗