[Diagnosis and evaluation of metabolic dysfunction associated steatotic liver disease (MASLD)]. / Diagnostic et évaluation de l'hépatopathie stéatosique métabolique.

Non-alcoholic fatty liver disease (NAFLD) or recently called Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD), is the leading cause of liver disease, with an estimated worldwide prevalence of 25%. MASLD is suspected, in a metabolic condition, in the presence of hepatic steatosis, moderate hepatic cytolysis or hyperferritinemia. The severity of the disease depends on the stage of liver fibrosis, which can be suspected in clinical practice by simple blood tests such as the FIB-4 or NAFLD fibrosis Score. The treatment is based on lifestyle intervention combining weight loss, increased physical activity and a Mediterranean-style diet. Only a small minority of patients with MASLD will develop advanced liver disease and require liver specialist. Given the high prevalence of MASLD, the identification of these patients cannot be envisaged without the taking part in the screening of all physicians (general practitioners and specialists).

Safety of sofosbuvir-based regimens after liver transplantation: longitudinal assessment of renal function in the prospective ANRS CO23 CUPILT study.

BACKGROUND: In liver transplant recipients with hepatitis C virus recurrence, there is concern about renal safety of sofosbuvir-based regimens. Changes in serum creatinine or in the estimated glomerular filtration rate (eGFR) under treatment are used to look for possible renal toxicity. However, serum creatinine and eGFR are highly variable. AIM: To analyse renal function trajectory with numerous assays of serum creatinine over a long period of time. METHODS: In a multicentre cohort of 139 patients, the eGFR was obtained from serum creatinine using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. Slopes of eGFR were defined as a change in eGFR during a period divided by time. Pre-treatment, on-treatment and post-treatment periods were 9 months, 3-9 months and 4.5 months. Interactions between eGFR slopes and the pre-treatment eGFR, use of ribavirin or mycophenolate mofetil, and stage of fibrosis were addressed. On-treatment eGFR slopes were separated in tertiles. Pre- and post-treatment eGFR slopes were compared globally and according to tertiles. RESULTS: The post-treatment eGFR slope was significantly better than pre-treatment eGFR slope (+0.18 (IQR -0.76 to +1.32) vs -0.11 (IQR -1.01 to +0.73) mL/min/1.73 m2 /month, P = 0.03) independently of the pre-treatment eGFR (P = 0.99), ribavirin administration (P = 0.26), mycophenolate mofetil administration (P = 0.51) and stage of fibrosis (F3 and F4 vs lower stages, P = 0.18; F4 vs lower stages, P = 0.08; F4 Child-Pugh B and C vs lower stages, P = 0.38). Tertiles of on-treatment eGFR slopes were -1.71 (IQR -2.54 to -1.48), -0.78 (IQR -1.03 to -0.36) and +0.75 (IQR +0.28 to +1.47) mL/min/1.73 m2 /month. Pre- and post-treatment eGFR slopes were not significantly different according to tertiles (respectively, P = 0.34, 0.08, 0.73). CONCLUSION: The eGFR varies during treatment and gives a confusing picture of the renal safety of sofosbuvir-based regimens. In contrast, longitudinal assessment of the eGFR shows a rising trajectory over longer time, meaning that these therapies are safe for the kidneys in our cohort of liver transplant recipients.

Screening for therapeutic trials and treatment indication in clinical practice: MACK-3, a new blood test for the diagnosis of fibrotic NASH.

