Pharmacokinetics of Mycophenolic Acid after Intravenous Administration of Mycophenolate Mofetil to Healthy Cats.

BACKGROUND: Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is becoming increasingly popular as an alternative immunosuppressant in feline medicine. Pharmacokinetic information is not available for cats. OBJECTIVE: The purpose of this study was to determine whether MMF is biotransformed into the active metabolite MPA and to evaluate the disposition of MPA after a 2-hour constant rate intravenous (IV) infusion of MMF in healthy cats. ANIMALS: Healthy cats (n = 6). METHODS: This was a prospective pilot study. All cats were administered MMF at 20 mg/kg every 12 hours over a 2-hour constant rate infusion for 1 day. The concentrations of MPA and its derivatives in blood were determined using a validated UHPLC-UV method. RESULTS: All cats biotransformed MMF into MPA. The mean AUC0-14 h ranged from 6 to 50 h*mg/L after IV dosing of MMF. Transient large bowel diarrhea was recorded in 2 of 6 cats after medication administration. CONCLUSION AND CLINICAL IMPORTANCE: The disposition of MPA in plasma was highly variable, which could result in high interindividual variability in the safety and efficacy of treatment with MMF in cats.

Open-Label Allopregnanolone Treatment of Men with Fragile X-Associated Tremor/Ataxia Syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting approximately 45% of male and 16% of female carriers of the FMR1 premutation over the age of 50 years. Currently, no effective treatment is available. We performed an open-label intervention study to assess whether allopregnanolone, a neurosteroid promoting regeneration and repair, can improve clinical symptoms, brain activity, and magnetic resonance imaging (MRI) measurements in patients with FXTAS. Six patients underwent weekly intravenous infusions of allopregnanolone (2-6 mg over 30 min) for 12 weeks. All patients completed baseline and follow-up studies, though MRI scans were not collected from 1 patient because of MRI contraindications. The MRI scans from previous visits, along with scans from 8 age-matched male controls, were also included to establish patients' baseline condition as a reference. Functional outcomes included quantitative measurements of tremor and ataxia and neuropsychological evaluations. Brain activity consisted of event-related potential N400 word repetition effect during a semantic memory processing task. Structural MRI outcomes comprised volumes of the hippocampus, amygdala, and fluid-attenuated inversion recovery hyperintensities, and microstructural integrity of the corpus callosum. The results of the study showed that allopregnanolone infusions were well tolerated in all subjects. Before treatment, the patients disclosed impairment in executive function, verbal fluency and learning, and progressive deterioration of all MRI measurements. After treatment, the patients demonstrated improvement in executive functioning, episodic memory and learning, and increased N400 repetition effect amplitude. Although MRI changes were not significant as a group, both improved and deteriorated MRI measurements occurred in individual patients in contrast to uniform deterioration before the treatment. Significant correlations between baseline MRI measurements and changes in neuropsychological test scores indicated the effects of allopregnanolone on improving executive function, learning, and memory for patients with relatively preserved hippocampus and corpus callosum, while reducing psychological symptoms for patients with small hippocampi and amygdalae. The findings show the promise of allopregnanolone in improving cognitive functioning in patients with FXTAS and in partially alleviating some aspects of neurodegeneration. Further studies are needed to verify the efficacy of allopregnanolone for treating FXTAS.

Broad autism spectrum and obsessive-compulsive symptoms in adults with the fragile X premutation.

OBJECTIVE: Clinical observations and a limited number of research studies provide evidence that the fragile X premutation may confer risk for autism, executive dysfunction, and psychopathology. The link to autism spectrum symptoms and social cognition deficits with the premutation remains uncertain, and thus was the focus of the present investigation. METHOD: Our sample included 131 individuals, 42 men/22 women with the FMR1 premutation (mean age = 31.83 ± 8.59 years) with a normal neurological exam, and 48 men/19 women healthy age-matched controls (mean age = 29.48 ± 7.29 years). Individuals completed a comprehensive neuropsychological battery with additional assessments for social cognition, broad autism spectrum, and obsessive-compulsive (OC) symptoms. RESULTS: Premutation carriers self-reported higher rates of autism-related symptoms (Autism Quotient; p = .001). Among males only, premutation carriers showed more atypical social interaction (p < .001) and stereotyped behavior (p = .014) during standardized clinical examination on the Autism Diagnostic Observation Schedule (ADOS) relative to controls. Female premutation carriers reported significantly higher rates of OC symptoms compared to control females (p = .012). Molecular measures defining the expanded premutation (FMR1 CGG repeat length and/or mRNA) were significantly associated with a measure of theory of mind (Reading the Mind in the Eyes Task). CONCLUSIONS: The results of this study indicate a higher rate of broad autism spectrum symptoms in some males with the premutation and provide evidence for an obsessive-compulsive subtype in female premutation carriers.

