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2-methylacetoacetyl-coenzyme A thiolase (beta-ketothiolase) deficiency: one disease - two pathways
(2019)
Background: 2-methylacetoacetyl-coenzyme A thiolase deficiency (MATD; deficiency of mitochondrial acetoacetyl-coenzyme A thiolase T2/ “beta-ketothiolase”) is an autosomal recessive disorder of ketone body utilization and isoleucine degradation due to mutations in ACAT1.
Methods: We performed a systematic literature search for all available clinical descriptions of patients with MATD. 244 patients were identified and included in this analysis. Clinical course and biochemical data are presented and discussed.
Results: For 89.6 % of patients at least one acute metabolic decompensation was reported. Age at first symptoms ranged from 2 days to 8 years (median 12 months). More than 82% of patients presented in the first two years of life, while manifestation in the neonatal period was the exception (3.4%). 77.0% (157 of 204 patients) of patients showed normal psychomotor development without neurologic abnormalities.
Conclusion: This comprehensive data analysis provides a systematic overview on all cases with MATD identified in the literature. It demonstrates that MATD is a rather benign disorder with often favourable outcome, when compared with many other organic acidurias.
Background 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is an autosomal recessive disorder of ketogenesis and leucine degradation due to mutations in HMGCL .
Method We performed a systematic literature search to identify all published cases. 211 patients of whom relevant clinical data were available were included in this analysis. Clinical course, biochemical findings and mutation data are highlighted and discussed. An overview on all published HMGCL variants is provided.
Results More than 95% of patients presented with acute metabolic decompensation. Most patients manifested within the first year of life, 42.4% already neonatally. Very few individuals remained asymptomatic. The neurologic long-term outcome was favorable with 62.6% of patients showing normal development.
Conclusion This comprehensive data analysis provides a systematic overview on all published cases with HMGCLD including a list of all known HMGCL mutations.
The number of studies on work breaks and the importance of this subject is growing rapidly, with research showing that work breaks increase employees’ wellbeing and performance and workplace safety. However, comparing the results of work break research is difficult since the study designs and methods are heterogeneous and there is no standard theoretical model for work breaks. Based on a systematic literature search, this scoping review included a total of 93 studies on experimental work break research conducted over the last 30 years. This scoping review provides a first structured evaluation regarding the underlying theoretical framework, the variables investigated, and the measurement methods applied. Studies using a combination of measurement methods from the categories “self-report measures,” “performance measures,” and “physiological measures” are most common and to be preferred in work break research. This overview supplies important information for ergonomics researchers allowing them to design work break studies with a more structured and stronger theory-based approach. A standard theoretical model for work breaks is needed in order to further increase the comparability of studies in the field of experimental work break research in the future.
Dysregulation of IL12 Signaling As a Novel Cause of an Autoimmune Lymphoproliferative like Syndrome
(2014)
BACKGROUND
In recent randomized clinical trials, an unusual reporting pattern of glycemic data and hypoglycemic events potentially related to an internet enabled blood glucose meter (MyGlucoHealth, BGM) was observed. Therefore, this clinical study was conducted to evaluate the system accuracy of the BGM in accordance with the ISO15197:2015 guidelines with additional data collection.
METHODS
To investigate system accuracy, 10 of 3088 devices and 6 of 23 strip lots, used in the trials, were selected by a randomization procedure and a standard repeatability assessment. YSI 2300 STAT Plus was used as the standard reference method. The samples were distributed as per the ISO15197:2015 recommendations with 20 additional samples in the hypoglycemic range. Each sample was tested with 6 devices and 6 strip lots with double determinations.
RESULTS
Overall, 121 subjects with blood glucose values 26-423 mg/dL were analyzed, resulting in 1452 data points. In all, 186/1452 readings (12.8%) did not meet the ISO acceptance criteria. Data evaluated according to the FDA guidelines showed that 336/1452 (23.1%) readings did not meet the acceptance criteria. A clear bias toward elevated values was observed for BG <100 mg/dL (MARD: 11.0%).
CONCLUSIONS
The results show that the BGM, although approved according to standard regulatory guidelines, did not meet the level of analytical accuracy required for clinical treatment decisions according to ISO 15197:2015 and FDA requirements. In general, caution should be exercised before selection of BGMs for patients and in clinical trials.
