Adults with PKU and brain damage : Composition and management of a protein restricted diet

Summary Phenylketonuria (PKU) is an inborn error of metabolism, due to a defective liver enzyme the conversion of the amino acid phenylalanine (phe) to tyrosine is not functioning. PKU was first described in 1934 by the Norwegian doctor and scientist Asbjørn Følling. Without treatment persons with PKU suffer permanent neurological damage and mental retardation. Today newborn screening programmes result in early diagnosis. Dietary treatment is started shortly after birth to prevent brain damage. The intake of phe is restricted by allowing only small amounts of protein in the diet. Requirements are met by taking a protein substitute containing amino acids, vitamins and minerals. Special low protein food secure energy requirement. For a person with brain damage due to late diagnosed PKU, dietary treatment may ease neurological and behavioural signs. Positive effects are reported for a majority of late diagnosed patients after treatment start. Literature on how these persons and their caregivers translate the advice and prescriptions from doctors and dietitians into an everyday diet is lacking. The objective of the present study was to analyse the composition of dietary intake and describe how adults with PKU and brain damage manage the diet. Methods: An observational cross-sectional study was performed on 21 subjects with brain damage and adhering to a PKU diet: 8 men, 13 women; 26 – 66 years of age. Seven mildly retarded subjects living independently constituted group A. Group B consisted of fourteen severely retarded subjects needing continuous support and living in group homes. Data were collected by a four-day weighed food registration, a semistructured interview, blood samples and hospital charts. Descriptive statistics were used in analysing. Results: Serum phe was lowered by the diet to a median 472µmol/L. Median intake of selected nutrient: 1.02 g/kg protein (substitute and natural protein), 26 E% from fat, 15 E% from added sugar and 1.7 g/MJ of dietary fibre. The median intake of fruit and vegetables was 370g/d, comparable to the Norwegian mean intake. Fortification resulted in excessive intakes of micronutrients and high blood concentrations of folate and vitamin B12. Other blood parameters as iron, zinc or magnesium, did not show the same effect despite high intakes. The intake was above estimated upper limit for a few nutrients, as iron. Discussion and conclusion: The study showed that adults with PKU and brain damage could manage a diet according to nutritional recommendations. However, this required great efforts and special considerations regarding food choice. The fortification of micronutrients is excessive and the doses and compounds used need evaluation in order to compose an optimal diet. The subjects in group A faced great challenges in adhering to the diet. Practical support was needed to maintain low serum phe levels and compose a varied diet. Managing the diet in group B depended on mutual agreement and a basic knowledge of PKU among the group home staff, this improved cooperation and supported the responsible caregivers. Caregivers in group B requested information and knowledge, whereas the psychological and emotional aspects of adhering were more important for subjects in group A. This study has provided new knowledge that can prove important in regard to giving dietary advice and in organising follow-up of persons with PKU and brain damage. It may also stimulate an improved cooperation between local and central systems for treatment and support. The results of the present study also show that further investigation into the nutritional impact of a semi-synthetic diet is required

Department of Health Research, Sintef Technology and Society, Oslo, Norway

Today most adults with phenylketonuria (PKU) have followed a protein restricted diet from early infancy. This makes their disorder an invisible impairment which becomes visible only when food is served. When adhering to medical advice in public, adults with PKU find themselves in a liminal space, betwixt and between being medically ill and socially healthy. The affected adults may pass as being ‘normal’ if they ignore medical advice and eat ordinary food. By doing this, they risk severe neurological health consequences. Due to the rarity of this illness and limited knowledge regarding the health consequences of dietary intervention in adulthood, implications of adult PKU can be difficult to explain to others. Conscious stigma-handling strategies are therefore required. This article, which is based on qualitative interviews, discusses stigma and management strategies in the lives of eleven adults aged 20–30 with PKU

Lecithin : cholesterol acyltransferase: symposium on 50 years of biomedical research from its discovery to latest findings

LCAT converts free cholesterol to cholesteryl esters in the process of reverse cholesterol transport. Familial LCAT deficiency (FLD) is a genetic disease that was first described by Kaare R. Norum and Egil Gjone in 1967. This report is a summary from a 2017 symposium where Dr. Norum recounted the history of FLD and leading experts on LCAT shared their results. The Tesmer laboratory shared structural findings on LCAT and the close homolog, lysosomal phospholipase A2. Results from studies of FLD patients in Finland, Brazil, Norway, and Italy were presented, as well as the status of a patient registry. Drs. Kuivenhoven and Calabresi presented data from carriers of genetic mutations suggesting that FLD does not necessarily accelerate atherosclerosis. Dr. Ng shared that LCAT-null mice were protected from diet-induced obesity, insulin resistance, and nonalcoholic fatty liver disease. Dr. Zhou presented multiple innovations for increasing LCAT activity for therapeutic purposes, whereas Dr. Remaley showed results from treatment of an FLD patient with recombinant human LCAT (rhLCAT). Dr. Karathanasis showed that rhLCAT infusion in mice stimulates cholesterol efflux and suggested that it could also enhance cholesterol efflux from macrophages. While the role of LCAT in atherosclerosis remains elusive, the consensus is that a continued study of both the enzyme and disease will lead toward better treatments for patients with heart disease and FLD.Peer reviewe