Analytical tools for the analysis of carotenoids in diverse materials.

High-performance liquid chromatography (HPLC) has become the method of choice for carotenoid analysis. Although a number of normal-phase columns have been reported, reverse-phase columns are the most widely used stationary phases for the analysis of these molecules. C18 and C30 stationary phases have provided good resolution for the separation of geometrical isomers and carotenoids with similar polarity. More recently ultra high-performance liquid chromatography (UHPLC) has been used. UHPLC has a number of distinct advantages over conventional HPLC. These include: faster analyses (due to shorter retention times), narrower peaks (giving increased signal-to-noise ratio) and higher sensitivity. High strength silica (HSS) T3 and C18 and ethylene bridged hybrid (BEH) C18 stationary phases, with sub-2 µm particles have been used successfully for UHPLC analysis and separation of carotenoids. A number of spectroscopic and mass spectrometric techniques have also been used for carotenoid qualitative and quantitative analysis. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI/TOF-MS), atmospheric-pressure solids-analysis probe (ASAP) and Raman spectroscopy are used to profile rapidly and qualitative carotenoids present in different crude extracts. Such detection methods can be used directly for the analysis of samples without the need for sample preparation or chromatographic separation. Consequently, they allow for a fast screen for the detection of multiple analytes. Quantitative carotenoid analysis can be carried out using absorbance or mass detectors. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is efficient for carotenoid identification through the use of transitions for the detection of analytes through precursor and daughter ions. This approach is suitable for the identification of carotenoids with the same molecular mass but different fragmentation patterns. Here we review critically the latest improvements for carotenoid resolution and detection and we discuss a number of analytical techniques for qualitative and quantitative analysis of carotenoids.

Psychological symptoms correlate with reduced hippocampal volume in fragile X premutation carriers.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder occurring in male and occasional female carriers of a premutation expansion (55-200 CGG repeats) of the fragile X mental retardation 1 gene (FMR1). This study assessed the relationship between hippocampal volume and psychological symptoms in carriers, both with and without FXTAS, and controls. Volumetric MRI measures, clinical staging, cognitive testing, molecular analysis, and measures of psychological symptoms were performed for female premutation carriers both with FXTAS (n = 16, age: 57.50 + or - 12.46) and without FXTAS (n = 17, age: 44.94 + or - 11.23), in genetically normal female controls (n = 8, age: 50.63 + or - 11.43), male carriers with FXTAS (n = 34, age: 66.44 + or - 6.77) and without FXTAS (n = 21, age: 52.38 + or - 12.11), and genetically normal male controls (n = 30, age: 57.20 + or - 14.12). We examined the relationship between psychological symptom severity and hippocampal volume, as well as correlations with molecular data. We found a significant negative correlation between total hippocampal volume and anxiety in female carriers, with and without FXTAS. This finding was mainly driven by the significant negative correlation between right hippocampal volume and anxiety. Other anxiety-related subscales also correlated with the right hippocampus in females. In male carriers with and without FXTAS, only paranoid ideation negatively correlated with hippocampal volume. Female premutation carriers demonstrated a negative association between hippocampal volume and the severity of anxiety-related psychological symptoms. Though the presentation of FXTAS symptoms is less common in females, anxiety-related problems are common both prior to and after the onset of FXTAS, and may be related to hippocampal changes.

AIDS stigma combinations in a sample of Puerto Rican health professionals: qualitative and quantitative evidence

The HIV/AIDS epidemic continues to impact Puerto Rico and the Caribbean region with growing numbers of cases each year. The stigma that surrounds the epidemic has harmful implications on the health of people living with the disease and public health in general, fostering health deterioration and new infections. When this stigma emanates from health professionals it can severely hinder access to health services, which are crucial for those living with the virus. Still, AIDS stigma has been previously explored among this population as a separate phenomenon from other pre-existing stigmas. This has yielded a limited perspective on the complexity of how AIDS stigma is manifested. In light of this limitation, the main objectives of this study were: 1) to document AIDS stigma among a sample of Puerto Rican health professionals and health professionals in training and 2) to explore the combination of other stigmas (sexism, homophobia, and negative attitudes towards drug users) with that associated to HIV/AIDS. Through an exploratory design, using a mixed method approach (qualitative in-depth interviews and quantitative questionnaires), we explored the objectives in a sample of 501 health professionals and health professionals in training. The results evidenced the combinations of other stigmas with that of HIV/AIDS. Homophobia yielded the strongest correlation and was the best predictor of AIDS stigma. These results evidence the need to develop interventions to reduce AIDS stigma and its combinations among this population.

