Biotinidase deficiency: What have we learned in forty years?

BACKGROUND: Biotinidase deficiency (BD) is an autosomal recessively inherited disorder that was first described in 1982. Forty years after its first description, we compiled available clinical data on BD with the aim of generating a more comprehensive picture of this condition. METHODS: A systematic search strategy was performed in relevant databases without limits for publication date or languages. We screened 3966 records and included 144 articles reporting individuals with BD and their clinical presentation as well as the outcomes, when available. RESULTS: This study included 1113 individuals with BD. More than half (51.5%) of these individuals were diagnosed by newborn screening, 43.3% in presence of clinical symptoms and 5.2% due to family screening. We grouped symptomatic individuals into four main clinical presentations: neonatal-onset (<1 month; 7.9%), early childhood-onset (<2 years; 59.2%), juvenile-onset (2-16 years; 25.1%) and adult-onset (>16 years; 7.7%). BD affected five main organ systems: nervous system (67.2%), skin (53.7%), eye (34.4%), auditory (26.9%) and respiratory system (17.8%). Involvement was mainly multisystemic (82.2%) of individuals, whereas isolated system presentation was seen in only 17.2% of individuals. When reported, metabolic acidosis was present in 42.4% of symptomatic individuals and characteristic abnormal organic acid metabolites were found in 57.1%. Biotin treatment led to clinical stability or improvement in 89.2% of individuals. 1.6% of reported individuals with BD died due to non-availability of treatment or late diagnosis. CONCLUSION: Newborn screening has had a major positive impact on the outcome of many individuals with BD. However, undiagnosed and non-treated BD remains a health concern. Given the risk of mortality or complications associated with late or missed diagnosis if newborn screening is not available, a trial of biotin should be considered in undiagnosed infants and adults exhibiting suspected clinical signs. Enzymatic activity and/or analysis of genetic variants can readily confirm the diagnosis of BD.

Investigating acceptability of a training programme in precision medicine for frontline healthcare professionals: a mixed methods study.

BACKGROUND: Precision Medicine offers tailored prevention, diagnosis, treatment and management to patients that considers genomics, lifestyle and environmental factors. If implementation of Precision Medicine is to advance, effective, focused upskilling of frontline healthcare professionals through quality continuing professional development is needed. This study reports on an evidence-based approach to needs assessment to investigate the current level of knowledge of Precision Medicine, acceptable content for training, the perceived potential of a more precision approach to patient care and motivation to participate in a training programme among pharmacists, advanced practice nurses and general practitioners. Investigating perceived needs can avoid a top-down approach and support a design that is fit for purpose to targeted professions. METHODS: This study reports on 2 focus groups (n = 12) delivered in French and German with equal professional participation of the targeted professions. The research objectives were investigated in two phases. During the first phase, a literature review and expert consultations were conducted to develop a definition of PM, patient cases and content for training. In a second phase, these investigations were further explored using focus groups to investigate acceptable learning objectives, the potential of PM to relevant professions and motivation of participants. Quantitative investigations using rating scales and visual analogues were incorporated. The focus groups were audio recorded, transcribed by intelligent verbatim and translated to English. NVivo was used for data analysis and interpretation following a hybrid approach using the Framework Method and thematic analysis. The analytical framework, Implementation Science, was applied to organise and present research data. RESULTS: Precision Medicine is considered a new topic area, largely unfamiliar to frontline healthcare professionals.. There was acceptance of a more precision approach to care among all participants with perceived positive implications for patients. Valuable insight was gathered on acceptable content and form for training. All participants expressed concerns on readiness within their professions which included an insufficient system infrastructure, a lack of time to attend needed training, a lack of clarity for use in practice and the time needed to build a support network. CONCLUSIONS: A precision approach to patient care is on the horizon for health care professionals not only in hospital settings but also at the community level. Our results conclude that an adaptable and flexible training programme in PM is timely, contextually relevant and conducive to the needs of targeted health professions for successful implementation. A training programme in PM will require support across sectors and stakeholders, supporting insurance models, educated patients and integrated care supported by innovative technology. Implementation Science outcomes are a useful strategy towards design of an effective training programme that can have measurable impact in practice.

[Pharmacogenomics : a toolbox to improve drug prescription]. / Pharmacogénomique et aide à la prescription médicamenteuse.

As a result of advances in pharmacogenomics (PGx), the paradigm that a single dose of a drug is extrapolated to an entire population is set to change. Personalising drug prescriptions according to individual genomic determinants would make it possible to increase the effectiveness and tolerance of treatments. In Switzerland, any doctor can prescribe validated PGx tests for five actionable drugs : abacavir, carbamazepine, thiopurines [azathioprine], fluoropyrimidines [5-FU, capecitabine] and irinotecan. Such an approach presupposes that PGx data are shared with trained clinicians and that prescribing aids can guide them.