Lecithin:cholesterol acyltransferase:symposium on 50 years of biomedical research from its discovery to latest findings

LCAT converts free cholesterol to cholesteryl esters in the process of reverse cholesterol transport. Familial LCAT deficiency (FLD) is a genetic disease that was first described by Kaare R. Norum and Egil Gjone in 1967. This report is a summary from a 2017 symposium where Dr. Norum recounted the history of FLD and leading experts on LCAT shared their results. The Tesmer laboratory shared structural findings on LCAT and the close homolog, lysosomal phospholipase A2. Results from studies of FLD patients in Finland, Brazil, Norway, and Italy were presented, as well as the status of a patient registry. Drs. Kuivenhoven and Calabresi presented data from carriers of genetic mutations suggesting that FLD does not necessarily accelerate atherosclerosis. Dr. Ng shared that LCAT-null mice were protected from diet-induced obesity, insulin resistance, and nonalcoholic fatty liver disease. Dr. Zhou presented multiple innovations for increasing LCAT activity for therapeutic purposes, whereas Dr. Remaley showed results from treatment of an FLD patient with recombinant human LCAT (rhLCAT). Dr. Karathanasis showed that rhLCAT infusion in mice stimulates cholesterol efflux and suggested that it could also enhance cholesterol efflux from macrophages. While the role of LCAT in atherosclerosis remains elusive, the consensus is that a continued study of both the enzyme and disease will lead toward better treatments for patients with heart disease and FLD.</p

Hyperoxia increases the uptake of 5-fluorouracil in mammary tumors independently of changes in interstitial fluid pressure and tumor stroma

<p>Abstract</p> <p>Background</p> <p>Hypoxia is associated with increased resistance to chemo- and radiation-therapy. Hyperoxic treatment (hyperbaric oxygen) has previously been shown to potentiate the effect of some forms of chemotherapy, and this has been ascribed to enhanced cytotoxicity or neovascularisation. The aim of this study was to elucidate whether hyperoxia also enhances any actual uptake of 5FU (5-fluorouracil) into the tumor tissue and if this can be explained by changes in the interstitium and extracellular matrix.</p> <p>Methods</p> <p>One group of tumor bearing rats was exposed to repeated hyperbaric oxygen (HBO) treatment (2 bar, pO₂= 2 bar, 4 exposures à 90 min), whereas one group was exposed to one single identical HBO treatment. Animals housed under normal atmosphere (1 bar, pO₂= 0.2 bar) served as controls. Three doses of 5FU were tested for dose response. Uptake of [³H]-5FU in the tumor was assessed, with special reference to factors that might have contributed, such as interstitial fluid pressure (P_if), collagen content, oxygen stress (measured as malondialdehyd levels), lymphatics and transcapillary transport in the tumors.</p> <p>Results</p> <p>The uptake of the cytostatic agent increases immediately after a single HBO treatment (more than 50%), but not 24 hours after the last repeated HBO treatment. Thus, the uptake is most likely related to the transient increase in oxygenation in the tumor tissue. Factors like tumor P_ifand collagen content, which decreased significantly in the tumor interstitium after repeated HBO treatment, was without effect on the drug uptake.</p> <p>Conclusion</p> <p>We showed that hyperoxia increases the uptake of [³H]-5FU in DMBA-induced mammary tumors <it>per se</it>, independently of changes in P_if, oxygen stress, collagen fibril density, or transendothelial transport alone. The mechanism by which such an uptake occur is still not elucidated, but it is clearly stimulated by elevated pO₂.</p

Investigation of perioperative work processes in provision of antibiotic prophylaxis: a prospective descriptive qualitative study across surgical specialties in Norway

