A rare and fatal disease resembling mucopolysaccharidosis in infants, is caused by impaired intracellular endocytic trafficking due to deficiency of core components of the intracellular ...membrane‐tethering protein complexes, HOPS, and CORVET. Whole exome sequencing identified a novel VPS33A mutation in a patient suffering from a variant form of mucopolysaccharidosis. Electron and confocal microscopy, immunoblotting, and glycosphingolipid trafficking experiments were undertaken to investigate the effects of the mutant VPS33A in patient‐derived skin fibroblasts. We describe an attenuated juvenile form of VPS33A‐related syndrome—mucopolysaccharidosis plus in a man who is homozygous for a hitherto unknown missense mutation (NM_022916.4: c.599 G>C; NP_075067.2:p. Arg200Pro) in a conserved region of the VPS33A gene. Urinary glycosaminoglycan (GAG) analysis revealed increased heparan, dermatan sulphates, and hyaluronic acid. We showed decreased abundance of VPS33A in patient derived fibroblasts and provided evidence that the p.Arg200Pro mutation leads to destablization of the protein and proteasomal degradation. As in the infantile form of mucopolysaccharidosis plus, the endocytic compartment in the fibroblasts also expanded—a phenomenon accompanied by increased endolysosomal acidification and impaired intracellular glycosphingolipid trafficking. Experimental treatment of the patient's cultured fibroblasts with the proteasome inhibitor, bortezomib, or exposure to an inhibitor of glucosylceramide synthesis, eliglustat, improved glycosphingolipid trafficking. To our knowledge this is the first report of an attenuated juvenile form of VPS33A insufficiency characterized by appreciable residual endosomal‐lysosomal trafficking and a milder mucopolysaccharidosis plus than the disease in infants. Our findings expand the proof of concept of redeploying clinically approved drugs for therapeutic exploitation in patients with juvenile as well as infantile forms of mucopolysaccharidosis plus disease.
IntroductionThe sense of agency (SoA) indicates a person’s ability to feel her/his own motor acts as actually being her/his, and through them to exert control over the course of external events. ...Disruptions in SoA may profoundly affect the individual’s functioning, as observed in several neuropsychiatric disorders.ObjectivesThis is the first article to systematically review studies that investigated intentional binding (IB), a quantitative proxy for SoA measurement, in neurological and psychiatric patients.MethodsEligible were studies of IB involving patients with neurological and/or psychiatric disorders. The research adhered to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).ResultsWe included 15 studies involving 692 individuals. Risk of bias was low throughout studies. Eligible studies dealt with data from 357 patients with neuropsychiatric disorders matched with 335 HCs. Of included patients, 95 were with schizophrenia (SCZ), 30 with a putative prodromal psychosis (PP), 21 with borderline personality disorder (BPD), 66 with Parkinson’s disease (PD), 38 with an autism spectrum disorder (ASD), 29 with functional movement disorders (FMDs), 25 with Gilles de la Tourette syndrome (GTS), 52 with anorexia nervosa (AN; 22 with active disorder and 30 after they had recovered), and 10 with Cortico-Basal syndrome (CBS).Temporal binding was calculated in eleven studies using variations of the experimental procedure introduced by Haggard et al. (Haggard et al. Nat Neurosci 2002;5 382-385)(Figure 1, A), while four studies utilized a different paradigm named interval estimation (IE)(Figure 1, B).Image:ConclusionsAbnormally increased action-outcome binding was found in schizophrenia and in patients with Parkinson’s disease taking dopaminergic medications or reporting impulsive-compulsive behaviours. A decreased IB effect was observed in Tourette’s disorder and functional movement disorders whereas increased action-outcome binding was found in patients with cortico-basal syndrome. The extent of IB deviation from healthy control values correlated with the severity of symptoms in several disorders. Inconsistent effects were found for autism spectrum disorders, anorexia nervosa, and borderline personality disorder. Findings pave the way for treatments specifically targeting SoA in neuropsychiatric disorders where IB is altered.Disclosure of InterestNone Declared
Aims
To investigate the relationship between HbA1c and glucose in people with co‐existing liver disease and diabetes awaiting transplant, and in those with diabetes but no liver disease.
