Psychiatric Manifestations in Early to Middle Stages of Fragile X-Associated Tremor-Ataxia Syndrome (FXTAS).

OBJECTIVE: The purpose of the present study was to assess the psychiatric manifestations of early to middle stages of fragile X-associated tremor-ataxia syndrome (FXTAS) and their relationship with executive function and FMR1 cytosine-guanine-guanine (CGG) repeat numbers across genders. METHODS: Cross-sectional data from 100 participants (62 men, 38 women; mean±SD age=67.11±7.90 years) with FXTAS stage 1, 2, or 3 were analyzed, including demographic information, cognitive measures, psychiatric assessments (Symptom Checklist-90-Revised and Behavioral Dyscontrol Scale-II [BDS-II]), and CGG repeat number. RESULTS: Participants with FXTAS stage 3 exhibited significantly worse psychiatric outcomes compared with participants with either stage 1 or 2, with distinct gender-related differences. Men showed differences in anxiety and hostility between stage 3 and combined stages 1 and 2, whereas women exhibited differences in anxiety, depression, interpersonal sensitivity, obsessive-compulsive symptoms, and somatization, as well as in the Global Severity Index, the Positive Symptom Distress Index, and the Positive Symptom Total. Among male participants, negative correlations were observed between BDS-II total scores and obsessive-compulsive symptoms, as well as between anxiety and CGG repeat number. CONCLUSIONS: These findings suggest that even at early FXTAS stages, patients have significant cognitive and other psychiatric symptoms, with notable gender-specific differences. This study underscores the clinical and prognostic relevance of comorbid psychiatric conditions in FXTAS, highlighting the need for early intervention and targeted support for individuals with relatively mild motor deficits.

The effects of chronic restraint on the morphology of ventral CA1 neurons in female Long Evans rats.

Women are more likely than men to develop psychopathology as a result of stress, but there is little research regarding the effects of a stressful condition and its treatment in female non-human animals, perhaps because of inherent hormonal activity. Recent studies have demonstrated that there are structural and functional differences between the dorsal and ventral hippocampus, but the effects of stress on the morphology of CA1 and CA3 neurons have been studied primarily in the dorsal hippocampus. This study assessed the effects of stress induced by restricted movement on the morphology of ventral hippocampal CA1 neurons in male and female rats. Male and female Long Evans (LE) rats were subjected to restraint stress for 6 h every day for 25 days. One group of rats was used to study the dendritic morphology of CA1 ventral hippocampal neurons using the Golgi-Cox stain. A second group of rats was used to analyze learning and memory using the Morris water maze. Stressed female rats exhibited a decrease in the density of basilar dendritic spines, an increase in the number of apical dendritic intersections and deficits in spatial memory. There were no apparent effects of stress on male rats. Our data support previous findings of a dimorphic response to chronic stress and indicate that the ventral hippocampus is not particularly susceptible to the effects of stress.

Negative effect of treatment with mGluR5 negative allosteric modulator AFQ056 on blood biomarkers in young individuals with Fragile X syndrome.

