Antioxidants in Photoaging: From Molecular Insights to Clinical Applications.

Photoaging (PA) is considered a silent disease affecting millions of people globally and is defined as skin damage due to prolonged exposure to ultraviolet radiation (UVR) from the sun. Physiologically, the skin is in a state of renewal and synthesis of components of the extracellular matrix (ECM). However, exposure to UVR affects the production of the ECM, and the functioning and response of skin cells to UVR begins to change, thus expressing clinical and phenotypic characteristics of PA. The primary mechanisms involved in PA are direct damage to the DNA of skin cells, increases in oxidative stress, the activation of cell signaling pathways responsible for the loss of skin integrity, and cytotoxicity. The medical and scientific community has been researching new therapeutic tools that counteract PA, considering that the damage caused by UVR exceeds the antioxidant defense mechanisms of the skin. Thus, in recent years, certain nutraceuticals and phytochemicals have been found to exhibit potential antioxidant and photoprotective effects. Therefore, the main objective of this review is to elucidate the molecular bases of PA and the latest pharmaceutical industry findings on antioxidant treatment against the progression of PA.

Sargassum macroalgae from Quintana Roo as raw material for the preparation of high-performance phosphate adsorbent from aqueous solutions.

Currently, the large volumes of Sargassum biomass (Sgs) arriving on Caribbean coasts are a problem that must be solved quickly. One alternative is to obtain value-added products from Sgs. In this work, Sgs is demonstrated to be a high-performance Ca - bioadsorbent for phosphate removal by a heat pretreatment at 800 °C that produces biochar. According to XRD analysis, calcined Sgs (CSgs) have a composition of 43.68%, 40.51%, and 8.69% of Ca(OH)2, CaCO3, and CaO, making CSgs a promising material for phosphate removal and recovery. Results demonstrated that CSgs have a high capacity to adsorb P over a wide range of concentrations (25-1000 mg P/L). After P removal, at low P concentration, the adsorbent material is rich in apatite (Ca5(PO4)3OH), and at high P concentration, brushite (CaHPO4•2H2O) was the main P compound. The CSg reached a Qmax of 224.58 mg P/g, which is higher than other high-performance adsorbents reported in the literature. The phosphate adsorption mechanism was dominated by chemisorption, followed by precipitation according to the pseudo-second-order kinetic model. The solubility of P (74.5 wt%) in formic acid solution and the water-soluble P (24.8 wt%) for CSgs after P adsorption indicated that the final product presents the potential to be used as fertilizer for acid soils. This biomass's processability and high phosphate adsorption performance for P removal make CSgs a potential material for wastewater treatment, and subsequent use of these residues as fertilizer offers a circular economy solution to this problem.

Parent, Teacher, and School Stakeholder Perspectives on Adolescent Pregnancy Prevention Programming for Latino Youth.

Teen pregnancy remains a public health concern particularly among Latinos, whose pregnancy rate of 83.5 per 1000 girls constitutes one of the highest rates of teen pregnancy among all ethnic and racial groups in the United States. To enhance the effectiveness of interventions for diverse Latino populations in the US, it is crucial to assess the community's understanding of the etiology of the problem of adolescent pregnancy and to implement programs that reflect the local community's beliefs and preferences. We present findings from six focus groups held with parents (n = 18), teachers (n = 23) and school stakeholders (n = 8) regarding teen pregnancy prevention among Latino youth at a high school located in a large, Midwestern city. Two investigators analyzed data iteratively using a template organizing approach. A consensus emerged across the groups regarding content that emphasized respect for oneself and one's family, a focus on personal and shared responsibility in reproductive health behavior, information about the "realities" or consequences associated with engaging in sexual activity, and information about contraceptives. The strong request from participants to include a parental education component reflects the community's belief that parents play a crucial, protective role in the socialization and development of adolescent sexual behavior, a view that is supported by empirical research. Findings highlight the importance of involving local school communities in identifying adolescent pregnancy prevention strategies that are responsive to the community's cultural values, beliefs, and preferences, as well as the school's capacity and teacher preferences.

Nitrogen-Rich Manganese Oxynitrides with Enhanced Catalytic Activity in the Oxygen Reduction Reaction.

