Novel biallelic variants expand the SLC5A6-related phenotypic spectrum

The sodium (Na+):multivitamin transporter (SMVT), encoded by SLC5A6, belongs to the sodium:solute symporter family and is required for the Na+-dependent uptake of biotin (vitamin B7), pantothenic acid (vitamin B5), the vitamin-like substance α-lipoic acid, and iodide. Compound heterozygous SLC5A6 variants have been reported in individuals with variable multisystemic disorder, including failure to thrive, developmental delay, seizures, cerebral palsy, brain atrophy, gastrointestinal problems, immunodeficiency, and/or osteopenia. We expand the phenotypic spectrum associated with biallelic SLC5A6 variants affecting function by reporting five individuals from three families with motor neuropathies. We identified the homozygous variant c.1285 A > G [p.(Ser429Gly)] in three affected siblings and a simplex patient and the maternally inherited c.280 C > T [p.(Arg94*)] variant and the paternally inherited c.485 A > G [p.(Tyr162Cys)] variant in the simplex patient of the third family. Both missense variants were predicted to affect function by in silico tools. 3D homology modeling of the human SMVT revealed 13 transmembrane helices (TMs) and Tyr162 and Ser429 to be located at the cytoplasmic facing region of TM4 and within TM11, respectively. The SLC5A6 missense variants p.(Tyr162Cys) and p.(Ser429Gly) did not affect plasma membrane localization of the ectopically expressed multivitamin transporter suggesting reduced but not abolished function, such as lower catalytic activity. Targeted therapeutic intervention yielded clinical improvement in four of the five patients. Early molecular diagnosis by exome sequencing is essential for timely replacement therapy in affected individuals.

Non-parental caregivers, low maternal education, gastrointestinal problems and high blood lead level: predictors related to the severity of autism spectrum disorder in Northeast China

Background The prevalence of autism spectrum disorder (ASD) has increased rapidly in recent years. Environmental factors may play an important role in the pathogenesis of ASD. These factors may include socioeconomic factors, nutritional factors, heavy metal exposure, air pollution, etc. Our aim is to analyze possible environmental factors associated with the severity of ASD. Methods All participating children were divided into two groups (mild and moderate/severe) according to the severity of their symptoms, as determined by their Childhood Autism Rating Scale (CARS) scores. The socioeconomic, demographic factors and the nutritional factors that may affect the severity of ASD were included in the logistic regression to analyze whether they were predictors that affected the severity of ASD. Results Logistic regression showed that caregivers(P = 0.042), maternal education (P = 0.030), gastrointestinal problems (P = 0.041) and a high serum concentration of lead (P = 0.003) were statistically significantly associated with ASD severity. Conclusion Many environmental factors affect the severity of ASD. We concluded that non-parental caregivers, low maternal education, gastrointestinal problems and high blood lead level maybe predictors that affected the severity of ASD in northeast China.

Does improving indoor air quality lessen symptoms associated with chemical intolerance?

Aim: To determine whether environmental house calls that improved indoor air quality (IAQ) is effective in reducing symptoms of chemical intolerance (CI). Background: Prevalence of CI is increasing worldwide. Those affected typically report symptoms such as headaches, fatigue, ‘brain fog’, and gastrointestinal problems – common primary care complaints. Substantial evidence suggests that improving IAQ may be helpful in reducing symptoms associated with CI. Methods: Primary care clinic patients were invited to participate in a series of structured environmental house calls (EHCs). To qualify, participants were assessed for CI with the Quick Environmental Exposure and Sensitivity Inventory. Those with CI volunteered to allow the EHC team to visit their homes to collect air samples for volatile organic compounds (VOCs). Initial and post-intervention IAQ sampling was analyzed by an independent lab to determine VOC levels (ng/L). The team discussed indoor air exposures, their health effects, and provided guidance for reducing exposures. Findings: Homes where recommendations were followed showed the greatest improvements in IAQ. The improvements were based upon decreased airborne VOCs associated with reduced use of cleaning chemicals, personal care products, and fragrances, and reduction in the index patients’ symptoms. Symptom improvement generally was not reported among those whose homes showed no VOC improvement. Conclusion: Improvements in both IAQ and patients’ symptoms occur when families implement an action plan developed and shared with them by a trained EHC team. Indoor air problems simply are not part of most doctors’ differential diagnoses, despite relatively high prevalence rates of CI in primary care clinics. Our three-question screening questionnaire – the BREESI – can help physicians identify which patients should complete the QEESI. After identifying patients with CI, the practitioner can help by counseling them regarding their home exposures to VOCs. The future of clinical medicine could include environmental house calls as standard of practice for susceptible patients.

