Artificial neural networks reveal sex differences in gene methylation, and connections between maternal risk factors and symptom severity in autism spectrum disorder.

Aim and methods: Artificial neural networks were used to unravel connections among blood gene methylation levels, sex, maternal risk factors and symptom severity evaluated using the Autism Diagnostic Observation Schedule 2 (ADOS-2) score in 58 children with autism spectrum disorder (ASD). Results: Methylation levels of MECP2, HTR1A and OXTR genes were connected to females, and those of EN2, BCL2 and RELN genes to males. High gestational weight gain, lack of folic acid supplements, advanced maternal age, preterm birth, low birthweight and living in rural context were the best predictors of a high ADOS-2 score. Conclusion: Artificial neural networks revealed links among ASD maternal risk factors, symptom severity, gene methylation levels and sex differences in methylation that warrant further investigation in ASD.

Nutrition and Autism Spectrum Disorder: Between False Myths and Real Research-Based Opportunities.

Autism Spectrum Disorder (ASD) is a multicomplex disorder characterized by an umbrella of specific issues in the areas of social communication, restricted interests, and repetitive behaviors [...].

Communication improvement reduces BPSD: a music therapy study based on artificial neural networks.

BACKGROUND: Literature showed the effects of music therapy on behavioral disturbances, cognitive functions, and on quality of life in people with dementia. Especially, relational active music therapy approach is oriented to reduce behavioral disturbances increasing communication, especially non-verbal communication. OBJECTIVE: This study aimed at exploring the connection between the baseline characteristics of responders and the positive outcome of the intervention, but also the close relationship between the behavioral disturbances and the core of the therapeutic intervention (the relationship/communication improvement). METHOD: Linear correlation index between input variables and the presence of a critical improvement of behavioral symptoms according Neuropsychiatric Inventory and a semantic connectivity map were used to determine, respectively, variables predictive of the response and complex connections between clinical variables and the relational nature of active music therapy intervention. The dataset was composed of 27 variables and 70 patients with a moderate-severe stage of dementia and behavioral disturbances. RESULTS: The main predictive factor is the Barthel Index, followed by NPI and some of its sub-items (mainly, Disinhibition, Depression, Hallucinations, Irritability, Aberrant Motor Activity, and Agitation). Moreover, the semantic map underlines how the improvement in communication/relationship is directly linked to "responder" variable. "Responder" variable is also connected to "age," "Mini Mental State Examination," and sex ("female"). CONCLUSIONS: The study confirms the appropriateness of active music therapy in the reduction of behavioral disturbances and also highlights how unsupervised artificial neural networks models can support clinical practice in defining predictive factors and exploring the correlation between characteristics of therapeutic-rehabilitative interventions and related outcomes.

Impact of delivery mode on the colostrum microbiota composition.

BACKGROUND: Breast milk is a rich nutrient with a temporally dynamic nature. In particular, numerous alterations in the nutritional, immunological and microbiological content occur during the transition from colostrum to mature milk. The objective of our study was to evaluate the potential impact of delivery mode on the microbiota of colostrum, at both the quantitative and qualitative levels (bacterial abundance and microbiota network). METHODS: Twenty-nine Italian mothers (15 vaginal deliveries vs 14 Cesarean sections) were enrolled in the study. The microbiota of colostrum samples was analyzed by next generation sequencing (Ion Torrent Personal Genome Machine). The colostrum microbiota network associated with Cesarean section and vaginal delivery was evaluated by means of the Auto Contractive Map (AutoCM), a mathematical methodology based on Artificial Neural Network (ANN) architecture. RESULTS: Numerous differences between Cesarean section and vaginal delivery colostrum were observed. Vaginal delivery colostrum had a significant lower abundance of Pseudomonas spp., Staphylococcus spp. and Prevotella spp. when compared to Cesarean section colostrum samples. Furthermore, the mode of delivery had a strong influence on the microbiota network, as Cesarean section colostrum showed a higher number of bacterial hubs if compared to vaginal delivery, sharing only 5 hubs. Interestingly, the colostrum of mothers who had a Cesarean section was richer in environmental bacteria than mothers who underwent vaginal delivery. Finally, both Cesarean section and vaginal delivery colostrum contained a greater number of anaerobic bacteria genera. CONCLUSIONS: The mode of delivery had a large impact on the microbiota composition of colostrum. Further studies are needed to better define the meaning of the differences we observed between Cesarean section and vaginal delivery colostrum microbiota.