Contrast detection in infants with fragile X syndrome.

Studies have reported that a selective deficit in visual motion processing is present in certain developmental disorders, including Williams syndrome and autism. More recent evidence suggests a visual motion impairment is also present in adults with fragile X syndrome (FXS), the most common form of inherited mental retardation. The goal of the current study was to examine low-level cortical visual processing in infants diagnosed with FXS in order to explore the developmental origin of this putative deficit. We measured contrast detection of first-order (luminance-defined) and second-order (contrast-defined) gratings at two levels of temporal frequency, 0 Hz (static) and 4 Hz (moving). Results indicate that infants with FXS display significantly higher detection thresholds only for the second-order, moving stimuli compared to mental age-matched typically developing controls.

Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS).

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder occurring in male and rare female carriers of a premutation expansion (55 to 200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. METHODS: Volumetric MRI studies, clinical staging, cognitive testing, and molecular analysis were conducted in 15 female premutation carriers affected by FXTAS (age 59.5 +/- 10.3 years), 20 unaffected female carriers (43.3 +/- 11.2 years), 11 genetically normal female controls (51.0 +/- 10.3 years), 36 affected male carriers (65.0 +/- 5.6 years), 25 unaffected male carriers (53.5 +/- 12.5 years), and 39 male controls (58.0 +/- 15.0 years). Female and male carriers with FXTAS were matched on duration of disease. RESULTS: We found less pronounced reductions of cerebellar volume and a lower incidence of involvement (symmetric high T2 signal) of the middle cerebellar peduncles (MCP sign) in females affected by FXTAS (13%) compared with affected males (58%). We found reduced brain volumes and increased white matter disease associated with the presence of FXTAS in females compared with female controls. We also observed significant associations between reduced cerebellar volume and both increased severity of FXTAS symptoms and increased length of the CGG repeat expansion in male premutation carriers, but not in females. CONCLUSIONS: Females affected by fragile X-associated tremor/ataxia syndrome (FXTAS) demonstrated milder brain changes than affected males, although they showed a similar pattern of radiologic findings consistent with brain atrophy and white matter disease. FXTAS should be considered (by ordering fragile X DNA testing) in females who present with late-onset ataxia, action tremor, or neuropathy, particularly in those with a family history of mental retardation, autism, or premature ovarian failure.

Developmental changes in mental arithmetic: evidence for increased functional specialization in the left inferior parietal cortex.

Arithmetic reasoning is arguably one of the most important cognitive skills a child must master. Here we examine neurodevelopmental changes in mental arithmetic. Subjects (ages 8-19 years) viewed arithmetic equations and were asked to judge whether the results were correct or incorrect. During two-operand addition or subtraction trials, for which accuracy was comparable across age, older subjects showed greater activation in the left parietal cortex, along the supramarginal gyrus and adjoining anterior intra-parietal sulcus as well as the left lateral occipital temporal cortex. These age-related changes were not associated with alterations in gray matter density, and provide novel evidence for increased functional maturation with age. By contrast, younger subjects showed greater activation in the prefrontal cortex, including the dorsolateral and ventrolateral prefrontal cortex and the anterior cingulate cortex, suggesting that they require comparatively more working memory and attentional resources to achieve similar levels of mental arithmetic performance. Younger subjects also showed greater activation of the hippocampus and dorsal basal ganglia, reflecting the greater demands placed on both declarative and procedural memory systems. Our findings provide evidence for a process of increased functional specialization of the left inferior parietal cortex in mental arithmetic, a process that is accompanied by decreased dependence on memory and attentional resources with development.