Methods
...HbA1c and random plasma glucose data were collected for 125 people with diabetes without liver disease and for 29 people awaiting liver transplant with diabetes and cirrhosis. Cirrhosis was caused by non‐alcoholic fatty liver disease, hepatitis C, alcoholic liver disease, hereditary haemochromatosis, polycystic liver/kidneys, cryptogenic/non‐cirrhotic portal hypertension and α‐1‐antitrypsin‐related disease.
Results
The median (interquartile range) age of the diabetes with cirrhosis group was 55 (49–63) years compared to 60 (50–71) years (P=0.13) in the group without cirrhosis. In the diabetes with cirrhosis group there were 21 men (72%) compared with 86 men (69%) in the group with diabetes and no cirrhosis (P=0.82). Of the group with diabetes and cirrhosis, 27 people (93%) were of white European ethnicity, two (7%) were South Asian and none was of Afro‐Caribbean/other ethnicity compared with 94 (75%), 16 (13%), 10 (8%)/5 (4%), respectively, in the group with diabetes and no cirrhosis (P=0.20). Median (interquartile range) HbA1c was 41 (32–56) mmol/mol 5.9 (5.1–7.3)% vs 61 (52–70) mmol/mol 7.7 (6.9–8.6)% (P<0.001), respectively, in the diabetes with cirrhosis group vs the diabetes without cirrhosis group. The glucose concentrations were 8.4 (7.0–11.2) mmol/l vs 7.3 (5.2–11.5) mmol/l (P=0.17). HbA1c was depressed by 20 mmol/mol (1.8%; P<0.001) in 28 participants with cirrhosis but elevated by 28 mmol/mol (2.6%) in the participant with α‐1‐antitrypsin disorder. Those with cirrhosis and depressed HbA1c had fewer larger erythrocytes, and higher red cell distribution width and reticulocyte count. This was reflected in the positive association of glucose with mean cell volume (r=0.39) and haemoglobin level (r=0.49) and the negative association for HbA1c (r=–0.28 and r=–0.26, respectively) in the diabetes group with cirrhosis.
Conclusion
HbA1c is not an appropriate test for blood glucose in people with cirrhosis and diabetes awaiting transplant as it reflects altered erythrocyte presentation.
What's new?
HbA1c may not be an accurate reflection of blood glucose for the diagnosis/monitoring of diabetes in people with other illnesses or on certain drugs; people with diabetes and liver disease awaiting transplantation are one such group.
HbA1c was found to be depressed relative to random plasma glucose by 20 mmol/mol in people with diabetes and cirrhosis (n = 28) compared to people with diabetes but no liver disease (n = 125); however, HbA1c was elevated in one person with cirrhosis attributable to α‐1‐antitrypsin disorder.
Compromised HbA1c may be related to haematological differences associated with liver disease involving erythrocyte half‐life, with shorter/longer times giving less/more opportunity for glycation of haemoglobin.
To investigate the relationship between HbA
and glucose in people with co-existing liver disease and diabetes awaiting transplant, and in those with diabetes but no liver disease.
HbA
and random ...plasma glucose data were collected for 125 people with diabetes without liver disease and for 29 people awaiting liver transplant with diabetes and cirrhosis. Cirrhosis was caused by non-alcoholic fatty liver disease, hepatitis C, alcoholic liver disease, hereditary haemochromatosis, polycystic liver/kidneys, cryptogenic/non-cirrhotic portal hypertension and α-1-antitrypsin-related disease.
The median (interquartile range) age of the diabetes with cirrhosis group was 55 (49-63) years compared to 60 (50-71) years (P=0.13) in the group without cirrhosis. In the diabetes with cirrhosis group there were 21 men (72%) compared with 86 men (69%) in the group with diabetes and no cirrhosis (P=0.82). Of the group with diabetes and cirrhosis, 27 people (93%) were of white European ethnicity, two (7%) were South Asian and none was of Afro-Caribbean/other ethnicity compared with 94 (75%), 16 (13%), 10 (8%)/5 (4%), respectively, in the group with diabetes and no cirrhosis (P=0.20). Median (interquartile range) HbA
was 41 (32-56) mmol/mol 5.9 (5.1-7.3)% vs 61 (52-70) mmol/mol 7.7 (6.9-8.6)% (P<0.001), respectively, in the diabetes with cirrhosis group vs the diabetes without cirrhosis group. The glucose concentrations were 8.4 (7.0-11.2) mmol/l vs 7.3 (5.2-11.5) mmol/l (P=0.17). HbA
was depressed by 20 mmol/mol (1.8%; P<0.001) in 28 participants with cirrhosis but elevated by 28 mmol/mol (2.6%) in the participant with α-1-antitrypsin disorder. Those with cirrhosis and depressed HbA
had fewer larger erythrocytes, and higher red cell distribution width and reticulocyte count. This was reflected in the positive association of glucose with mean cell volume (r=0.39) and haemoglobin level (r=0.49) and the negative association for HbA
(r=-0.28 and r=-0.26, respectively) in the diabetes group with cirrhosis.