BACKGROUND
In recent clinical trials, use of the MyGlucoHealth blood glucose meter (BGM) and electronic diary was associated with an unusual reporting pattern of glycemic data and hypoglycemic events. Therefore, the performance of representative BGMs used by the patients was investigated to assess repeatability, linearity, and hematocrit interference in accordance with regulatory guidelines.
METHOD
Ten devices and 6 strip lots were selected using standard randomization and repeatability procedures. Venous heparinized blood was drawn from healthy subjects, immediately aliquoted and adjusted to 5 target blood glucose (BG) ranges for the repeatability and 11 BG concentrations for the linearity tests. For the hematocrit interference test, each sample within 5 target BG ranges was split into 5 aliquots and adjusted to hematocrit levels across the acceptance range. YSI 2300 STAT Plus was used as the laboratory reference method in all experiments.
RESULTS
Measurement repeatability or precision was acceptable across the target BG ranges for all devices and strip lots with coefficient of variation (CV) between 3.4-9.7% (mean: 5.7%). Linearity was shown by a correlation coefficient of .991; however, a positive bias was seen for BG <100 mg/dL (86% measurements did not meet ISO15197:2015 acceptance criteria). Significant hematocrit interference (up to 20%) was observed for BG >100 mg/dL (ISO15197:2015 acceptance criteria: ±10%), while the results were acceptable for BG <100 mg/dL.
CONCLUSIONS
The BGM met repeatability requirements but demonstrated a significant measurement bias in the low BG range. In addition, it failed the ISO15197:2015 criteria for hematocrit interference.
In der folgenden Übersicht werden die allgemeinen Vorteile von Bewegungsinterventionen im Wasser innerhalb der physikalischen Therapiemöglichkeiten sowie bei den Diagnosen Lip- und Lymphödem angesprochen. Aufgrund von positiven Erfahrungen bei Lymphödempatientinnen werden hier Einzelfallkasuistiken bzgl. des Einsatzes von Aqua-Cycling bei Lipödem vorgestellt, die weitere Untersuchungen anstoßen sollten.
CD is a rare, autosomal recessive neurometabolic disorder with often devastating clinical consequences. It typically presents in early infancy. Clinical symptoms and MRI-based findings are chronic neurological deterioration with irritability and severe global developmental delay, loss of early milestones, macrocephaly, and seizures together with white matter abnormalities in the brain (“leukodystrophy”). CD is biochemically characterized by a deficiency of aspartoacylase along with the accumulation of NAA in the brain and in body fluids, particularly in urine. In the majority of CD patients, the disease leads to early death. As there is no cure for this condition, management of affected children and their families is symptom orientated and supportive and includes a multidisciplinary medical team.
Fixed-dose combination of pioglitazone and glimepiride in the treatment of Type 2 diabetes mellitus
(2007)
Type 2 diabetes is characterized by impaired insulin sensitivity and disturbances in β-cell function. While glimepiride stimulates β-cell secretion and leads to a reduction of blood glucose levels, pioglitazone activates peroxisome proliferator-activated receptor-γ and improves insulin resistance. Combining these two modes of action has been shown to improve glucose and lipid metabolism, and to improve the overall cardiovascular risk in patients with Type 2 diabetes. The combination of glimepiride and pioglitazone is generally well tolerated and a fixed combination may lead to an improved compliance in patients. The purpose of this review is to evaluate the clinical data that has been published on this combination, appearing to represent a convenient way to obtain therapeutic targets in patients with Type 2 diabetes mellitus.
Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD+ and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD+, whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML. Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML.