Effects of Improvisational Music Therapy vs Enhanced Standard Care on Symptom Severity Among Children With Autism Spectrum Disorder: The TIME-A Randomized Clinical Trial.

Importance: Music therapy may facilitate skills in areas affected by autism spectrum disorder (ASD), such as social interaction and communication. Objective: To evaluate effects of improvisational music therapy on generalized social communication skills of children with ASD. Design, Setting, and Participants: Assessor-blinded, randomized clinical trial, conducted in 9 countries and enrolling children aged 4 to 7 years with ASD. Children were recruited from November 2011 to November 2015, with follow-up between January 2012 and November 2016. Interventions: Enhanced standard care (n = 182) vs enhanced standard care plus improvisational music therapy (n = 182), allocated in a 1:1 ratio. Enhanced standard care consisted of usual care as locally available plus parent counseling to discuss parents' concerns and provide information about ASD. In improvisational music therapy, trained music therapists sang or played music with each child, attuned and adapted to the child's focus of attention, to help children develop affect sharing and joint attention. Main Outcomes and Measures: The primary outcome was symptom severity over 5 months, based on the Autism Diagnostic Observation Schedule (ADOS), social affect domain (range, 0-27; higher scores indicate greater severity; minimal clinically important difference, 1). Prespecified secondary outcomes included parent-rated social responsiveness. All outcomes were also assessed at 2 and 12 months. Results: Among 364 participants randomized (mean age, 5.4 years; 83% boys), 314 (86%) completed the primary end point and 290 (80%) completed the last end point. Over 5 months, participants assigned to music therapy received a median of 19 music therapy, 3 parent counseling, and 36 other therapy sessions, compared with 3 parent counseling and 45 other therapy sessions for those assigned to enhanced standard care. From baseline to 5 months, mean ADOS social affect scores estimated by linear mixed-effects models decreased from 14.08 to 13.23 in the music therapy group and from 13.49 to 12.58 in the standard care group (mean difference, 0.06 [95% CI, -0.70 to 0.81]; P = .88), with no significant difference in improvement. Of 20 exploratory secondary outcomes, 17 showed no significant difference. Conclusions and Relevance: Among children with autism spectrum disorder, improvisational music therapy, compared with enhanced standard care, resulted in no significant difference in symptom severity based on the ADOS social affect domain over 5 months. These findings do not support the use of improvisational music therapy for symptom reduction in children with autism spectrum disorder. Trial Registration: isrctn.org Identifier: ISRCTN78923965.

Microbiota network and mathematic microbe mutualism in colostrum and mature milk collected in two different geographic areas: Italy versus Burundi.

Human milk is essential for the initial development of newborns, as it provides all nutrients and vitamins, such as vitamin D, and represents a great source of commensal bacteria. Here we explore the microbiota network of colostrum and mature milk of Italian and Burundian mothers using the auto contractive map (AutoCM), a new methodology based on artificial neural network (ANN) architecture. We were able to demonstrate the microbiota of human milk to be a dynamic, and complex, ecosystem with different bacterial networks among different populations containing diverse microbial hubs and central nodes, which change during the transition from colostrum to mature milk. Furthermore, a greater abundance of anaerobic intestinal bacteria in mature milk compared with colostrum samples has been observed. The association of complex mathematic systems such as ANN and AutoCM adopted to metagenomics analysis represents an innovative approach to investigate in detail specific bacterial interactions in biological samples.