HbA
is not an appropriate test for blood glucose in people with cirrhosis and diabetes awaiting transplant as it reflects altered erythrocyte presentation.
Background The last decades have witnessed an increasing interest for the psychosocial aspects of chronic skin diseases, such as psoriasis. Nonetheless, systematic assessments of the impact of ...psoriasis on patients’ lives are rarely done in daily clinical practice. The existing instruments are mostly meant to be completed by patients alone, and rarely comprise a graphical representation of the results.
Objective To develop a questionnaire allowing both a quick assessment of the impact of psoriasis on patients and, at the same time, an intuitive graphic visualization of the outcome of the test.
Methods A preliminary version of an Italian questionnaire aimed to assess the global impact of psoriasis on patients, meant to be filled in together by the patient and the dermatologist and to produce visual, intuitive results, was developed through focus groups. The instrument was then the object of a Delphi survey addressed to a panel of experts, to assess both the need of possible improvements of the questionnaire (in terms of the formulations of the questions and of the domains to be explored) and the usefulness of the questionnaire.
Results A 10‐item questionnaire in Italian, taking into account different aspects of the burden of psoriasis on the patient, was developed. The answers are given on a 10‐point visual analogue scale and graphically represented on a disc as a polygon.
Conclusions A formal validation of the questionnaire and a study to assess potential clinical and psychological benefits of a systematic implementation of the instrument in daily practice are planned.
This document summarises the current theoretical and experimental status of the di-Higgs boson production searches, and of the direct and indirect constraints on the Higgs boson self-coupling, with ...the wish to serve as a useful guide for the next years. The document discusses the theoretical status, including state-of-the-art predictions for di-Higgs cross sections, developments on the effective field theory approach, and studies on specific new physics scenarios that can show up in the di-Higgs final state. The status of di-Higgs searches and the direct and indirect constraints on the Higgs self-coupling at the LHC are presented, with an overview of the relevant experimental techniques, and covering all the variety of relevant signatures. Finally, the capabilities of future colliders in determining the Higgs self-coupling are addressed, comparing the projected precision that can be obtained in such facilities. The work has started as the proceedings of the Di-Higgs workshop at Colliders, held at Fermilab from the 4th to the 9th of September 2018, but it went beyond the topics discussed at that workshop and included further developments. FERMILAB-CONF-19-468-E-T, LHCHXSWG-2019-005
Background Some studies have shown that switching patients from one tumor necrosis factor (TNF)-alfa inhibitor to another may be beneficial when they have an inadequate response or an adverse event. ...Objective We sought to assess the variables predicting the efficacy of the second TNF-alfa inhibitor in patients discontinuing the first TNF-alfa inhibitor. Methods Data from all 5423 consecutive patients starting TNF-alfa inhibitor therapy for psoriasis between September 2005 and September 2010 who were included in the Italian Psocare registry were analyzed. Results In 105 patients who switched to a second TNF-alfa inhibitor who had complete follow-up data, 75% improvement in the Psoriasis Area Severity Index score (PASI 75) was reached by 29% after 16 weeks and by 45.6% after 24 weeks. Patients who switched because of secondary loss of efficacy (loss of initial PASI 75 response) or adverse events/intolerance were more likely to reach PASI 75 than those who switched as a result of primary inefficacy (PASI 75 never achieved) (hazard ratio 2.7, 95% confidence interval 1.3-5.5 vs hazard ratio 2.0, 95% confidence interval 1.0-3.9 and 1, respectively). Limitations There was a small number of patients with complete follow-up data. Conclusion PASI 75 response in patients who switched from one anti–TNF-alfa agent to another was significantly reduced in patients who showed primary inefficacy of the first anti–TNF-alfa.
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