Bioassay screening of Amazonian plants

OBJECTIVE: The purpose of this study was to evaluate several biological activities of thirty plant extracts collected in the North West Amazon (Ecuador). Some of these plants are being used for their reputed medicinal properties by the natives of this region. METHODS: Five in vitro bioassays were used to screen the plant material. 1. The brine shrimp lethality examination (BSLT) in microplate is a general test that seems capable of detecting a broad spectrum of bioactivity present in crude plant extracts. 2. Free radical scavenging properties were studied in a colorimetric assay using 2,2-diphenyl-1-picrylhydrazyl (DPPH). 3. The beta-glucosidase inhibition test is thought to be a method for the evaluation of anti-AIDS, anti-diabetic or anti-obesity compounds. 4. The xanthine oxidase inhibition assay is used to identify potential anti-gout agents. 5. The antibacterial activity that is being used to isolate and identify antibiotic drugs. RESULTS: In the BSLT, we found that Piscidia carthagenensis demonstrated very good activity with a LC50: 21.81 micrograms/mL. It is considered that plant extracts with low LC50 values may contain metabolites with cytotoxic, antifungal, insecticidal or pesticide activities. In the antioxidant activity bioassay, several plant extracts were confirmed to have excellent free radical scavenging properties. Rhus juglandifolia and Clusia venusta leaves exhibited an ED50: 3.12 micrograms/mL and 3.61 micrograms/mL, respectively. Piper reticulatum (84 per cent), Inga heteroptera (77 per cent), Clusia venusta (70.9 per cent), and Rhus juglandifolia (70.5 per cent) showed fairly good inhibition activity for beta-glucosidase. On the other hand, none of the plant extracts was capable of inhibiting xanthine oxidase. Finally, the Gram-positive microorganisms Staphylococcus aureus and Corynebacterium diphteriae were found to be sensitive to the majority of the plant extracts, whereas the Gram-negative bacteria Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, and Salmonella typhi were proved to be resistant toward the plant extracts. CONCLUSIONS: It is important to continue investigating our plant kingdom, especially the world tropical reserves as an alternative for finding new or better drugs. It should be essential to follow-up this type of investigation to isolate and elucidate the active principles of the bio-positive plants.

Dissociating prefrontal and parietal cortex activation during arithmetic processing.

Lesion and brain-imaging studies have implicated the prefrontal and parietal cortices in arithmetic processing, but do not exclude the possibility that these brain areas are also involved in nonarithmetic operations. In the present study, we used functional magnetic resonance imaging to explore which brain areas contribute uniquely to numeric computation. Task difficulty was manipulated in a factorial design by varying the number of operands and the rate of stimulus presentation. Both manipulations increased the number of operations to be performed in unit time. Manipulating the number of operands allowed us to investigate the specific effect of calculation, while manipulating the rate of presentation allowed us to increase task difficulty independent of calculation. We found quantitative changes in activation patterns in the prefrontal and parietal cortices as well as the recruitment of additional brain regions, including the caudate and midcerebellar cortex, with increasing task difficulty. More importantly, the main effect of arithmetic complexity was observed in the left and right angular gyrus, while the main effect of rate of stimulus presentation was observed in the left insular/orbitofrontal cortex. Our findings indicate a dissociation in prefrontal and parietal cortex function during arithmetic processing and further provide the first evidence for a specific role for the angular gyrus in arithmetic computation independent of other processing demands.

Patients' own reasons and patient-perceived recommendations for orthognathic surgery.

In an attempt to learn more about patients' decision-making processes, an analysis was performed to examine patients' reasons for undergoing orthognathic surgery and their understanding of the reasons surgery was recommended. Before surgery, 105 females and 38 males completed an open-ended questionnaire in which they listed their reasons for choosing orthognathic surgery and their perceptions of their orthodontists' recommendations. Three raters classified the responses into 7 categories: esthetics, psychosocial, functional, TMJ/pain, authority, prevention, and other. Rater agreement ranged from a kappa of.55 to 1.00. Patients reported undergoing orthognathic surgery primarily for esthetic, functional, and TMJ improvements, 71%, 47%, and 28%, respectively. Females reported more TMJ-related reasons than males (P <.05). Patients reporting function (P <. 05), TMJ (P <.05), and prevention of future problems (P <.05) were older than patients not reporting these reasons. Mexican American patients indicated more psychosocial reasons (P <.05) than European Americans. Patients understood that orthognathic surgery was recommended primarily for esthetic, functional, and TMJ improvements, 52%, 44%, and 18%, respectively. Males reported receiving more preventative recommendations (23%) than females (10%). Mexican American patients reported receiving more psychosocial recommendations (P <.05) than European Americans. Agreement between each paired patient/patient-perceived reason was highest for TMJ problems (kappa = 0.588). In conclusion, patients underwent orthognathic surgery to improve esthetic, functional and TMJ problems and interpreted orthodontists' recommendations for similar reasons. On a case-to-case basis, agreement between patient and orthodontist-represented reasons was modest, suggesting differences between patients' own reasons and their perceptions of orthodontists' recommendations.

Functional optimization of arithmetic processing in perfect performers.

Lesion and imaging studies to date have not clarified which sub-regions of the parietal lobe are specialized for arithmetic processing, and which perform supporting functions. We used functional magnetic resonance imaging to investigate parietal lobe function during arithmetic processing. Functional optimization was examined by analyzing regional differences in brain activation between perfect (100% accuracy) and imperfect performers. Perfect performers had significantly less activation only in the left angular gyrus, a finding that may be associated with skill mastery and long-term practice effects. The present results provide the first direct evidence of localized functional optimization for arithmetic processing in the human brain.