Disorders caused by contaminated fish meat consumption: Literature review / Doenças causadas por consume de carne de peixe contaminada: Revisão de literatura

Between 2007 and 2017, Brazil registered 99,826 outbreaks of foodborne diseases and 0.84% of those were associated with fish meat intake. It is estimated that approximately 56 million infection cases occur worldwide due to raw or undercooked fish meat containing several disease-causing parasites. Hence, this study aimed to review the literature concerning diseases caused by ingestion of contaminated fish meat. Reviews, case reports and epidemiologic studies were searched in Portuguese, Spanish and English in the databases LILACS, Pubmed, Science Direct, SciElo and Scholar Google using as keywords: transmissive diseases, contaminated fish and human infections were used to retrieve papers from 2014 to 2020. Nine papers, including seven reviews, one case report and one case-control study fulfilled inclusion criteria and presented several consequences of contaminated raw or undercooked fish meat ingestion, which ranged from nemathode, bacterial and toxin diseases that may cause gastrointestinal problems to allergic reactions, lung infection, endemic acute myalgia, bacteremia, meningitis and death. Growing fish meat intake in several dishes presents significant health risk due to the pathogenic potential of toxins and parasites that remain when food is consumed raw or undercooked. Tighter sanitary surveillance, population health education, training and sensitization of health professionals in recognizing and notifying cases might contribute to minimize risk.

Profiling the most elderly parkinson’s disease patients: Does age or disease duration matter?

Background Despite our ageing populations, elderly patients are underrepresented in clinical research, and ageing research is often separate from that of Parkinson’s disease (PD). To our knowledge, no previous study has focused on the most elderly (‘old-old’, age ≥ 85 years) patients with PD to reveal how age directly influences PD clinical progression. Objective We compared the clinical characteristics and pharmacological profiles, including complications of levodopa treatment, disease progression, disabilities, and comorbidities of the old-old with those of comparable younger (‘young-old’, age 60–75 years) PD patients. In addition, within the old-old group, we compared those with a short disease duration (< 10 years at the time of diagnosis) to those with a long disease duration ≥10 years to investigate whether prognosis was related to disease progression or aging. Methods This single-centre, case-control study compared 60 old-old to 92 young-old PD patients, matched for disease duration. Patients in the old-old group were also divided equally (30:30) into two subgroups (short and long disease duration) with the same mean age. We compared the groups based on several clinical measures using a conditional logistic regression. Results By study design, there were no differences between age groups when comparing disease duration, however, the proportion of men decreased with age (p = 0.002). At a comparable length of PD duration of 10 years, the old-old PD patients predominantly had significantly greater postural instability and gait disturbance (p = 0.006), higher motor scope of the Unified Parkinson’s Disease Rating Scale (UPDRS-III, p<0.0001), and more advanced Hoehn & Yahr (H&Y) stage (p<0.0001). The Non-Motor Symptoms Questionnaire (NMSQuest) score was also significantly higher among the old-old (p<0.0001) compared to the young-old patients. Moreover, the distribution of NMS also differed between ages, with features of gastrointestinal problems (p<0.0001), urinary problems (p = 0.004), sleep disturbances and fatigue (p = 0.032), and cognitive impairment (p<0.0001) significantly more common in the old-old group, whereas sexual problems (p = 0.012), depression, and anxiety (p = 0.032) were more common in the young-old. No differences were found in visual hallucinations, cerebrovascular disease, and miscellaneous domains. While young-old PD patients received higher levodopa equivalent daily doses (p<0.0001) and developed a significant greater rate of dyskinesia (p = 0.002), no significant difference was observed in the rate of wearing-off (p = 0.378). Old-old patients also had greater disability, as measured by the Schwab and England scale (p<0.0001) and had greater milestone frequency specifically for dementia (p<0.0001), wheelchair placement (p<0.0001), nursing home placement (p = 0.019), and hospitalisation in the past 1 year (p = 0.05). Neither recurrent falls (p = 0.443) nor visual hallucinations (p = 0.607) were documented significantly more often in the old-old patients. Conclusions Age and disease duration were independently associated with clinical presentation, course, and progression of PD. Age was the main predictor, but disease duration also had a strong effect, suggesting that factors of the ageing process beyond the disease process itself cause PD in the most elderly to be more severe.

