A survey of gastroprotective drugs: prescription-indication in hospitalized patients

La prescripción de fármacos antiulcerosos en medio hospitalario, y su influencia posterior en atención primaria, se incrementó en los últimos años y con ello el gasto farmacéutico. El objetivo del presente estudio es analizar la prevalencia de prescripción de antiulcerosos en nuestro centro hospitalario y la adecuación a las indicaciones establecidas. Se realizó un estudio observacional de prescripción-indicación con 2 cortes transversales separados en 6 meses para evitar sesgos de selección. Se constata el uso elevado de gastroprotectores, principalmente inhibidores de bomba de protones, sobre todo en profilaxis de gastropatía por antiinflamatorios no esteroideos (AINE) (17,1%), con una tasa de prescripciones incorrectas del 77,6% a pesar de la existencia de un protocolo específico elaborado por el comité de farmacia y terapéutica de nuestro centro. Destaca el número elevado de prescripciones en pacientes con corticoterapia sin asociación con AINE (25,7%). Se requieren nuevas herramientas que impliquen al facultativo y a los gestores clínicos en el uso racional de medicamentosPrescription rates of antiulcer drugs in hospitals and their spill-over to general practice have risen over the last few years, increasing pharmaceutical expenses. The aim of this study was to analyze gastroprotective drug prescription habits in our hospital by assessing both prevalence and adherence to approved indications. An observational study of prescription-indication was performed with 2 cross sections separated by 6 months to avoid selection bias. We found overprescription of gastroprotective drugs, mainly proton pump inhibitors for the prevention of non-steroidal antiinflammatory drug-induced ulcer (17.1%). Overall, 77.6% of prescriptions had no acceptable indication, despite the availability of a specific protocol produced by the Pharmacy and Therapeutics Committee in our center. There was a high prevalence of prescriptions for non-approved indications such as prophylaxis in patients administered cor-ticosteroids without non-steroidal anti-inflammatory agents (25.7%). New programs to train clinicians and clinical mana-gers in rational drug use are requiredS

Autoxidation and MAO-mediated metabolism of dopamine as a potential cause of oxidative stress: role of ferrous and ferric ions

The autoxidation and monoamine oxidase (MAO)-mediated metabolism of dopamine (3-hydroxytyramine; DA) cause a continuous production of hydroxyl radical (radical dotOH), which is further enhanced by the presence of iron (ferrous iron, Fe2+ and ferric ion, Fe3+). The accumulation of hydrogen peroxide (H2O2) in the presence of Fe2+ appears to discard the involvement of the Fenton reaction in this process. It has been found that the presence of DA significantly reduces the formation of thiobarbituric acid reagent substances (TBARS), which under physiological conditions takes place in mitochondrial preparations. The presence of DA is also able to reduce TBARS formation in mitochondrial preparations even in the presence of iron (Fe2+ and Fe3+). However, DA boosted the carbonyl content of mitochondrial proteins, which was further increased in the presence of iron (Fe2+ and Fe3+). This latter effect is also accompanied by a significant reduction in thiol content of mitochondrial proteins. It has also been observed how the pre-incubation of mitochondria with pargyline, an acetylenic MAO inhibitor, reduces the production of radical dotOH and increases the formation of TBARS. Although, the MAO-mediated metabolism of DA increases MAO-B activity, the presence of iron inhibits both MAO-A and MAO-B activities. Consequently, DA has been shown to be a double-edged sword, because it displays antioxidant properties in relation to both the Fenton reaction and lipid peroxidation and exhibits pro-oxidant properties by causing both generation radical dotOH and oxidation of mitochondrial proteins. Evidently, these pro-oxidant properties of DA help explain the long-term side effects derived from l-DOPA treatment of Parkinson’s disease and its exacerbation by the concomitant use of DA metabolism inhibitors.This study was supported by Grant BFI2003-00493 from the Ministerio de Ciencia y Tecnologı́a, Madrid (Spain).S

Familial partial lipodystrophy syndromes

Lipodystrophies are a heterogeneous group of rare conditions characterised by the loss of adipose tissue. The most common forms are the familial partial lipodystrophy (FPLD) syndromes, which include a set of disorders, usually autosomal dominant, due to different pathogenetic mechanisms leading to improper fat distribution (loss of fat in the limbs and gluteal region and variable regional fat accumulation). Affected patients are prone to suffering serious morbidity via the development of metabolic complications associated to insulin resistance and an inability to properly store lipids. Although no well-defined diagnostic criteria have been established for lipodystrophy, there are certain clues related to medical history, physical examination and body composition evaluation that may suggest FPLD prior to confirmatory genetic analysis. Its treatment must be fundamentally oriented towards the control of the metabolic abnormalities. In this sense, metreleptin therapy, the newer classes of hypoglycaemic agents and other investigational drugs are showing promising results. This review aims to summarise the current knowledge of FPLD syndromes and to describe their clinical and molecular picture, diagnostic approaches and recent treatment modalities.This study was supported by the Instituto de Salud Carlos III and the European Regional Development Fund, ERDF (Grant No. PI081449), and an intramural grant from the Xunta de Galicia (GPC2014/036, ED341b 2017/19, ED431B 2020/37). A.F.-P. is a Rio Hortega researcher (ISCIII; CM20/00155). S.S.I. was awarded a Research Fellowship, granted by the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP).S