Background: Fragile X syndrome, with an approximate incidence rate of 1 in 4000 males to 1 in 8000 females, is the most prevalent genetic cause of heritable intellectual disability and the most common monogenic cause of autism spectrum disorder. The full mutation of the Fragile X Messenger Ribonucleoprotein-1 gene, characterized by an expansion of CGG trinucleotide repeats (>200 CGG repeats), leads to fragile X syndrome. Currently, there are no targeted treatments available for fragile X syndrome. In a recent large multi-site trial, FXLEARN, the effects of the mGluR5 negative allosteric modulator, AFQ056 (mavoglurant), were investigated, but did not show a significant impact of AFQ056 on language development in children with fragile X syndrome aged 3-6 years. Objectives: The current analyses from biospecimens collected in the FXLEARN study aimed to determine whether AFQ056 affects the level of potential biomarkers associated with Akt/mTOR and matrix metalloproteinase 9 signaling in young individuals with fragile X syndrome. Previous research has indicated that these biomarkers play crucial roles in the pathophysiology of fragile X syndrome. Design: A double-blind placebo-controlled parallel-group flexible-dose forced titration design. Methods: Blood samples for biomarkers were collected during the FXLEARN at baseline and subsequent visits (1- and 8-month visits). Biomarker analyses included fragile X messenger ribonucleoprotein-1 genotyping by Southern blot and PCR approaches, fragile X messenger ribonucleoprotein-1 mRNA levels determined by PCR, matrix metalloproteinase 9 levels' detection using a magnetic bead panel, and targets of the Akt/mTOR signaling pathway with their phosphorylation levels detected. Results: This research revealed that administering AFQ056 does not affect the expression levels of the investigated blood biomarkers in young children with fragile X syndrome. Conclusion: Our findings of the lack of association between clinical improvement and biomarkers' levels in the treatment group are in line with the lack of benefit observed in the FXLEARN study. These findings indicate that AFQ056 does not provide benefits as assessed by primary or secondary endpoints. Registration: ClincalTrials.gov NCT02920892.

Activation Ratio Correlates with IQ in Female Carriers of the FMR1 Premutation.

Carriers of the FMR1 premutation (PM) allele are at risk of one or more clinical conditions referred to as FX premutation-associated conditions (FXPAC). Since the FMR1 gene is on the X chromosome, the activation ratio (AR) may impact the risk, age of onset, progression, and severity of these conditions. The aim of this study was to evaluate the reliability of AR measured using different approaches and to investigate potential correlations with clinical outcomes. Molecular and clinical assessments were obtained for 30 PM female participants, and AR was assessed using both Southern blot analysis (AR-Sb) and methylation PCR (AR-mPCR). Higher ARs were associated with lower FMR1 transcript levels for any given repeat length. The higher AR-Sb was significantly associated with performance, verbal, and full-scale IQ scores, confirming previous reports. However, the AR-mPCR was not significantly associated (p > 0.05) with these measures. Similarly, the odds of depression and the number of medical conditions were correlated with higher AR-Sb but not correlated with a higher AR-mPCR. This study suggests that AR-Sb may be a more reliable measure of the AR in female carriers of PM alleles. However, further studies are warranted in a larger sample size to fully evaluate the methylation status in these participants and how it may affect the clinical phenotype.

Intercorrelation of Molecular Biomarkers and Clinical Phenotype Measures in Fragile X Syndrome.

This study contributes to a greater understanding of the utility of molecular biomarkers to identify clinical phenotypes of fragile X syndrome (FXS). Correlations of baseline clinical trial data (molecular measures-FMR1 mRNA, CYFIP1 mRNA, MMP9 and FMRP protein expression levels, nonverbal IQ, body mass index and weight, language level, NIH Toolbox, adaptive behavior rating, autism, and other mental health correlates) of 59 participants with FXS ages of 6-32 years are reported. FMR1 mRNA expression levels correlated positively with adaptive functioning levels, expressive language, and specific NIH Toolbox measures. The findings of a positive correlation of MMP-9 levels with obesity, CYFIP1 mRNA with mood and autistic symptoms, and FMR1 mRNA expression level with better cognitive, language, and adaptive functions indicate potential biomarkers for specific FXS phenotypes. These may be potential markers for future clinical trials for targeted treatments of FXS.

De Novo Large Deletion Leading to Fragile X Syndrome.

Fragile X syndrome (FXS) is the most frequent cause of X-linked inherited intellectual disabilities (ID) and the most frequent monogenic form of autism spectrum disorders. It is caused by an expansion of a CGG trinucleotide repeat located in the 5'UTR of the FMR1 gene, resulting in the absence of the fragile X mental retardation protein, FMRP. Other mechanisms such as deletions or point mutations of the FMR1 gene have been described and account for approximately 1% of individuals with FXS. Here, we report a 7-year-old boy with FXS with a de novo deletion of approximately 1.1 Mb encompassing several genes, including the FMR1 and the ASFMR1 genes, and several miRNAs, whose lack of function could result in the observed proband phenotypes. In addition, we also demonstrate that FMR4 completely overlaps with ASFMR1, and there are no sequencing differences between both transcripts (i.e., ASFMR1/FMR4 throughout the article).