The Brain-Gut-Microbiome System: Pathways and Implications for Autism Spectrum Disorder

Gastrointestinal dysfunction is one of the most prevalent physiological symptoms of autism spectrum disorder (ASD). A growing body of largely preclinical research suggests that dysbiotic gut microbiota may modulate brain function and social behavior, yet little is known about the mechanisms that underlie these relationships and how they may influence the pathogenesis or severity of ASD. While various genetic and environmental risk factors have been implicated in ASD, this review aims to provide an overview of studies elucidating the mechanisms by which gut microbiota, associated metabolites, and the brain interact to influence behavior and ASD development, in at least a subgroup of individuals with gastrointestinal problems. Specifically, we review the brain-gut-microbiome system and discuss findings from current animal and human studies as they relate to social-behavioral and neurological impairments in ASD, microbiota-targeted therapies (i.e., probiotics, fecal microbiota transplantation) in ASD, and how microbiota may influence the brain at molecular, structural, and functional levels, with a particular interest in social and emotion-related brain networks. A deeper understanding of microbiome-brain-behavior interactions has the potential to inform new therapies aimed at modulating this system and alleviating both behavioral and physiological symptomatology in individuals with ASD.

Enteric Coated Oral Delivery of Hydroxyapatite Nanoparticle for Modified Release Vitamin D3 Formulation

Vitamin D3 (VD) and calcium phosphate play a vital role in bone homeostasis. Factors such as obesity or gastrointestinal problems can render the use of pure VD and calcium phosphate supplements ineffective. This study investigated the possibility of using VD-loaded hydroxyapatite nanoparticles for the codelivery of VD and Ca3(PO4)2. Due to the high affinity of Ca3(PO4)2 for bone tissue, HA is an ideal delivery system to deliver VD to target tissue. Herein, HA nanoparticles were synthesized and loaded with VD using a vacuum evaporation method. The synthesized HA-VD nanoparticles were morphologically and chemically characterized by SEM, FTIR, and TGA. The system exhibited a two-stage release pattern, which includes a first-day burst release (35%) and sustained release for a further ten days. The cytocompatibility and cell penetrative ability of the nanoparticle system were assessed in vitro using preosteoblast cells: the system is nontoxic and well-tolerated. Finally, the VD-loaded HA nanoparticles were coated with a gastroresistant polymer, hypromellose phtalate-55 (HP-55) in order to protect the pH-sensitive HA from degradation at lower pHs. A coaxial electrospray technique was employed to achieve this. In all, the tested HA-VD system is a viable alternative for codelivery of VD, Ca2+, and PO43- to their target tissues.

Gastrointestinal concerns in children with autism spectrum disorder: A qualitative study of family experiences