The catalytic activity of manganese oxynitrides in the oxygen reduction reaction (ORR) was investigated in alkaline solutions to clarify the effect of the incorporated nitrogen atoms on the ORR activity. These oxynitrides, with rock-salt-like structures with different nitrogen contents, were synthesized by reacting MnO, Mn2 O3 , or MnO2 with molten NaNH2 at 240-280 °C. The anion contents and the Mn valence states were determined by combustion analysis, powder X-ray diffraction, and X-ray absorption near-edge structure analysis. An increase in the nitrogen content of rock-salt-based manganese oxynitrides increases the valence of the manganese ions and reinforces the catalytic activity for the ORR in 1 m KOH solution. Nearly single-electron occupancy of the antibonding eg states and highly covalent Mn-N bonding thus enhance the ORR activity of nitrogen-rich manganese oxynitrides.

Imported malaria including HIV and pregnant woman risk groups: overview of the case of a Spanish city 2004-2014.

BACKGROUND: Arrival of inmigrants from malaria endemic areas has led to a emergence of cases of this parasitic disease in Spain. The objective of this study was to analyse the high incidence rate of imported malaria in Fuenlabrada, a city in the south of Madrid, together with the frequent the lack of chemoprophylaxis, for the period between 2004 and 2014. Both pregnant women and HIV risk groups have been considered. METHODS: Retrospective descriptive study of laboratory-confirmed malaria at the Fuenlabrada University Hospital, in Madrid, during a 10-year period (2004-2014). These data were obtained reviewing medical histories of the cases. Relevant epidemiological, clinical and laboratory results were analysed, with focus on the following risk groups: pregnant women and individuals with HIV. RESULTS: A total of 185 cases were diagnosed (90.3 % Plasmodium falciparum). The annual incidence rate was 11.9/100,000 inhabitants/year. The average age was 30.8 years (SD: 14.3). Infections originating in sub-Saharan Africa comprised the 97.6 % of the cases. A total of 85.9 % were Visiting Friends and Relatives. Only a 4.3 % completed adequate prophylaxis. A total of 14.28 % of the fertile women were pregnant, and 8 cases (4.3 %) had HIV. None of them in these special groups completed prophylaxis. CONCLUSIONS: The incidence rate in Fuenlabrada is higher than in the rest of Spain, due to the large number of immigrants from endemic areas living in the municipality. However, the results are not representative of all the country. It seems to be reasonable to implement prevention and pre-travel assessment programs to increase chemoprophylaxis. Pregnancy tests and HIV serology should be completed for all patients to improve prophylactic methods.

Primary Leiomyoma of the Liver: Case Report and Review of the Literature.

Primary leiomyoma of the liver is an extremely rare benign hepatic tumor in asymptomatic patients. While leiomyoma is frequently found in the genitourinary tract, to the best of our knowledge only 29 cases of primary hepatic leiomyoma have been reported in the English language medical literature. Primary hepatic leiomyoma in patients without an underlying systemic disease (immunosuppression) is even more uncommon. A leiomyoma is composed of bundles of smooth muscle fibers and rarely transforms into a malignant tumor. We present a previously healthy 44-year-old woman who was incidentally found to have a focal liver lesion while undergoing radiologic studies for evaluation of her low back pain. The primary leiomyoma of the liver has characteristic radiologic findings that distinguish it from other hepatic tumors. In this article we discuss the typical radiologic and pathologic findings of leiomyoma compared with other primary liver tumors.

Mapping climate adaptation corridors for biodiversity-A regional-scale case study in Central America.

Climate adaptation corridors are widely recognized as important for promoting biodiversity resilience under climate change. Central America is part of the Mesoamerican biodiversity hotspot, but there have been no regional-scale analyses of potential climate adaptation corridors in Central America. We identified 2375 potential corridors throughout Central America that link lowland protected areas (≤ 500 m) with intact, high-elevation forests (≥ 1500 m) that represent potential climate change refugia. Whereas we found potential corridors in all Central American countries, potential corridors in Panama, Belize, and Honduras were most protected (medians = 64%, 49%, and 47%, respectively) and potential corridors in El Salvador were least protected (median = 10%). We also developed a corridor priority index based on the ecological characteristics and protected status of potential corridors and their associated start and end points. Compared to low- and medium-priority corridors, high-priority corridors (n = 160; top 7% of all corridors) were generally more protected, forested, and distributed across wider elevational gradients and more Key Biodiversity Areas, but also generally linked larger lowland protected areas to target areas that were larger, more protected, and spanned wider elevational gradients. For example, based on median values, high-priority corridors were 9% more protected and overlapped with 2-3 more Key Biodiversity Areas than low- and medium-priority corridors. Although high-elevation targets spanned considerably wider elevational gradients than lowland protected areas (medians = 695 vs. 142 m, respectively) and thus may be more likely to support refugia, they were considerably smaller than lowland protected areas (medians = 11 vs. 50 km2 respectively) and mostly unprotected (median = 4% protection). This initial, regional assessment can help prioritize locations for finer-scale research, conservation, and restoration activities in support of climate adaptation corridors throughout Central America and highlights the need for greater conservation of potential high-elevation refugia.