Misperception of the Cardiovascular Risk in Patients with Rheumatoid Arthritis.

The risk of cardiovascular (CV) disease and mortality is increased by rheumatoid arthritis (RA). However, data on how RA patients perceive their own CV risk and their adherence to CV prevention factors are scarce. We conducted an observational study on 266 patients with RA to determine whether the perceived CV risk correlates to the objective CV risk, and if it influences their compliance with a Mediterranean diet and physical exercise. The objective CV risk was calculated according to the modified European League Against Rheumatism (EULAR) Systematic Coronary Risk Evaluation (SCORE). The perceived CV risk did not correlate to the objective CV risk. The correlation was even lower when carotid ultrasound was used. Notably, 64.62% of patients miscalculated their CV risk, with 43.08% underestimating it. Classic CV risk factors, carotid ultrasound markers and ESR and CRP showed significant correlation with the objective CV risk. However, only hypertension and RA disease features showed association with the perceived CV risk. Neither the objective CV risk nor the perceived CV risk were associated with the accomplishment of a Mediterranean diet or physical activity. In conclusion, RA patients tend to underestimate their actual CV risk, giving more importance to RA features than to classic CV risk factors. They are not concerned enough about the beneficial effects of physical activity or diet.

Weight gain in preterm infants following parent-administered Vimala massage: a randomized controlled trial.

Massage has been proposed as a way of facilitating development and growth of newborns through its effects on increasing blood flow, heart rate, digestion, and immunity. Massage might increase basal metabolism and nutrient absorption through endocrine effects such as increase in insulin and adrenaline and decrease in cortisol. Preliminary studies have suggested significant impact on weight gain with shortening of in-hospital stays of up to 6 days. We compared weight gain among preterm infants receiving Vimala massage plus usual care versus usual care alone. A randomized controlled trial was conducted. Sixty clinically stable preterm newborns with a corrected gestational age of 30 to 35 weeks receiving enteral nutrition in the hospital nursery were included. Half of them were assigned at random to receive Vimala massage twice daily for 10 days plus usual nursery care; the others received usual nursery care. Weight, head circumference, caloric intake, and nutritional method were recorded daily. Group characteristics were compared with analysis of variance, T test, and chi (2) test as appropriate. There were no differences between groups in gender, gestational age, initial weight, head circumference, and caloric intake and type of nutrition at baseline. Infants receiving massage had a larger weight gain versus the control group since the third day (188.2 +/- 41.20 g/kg versus 146.7 +/- 56.43 g/kg, P < 0.001). Hospital stay was shorter in infants receiving massage and usual nursery care (15.63 +/- 5.41 days versus 19.33 +/- 7.92 days, P = 0.03). The addition of parent-administered Vimala massage to usual nursery care resulted in increased weight gain and shorter hospital stay among clinically stable preterm newborns.

Validation of a 2-day water maze protocol in mice.

We present a 2-day water maze protocol that addresses some of potential confounds present in the water maze when using the aged subjects typical of studies of neurodegenerative disorders, such as Alzheimer's disease. This protocol is based on an initial series of training trials with a visible platform, followed by a memory test with a hidden platform 24h later. We validated this procedure using aged (15-18m) mice expressing three Alzheimer's disease-related transgenes, PS1(M146 V), APP(Swe), and tau(P301L). We also tested these triple transgenic mice (3xTG) and age and sex-matched wild-type (WT) in a behavioral battery consisting of tests of motor coordination (balance beam), spatial memory (object displacement task) visual acuity (novel object recognition task) and locomotor activity (open field). 3xTG mice had significantly longer escape latencies in the memory trial of the 2-day water maze test than WT and than their own baseline performance in the last visible platform trial. In addition, this protocol had improved sensitivity compared to a typical probe trial, since no significant differences between genotypes were evident in a probe trial conducted 24h after the final training trial. The 2-day procedure also resulted in good reliability between cohorts, and controlled for non-cognitive factors that can confound water maze assessments of memory, such as the significantly lower locomotor activity evident in the 3xTG mice. A further benefit of this method is that large numbers of animals can be tested in a short time.