Serine/threonine kinase 4 (STK4) deficiency is an autosomal recessive genetic condition that leads to primary immunodeficiency (PID) typically characterized by lymphopenia, recurrent infections and Epstein Barr Virus (EBV) induced lymphoproliferation and -lymphoma. State-of-the-art treatment regimens consist of prevention or treatment of infections, immunoglobulin substitution (IVIG) and restoration of the immune system by hematopoietic stem cell transplantation. Here, we report on two patients from two consanguineous families of Turkish (patient P1) and Moroccan (patient P2) decent, with PID due to homozygous STK4 mutations. P1 harbored a previously reported frameshift (c.1103 delT, p.M368RfsX2) and P2 a novel splice donor site mutation (P2; c.525+2 T>G). Both patients presented in childhood with recurrent infections, CD4 lymphopenia and dysregulated immunoglobulin levels. Patient P1 developed a highly malignant B cell lymphoma at the age of 10 years and a second, independent Hodgkin lymphoma 5 years later. To our knowledge she is the first STK4 deficient case reported who developed lymphoma in the absence of detectable EBV or other common viruses. Lymphoma development may be due to the lacking tumor suppressive function of STK4 or the perturbed immune surveillance due to the lack of CD4+ T cells. Our data should raise physicians' awareness of [1] lymphoma proneness of STK4 deficient patients even in the absence of EBV infection and [2] possibly underlying STK4 deficiency in pediatric patients with a history of recurrent infections, CD4 lymphopenia and lymphoma and unknown genetic make-up. Patient P2 experienced recurrent otitis in childhood, but when she presented at the age of 14, she showed clinical and immunological characteristics similar to patients suffering from Autoimmune Lymphoproliferative Syndrome (ALPS): elevated DNT cell number, non-malignant lymphadenopathy and hepatosplenomegaly, hematolytic anemia, hypergammaglobulinemia. Also patient P1 presented with ALPS-like features (lymphadenopathy, elevated DNT cell number and increased Vitamin B12 levels) and both were initially clinically diagnosed as ALPS-like. Closer examination of P2, however, revealed active EBV infection and genetic testing identified a novel STK4 mutation. None of the patients harbored typically ALPS-associated mutations of the Fas receptor mediated apoptotic pathway and Fas-mediated apoptosis was not affected. The presented case reports extend the clinical spectrum of STK4 deficiency.
Funktionseinschränkungen nach erworbener Hirnschädigung können die Mobilität der Betroffenen beeinträchtigen und zu gravierenden Änderungen des Lebensstils bis hin zur Inaktivität führen. Es ist davon auszugehen, dass ein inaktiver Lebensstil den Gesundheitszustand weiter verschlechtert und sich für die Betroffenen daraus ein erhöhtes Risiko für weitere chronische Erkrankungen ergibt. Bisherige Studienergebnisse beschreiben weder das Aktivitätsverhalten von Menschen mit erworbener Hirnschädigung noch wurden geeignete Interventionen zur nachhaltigen Steigerung der körperlichen Aktivität (KA) entwickelt. Ziel der vorliegenden Arbeit war es ein umfassendes Abbild des Aktivitätsverhaltens im Alltag von Menschen mit erworbener Hirnschädigung zu erstellen sowie die Machbarkeit und die Auswirkungen einer Bewegungsintervention auf das Aktivitätsverhalten und die Lebensqualität zu untersuchen.
In 2018, in the US alone, it is estimated that 268,670 people will be diagnosed with breast cancer, and that 41,400 will die from it. Since breast cancers often become resistant to therapies, and certain breast cancers lack therapeutic targets, new approaches are urgently required. A cell-stress response pathway, the unfolded protein response (UPR), has emerged as a promising target for the development of novel breast cancer treatments. This pathway is activated in response to a disturbance in endoplasmic reticulum (ER) homeostasis but has diverse physiological and disease-specific functions. In breast cancer, UPR signalling promotes a malignant phenotype and can confer tumours with resistance to widely used therapies. Here, we review several roles for UPR signalling in breast cancer, highlighting UPR-mediated therapy resistance and the potential for targeting the UPR alone or in combination with existing therapies.
Once aberrantly activated, the Wnt/βcatenin pathway may result in uncontrolled proliferation and eventually cancer. Efforts to counter and inhibit this pathway are mainly directed against βcatenin, as it serves a role on the cytoplasm and the nucleus. In addition, speciallygenerated lymphocytes are recruited for the purpose of treating liver cancer. Peripheral blood mononuclear lymphocytes are expanded by the timely addition of interferon γ, interleukin (IL)1β, IL2 and anticluster of differentiation 3 antibody. The resulting cells are called cytokineinduced killer (CIK) cells. The present study utilised these cells and combine them with drugs inhibiting the Wnt pathway in order to examine whether this resulted in an improvement in the killing ability of CIK cells against liver cancer cells. Drugs including ethacrynic acid (EA) and ciclopirox olamine (CPX) were determined to be suitable candidates, as determined by previous studies. Drugs were administered on their own and combined with CIK cells and then a cell viability assay was performed. These results suggest that EAtreated cells demonstrated apoptosis and were significantly affected compared with untreated cells. Unlike EA, CPX killed normal and cancerous cells even at low concentrations. Subsequent to combining EA with CIK cells, the potency of killing was increased and a greater number of cells died, which proves a synergistic action. In summary, EA may be used as an antihepatocellular carcinoma drug, while CPX possesses a high toxicity to cancerous as well as to normal cells. It was proposed that EA should be integrated into present therapeutic methods for cancer.
