Altered gut microbiome diversity and function in patients with propionic acidemia.

Propionic acidemia (PA) is an inherited metabolic disorder of propionate metabolism, where the gut microbiota may play a role in pathophysiology and therefore, represent a relevant therapeutic target. Little is known about the gut microbiota composition and activity in patients with PA. Although clinical practice varies between metabolic treatment centers, management of PA requires combined dietary and pharmaceutical treatments, both known to affect the gut microbiota. This study aimed to characterize the gut microbiota and its metabolites in fecal samples of patients with PA compared with healthy controls from the same household. Eight patients (aged 3-14y) and 8 controls (4-31y) were recruited from Center 1 (UK) and 7 patients (11-33y) and 6 controls (15-54y) from Center 2 (Austria). Stool samples were collected 4 times over 3 months, alongside data on dietary intakes and medication usage. Several microbial taxa differed between patients with PA and controls, particularly for Center 1, e.g., Proteobacteria levels were increased, whereas butyrate-producing genera, such as Roseburia and Faecalibacterium, were decreased. Most measured microbial metabolites were lower in patients with PA, and butyrate was particularly depleted in patients from Center 1. Furthermore, microbiota profile of these patients showed the lowest compositional and functional diversity, and lowest stability over 3 months. As the first study to map the gut microbiota of patients with PA, this work represents an important step forward for developing new therapeutic strategies to further improve PA clinical status. New dietary strategies should consider microbial propionate production as well as butyrate production and microbiota stability.

Protein Substitute Requirements of Patients with Phenylketonuria on BH4 Treatment: A Systematic Review and Meta-Analysis.

The traditional treatment for phenylketonuria (PKU) is a phenylalanine (Phe)-restricted diet, supplemented with a Phe-free/low-Phe protein substitute. Pharmaceutical treatment with synthetic tetrahydrobiopterin (BH4), an enzyme cofactor, allows a patient subgroup to relax their diet. However, dietary protocols guiding the adjustments of protein equivalent intake from protein substitute with BH4 treatment are lacking. We systematically reviewed protein substitute usage with long-term BH4 therapy. Electronic databases were searched for articles published between January 2000 and March 2020. Eighteen studies (306 PKU patients) were eligible. Meta-analyses demonstrated a significant increase in Phe and natural protein intakes and a significant decrease in protein equivalent intake from protein substitute with cofactor therapy. Protein substitute could be discontinued in 51% of responsive patients, but was still required in 49%, despite improvement in Phe tolerance. Normal growth was maintained, but micronutrient deficiency was observed with BH4 treatment. A systematic protocol to increase natural protein intake while reducing protein substitute dose should be followed to ensure protein and micronutrient requirements are met and sustained. We propose recommendations to guide healthcare professionals when adjusting dietary prescriptions of PKU patients on BH4. Studies investigating new therapeutic options in PKU should systematically collect data on protein substitute and natural protein intakes, as well as other nutritional factors.

Long-term dietary intervention with low Phe and/or a specific nutrient combination improve certain aspects of brain functioning in phenylketonuria (PKU).

INTRODUCTION: In phenylketonuria (PKU), a gene mutation in the phenylalanine metabolic pathway causes accumulation of phenylalanine (Phe) in blood and brain. Although early introduction of a Phe-restricted diet can prevent severe symptoms from developing, patients who are diagnosed and treated early still experience deficits in cognitive functioning indicating shortcomings of current treatment. In the search for new and/or additional treatment strategies, a specific nutrient combination (SNC) was postulated to improve brain function in PKU. In this study, a long-term dietary intervention with a low-Phe diet, a specific combination of nutrients designed to improve brain function, or both concepts together was investigated in male and female BTBR PKU and WT mice. MATERIAL & METHODS: 48 homozygous wild-types (WT, +/+) and 96 PKU BTBRPah2 (-/-) male and female mice received dietary interventions from postnatal day 31 till 10 months of age and were distributed in the following six groups: high Phe diet (WT C-HP, PKU C-HP), high Phe plus specific nutrient combination (WT SNC-HP, PKU SNC-HP), PKU low-Phe diet (PKU C-LP), and PKU low-Phe diet plus specific nutrient combination (PKU SNC- LP). Memory and motor function were tested at time points 3, 6, and 9 months after treatment initiation in the open field (OF), novel object recognition test (NOR), spatial object recognition test (SOR), and the balance beam (BB). At the end of the experiments, brain neurotransmitter concentrations were determined. RESULTS: In the NOR, we found that PKU mice, despite being subjected to high Phe conditions, could master the task on all three time points when supplemented with SNC. Under low Phe conditions, PKU mice on control diet could master the NOR at all three time points, while PKU mice on the SNC supplemented diet could master the task at time points 6 and 9 months. SNC supplementation did not consistently influence the performance in the OF, SOR or BB in PKU mice. The low Phe diet was able to normalize concentrations of norepinephrine and serotonin; however, these neurotransmitters were not influenced by SNC supplementation. CONCLUSION: This study demonstrates that both a long-lasting low Phe diet, the diet enriched with SNC, as well as the combined diet was able to ameliorate some, but not all of these PKU-induced abnormalities. Specifically, this study is the first long-term intervention study in BTBR PKU mice that shows that SNC supplementation can specifically improve novel object recognition.