[Factors associated with functional dependence in older adults: a secondary analysis of the National Study on Health and Aging, Mexico, 2001]. / Factores asociados con la dependencia funcional en los adultos mayores: un análisis secundario del Estudio Nacional sobre Salud y Envejecimiento en México, 2001.

OBJECTIVES: To identify factors associated with dependence for basic activities of daily living (BADL) and instrumental activities of daily living (IADL) in elderly adults in Mexico. METHODS: A cross-sectional study of data from the first round of Mexico's National Study on Health and Aging, 2001, was undertaken. The sample consisted of 7 171 participants, 60 years of age or older. Multifactorial regression analysis was used to identify associations between BADL and IADL dependence and lifestyle, sociodemographics, family background, and health history, from childhood to present. RESULTS: The mean age of the participants was 69.4 +/- 7.6 years of age, with a range of 60-105 years; females made up 53.4% of the sample. The BADL- and IADL-dependent groups had a higher mean age (P < 0.01), were predominantly female (P < 0.01), had a greater incidence of illiteracy, and reported a significantly higher number of chronic diseases and greater frequency of pain than did the independent participants. Among the 521 (7.3%) BADL-dependent, there was a higher percentage who were single or widowed (P < 0.01), and their self-assessed health was poorer, than that of the independent (P < 0.01). Among the 603 (8.4%) IADL-dependent, significant, independently associated factors were age, cerebrovascular and other chronic diseases, depression, vision issues, excessive pain, and amputation of a limb. Absence of childhood trauma and fewer years of employment were related to a lower incidence of IADL dependence. CONCLUSIONS: Functional dependence in older adults is directly related to aging and has multiple determinants. Awareness of these determinants should help design health programs that can identify individuals who are at high risk of losing their independence, and implement interventions for slowing or reversing the process.

Factores asociados con la dependencia funcional en los adultos mayores: un análisis secundario del Estudio Nacional sobre Salud y Envejecimiento en México, 2001 / Factors associated with functional dependence in older adults: a secondary analysis of the National Study on Health and Aging, Mexico, 2001

OBJETIVO: Identificar los factores asociados con la dependencia funcional de los adultos mayores para realizar actividades básicas de la vida diaria (ABVD) y actividades instrumentales de la vida diaria (AIVD). MÉTODO: Estudio transversal de la información obtenida en la primera vuelta del Estudio Nacional sobre Salud y Envejecimiento en México (ENASEM) en 2001. La muestra estuvo compuesta por 7 171 personas de 60 años o más. Mediante el análisis de regresión logística multifactorial se analizó la asociación de la dependencia funcional para realizar ABVD y AIVD con los hábitos de vida y los antecedentes personales sociales, familiares y de salud desde la infancia de los participantes. RESULTADOS: La edad promedio fue de 69,4 ± 7,6 años (de 60 a 105 años); 53,4 por ciento eran mujeres. Los grupos de dependientes para realizar ABVD y AIVD tenían en promedio mayor edad (P < 0,01), en él predominaban las mujeres (P < 0,01) y había más personas analfabetas y que declararon haber tenido un número significativamente mayor de enfermedades crónicas y haber sufrido dolor con mayor frecuencia en los grupos de personas independientes (P < 0,01). Entre los 521 (7,3 por ciento) dependientes para realizar ABVD se observó una mayor proporción de personas sin pareja (P < 0,01), viudos (P < 0,01) y con una peor percepción de su salud que entre los independientes (P < 0,01). Seiscientos tres (8,4 por ciento) de los entrevistados eran dependientes para realizar AIVD. La mayor edad, padecer de enfermedad cerebrovascular, un mayor número de enfermedades crónicas, síntomas depresivos, deficiencia visual, dolores que limitan sus actividades diarias y tener algún miembro amputado resultaron ser factores significativa e independientemente asociados con la dependencia para realizar AIVD. Un menor número de problemas sociales durante la infancia y menos años de trabajo remunerado estuvieron asociados con una menor dependencia para realizar AIVD. CONCLUSIONES: La dependencia funcional en los adultos mayores está directamente relacionada con el envejecimiento y depende de múltiples factores determinantes. El conocimiento de estos factores debe contribuir a diseñar programas de salud que permitan identificar a los individuos en riesgo de perder su autonomía e implementar intervenciones dirigidas a detener o revertir ese proceso.