Suite aux progrès de la pharmacogénomique (PGx), le paradigme qui veut qu'une dose unique d'un médicament soit extrapolée à l'ensemble d'une population est appelé à évoluer. Une personnalisation de la prescription médicamenteuse en fonction de déterminants génomiques individuels permettrait d'augmenter l'efficacité et la tolérance aux traitements. En Suisse, tout médecin peut réaliser des tests PGx validés pour cinq médicaments actionnables qui sont : l'abacavir, la carbamazépine, les thiopurines (azathioprine), les fluoropyrimidines (5-fluoro-uracile, capécitabine) et l'irinotécan. Une telle approche présuppose que les données PGx soient partagées avec des cliniciens formés et que des outils d'aide à la prescription puissent les orienter.

[Rhabdomyolysis: early management]. / Rhabdomyolyse: prise en charge médicale initiale.

Rhabdomyolysis is defined by myalgia, potentially painful myoedema and muscular weakness due to death of muscular fiber in the striated muscle. Frequent etiologies include physical effort, intoxication (alcohol, drugs and medication) and physical trauma. Depletion of myocyte' s adenosine triphosate (ATP) leads to an increase in intracellular calcium and myocyte death. Diagnosis relies on creatine kinase (CK) levels. The clinical spectrum of rhabdomyolysis includes an asymptomatic increased amount of CK as well as severe, life threatening complications such as acute renal failure and electrolyte disorders. Treatment is based on prevention and addressing complications.

La rhabdomyolyse, définie comme étant les conséquences de la destruction du muscle strié, se caractérise par l'association de myalgies, d'un myo-œdème éventuellement douloureux et d'une faiblesse musculaire. Parmi les étiologies fréquentes, on peut citer l'effort, les causes toxiques (alcool et médicament) et traumatiques. Elle résulte d'un épuisement de l'adénosine triphosphate du myocyte, menant à une augmentation du calcium intracellulaire et à sa destruction. Le diagnostic repose sur le dosage de la créatine kinase (CK). Le spectre de la rhabdomyolyse englobe une élévation asymptomatique des CK, mais aussi des complications redoutables telles qu'une insuffisance rénale aiguë sévère ou des troubles électrolytiques pouvant mettre en jeu le pronostic vital. Le traitement est centré sur la prévention et la prise en charge de ces complications.

[The internal medicine articles that struck us the most in 2017]. / L'année 2017 mise en perspective par les internistes hospitaliers.

2017 has continued to bring important progress in all areas of internal medicine, impacting our daily practice. From bedside screening for beta-lactam allergies, to statins as primary prevention in the elderly, SGLT2 inhibitors in heart failure, azithromycin in severe asthmatics and tofacitinib in ulcero-haemorrhagic recto-colitis, internal medicine journals are full of novelties. Every year, the chief residents of the CHUV internal medicine ward meet up to share their readings: here is their selection of eleven articles, chosen, summarized and commented for you.

L'année 2017 a vu d'importants progrès dans tous les domaines de la médecine interne, avec un impact important sur notre pratique quotidienne. Du dépistage au lit du patient des allergies aux bêta-lactames, aux statines en prévention primaire chez les personnes âgées, en passant par l'utilisation des inhibiteurs SGLT2 dans l'insuffisance cardiaque, de l'azithromycine chez les asthmatiques sévères et du tofacitinib en cas de rectocolite ulcéro-hémorragique (RCUH), les nouveautés abondent dans la littérature. Chaque année, les chefs de clinique du Service de médecine interne du Centre hospitalier universitaire vaudois (CHUV) se réunissent pour partager leurs lectures : voici une sélection de onze articles choisis, revus et commentés pour vous.

[What is new in 2016 for the specialist in hospital internal medicine?] / L'année 2016 mise en perspective par les internistes hospitaliers.

The year 2016 was rich in significant advances in all areas of internal medicine. Many of them have an impact on our daily practice in general internal medicine. From the treatment of NSTEMI in population older than 80, to new sepsis and septic shock criteria to antidotes of new oral anticoagulants, this selection offers to the readers a brief overview of the major advances. The chief residents in the Service of internal medicine of the Lausanne University hospital are pleased to share their readings.

L'année 2016 a été riche en avancées importantes dans tous les domaines de la médecine. L'impact de ces avancées sera palpable dans notre pratique en médecine interne générale. De la prise en charge du NSTEMI (infarctus myocardique sans élévation ST) dans la population des plus de 80 ans, aux nouveaux critères du sepsis et du choc septique, aux antidotes des nouveaux anticoagulants oraux en passant par la déprescription médicamenteuse, les nouveautés dans la littérature ont été abondantes. Chaque année, les chefs de clinique du Service de médecine interne du Centre hospitalier universitaire vaudois (CHUV) se réunissent pour partager leurs lectures. Onze de leurs choix sont ici revus et commentés.