Discrepancy in medications reported by elderly patients in the dental office and in their electronic medical records: A pilot study.

AIMS: This study's main objective was to analyze the discrepancy between the dental medication record (DMR) and the physician-prescribed active medications recorded in the medical medication record (MMR). METHODS: The study group consisted of 100 adults who attended the University Dental Clinic (Santiago de Compostela, Spain) requesting dental care. A dental history was created for all participants that included the DMR. The MMR were compiled from their electronic medical records. RESULTS: About 80% of the patients consumed at least one drug (94.2% of those >65 years) and 19% took more than five drugs (26.4% of those > 65 years). In total, 54% of the patients had some discrepancy between the medications recorded in the DMR and those in the MMR (48.4% for those ≤65 years and 64.7% for those >65 years). The rate of participants who omitted some drugs was higher for those >65 years. The drugs most omitted from the DMR were analgesics/opioids, antihypertensives and anxiolytics/hypnotics/sedatives. CONCLUSIONS: It is imperative to access the MMR of patients requesting dental care because a significant number of medications are not reflected in their DMR. These discrepancies may be particularly common and relevant in elderly patients, in whom multimorbidity and polypharmacy are more frequent.

A bolder conservation future for Indonesia by prioritising biodiversity, carbon and unique ecosystems in Sulawesi.

As more ambitious protected area (PA) targets for the post-2020 global biodiversity framework are set beyond Aichi Target 11, renew thinking into spatial prioritisation is required to enable PA expansion that maximises environmental values. Our study focuses on the biodiverse and forest-rich Indonesian island of Sulawesi, which has a terrestrial PA network that covers 10% of the island. We used Marxan to investigate trade-offs in the design of an expanded PA network that prioritised different conservation features (biodiversity, forest cover, carbon stock, karst and valuable metal-rich areas) under varying island-wide coverage targets (17%, 30%, and 50%). Our first scenario, which required existing PAs to be selected, required larger areas to meet these coverage targets, in contrast to our second scenario, which allowed for any part of the island to be chosen, irrespective of PA status. The vast Mekongga and Bangkiriang Landscapes, and Gorontalo corridor were consistently identified as a high priority for protection under all scenarios. To meet our conservation targets through expanding current PAs, creating new PAs, and creating corridors that connect existing PAs, we used a spatially explicit three-phase approach. Our findings identified 26,508 km2 of priority areas to be included in the current PA network, potentially assisting Indonesia in meeting its post-2020 GBF target, if our approach is replicated across Indonesia as a national or sub-national analysis. We discuss various land management options through other effective area-based conservation measures (OECMs) and the costs to deliver this strategy.

Point-of-Care Ultrasound for the Diagnosis of Frequent Cardiovascular Diseases: A Review.

Point-of-care ultrasound (POCUS) has emerged as an indispensable diagnostic tool in cardiology, particularly within the emergency department. This narrative synthesis provides a comprehensive exploration of POCUS applications in cardiovascular diseases, elucidating its multifaceted roles and addressing challenges. The review delves into the technical attributes of POCUS, emphasizing its non-invasive nature, radiation-free qualities, and suitability for non-radiologists. It navigates through educational strategies, stressing the importance of structured programs for the seamless integration of POCUS into clinical practice. Highlighting its efficacy, the synthesis discusses POCUS applications in various scenarios such as dyspnea, chest pain, cardiac arrest, aortic dissection, pericardial effusion, and pulmonary embolism. Beyond acute care, the review explores the role of POCUS in outpatient and inpatient settings, focusing on chronic and acute heart failure, valvular heart diseases, and more. Acknowledging operator-dependent challenges and the need for continuous education, the review underscores the transformative potential of POCUS across diverse healthcare settings. This narrative synthesis accentuates POCUS as a valuable and versatile diagnostic tool in cardiology, offering efficiency, safety, and cost-effectiveness. Despite challenges, POCUS stands out as a transformative addition to clinical practices, poised to enhance patient outcomes and reshape the landscape of cardiovascular diagnostics.