Abstract Objective: Surgical site infections are known postoperative complications, yet the most preventable of healthcare-associated infections. Correct provision of surgical antibiotic prophylaxis (SAP) is crucial. Use of the WHO Safe Surgical Checklist (SSC) has been reported to improve provision of SAP, and reduce infections postoperatively. To understand possible mechanisms and interactions generating such effects, we explored the underlying work processes of SAP provision and SSC performance at the intersection of perioperative procedures and actual team working. Design: An ethnographic study including observations and in-depth interviews. A combination of deductive and inductive content analysis of the data was conducted. Setting: Operating theatres with different surgical specialities, in three Norwegian hospitals. Participants: Observations of perioperative team working (40 hours) and in-depth interviews of 19 experienced perioperative team members were conducted. Interview participants followed a maximum variation purposive sampling strategy. Results: Analysis identified provision of SAP as a process of linked activities; sequenced, yet disconnected in time and space throughout the perioperative phase. Provision of SAP was handled in relation to several interactive factors: preparation and administration, prescription accuracy, diversity of prescription order systems, patient-specific conditions and changes in operating theatre schedules. However, prescription checks were performed either as formal SSC reviews of SAP items or as informal checks of relevant documents. In addition, use of cognitive reminders and clinical experiences were identified as mechanisms used to enable administration of SAP within the 60 min timeframe described in the SSC. Conclusion: Provision of SAP was identified as a complex process. Yet, a key element in provision of SAP was the given 60 min. timeframe of administration before incision, provided in the SSC. Thus, the SSC seems beneficial in supporting timely SAP administration practice by either being a cognitive tool and/or as a cognitive intervention

Primary Immunodeficiency Diseases and Gastrointestinal Distress: Coping Strategies and Dietary Experiences to Relieve Symptoms

In this article, we focus on adults with primary immunodeficiency disease (PID) and their experiences with gastrointestinal (GI) distress with the aim of exploring how they experience living with their condition and the actions they take to relieve GI distress. Twelve adults with PID and GI distress participated in semi-structured, in-depth interviews. The interviews were analyzed following the steps of thematic analysis (TA). The study revealed the complexity of the psychosocial aspects of living with PID and GI distress. Participants experienced GI distress to be highly challenging in daily life and felt they had to cope with the condition alone, without adequate help from the health care service. Participants used a wide and diverse range of coping strategies, and the search for normalcy was evident. Health care professionals should be more proactive in supporting individuals with PID in their struggle to find solutions to problems arising from GI distress

Atrial natriuretic peptide modulation of albumin clearance and contrast agent permeability in mouse skeletal muscle and skin: role in regulation of plasma volume

Atrial natriuretic peptide (ANP) via its guanylyl cyclase-A (GC-A) receptor participates in regulation of arterial blood pressure and vascular volume. Previous studies demonstrated that concerted renal diuretic/natriuretic and endothelial permeability effects of ANP cooperate in intravascular volume regulation. We show that the microvascular endothelial contribution to the hypovolaemic action of ANP can be measured by the magnitude of the ANP-induced increase in blood-to-tissue albumin transport, measured as plasma albumin clearance corrected for intravascular volume change, relative to the corresponding increase in ANP-induced renal water excretion. We used a two-tracer method with isotopically labelled albumin to measure clearances in skin and skeletal muscle of: (i) C57BL6 mice; (ii) mice with endothelium-restricted deletion of GC-A (floxed GC-A × tie2-Cre: endothelial cell (EC) GC-A knockout (KO)); and (iii) control littermates (floxed GC-A mice with normal GC-A expression levels). Comparison of albumin clearances in hypervolaemic EC GC-A KO mice with normovolaemic littermates demonstrated that skeletal muscle albumin clearance with ANP treatment accounts for at most 30% of whole body clearance required for ANP to regulate plasma volume. Skin microcirculation responded to ANP similarly. Measurements of permeability to a high molecular mass contrast agent (35 kD Gadomer) by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) enabled repeated measures in individual animals and confirmed small increases in muscle and skin microvascular permeability after ANP. These quantitative methods will enable further evaluation of the contribution of ANP-dependent microvascular beds (such as gastro-intestinal tract) to plasma volume regulation

Matrix metalloproteinase-2 governs lymphatic vessel formation as an interstitial collagenase.

Lymphatic dysfunctions are associated with several human diseases, including lymphedema and metastatic spread of cancer. Although it is well recognized that lymphatic capillaries attach directly to interstitial matrix mainly composed of fibrillar type I collagen, the interactions occurring between lymphatics and their surrounding matrix have been overlooked. In this study, we demonstrate how matrix metalloproteinase (MMP)–2 drives lymphatic morphogenesis through Mmp2-gene ablation in mice, mmp2 knockdown in zebrafish and in 3D-culture systems, and through MMP2 inhibition. In all models used in vivo (3 murine models and thoracic duct development in zebrafish) and in vitro (lymphatic ring and spheroid assays), MMP2 blockage or down-regulation leads to reduced lymphangiogenesis or altered vessel branching. Our data show that lymphatic endothelial cell (LEC) migration through collagen fibers is affected by physical matrix constraints (matrix composition, density and cross-linking). Transmission electron microscopy (TEM) and confocal reflection microscopy using DQ-collagen highlight the contribution of MMP2 to mesenchymal-like migration of LEC associated with collagen fiber remodeling. Our findings provide new mechanistic insight into how LEC negotiate an interstitial type I collagen barrier and reveal an unexpected MMP2-driven collagenolytic pathway for lymphatic vessel formation and morphogenesis