Gastrointestinal distress is a prevalent issue in the autism spectrum disorder community, with implications for the person living with autism spectrum disorder and their families. However, the experiences of families caring for a child with co-occurring autism spectrum disorder and gastrointestinal symptoms have not been explored to date. We conducted one-on-one semi-structured interviews with 12 parents of children with co-occurring autism spectrum disorder and gastrointestinal symptoms. Using an inductive analysis approach, drawing on phenomenology, we identified four major themes across interviews. First, parents reported that their child had difficulty verbally communicating the presence of gastrointestinal symptoms, leading parents to rely on bodily signs and non-verbal behaviors to recognize when their child was experiencing gastrointestinal distress (Theme 1). Next, gastrointestinal issues impacted the child’s well-being and the ability to participate in and fully engage in activities (Theme 2), and the family’s well-being (Theme 3). Finally, parents often experienced challenges with seeking accessible and quality healthcare for their child’s gastrointestinal problems (Theme 4). These findings elucidate the incredible toll that gastrointestinal symptoms have on the overall wellness of children with autism spectrum disorder and their families. Lay abstract Gastrointestinal problems are common in the autism spectrum disorder community and may affect both the person with autism spectrum disorder and their families. However, little research is available on the experiences of families who have a child with both autism spectrum disorder and gastrointestinal symptoms. We held one-on-one interviews with 12 parents of children who had both autism spectrum disorder and gastrointestinal symptoms. We analyzed the raw text responses from these interviews and identified four main themes. First, parents shared that their children had trouble verbally communicating when they were experiencing gastrointestinal symptoms (Theme 1). This led parents to use bodily signs, such as changes in the stool, and non-verbal behaviors, such as irritability, to recognize when their child was having gastrointestinal symptoms. Next, gastrointestinal issues affected both the child’s well-being and their ability to attend class and extracurricular or social activities (Theme 2). The gastrointestinal issues also affected the family’s routines, overall well-being, and their ability to go out and do activities together as a family (Theme 3). Finally, parents often had challenges receiving accessible and quality healthcare for their child’s gastrointestinal problems (Theme 4). Together, these findings highlight the enormous burden that gastrointestinal symptoms have on the wellness of children with autism spectrum disorder and their families.

An In Vitro Approach to Studying the Microbial Community and Impact of Pre and Probiotics under Anorexia Nervosa Related Dietary Restrictions

Individuals with anorexia nervosa (AN) often suffer psychological and gastrointestinal problems consistent with a dysregulated gut microbial community. Psychobiotics have been postulated to modify microbiota and improve mental well-being and gut symptoms, but there is currently a lack of evidence for such approaches in AN. The aim of this study was to use an in vitro colonic model to evaluate the impact of dietary restrictions associated with AN on the intestinal ecosystem and to assess the impact of pre and probiotic intervention. Bacteriology was quantified using flow cytometry combined with fluorescence in situ hybridisation and metabolic end products (including neurotransmitters) by gas chromatography and liquid chromatography mass spectrometry Consistent with previous research, the nutritional changes significantly reduced total microbiota and metabolites compared with healthy conditions. Pre and probiotic supplementation on restricted conditions enhanced the microbial community and modulated metabolic activity to resemble that of a healthy diet. The model system indicates that nutritional changes associated with AN can impact the microbial community, and that these changes can, at least in part, be restored through the use of pre and probiotic interventions.

α-Amylase Inhibitory Activity of Catunaregam spinosa (Thunb.) Tirveng.: In Vitro and In Silico Studies

α-Amylase is an enzyme involved in the breaking down of large insoluble starch molecules into smaller soluble glucose molecules. Catunaregam spinosa (Thunb.) Tirveng. (syn. Randia dumetorum (Retz.) Lam., Family: Rubiaceace) has been used as traditional medicine for the treatment of gastrointestinal problems, skin diseases, and diabetes. In this context, we studied the in vitro α-amylase inhibiting properties of methanol extracts of leaves and bark of C. spinosa. The methanol extract of bark was further fractionated into hexane, dichloromethane and ethyl acetate, and water-soluble fractions, and their α-amylase inhibitory activity was evaluated. In silico molecular docking and ADMET analysis of several compounds previously reported from the bark of C. spinosa were also performed. The in vitro α-amylase inhibition activity assay of the dichloromethane fraction of extract of bark (IC50: 77.17 ± 1.75 μg/mL) was more potent as compared to hexane and ethyl acetate fractions. The in silico molecular docking study showed that previously reported compounds from the stem bark such as balanophonin, catunaregin, β-sitosterol, and medioresinol were bounded well with the active catalytic residue of porcine pancreatic α-amylase indicating better inhibition. The ADMET analysis showed the possible drug-likeness and structure-activity relationship of selected compounds. These compounds should be studied further for their potential α-amylase inhibition in animal models.