Development of a Scale to Measure Healthy Behaviors in Spanish-Speaking University Students.

Chronic non-communicable diseases (NCDs) are a public health problem that affect the quality of life and well-being of people, especially the youth, who have been identified as a high-risk population. Physical inactivity is a key risk factor for NCDs, and an unhealthy diet is a significant driver of NCDs. On the other hand, physical exercise and healthy habits are effective methods of prevention. Although there are scales that measure different behaviors related to NCDs, most of them have been developed in another language (e.g., English) or only focus on one aspect of NCDs. The present study aimed to develop a scale to assess healthy behaviors (i.e., healthy eating and physical exercise) in Spanish-speaking university students, using an instrumental design, with a sample of 369 Chilean university students between 18 and 25 years of age. The results presented show evidence of validity through an exploratory structural equation model (ESEM), reliability estimation through McDonald's omega and Cronbach's alpha, evidence of invariance by sex, and evidence of validity in relation to other variables with an SEM model. It is concluded that the Healthy Behavior Scale, consisting of nine items to measure healthy eating and physical exercise, is a brief instrument with evidence of reliability and validity (CFI = 0.998; TLI = 0.995; and RMSEA = 0.063) for application in a Spanish-speaking university population, offering potential applications in research instruments, screening studies, and the development of new studies for other contexts.

Late Paleocene fossils from the Cerrejon Formation, Colombia, are the earliest record of Neotropical rainforest.

Neotropical rainforests have a very poor fossil record, making hypotheses concerning their origins difficult to evaluate. Nevertheless, some of their most important characteristics can be preserved in the fossil record: high plant diversity, dominance by a distinctive combination of angiosperm families, a preponderance of plant species with large, smooth-margined leaves, and evidence for a high diversity of herbivorous insects. Here, we report on an approximately 58-my-old flora from the Cerrejón Formation of Colombia (paleolatitude approximately 5 degrees N) that is the earliest megafossil record of Neotropical rainforest. The flora has abundant, diverse palms and legumes and similar family composition to extant Neotropical rainforest. Three-quarters of the leaf types are large and entire-margined, indicating rainfall >2,500 mm/year and mean annual temperature >25 degrees C. Despite modern family composition and tropical paleoclimate, the diversity of fossil pollen and leaf samples is 60-80% that of comparable samples from extant and Quaternary Neotropical rainforest from similar climates. Insect feeding damage on Cerrejón fossil leaves, representing primary consumers, is abundant, but also of low diversity, and overwhelmingly made by generalist feeders rather than specialized herbivores. Cerrejón megafossils provide strong evidence that the same Neotropical rainforest families have characterized the biome since the Paleocene, maintaining their importance through climatic phases warmer and cooler than present. The low diversity of both plants and herbivorous insects in this Paleocene Neotropical rainforest may reflect an early stage in the diversification of the lineages that inhabit this biome, and/or a long recovery period from the terminal Cretaceous extinction.

COVID-19 lockdown and housing deprivation across European countries.

Housing deprivation is a key determinant of the capacity to prevent infection and to recover from a disease because poor housing prevents adequate sheltering during a quarantine. We analyze the degree of housing deprivation faced by households in European countries when COVID-19 lockdown measures were enacted. To do so, we propose a synthetic measure that includes more dimensions than the official Eurostat indicator of severe housing deprivation. We use a fuzzy set approach to measure housing deprivation so that, unlike traditional deprivation approaches, based on a dichotomous variable, we can identify different degrees of housing deprivation for each household in the population. We find similar orderings of housing deprivation dimensions by country with the highest degree of deprivation in the living space dimension and the lowest one in the standard housing or technology deprivation dimension. Nonetheless, housing deprivation levels differ across countries, with Eastern European households being significantly more housing deprived than the rest when the lockdown began. This result shows that the effects of the lockdown on social well-being have not affected all Europeans equally and emphasizes the need for government measures that promote decent housing.