Gut to brain interaction in Autism Spectrum Disorders: a randomized controlled trial on the role of probiotics on clinical, biochemical and neurophysiological parameters.

BACKGROUND: A high prevalence of a variety of gastrointestinal (GI) symptoms is frequently reported in patients with Autism Spectrum Disorders (ASD). The GI disturbances in ASD might be linked to gut dysbiosis representing the observable phenotype of a "gut-brain axis" disruption. The exploitation of strategies which can restore normal gut microbiota and reduce the gut production and absorption of toxins, such as probiotics addition/supplementation in a diet, may represent a non-pharmacological option in the treatment of GI disturbances in ASD. The aim of this randomized controlled trial is to determine the effects of supplementation with a probiotic mixture (Vivomixx®) in ASD children not only on specific GI symptoms, but also on the core deficits of the disorder, on cognitive and language development, and on brain function and connectivity. An ancillary aim is to evaluate possible effects of probiotic supplementation on urinary concentrations of phthalates (chemical pollutants) which have been previously linked to ASD. METHODS: A group of 100 preschoolers with ASD will be classified as belonging to a GI group or to a Non-GI (NGI) group on the basis of a symptom severity index specific to GI disorders. In order to obtain four arms, subjects belonging to the two groups (GI and NGI) will be blind randomized 1:1 to regular diet with probiotics or with placebo for 6 months. All participants will be assessed at baseline, after three months and after six months from baseline in order to evaluate the possible changes in: (1) GI symptoms; (2) autism symptoms severity; (3) affective and behavioral comorbid symptoms; (4) plasmatic, urinary and fecal biomarkers related to abnormal intestinal function; (5) neurophysiological patterns. DISCUSSION: The effects of treatments with probiotics on children with ASD need to be evaluated through rigorous controlled trials. Examining the impact of probiotics not only on clinical but also on neurophysiological patterns, the current trial sets out to provide new insights into the gut-brain connection in ASD patients. Moreover, results could add information to the relationship between phthalates levels, clinical features and neurophysiological patterns in ASD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02708901 . Retrospectively registered: March 4, 2016.

Long-Term Treatment with High-Dose Thiamine in Parkinson Disease: An Open-Label Pilot Study.

OBJECTIVES: To investigate the potential clinical, restorative, and neuroprotective effects of long-term treatment with thiamine in Parkinson disease (PD). DESIGN: Observational open-label pilot study. SETTING: Outpatient neurologic rehabilitation clinic. PATIENTS AND METHODS: Starting in June 2012, we have recruited 50 patients with PD (33 men and 17 women; mean age, 70.4 ± 12.9 years; mean disease duration, 7.3 ± 6.7 years). All the patients were assessed at baseline with the Unified Parkinson's Disease Rating Scale (UPDRS) and the Fatigue Severity Scale (FSS) and began treatment with 100 mg of thiamine administered intramuscularly twice a week, without any change to personal therapy. All the patients were re-evaluated after 1 month and then every 3 months during treatment. RESULTS: Thiamine treatment led to significant improvement of motor and nonmotor symptoms: mean UPDRS scores (parts I-IV) improved from 38.55 ± 15.24 to 18.16 ± 15.08 (p = 2.4 × 10(-14), t test for paired data) within 3 months and remained stable over time; motor UPDRS part III score improved from 22.01 ± 8.57 to 9.92 ± 8.66 (p = 3.1 × 10(-22)). Some patients with a milder phenotype had complete clinical recovery. FSS scores, in six patients who had fatigue, improved from 53.00 ± 8.17 to 23.60 ± 7.77 (p < 0.0001, t test for paired data). Follow-up duration ranged from 95 to 831 days (mean, 291.6 ± 207.2 days). CONCLUSIONS: Administration of parenteral high-dose thiamine was effective in reversing PD motor and nonmotor symptoms. The clinical improvement was stable over time in all the patients. From our clinical evidence, we hypothesize that a dysfunction of thiamine-dependent metabolic processes could cause selective neural damage in the centers typically affected by this disease and might be a fundamental molecular event provoking neurodegeneration. Thiamine could have both restorative and neuroprotective action in PD.