[2015 highlights in hospital-based internal medicine by chief residents]. / L'année 2015 mise en perspective par les internistes hospitaliers.

The year 2015 gave us many scientific publications, among whom some will have an impact on our daily practice and some will influence our way of considering some well known diseases. Chief residents in the Service of internal medicine of the Lausanne University hospital, gathered like every year, to share their readings together in order to presentyou a small part of the many publications of 2015, which have been considered to have an impact on our future daily practice.

Effect of acute iron infusion on insulin secretion: A randomized, double-blind, placebo-controlled trial.

Background: Chronic exposure to high iron levels increases diabetes risk partly by inducing oxidative stress, but the consequences of acute iron administration on beta cells are unknown. We tested whether the acute administration of iron for the correction of iron deficiency influenced insulin secretion and the production of reactive oxygen species. Methods: Single-center, double-blinded, randomized controlled trial conducted between June 2017 and March 2020. 32 women aged 18 to 47 years, displaying symptomatic iron deficiency without anaemia, were recruited from a community setting and randomly allocated (1:1) to a single infusion of 1000 mg intravenous ferric carboxymaltose (iron) or saline (placebo). The primary outcome was the between group mean difference from baseline to day 28 in first and second phase insulin secretion, assessed by a two-step hyperglycaemic clamp. All analyses were performed by intention to treat. This trial was registered in ClinicalTrials.gov NCT03191201. Findings: Iron infusion did not affect first and second phase insulin release. For first phase, the between group mean difference from baseline to day 28 was 0 µU × 10 min/mL [95% CI, -22 to 22, P = 0.99]. For second phase, it was -5 µUx10min/mL [95% CI, -161 to 151; P = 0.95] at the first plateau of the clamp and -249 µUx10min/mL [95% CI, -635 to 137; P = 0.20] at the second plateau. Iron infusion increased serum ascorbyl/ascorbate ratio, a marker of plasma oxidative stress, at day 14, with restoration of normal ratio at day 28 relative to placebo. Finally, high-sensitive C-reactive protein levels remained similar among groups. Interpretation: In iron deficient women without anaemia, intravenous administration of 1000 mg of iron in a single sitting did not impair glucose-induced insulin secretion despite a transient increase in the levels of circulating reactive oxygen species. Funding: The Swiss National Science Foundation, University of Lausanne and Leenaards, Raymond-Berger and Placide Nicod Foundations.

Risk stratification for hospital-acquired venous thromboembolism in medical patients (RISE): Protocol for a prospective cohort study.

BACKGROUND: Hospital-acquired venous thromboembolism (VTE) is one of the leading preventable causes of in-hospital mortality. However, its risk assessment in medically ill inpatients is complicated due to the patients' heterogeneity and complexity of currently available risk assessment models (RAMs). The simplified Geneva score provides simplicity but has not yet been prospectively validated. Immobility is an important predictor for VTE in RAMs, but its definition is inconsistent and based on subjective assessment by nurses or physicians. In this study, we aim to prospectively validate the simplified Geneva score and to examine the predictive performance of a novel and objective definition of in-hospital immobilization using accelerometry. METHODS AND ANALYSIS: RISE is a multicenter prospective cohort study. The goal is to recruit 1350 adult inpatients admitted for medical illness in three Swiss tertiary care hospitals. We collect data on demographics, comorbidities, VTE risk and thromboprophylaxis. Mobility from admission to discharge is objectively measured using a wrist-worn accelerometer. Participants are followed for 90 days for the occurrence of symptomatic VTE (primary outcome). Secondary outcomes are the occurrence of clinically relevant bleeding, and mortality. The evolution of autonomy in the activities of daily living, the length of stay, and the occurrence of readmission are also recorded. Time-dependent area under the curve, sensitivity, specificity, and positive and negative predictive values are calculated for each RAM (i.e. the simplified and original Geneva score, Padua, and IMPROVE score) with and without the objective mobility measures to assess their accuracy in predicting hospital-acquired VTE at 90 days. ETHICS AND EXPECTED IMPACT: The ethics committee approved the protocol and the study was registered on ClinicalTrials.gov as NCT04439383. RISE has the potential to optimize VTE risk stratification, and thus to improve the quality of care of medically hospitalized patients.

RasGAP-derived fragment N increases the resistance of beta cells towards apoptosis in NOD mice and delays the progression from mild to overt diabetes.