Amaç: Keton cisim oluşumu (ketogenez) bozuklukları; mitokondriyel 3-hidroksi-3metil glutaril CoA sentaz (Mhs) ve 3-hidroksi-3-metil glutaril CoA liyaz (HL) enzim eksiklikleri sonucu oluşur. Keton cisim yıkımı (ketoliz) bozuklukları ise suksinil CoA: 3 oksoasit CoA transferaz (SCOT) ve asetoasetil CoA thiolaz-beta ketotiolaz (MAT) enzim eksiklikleri sonucu oluşmaktadır. Keton metabolizma bozukluğu tanısıyla izlenen hastaların klinik ve laboratuvar bulguları ile değerlendirilmesi amaçlandı.
Yöntem: Keton metabolizması bozukluğu tanısıyla izlenen hasta verileri retrospektif olarak incelendi.
Bulgular: Dört hastada HL eksikliği, 3 hastada MAT eksikliği ve 2 hastada SCOT eksikliği tanısı mevcuttu. Hastaların ortanca yaşı 5 yıl (6 ay-15,5 yıl), ilk metabolik dekompanzasyon atak yaşı ortalama 7,7 ay (22 gün-19 ay) idi. MAT eksikliği olan bir hasta, kardeş taraması ile asemptomatik dönemde tanı aldı. İki hastada spastik tetraparezi gibi ağır nörolojik defisit gelişti. Dekompanzasyon ataklarının beslenememe, kusma ve gastroenterit gibi infeksiyon sonrası geliştiği görüldü.
Sonuç: Açıklanamayan metabolik asidoz atakları durumunda keton metabolizma bozuklukları akılda tutulmalıdır. Akut dekompanzasyon değişik yaşlarda ortaya çıkabilir, klinik şiddeti değişken olabilir. Erken tanı ve uygun tedavi mortalite ve morbidite açısından çok önemlidir.
The efficiency of nitrous oxide in an equimolar mixture with oxygen or in concentrations up to 70% is approved for short painful procedures. Evaluation of the vitamin B12 levels in anesthetic staff applying nitrous oxide showed reduced vitamin B12 plasma levels. This study examines the vitamin B12 status of medical staff working with nitrous oxide in a pediatric emergency department (ED). Medical staff of the ED at the University Children's Hospital Zurich participated. The vitamin B12 status was evaluated by measuring homocysteine, methylmalonic acid, vitamin B12, blood count, and the MTHFR C677T genotype. As a control group, medical personnel working in the “nitrous oxide–free” pediatric intensive care unit were recruited.
Gene expression and cell growth rely on the intracellular concentration of amino acids, which in metazoans depends on extracellular amino acid availability and transmembrane transport. To investigate the impact of extracellular amino acid concentrations on the expression of a concentrative amino acid transporter, we overexpressed the main kidney proximal tubule luminal neutral amino acid transporter B0AT1-collectrin (SLC6A19-TMEM27) in MDCK cell epithelia. Exogenously expressed proteins co-localized at the luminal membrane and mediated neutral amino acid uptake. However, the transgenes were lost over few cell culture passages. In contrast, the expression of a control transgene remained stable. To test whether this loss was due to inappropriately high amino acid uptake, freshly transduced MDCK cell lines were cultivated either with physiological amounts of amino acids or with the high concentration found in standard cell culture media. Expression of exogenous transporters was unaffected by physiological amino acid concentration in the media. Interestingly, mycoplasma infection resulted in a significant increase in transgene expression and correlated with the rapid metabolism of L-arginine. However, L-arginine metabolites were shown to play no role in transgene expression. In contrast, activation of the GCN2 pathway revealed by an increase in eIF2α phosphorylation may trigger transgene derepression. Taken together, high extracellular amino acid concentration provided by cell culture media appears to inhibit the constitutive expression of concentrative amino acid transporters whereas L-arginine depletion by mycoplasma induces the expression of transgenes possibly via stimulation of the GCN2 pathway.