Effects of a diet integration with an oily emulsion of DHA-phospholipids containing melatonin and tryptophan in elderly patients suffering from mild cognitive impairment.

Age-related changes in nutritional status can play an important role in brain functioning. Specific nutrient deficiencies in the elderly may exacerbate pathological processes in the brain. Consequently, the potential of nutritional intervention to prevent or delay cognitive impairment and the development of dementia is an important topic. A randomized, double-blind, placebo-controlled trial has been performed in 25 elderly subjects (86 ± 6 years, 20 females, 5 males) with mild cognitive impairment (MCI). These subjects were randomly assigned to supplement their diet with either an oily emulsion of docosahexaenoic acid (DHA)-phospholipids containing melatonin and tryptophan (11 subjects) or a placebo (14-matched subjects) for 12 weeks. The main aim of this study was to evaluate the efficacy of the dietary supplement on cognition, by the assessment at the start and after 12 weeks of: (1) Orientation and other cognitive functions: Mini-Mental State Examination (MMSE); (2) Short-term memory: digit, verbal, and spatial span (digit span; verbal span; Corsi's test); (3) Long-term memory: Rey's auditory-verbal learning test; 'short story' test; Rey-Osterrieth complex figure (recall); (4) Attentional abilities: attentive matrices; (5) Executive functions: Weigl's sorting test; phonological fluency 'FAS'; (6) Visuo-constructional and visuo-spatial abilities: copy of simple drawings; Rey-Osterrieth complex figure (copy); (7) Language: semantic fluency; (8) Mood: Geriatric Depression Scale (GDS). Moreover, Sniffin' Sticks olfaction test and Mini Nutritional Assessment (MNA) have been performed. After 12 weeks, a significant treatment effect for the MMSE (P < 0.001) and a positive trend for the semantic verbal fluency was found in the supplement group (P < 0.06). A significant treatment effect was found out for the olfactory sensitivity assessment (P < 0.009). As regards the nutrition evaluation, after 12 weeks of treatment the supplemented group showed an improvement in the MNA score with a significant difference relative to placebo (P < 0.005). Older adults with MCI had significant improvements in several measures of cognitive function when supplemented with an oily emulsion of DHA-phospholipids containing melatonin and tryptophan for 12 weeks, compared with the placebo.

Gastroesophageal reflux disease management according to contemporary international guidelines: a translational study.

AIM: To test the Genval recommendations and the usefulness of a short trial of proton pump inhibitor (PPI) in the initial management and maintenance treatment of gastroesophageal reflux disease (GERD) patients. METHODS: Five hundred and seventy seven patients with heartburn were recruited. After completing a psychometric tool to assess quality of life (PGWBI) and a previously validated GERD symptom questionnaire (QUID), patients were grouped into those with esophagitis (EE, n = 306) or without mucosal damage (NERD, n = 271) according to endoscopy results. The study started with a 2-wk period of high dose omeprazole (omeprazole test); patients responding to this PPI test entered an acute phase (3 mo) of treatment with any PPI at the standard dose. Finally, those patients with a favorable response to the standard PPI dose were maintained on a half PPI dose for a further 3-mo period. RESULTS: The test was positive in 519 (89.9%) patients, with a greater response in EE patients (96.4%) compared with NERD patients (82.6%) (P = 0.011). Both the percentage of completely asymptomatic patients, at 3 and 6 mo, and the reduction in heartburn intensity were significantly higher in the EE compared with NERD patients (P < 0.01). Finally, the mean PGWBI score was significantly decreased before and increased after therapy in both subgroups when compared with the mean value in a reference Italian population. CONCLUSION: Our study confirms the validity of the Genval guidelines in the management of GERD patients. In addition, we observed that the overall response to PPI therapy is lower in NERD compared to EE patients.