OBJECTIVES: To identify factors associated with dependence for basic activities of daily living (BADL) and instrumental activities of daily living (IADL) in elderly adults in Mexico. METHODS: A cross-sectional study of data from the first round of MexicoÆs National Study on Health and Aging, 2001, was undertaken. The sample consisted of 7 171 participants, 60 years of age or older. Multifactorial regression analysis was used to identify associations between BADL and IADL dependence and lifestyle, sociodemographics, family background, and health history, from childhood to present. RESULTS: The mean age of the participants was 69.4 ± 7.6 years of age, with a range of 60-105 years; females made up 53.4 percent of the sample. The BADL- and IADL-dependent groups had a higher mean age (P < 0.01), were predominantly female (P < 0.01), had a greater incidence of illiteracy, and reported a significantly higher number of chronic diseases and greater frequency of pain than did the independent participants. Among the 521 (7.3 percent) BADL-dependent, there was a higher percentage who were single or widowed (P < 0.01), and their self-assessed health was poorer, than that of the independent (P < 0.01). Among the 603 (8.4 percent) IADL-dependent, significant, independently associated factors were age, cerebrovascular and other chronic diseases, depression, vision issues, excessive pain, and amputation of a limb. Absence of childhood trauma and fewer years of employment were related to a lower incidence of IADL dependence. CONCLUSIONS: Functional dependence in older adults is directly related to aging and has multiple determinants. Awareness of these determinants should help design health programs that can identify individuals who are at high risk of losing their independence, and implement interventions for slowing or reversing the process.

Teofilina en asma / Teophylline in asthma

La teofilina ha sido uno de los medicamentos más ampliamente utilizados e intensivamente estudiado para el tratamiento del asma. La teofilina es una xantina metilada, relacionada con las xantinas de la dieta, cafeína, y teobromina. Tradicionalmente utilizada como broncodilatador, su uso actual es predominante como medicamento de mantenimiento para el asma crónica. Para el tratamiento del asma aguda, la teofilina es menos efectiva que los ß-2 agonistas inhalados o inyectados y permanece como una importante medicación en el manejo de síntomas nocturnos refractarios a tratamietno antiinflamatorio; es también útil como manejo de primera línea en pacientes que no cumplen o sin apego al tratamiento antiinflamatorio inhalado. El beneficio y toxicidad de la teofilina está en estrecha relación a las concentraciones séricas, y óptimos beneficios se obtienen a concentraciones de 10µg/mL y la toxicidad es frecuente a concentraciones que exceden 20 µg/mL. El rango de eliminación varía entre individuos, pero generalmente permanece estable en el paciente, excepto cuando cursa con alteraciones fisiológicas o con interacciones medicamentosas. Su uso clínico requiere cuidadosas consideraciones, de las características de absorción, individualización de la dosis, guiada por las concentraciones séricas y educación al paciente sobre los potenciales efectos secundarios y de las interacciones con medicamentos. Recientemente, parece renovarse el entusiasmo por el uso de la teofilina para el tratamiento del asma por sus propiedades antiinflamatorias y efecto inmunomodulador