Status of nutrients important in brain function in phenylketonuria: a systematic review and meta-analysis.

BACKGROUND: Despite early and ongoing dietary management with a phe-restricted diet, suboptimal neuropsychological function has been observed in PKU. The restrictive nature of the PKU diet may expose patients to sub-optimal nutritional intake and deficiencies which may impact normal brain function. A systematic review of the published literature was carried out, where possible with meta-analysis, to compare the status of nutrients (Nutrients: DHA, EPA phospholipids, selenium, vitamins B6, B12, E, C, A, D, folic acid, choline, uridine, calcium, magnesium, zinc, iron, iodine and cholesterol) known to be important for brain development and functioning between individuals with PKU and healthy controls. RESULTS: Of 1534 publications identified, 65 studies met the entry criteria. Significantly lower levels of DHA, EPA and cholesterol were found for PKU patients compared to healthy controls. No significant differences in zinc, vitamins B12, E and D, calcium, iron and magnesium were found between PKU patients and controls. Because of considerable heterogeneity, the meta-analyses findings for folate and selenium were not reported. Due to an insufficient number of publications (< 4) no meta-analysis was undertaken for vitamins A, C and B6, choline, uridine, iodine and phospholipids. CONCLUSIONS: The current data show that PKU patients have lower availability of DHA, EPA and cholesterol. Compliance with the phe-restricted diet including the micronutrient fortified protein substitute (PS) is essential to ensure adequate micronutrient status. Given the complexity of the diet, patients' micronutrient and fatty acid status should be continuously monitored, with a particular focus on patients who are non-compliant or poorly compliant with their PS. Given their key role in brain function, assessment of the status of nutrients where limited data was found (e.g. choline, iodine) should be undertaken. Standardised reporting of studies in PKU would strengthen the output of meta-analysis and so better inform best practice for this rare condition.

A Specific Nutrient Combination Attenuates the Reduced Expression of PSD-95 in the Proximal Dendrites of Hippocampal Cell Body Layers in a Mouse Model of Phenylketonuria.

The inherited metabolic disease phenylketonuria (PKU) is characterized by increased concentrations of phenylalanine in the blood and brain, and as a consequence neurotransmitter metabolism, white matter, and synapse functioning are affected. A specific nutrient combination (SNC) has been shown to improve synapse formation, morphology and function. This could become an interesting new nutritional approach for PKU. To assess whether treatment with SNC can affect synapses, we treated PKU mice with SNC or an isocaloric control diet and wild-type (WT) mice with an isocaloric control for 12 weeks, starting at postnatal day 31. Immunostaining for post-synaptic density protein 95 (PSD-95), a post-synaptic density marker, was carried out in the hippocampus, striatum and prefrontal cortex. Compared to WT mice on normal chow without SNC, PKU mice on the isocaloric control showed a significant reduction in PSD-95 expression in the hippocampus, specifically in the granular cell layer of the dentate gyrus, with a similar trend seen in the cornus ammonis 1 (CA1) and cornus ammonis 3 (CA3) pyramidal cell layer. No differences were found in the striatum or prefrontal cortex. PKU mice on a diet supplemented with SNC showed improved expression of PSD-95 in the hippocampus. This study gives the first indication that SNC supplementation has a positive effect on hippocampal synaptic deficits in PKU mice.

Effect of different incisor movements on the soft tissue profile measured in reference to a rough-surfaced palatal implant.