Artificial Adaptive Systems and predictive medicine: a revolutionary paradigm shift.

An individual patient is not the average representative of the population. Rather he or she is a person with unique characteristics. An intervention may be effective for a population but not necessarily for the individual patient. The recommendation of a guideline may not be right for a particular patient because it is not what he or she wants, and implementing the recommendation will not necessarily mean a favourable outcome.The author will describe a reconfiguration of medical thought which originates from non linear dynamics and chaos theory. The coupling of computer science and these new theoretical bases coming from complex systems mathematics allows the creation of "intelligent" agents able to adapt themselves dynamically to problem of high complexity: the Artificial Adaptive Systems, which include Artificial Neural Networks( ANNs ) and Evolutionary Algorithms ( EA).ANNs and EA are able to reproduce the dynamical interaction of multiple factors simultaneously, allowing the study of complexity; they can also help medical doctors in making decisions under extreme uncertainty and to draw conclusions on individual basis and not as average trends. These tools can allow a more efficient Technology Transfer from the Science of Medicine to the Real World overcoming many obstacles responsible for the present translational failure. They also contribute to a new holistic vision of the human subject contrasting the statistical reductionism which tends to squeeze or even delete the single subject sacrificing him to his group of belongingness. A remarkable contribution to this individual approach comes from Fuzzy Logic, according to which there are no sharp limits between opposite things, like health and disease. This approach allows to partially escape from probability theory trap in situations where is fundamental to express a judgment based on a single case and favours a novel humanism directed to the management of the patient as individual subject.

Treatment of periocular wrinkles with topical nifedipine.

The appearance of facial expression wrinkles is the result of chronic contraction of mimic muscles. Nifedipine is a dihydropyridinic calcium antagonist which blocks muscular cells' calcium channels, therefore inhibiting their contraction. We assumed that topical nifedipine was able to relax mimic muscular fibres in the same way, thus reducing the depth of wrinkles. We performed a clinical and experimental study, enrolling 64 female patients with periocular wrinkles. They applied a cream containing 0.5% nifedipine (Antrox; Bracco, Milan, Italy) once daily for 90 days. The length and depth of wrinkles (measured by a digital profilometer), moisturizing of periocular skin (measured by a corneometer), and trans-epidermal water loss (TEWL; measured by a tewameter), were evaluated. All parameters were measured before the beginning of treatment, and 45 and 90 days later. At the end of the study, topical nifedipine proved statistically effective in reducing the depth of wrinkles. No significant differences in the length of wrinkles were recorded. No significant changes were observed in moisturizing. TEWL gradually improved, although without statistical significance. On the basis of the results of this study, 0.5% nifedipine cream seems to be effective in reducing the depth of periocular wrinkles. Other studies are necessary in order to confirm these results.

Technology transfer from the science of medicine to the real world: the potential role played by artificial adaptive systems.

The author describes a refiguration of medical thought that originates from nonlinear dynamics and chaos theory. The coupling of computer science and these new theoretical bases coming from complex systems mathematics allows the creation of "intelligent" agents capable of adapting themselves dynamically to problems of high complexity: the artificial neural networks (ANNs). ANNs are able to reproduce the dynamic interaction of multiple factors simultaneously, allowing the study of complexity; they can also draw conclusions on an individual basis and not as average trends. These tools can allow a more efficient technology transfer from the science of medicine to the real world, overcoming many obstacles responsible for the present translational failure. They also contribute to a new holistic vision of the human subject person, contrasting the statistical reductionism that tends to squeeze or even delete the single subject, sacrificing him to his group of belongingness. A remarkable contribution to this individual approach comes from fuzzy logic, according to which there are no sharp limits between opposite things, such as wealth and disease. This approach allows one to partially escape from the probability theory trap in situations where it is fundamental to express a judgement based on a single case and favor a novel humanism directed to the management of the patient as an individual subject person.