Analysis of the Oral Microbiome in a Patient with Cardiofaciocutaneous Syndrome and Severe Periodontal Disease: Impact of Systemic Antibiotic Therapy.

An 8-year-old girl diagnosed with cardiofaciocutaneous syndrome presented to our department with gingival pain, inflammation, and bleeding. Her medical history included hypoplasia of the corpus callosum, intellectual disability, trichothiodystrophy, global developmental delay, myopia, laryngomalacia, hypothyroidism, and osteoporosis. A diagnosis was reached of "periodontitis as a direct manifestation of systemic diseases". During 9 years of follow-up, there were exacerbation episodes with spontaneous gum bleeding, ulcers in the interdental papilla, tooth mobility, and progressive tooth loss. Some of these exacerbation episodes resolved clinically with the administration of amoxicillin and metronidazole. We therefore proposed an oral microbiome study (subgingival and saliva samples) before and after antibiotic therapy. The most abundant genera at the subgingival level before administering antibiotics were Prevotella, Streptococcus, Fusobacterium, Leptotrichia, and Aggregatibacter. Of the 94 genera sequenced, 57 were less abundant in the post-treatment state than at baseline, particularly certain Gram-negative periodontal pathogens such as Porphyromonas, Treponema, Aggregatibacter, Fusobacterium, and Campylobacter. In contrast, other genera related to oral health, such as Haemophilus, Granulicatella, and Abiotrophia, showed an increase after administering the antibiotic. In conclusion, periodontitis exacerbations as a direct manifestation of systemic disease can occasionally be controlled exclusively with systemic antibiotics, without the need for performing mechanical periodontal therapy. This clinical recovery is correlated to substantial changes in the oral microbiome, which lead to the recovery of eubiosis of the microbiota.

Challenges in translating interview protocols for alleged child victims of sexual abuse to different languages: A case study.

Adequate interviewing of alleged victims of child sexual abuse is critical for the investigation and for preserving the welfare of the child. Investigative interview protocols for children (IIPCs) have been developed to meet this twofold purpose. This article focuses on one previously unexplored issue related to applicability of IIPCs: how well they translate into other languages. This case study provides an in-depth analysis of an example of the translation of an IIPC to a new language and its adaptation to a particular cultural setting. Using an interpretive description approach and a mixed-method, stages and outputs of the adaptation process are described, as well as the amount, type and nature of difficulties in translation that were identified and corrected across the process. The main threats to translation equivalence arose from differences among languages, but also from cultural and contextual differences. Prompts to children and interviewers within the protocol presented different translation challenges. Consultation with experts and the protocol's advisors, along with team discussions, were beneficial in identifying and solving translation issues. Typical translation issues and practical recommendations on how to translate and culturally adapt IIPCs effectively are discussed.

Acrilamida en los alimentos: Valores de referencia, recomendaciones y acciones de mitigación

RESUMEN Diversas agencias internacionales han considerado que la acrilamida puede producir efectos dañinos en la salud de la población debido a una serie de estudios toxicológicos realizados en modelos animales, en los cuales se observan efectos cancerígenos, genotóxicos, neurotóxicos, inmunológicos y en la salud reproductiva. A pesar de la creciente preocupación en diversos países sobre los potenciales efectos en salud humana, los organismos encargados de determinar límites toxicológicos no han definido aún los límites máximos de acrilamida que pueden estar presente en los diferentes tipos de alimentos para que sean inocuos para la población. El objetivo de esta actualización es revisar las regulaciones existentes sobre la acrilamida y enfatizar la necesidad de establecer límites que la industria alimentaria pueda aplicar efectivamente, además de la necesidad de contar con valores máximos diarios tolerables para prevenir los efectos nocivos para la salud de la población.

ABSTRACT Several international agencies have considered that acrylamide can induce deleterious effects in human health due to a series of toxicological studies conducted in animal models, in which carcinogenic, genotoxic, neurotoxic, immunological and reproductive effects have been observed. Despite a growing concern about these effects on human health, agencies responsible for determining toxicological limits in various countries have not yet defined the maximum levels of acrylamide that may be present in the different types of food to be safe for the population. The objective of this updated review is to evaluate the existing regulations on acrylamide and emphasize the need to establish limits that the food industry can effectively apply, in addition to the need to have tolerable daily maximum values to prevent harmful effects on the population health.