INTRODUCTION: The aim of this study was to evaluate soft tissue profile changes after a wide range of incisor movements in the anterior and posterior directions in nongrowing patients. Identifying baseline values more prone to substantial soft tissue profile changes was of high interest. METHODS: For this retrospective study, 47 pairs of lateral cephalograms of nongrowing white patients were superimposed. The cephalograms were taken with the same palatal implant in situ before and after treatment. To increase the accuracy of the measurements, the palatal implants were used as stable reference structures in close relation to the incisors. RESULTS: Horizontal changes of the most anterior point of the maxillary incisor showed a significant correlation to horizontal changes of the upper and lower lips (P <0.001). For every millimeter of horizontal change of the most anterior point of the maxillary central incisor, a change of 0.59 mm at labrale superior can be expected. Also, the angulations of the upper and lower lips were significantly correlated to the most anterior point of the maxillary incisor. Lip retraction was less pronounced in patients with initially thicker lips than in those with thinner lips. CONCLUSIONS: The major contributing factors for predicting the soft tissue profile change during orthodontic treatment are the amount of horizontal movement of the most anterior point of the maxillary incisor, the amount of bite opening, and the initial lip thickness. Although there are significant correlations between dental movements and soft tissue changes in larger samples, predictions for individuals may be inconsistent.

Non-invasive removal of sandblasted and acid-etched titanium palatal implants, a retrospective study.

BACKGROUND: Short, rough-surfaced palatal implants are an established and reliable anchor for orthodontic treatment. Until recently, removal was only possible surgically using a hollow cylinder trephine. This standard method retrieves the implant combined with a larger bone volume and is therefore considered invasive and has known complications. Lately, an explantation tool which allows a sufficient force application to break the bone-implant-connection and unscrew the palatal implant was developed and, since its introduction, has been used as the method of choice in several orthodontic offices. OBJECTIVES: The aim of this study was to assess the complications caused by removing rough-surfaced palatal implants simply by unscrewing them with an explantation tool in contrast to standard protocol by surgical removal with a trephine. MATERIAL AND METHODS: The removal of 73 palatal implants using a customized explantation tool has been evaluated retrospectively and was compared to an existing sample of 44 conventional surgical explantations. RESULTS: The new clinical procedure resulted in successful removal of 71 (97.3 per cent) palatal implants. In two cases, the new method failed but removal with the established surgical method was still possible with no further complications. The non-invasive palatal implant removal with a customized explantation tool had less medical complications compared to an existing sample of surgical explantations. CONCLUSIONS: User's opinion was that the new method is more easily executed, less invasive, and also applicable without local anaesthesia. Therefore, it is considered to be beneficial for patients and the treatment approach of choice. However, further research is needed for verification.

Noninvasive palatal implant removal.

OBJECTIVE: Orthodontic palatal implants are commonly used and do provide reliable absolute anchorage to assist orthodontic treatment. However, once treatment is completed, removal of these temporary implants is not considered easy or risk free. This short communication presents a clinical case in which a novel noninvasive procedure was applied to remove an osseointegrated palatal implant. MATERIAL AND METHODS: A customized explantation tool, tightly fixed to the implant and precisely grasping the implant's head, was used in combination with a ratchet to unscrew the implant instead of the traditional removal by trephine. RESULTS: Only a topical anesthetic was necessary before the implant-bone contact was broken by turning the ratchet counterclockwise. The implant was retrieved without any local anesthesia. The explanted palatal implant had no bone appending to it, except in its apical anti-rotational grooves, and the healing process thereafter was unproblematic. CONCLUSIONS: Noninvasive palatal implant removal offers a simple and fast approach for explantation. Moreover, it might reduce the risk of adverse patient reactions, iatrogenic tooth and nerve injuries, and possible oro-antral communications.

Nutritional status in community-dwelling elderly in France in urban and rural areas.

UNLABELLED: Malnutrition is a frequent condition in elderly people, especially in nursing homes and geriatric wards. Its frequency is less well known among elderly living at home. The objective of this study was to describe the nutritional status evaluated by the Mini Nutritional Assessment (MNA) of elderly community-dwellers living in rural and urban areas in France and to investigate its associated factors. METHODS: Subjects aged 65 years and over from the Approche Multidisciplinaire Intégrée (AMI) cohort (692 subjects living in a rural area) and the Three-City (3C) cohort (8,691 subjects living in three large urban zones) were included. A proxy version of the MNA was reconstructed using available data from the AMI cohort. Sensitivity and specificity were used to evaluate the agreement between the proxy version and the standard version in AMI. The proxy MNA was computed in both cohorts to evaluate the frequency of poor nutritional status. Factors associated with this state were investigated in each cohort separately. RESULTS: In the rural sample, 38.0% were females and the mean age was 75.5 years. In the urban sample, 60.3% were females and the mean age was 74.1 years. Among subjects in living in the rural sample, 7.4% were in poor nutritional status while the proportion was 18.5% in the urban sample. Female gender, older age, being widowed, a low educational level, low income, low body mass index, being demented, having a depressive symptomatology, a loss of autonomy and an intake of more than 3 drugs appeared to be independently associated with poor nutritional status. CONCLUSION: Poor nutritional status was commonly observed among elderly people living at home in both rural and urban areas. The associated factors should be further considered for targeting particularly vulnerable individuals.