The caspase-3-generated RasGAP N-terminal fragment (fragment N) inhibits apoptosis in a Ras-PI3K-Akt-dependent manner. Fragment N protects various cell types, including insulin-secreting cells, against different types of stresses. Whether fragment N exerts a protective role during the development of type 1 diabetes is however not known. Non-obese diabetic (NOD) mice represent a well-known model for spontaneous development of type 1 diabetes that shares similarities with the diseases encountered in humans. To assess the role of fragment N in type 1 diabetes development, a transgene encoding fragment N under the control of the rat insulin promoter (RIP) was back-crossed into the NOD background creating the NOD-RIPN strain. Despite a mosaic expression of fragment N in the beta cell population of NOD-RIPN mice, islets isolated from these mice were more resistant to apoptosis than control NOD islets. Islet lymphocytic infiltration and occurrence of a mild increase in glycemia developed with the same kinetics in both strains. However, the period of time separating the mild increase in glycemia and overt diabetes was significantly longer in NOD-RIPN mice compared to the control NOD mice. There was also a significant decrease in the number of apoptotic beta cells in situ at 16 weeks of age in the NOD-RIPN mice. Fragment N exerts therefore a protective effect on beta cells within the pro-diabetogenic NOD background and this prevents a fast progression from mild to overt diabetes.

Expression of the NH(2)-terminal fragment of RasGAP in pancreatic beta-cells increases their resistance to stresses and protects mice from diabetes.

OBJECTIVE: Our laboratory has previously established in vitro that a caspase-generated RasGAP NH(2)-terminal moiety, called fragment N, potently protects cells, including insulinomas, from apoptotic stress. We aimed to determine whether fragment N can increase the resistance of pancreatic beta-cells in a physiological setting. RESEARCH DESIGN AND METHODS: A mouse line, called rat insulin promoter (RIP)-N, was generated that bears a transgene containing the rat insulin promoter followed by the cDNA-encoding fragment N. The histology, functionality, and resistance to stress of RIP-N islets were then assessed. RESULTS: Pancreatic beta-cells of RIP-N mice express fragment N, activate Akt, and block nuclear factor kappaB activity without affecting islet cell proliferation or the morphology and cellular composition of islets. Intraperitoneal glucose tolerance tests revealed that RIP-N mice control their glycemia similarly as wild-type mice throughout their lifespan. Moreover, islets isolated from RIP-N mice showed normal glucose-induced insulin secretory capacities. They, however, displayed increased resistance to apoptosis induced by a series of stresses including inflammatory cytokines, fatty acids, and hyperglycemia. RIP-N mice were also protected from multiple low-dose streptozotocin-induced diabetes, and this was associated with reduced in vivo beta-cell apoptosis. CONCLUSIONS: Fragment N efficiently increases the overall resistance of beta-cells to noxious stimuli without interfering with the physiological functions of the cells. Fragment N and the pathway it regulates represent, therefore, a potential target for the development of antidiabetes tools.

Glucagon-like peptide-1 protects beta-cells against apoptosis by increasing the activity of an IGF-2/IGF-1 receptor autocrine loop.

OBJECTIVE: The gluco-incretin hormones glucagon-like peptide (GLP)-1 and gastric inhibitory peptide (GIP) protect beta-cells against cytokine-induced apoptosis. Their action is initiated by binding to specific receptors that activate the cAMP signaling pathway, but the downstream events are not fully elucidated. Here we searched for mechanisms that may underlie this protective effect. RESEARCH DESIGN AND METHODS: We performed comparative transcriptomic analysis of islets from control and GipR(-/-);Glp-1-R(-/-) mice, which have increased sensitivity to cytokine-induced apoptosis. We found that IGF-1 receptor expression was markedly reduced in the mutant islets. Because the IGF-1 receptor signaling pathway is known for its antiapoptotic effect, we explored the relationship between gluco-incretin action, IGF-1 receptor expression and signaling, and apoptosis. RESULTS: We found that GLP-1 robustly stimulated IGF-1 receptor expression and Akt phosphorylation and that increased Akt phosphorylation was dependent on IGF-1 but not insulin receptor expression. We demonstrated that GLP-1-induced Akt phosphorylation required active secretion, indicating the presence of an autocrine activation mechanism; we showed that activation of IGF-1 receptor signaling was dependent on the secretion of IGF-2. We demonstrated, both in MIN6 cell line and primary beta-cells, that reducing IGF-1 receptor or IGF-2 expression or neutralizing secreted IGF-2 suppressed GLP-1-induced protection against apoptosis. CONCLUSIONS: An IGF-2/IGF-1 receptor autocrine loop operates in beta-cells. GLP-1 increases its activity by augmenting IGF-1 receptor expression and by stimulating secretion; this mechanism is required for GLP-1-induced protection against apoptosis. These findings may lead to novel ways of preventing beta-cell loss in the pathogenesis of diabetes.