BACKGROUND: The composite histological endpoint comprising nonalcoholic steatohepatitis (NASH) and NAFLD activity score ≥4 and advanced fibrosis (F ≥ 2) ("fibrotic NASH") is becoming an important diagnostic target in NAFLD: it is currently used to select patients for inclusion in phase III therapeutic trials and will ultimately be used to indicate treatment in clinical practice once the new drugs are approved. AIM: To develop a new blood test specifically dedicated for this new diagnostic target of interest. METHODS: Eight Hundred and forty-six biopsy-proven NAFLD patients from three centres (Angers, Nice, Antwerp) were randomised into derivation and validation sets. RESULTS: The blood fibrosis tests BARD, NFS and FIB4 had poor accuracy for fibrotic NASH with respective AUROC: 0.566 ± 0.023, 0.654 ± 0.023, 0.732 ± 0.021. In the derivation set, fibrotic NASH was independently predicted by AST, HOMA and CK18; all three were combined in the new blood test MACK-3 (hoMa, Ast, CK18) for which 90% sensitivity and 95% specificity cut-offs were calculated. In the validation set, MACK-3 had a significantly higher AUROC (0.847 ± 0.030, P ≤ 0.002) than blood fibrosis tests. Using liver biopsy in the grey zone between the two cut-offs (36.0% of the patients), MACK-3 provided excellent accuracy for the diagnosis of fibrotic NASH with 93.3% well-classified patients, sensitivity: 90.0%, specificity: 94.2%, positive predictive value: 81.8% and negative predictive value: 97.0%. CONCLUSION: The new blood test MACK-3 accurately diagnoses fibrotic NASH. This new test will facilitate patient screening and inclusion in NAFLD therapeutic trials and will enable the identification of patients who will benefit from the treatments once approved.

[A therapeutic educational program in Parkinson's disease: ETPARK]. / Éducation thérapeutique chez le patient parkinsonien: le programme ETPARK.

We developed a therapeutic educational program in Parkinson's disease (PD). The needs analysis for this program was performed through a survey involving 41 PD patients. This survey questionnaire was elaborated through the analysis of 395 patients' semi-directive interviews, performed in our specialized hospitalisation unit during explanation workshops between 2005 and 2007. We managed to design an educational program tailored to specificities of PD and according to the recommendations of the High Authority of Health in France (HAS). This program was based on individual sessions conducted by a nurse experienced in PD and trained in education. Collective workshops concerning specific themes such as physical therapy, communication, social supports, sleep disorders, stress management, therapies in PD could be proposed to volunteer patients and were performed by the nurse, a physiotherapist and a specialized practitioner. This program focused on skills structured in knowledge, expertise, and learning. It was intended for patients without any motor or cognitive severe impairment. We educated 231 patients between 2008 and 2012 individually and 113 in collective workshops. Patients had an interesting improvement in their self-esteem (6.2±1.4 before and 7.3±1.1 after one year of this educational program). This program has been validated by our regional medical agency and we performed a medico-economic study demonstrating a significant improvement in quality-of-life of educated patients without extra costs.

HLA class I antibodies provoke graft arteriosclerosis in human arteries transplanted into SCID/beige mice.

Antibodies toward HLA class I and/or MICA are commonly observed in transplanted patients suffering from allograft arteriosclerosis, also called chronic vascular rejection (CVR). The relative importance of cellular versus humoral alloreactivity for CVR is still disputed. We demonstrate that antibodies toward HLA class I provoke lesions typical for CVR in human arteries in vivo in the absence of cellular immunity. To show this, we grafted segments of human mesenteric arteries from 8 deceased organ donors into 36 immunodeficient SCID/beige mice in the infrarenal aortic position. Three mice died postoperatively. The remaining 33 mice received weekly i.v. injections of either a monoclonal antibody toward HLA class I, toward MICA or an irrelevant monoclonal antibody. At sacrifice after 6 weeks, mice receiving the HLA antibody showed a significant neointimal thickening in the grafted artery due to smooth muscle cell (SMC) proliferation while control mice receiving anti-MICA or irrelevant antibody showed little or no thickening. Whereas antibodies toward HLA class I were mitogenic to SMC in vitro, those directed toward MICA did not have any effect. Humoral alloreactivity toward HLA may thus play a causal role for the development of CVR and this opens new possibilities for the treatment of CVR.

FTY720 Inhibits Tumor Necrosis Factor-alpha-Induced Proliferation and Extracellular Signal-Regulated Kinase Phosphorylation of Human Smooth Muscle Cells.

We investigated the effects of the sphingolipid FTY720 on tumor necrosis factor-alpha (TNF-alpha)-induced proliferation and signal transduction in human smooth muscle cells (SMC). We showed that clinically relevant concentrations of FTY720 inhibited TNF-alpha-induced SMC proliferation and extracellular signal-regulated kinase (ERK) phosphorylation. We concluded that FTY720 may be a useful drug to inhibit chronic vascular rejection.