Patterns and Trends in Scientific Research on Generic Drugs.

PURPOSE: The purpose of this study to investigate the evolution and current status of peer-reviewed publications concerning generic drugs during the past few decades. METHODS: Scientific articles about generic drugs published until 2012 were retrieved through the PubMed/MEDLINE database, and a content analysis was performed. FINDINGS: Our study revealed an increasing number of publications on generics since 1984. Statins, antiretroviral therapies, and antiepileptics, followed by immunosuppressants and antithrombotic agents, were the most common therapeutic drug categories. IMPLICATIONS: Almost 60% of the generics detailed in studies indexed in MEDLINE were acting on the cardiovascular system as anti-infectives and on the nervous system, which is not surprising considering the leading causes of death and disability worldwide.

QRS distortion in pre-reperfusion electrocardiogram is a bedside predictor of large myocardium at risk and infarct size (a METOCARD-CNIC trial substudy).

BACKGROUND: QRS distortion is an electrocardiographic (ECG) sign of severe ongoing ischemia in the setting of ST-segment elevation acute myocardial infarction (STEMI). We sought to evaluate the association between the degree of QRS distortion and myocardium at risk and final infarct size, measured by cardiac magnetic resonance (CMR). METHODS: A total of 174 patients with a first anterior STEMI reperfused by primary angioplasty were prospectively recruited. Pre-reperfusion ECG was used to divide the study population into three groups according to the absence of QRS distortion (D0) or its presence in a single lead (D1) or in 2 or more contiguous leads (D2+). Myocardium at risk and infarct size were determined by CMR one week after STEMI. Multiple regression analysis was used to study the association of QRS distortion with myocardium at risk and infarct size, with adjustment for relevant clinical and ECG variables. RESULTS: 101 patients (58%) were in group D0, 30 (17%) in group D1, and 43 (25%) in group D2+. Compared with group D0, presence of QRS distortion (groups D2+ and D1) was associated with a significantly adjusted larger extent of myocardium at risk (group D2+: absolute increase 10.4%, 95% CI 6.1-14.8%, p<0.001; group D1: absolute increase 3.3%, 95% CI 1.3-7.9%, p=0.157) and larger infarct size (group D2+: absolute increase 10.1%, 95% CI 5.5-14.7%, p<0.001; group D1: absolute increase 4.9%, 95% CI 0.08-9.8%, p=0.046). CONCLUSIONS: Distortion in the terminal portion of the QRS complex on pre-reperfusion ECG in two or more leads is independently associated with larger myocardium at risk and infarct size in the setting of primary angioplasty-reperfused anterior STEMI. QRS distortion in only one lead is independently associated with larger infarct size in this setting. Our findings suggest that QRS distortion analysis could be included in risk-stratification of patients presenting with anterior STEMI.

An Abnormal Nitric Oxide Metabolism Contributes to Brain Oxidative Stress in the Mouse Model for the Fragile X Syndrome, a Possible Role in Intellectual Disability.

BACKGROUND: Fragile X syndrome is the most common genetic cause of mental disability. Although many research has been performed, the mechanism underlying the pathogenesis is unclear and needs further investigation. Oxidative stress played major roles in the syndrome. The aim was to investigate the nitric oxide metabolism, protein nitration level, the expression of NOS isoforms, and furthermore the activation of the nuclear factor NF-κB-p65 subunit in different brain areas on the fragile X mouse model. METHODS: This study involved adult male Fmr1-knockout and wild-type mice as controls. We detected nitric oxide metabolism and the activation of the nuclear factor NF-κBp65 subunit, comparing the mRNA expression and protein content of the three NOS isoforms in different brain areas. RESULTS: Fmr1-KO mice showed an abnormal nitric oxide metabolism and increased levels of protein tyrosine nitrosylation. Besides that, nuclear factor NF-κB-p65 and inducible nitric oxide synthase appeared significantly increased in the Fmr1-knockout mice. mRNA and protein levels of the neuronal nitric oxide synthase appeared significantly decreased in the knockout mice. However, the epithelial nitric oxide synthase isoform displayed no significant changes. CONCLUSIONS: These data suggest the potential involvement of an abnormal nitric oxide metabolism in the pathogenesis of the fragile X syndrome.