Psychosocial predictors of satisfaction among orthognathic surgery patients.

This study assessed the usefulness of selected psychosocial tests and demographic measures in identifying satisfied versus dissatisfied patients who received orthognathic surgery. Data were collected prior to placement of orthodontic appliances, 1 to 2 weeks presurgery, and at 1 week, 8 weeks, 6 months, 12 months and and 2 years postsurgery. The Revised Symptom Checklist-90 (SCL-90-R) scales, the Eysenck Personality Inventory (EPI), the Sickness Impact Profile (SIP), and the Oral Health Status Questionnaire (OHSQ) were used as independent variables. Indicators from the Post-Surgical Patient Satisfaction Questionnaire (PSPSQ), which assesses patient satisfaction regarding psychosocial issues, oral functioning, and esthetics, served as a postsurgical dependent measure of patient satisfaction. Thirty-one male and 86 female subjects participated in the multisite randomized trial comparing rigid and wire fixation. Patient age was significantly correlated with patient satisfaction from 8 weeks postsurgery through 2 years postsurgery. Older patients appear to report greater postsurgical satisfaction in comparison to younger patients. The postsurgical OHSQ (esthetics subscale) and postsurgical PSPSQ (satisfaction) were significantly related at 8 weeks, 6 months, 12 months, and 2 years postsurgery. Additionally, PSPSQ (satisfaction) and postsurgical OHSQ (general oral health scale) were correlated at 12 months. The EPI, SIP, and SCL-90-R were not significantly associated with postsurgical satisfaction when assessing the entire study sample. Postsurgical qualitative data from the PSPSQ indicated that 50% of the patients reported positive outcomes in oral functioning. Sixty-five percent reported esthetic improvements, and 37% reported neurosensory loss.

The drawbridge phenomenon: representational reasoning or perceptual preference?

Two experiments investigated whether infants would look longer at a rotating "drawbridge" that appeared to violate physical laws because they knew that it was causally impossible, as claimed by R. Baillargeon, E. S. Spelke, and S. Wasserman (1985) and R. Baillargeon (1987a). Using a habituation paradigm, they reported that infants looked longer at a display that appeared impossible (rotated 180 degrees while an obstructing box was behind it) than at one that appeared possible (rotated only 112 degrees, appearing to stop at the box). Experiment 1 eliminated habituation to 180 degree screen rotations. Still, infants looked longer at the 180 degree impossible rotations. Critically, however, infants also looked longer at possible 180 degree rotations in Experiment 2, in which no obstruction was present. Moreover, no difference in effect size was found between the 2 experiments. These findings indicate that infants' longer looking at 180 degree rotations is due to simple perceptual preference for more motion. They question R. Baillargeon's (1987a) claim that it is due to infants' representational reasoning about physically impossible object permanence events.

Psychosocial predictors of high-risk patients undergoing orthognathic surgery.

The purpose of this analysis was to identify a set of predictor variables that are prospectively related to postsurgical outcomes. Specifically, psychosocial characteristics were sought to predict postsurgical outcomes. The 5 Revised Symptom Checklist-90 (SCL-90-R) scales, the neuroticism score of the Eysenck Personality Inventory (EPI), the psychosocial domain score from the Sickness Impact Profile (SIP), and 4 scales from the Oral Health Status Questionnaire (OHSQ) were used as the predictors. A total of 31 male and 86 female subjects participated in this multicenter randomized trial, which compared rigid and wire fixation. Data were collected prior to placement of orthodontic appliances, 1 to 2 weeks presurgery, and at 1 week, 8 weeks, 6 months, and 2 years after surgery. Baseline oral health was used as an indicator of postsurgical oral health functioning. A path analytic model of influences on presurgical oral health was estimated (R2 = 0.43). The results suggest that presurgical screening of demographic characteristics (age, sex, and ethnicity), oral health (the OHSQ), quality of life issues (SIP), and personality features (SCL-90-R), accounts for 23% to 39% of the variance in postsurgical oral health outcomes. The path analysis conducted suggests that a patient's age, ethnicity, gender, and elevated scores on the EPI have indirect effects on postsurgical health. As determined by a 2-stage least squares regression model, 3 variables--the patient's presurgical oral health (per the OHSQ), pre- and postsurgical Global Severity Index (GSI) score from the SCL-90-R, and the psychosocial scale score from the SIP--were found to have a statistically significant impact on postsurgical outcomes. Additionally, the GSI, SIP, and OHSQ are reliable measures in predicting oral health outcomes.