T-cell function in maintenance renal transplant patients receiving mycophenolate mofetil and steroids with or without tacrolimus.

Nephrotoxicity-sparing protocols, using mycophenolate mofetil (MMF) and steroids without calcineurin inhibitors (CNIs) or mammalian target rapamycin (mTOR), could be used to treat maintenance renal transplant patients. However, the risk for acute rejection seems to be high. The aim of this pharmacodynamic study was to analyze T-cell function, T-cell activation, and T-cell proliferation among patients receiving MMF and steroids (n = 15) compared with patients receiving immunosuppression with CNI-based therapy including tacrolimus, MMF, and steroids. Our data suggested that among stable maintenance patients, dual therapy with MMF and steroids might provide a similar reduction in T-cell proliferation and T-cell activation as that observed among patients on standard immunosuppressive therapy. As expected, intralymphocytic interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha) expressions were higher in patients not receiving CNIs.

Effect of FTY720 on apoptosis of smooth muscle cells.

BACKGROUND: Hyperproliferation of smooth muscle cells (SMCs) plays a key role in allograft arteriosclerosis. This prompted us to investigate the effect of the novel immune modulator and synthetic sphingolipid FTY720 on apoptosis of SMCs. METHODS: Rabbit SMC cultures were treated with FTY720 and apoptosis and necrosis were detected by fluorescence microscopy. RESULTS: We investigated dose- and time-dependent effects of FTY720 and found that clinically relevant low doses of FTY720 (<1 micromol/L) did not induce apoptosis, whereas 10 micromol/L FTY720 induced apoptosis after 48 hours incubation. CONCLUSION: At doses of FTY720 used in clinics for treatment of renal allografts and multiple sclerosis. FTY720 did not induce SMC apoptosis.

[Infants with and without "vivacità". Crying can be apprehended quite differently in different cultures]. / Spädbarn med och utan "vivacità". Skrikighet kan uppfattas helt olika i olika kulturer.

The incidence of infantile colic seems to be diminishing, but 10 per cent of infants are still affected. Several different conditions loom under the umbrella of infantile colic--the most serious of which implies a disturbed parent-infant relationship. The interpretation of infant behaviour is dependent on the cultural context, and thus a "difficult" infant can be apprehended as full of "vivacità"--"liveliness". Some of the recent research focuses on aetiology in the CNS rather than in the gastrointestinal tract. Interventional studies on a population level are required in order to clarify to what extent the elimination of cow's milk protein is a cure for infantile colic. The advice given, for instance at well-baby clinics, to parents with crying infants varies, and should be evaluated systematically.

Infantile colic. Follow-up at four years of age: still more "emotional".

This paper presents a follow-up at 4 y of formerly colicky infants and controls, with respect to behaviour, temperament, eating and sleeping habits, psychosomatic complaints, number of hospital stays, growth and "family climate". There were no differences between the two groups in most parameters studied. However, ex-colicky children displayed more negative emotions according to the temperament scale. There were also more negative moods during meals, and more reported stomach-ache. Although relationships regarding crying and mother-infant interaction remain extremely complex, the findings point toward a possible temperamental contribution to the pathogenesis of the infantile colic syndrome.

Infantile colic--less common than previously estimated?

A two-part population-based study investigating the occurrence of infantile colic was undertaken, in which 92% of mothers with newborn healthy infants were reached. In the prospective part 152 mothers ("diary group") registered crying and fussing in their infants during 12 weeks. In the retrospective part 224 mothers ("interview group") were contacted by telephone at an infant age of 5-7 months. The colic occurrence was determined according to four different definitions; the rate varied from 3.3 to 17.1%. The classical "Wessel-type" colic was present in 9.3%. Colic defined as "crying seen as a problem by parent" was present in 12.1% of the "interview group", but in only 3.3% of the "diary group". Some earlier studies may have overestimated colic occurrence. Another possibility is an actual decline. The contributive part of preventive measures is discussed.