Interactions between ω3 polyunsaturated fatty acids and arginine on nutritional and immunological aspects in severe inflammation.

BACKGROUND & AIMS: Immune-enhancing diets (IEDs) contain a mixture of nutrients claimed to have immunological properties. Therefore, it seemed relevant to determine the effect of each of their components. The aim of this study was to examine the role of arginine (Arg) and ω3 polyunsaturated fatty acids (ω3 PUFAs) in the effect of an IED (Crucial(®)) in a validated rat model of inflammation induced by turpentine (TI). METHODS: Forty-two rats were randomized into five groups: AL (ad libitum), TI-EN (TI+standard enteral nutrition (EN): Sondalis(®)HP), TI-EN-Arg (TI+standard EN+Arg in equimolar concentration to Arg in the IED), TI-M-IED (TI+modified IED containing the same ω6/ω3 ratio as in standard EN) and TI-IED (TI+Crucial(®)). Blood was sampled to determine CD25 receptor density on lymphocytes. TNF-α, IL-6 and NO (production and expression) were evaluated on isolated macrophages. Mesenteric lymph nodes, spleen and liver were cultured for analysis of enterobacterial translocation and dissemination. RESULTS: CD25 density was decreased after TI and was corrected in the TI-EN-Arg, TI-M-IED and TI-IED groups (p<0.05). TI induced an alteration of macrophage mRNA expression of IL-6, TNF-α and iNOS, corrected in the TI-EN-Arg and TI-M-IED groups (p<0.05), but not by the IED. Enterobacterial translocation was observed in all treated groups, nevertheless the amount tended (p=0.054) to be lower in the TI-EN-Arg group. CONCLUSIONS: Arg and ω3 PUFAs make a major contribution to IED effects, but our study shows interaction between them on macrophage reactivity. This indicates that the individual properties of each pharmaconutrient are not additive in IEDs.

Abrasion of eroded dentin caused by toothpaste slurries of different abrasivity and toothbrushes of different filament diameter.

OBJECTIVE: This study aimed to evaluate the impact of toothpaste slurry abrasivity and toothbrush filament diameter on abrasion of eroded dentin in vitro. METHODS: Eroded dentin samples (hydrochloric acid, pH 2.6, 15s) were brushed with 40 strokes in an automatic brushing machine using manual toothbrushes with different filament diameter (0.15, 0.20 or 0.25 mm). The toothbrushes were applied with a control slurry free of abrasive particles (RDA-value 10) or toothpastes slurries with different abrasivity (RDA-values 20, 50 or 100). Each erosive-abrasive cycle was followed by storage of the dentin samples in artificial saliva for 3h. After each 4 cycles, the samples were stored in artificial saliva for 15 h. After 60 cycles, dentin loss was measured by profilometry and statistically analysed by ANOVA and linear regression analysis. RESULTS: Dentin loss increased along with the RDA-value of the toothpaste slurries. The impact of the filament diameter on dentin loss was less evident compared to the RDA-value. However, toothbrushes with smaller filament stiffness caused higher dentin wear in all toothpaste slurry groups (RDA 20, 50 and 100) except for the paste-free control group (RDA 10). CONCLUSION: Abrasion of eroded dentin increased along with the RDA-value of the toothpaste slurry and with decreasing filament diameter of the toothbrush.

Tolerance and efficacy of a new enteral formula specifically designed for elderly persons: an experimental study in the aged rat.

For the first time, a formula was specifically designed for the nutritional support of tube-fed elderly patients (Elderly-Specific Formula [ESF], Nestlé, Switzerland). It was tested against a standard formula (Sondalis Iso [SI], Nestlé Clinical Nutrition, Marne la Vallée, France) in sixteen 22-month-old Sprague Dawley rats fed by total continuous enteral infusion for 7 days. Body weight, stool weight, and nitrogen balance were measured daily. After death, muscle weight, plasma levels of amino acids, tissue protein, and amino acid content were measured. The ESF curbed weight loss, improved cumulative nitrogen balance, and increased jejunum protein content. Plasma levels of threonine, leucine, and isoleucine and the sum of total amino acids were higher in ESF-fed than in SF-fed rats. Threonine and isoleucine content in the soleus and gastrocnemius were higher in ESF-fed rats than SI-fed ones. ESF improved intestinal transit. Thus, in old rats, the ESF favored nutritional status more than a standard formula.