Effects of aluminum and zinc on the oxidative stress caused by 6-hydroxydopamine autoxidation: relevance for the pathogenesis of Parkinson’s disease

AbstractAluminum and zinc have been related to the pathogenesis of Parkinson’s disease (PD), the former for its neurotoxicity and the latter for its apparent antioxidant properties. 6-Hydroxydopamine (6-OHDA) is an important neurotoxin putatively involved in the pathogenesis of PD, its neurotoxicity often being related to oxidative stress. The potential effect of these metals on the oxidative stress induced by 6-OHDA autoxidation and the potential of ascorbic acid (AA), cysteine, and glutathione to modify this effect were investigated. Both metals, particularly Al3+, induced a significant reduction in ⋅OH production by 6-OHDA autoxidation. The combined action of AA and a metal caused a significant and sustained increase in ⋅OH generation, particularly with Al3+, while the effect of sulfhydryl reductants was limited to only the first few minutes of the reaction. However, both Al3+ and Zn2+ provoked a decrease in the lipid peroxidation induced by 6-OHDA autoxidation using mitochondrial preparations from rat brain, assessed by TBARS formation. In the presence of AA, only Al3+ induced a significant reduction in lipid peroxidation. After intrastriatal injections of 6-OHDA in rats, tyrosine hydroxylase immunohistochemistry revealed that Al3+ reduces 6-OHDA-induced dopaminergic lesion in the striatum, which corroborates the involvement of lipid peroxidation in 6-OHDA neurotoxicity and appears to discard the participation of this mechanism on PD by Al3+ accumulation. The previously reported antioxidant properties of Zn2+ appear to be related to the induction of Zn2+-containing proteins and not to the metal per se

Variable expressivity in type 2 familial partial lipodystrophy related to R482 and N466 variants in the LMNA gene

Patients with Dunnigan disease (FPLD2) with a pathogenic variant affecting exon 8 of the LMNA gene are considered to have the classic disease, whereas those with variants in other exons manifest the “atypical” disease. The aim of this study was to investigate the degree of variable expressivity when comparing patients carrying the R482 and N466 variants in exon 8. Thus, 47 subjects with FPLD2 were studied: one group of 15 patients carrying the N466 variant and the other group of 32 patients with the R482 variant. Clinical, metabolic, and body composition data were compared between both groups. The thigh skinfold thickness was significantly decreased in the R482 group in comparison with the N466 group (4.2 ± 1.8 and 5.6 ± 2.0 mm, respectively, p = 0.002), with no other differences in body composition. Patients with the N466 variant showed higher triglyceride levels (177.5 [56–1937] vs. 130.0 [55–505] mg/dL, p = 0.029) and acute pancreatitis was only present in these subjects (20%). Other classic metabolic abnormalities related with the disease were present regardless of the pathogenic variant. Thus, although FPLD2 patients with the R482 and N466 variants share most of the classic characteristics, some phenotypic and metabolic differences suggest possible heterogeneity even within exon 8 of the LMNA gene.This study was supported by the Instituto de Salud Carlos III and the European Regional Development Fund, ERDF (grant no. PI081449), and an intramural grant from the Xunta de Galicia, ED431B 2020/37. S.S.-I. was awarded a Research Fellowship, granted by the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP).S

Variable Expressivity and Allelic Heterogeneity in Type 2 Familial Partial Lipodystrophy: The p.(Thr528Met) LMNA Variant

Type 2 familial partial lipodystrophy, or Dunnigan disease, is a metabolic disorder characterized by abnormal subcutaneous adipose tissue distribution. This rare condition results from variants principally affecting exons 8 and 11 of the LMNA gene. In this study, five FPLD2-diagnosed patients carrying the c.1583C>T, p.(Thr528Met) variant in exon 9 of the LMNA gene and with obvious clinical heterogeneity were evaluated. Specific polymorphisms in LMNA and in PPARG were also detected. Exhaustive clinical course, physical examination, biochemical features and family history were recorded, along with the assessment of anthropometric features and body composition by dual-energy X-ray absorptiometry. Preadipocytes obtained from a T528M patient were treated with the classic adipose differentiation medium with pioglitazone. Various adipogenes were evaluated by real-time PCR, and immunofluorescence was used to study intracellular localization of emerin, lamin A and its precursors. As demonstrated with Oil red O staining, the preadipocytes of the T528M patient failed to differentiate, the expression of various adipogenic genes was reduced in the lipodystrophic patient and immunofluorescence studies showed an accumulation of farnesylated prelamin A in T528M cells. We conclude that the T528M variant in LMNA could lead to FPLD2, as the adipogenic machinery is compromisedThis research was funded by the Instituto de Salud Carlos III and the European Regional Development Fund, FEDER (grant number PI081449), and an intramural grant from the Xunta de Galicia (grant number ED431B 2020/37). S.S.I. was awarded a Research Fellowship by the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP)S

Celia’s Encephalopathy (BSCL2-Gene-Related): Current Understanding

Seipin, encoded by the BSCL2 gene, is a protein that in humans is expressed mainly in the central nervous system. Uniquely, certain variants in BSCL2 can cause both generalized congenital lipodystrophy type 2, upper and/or lower motor neuron diseases, or progressive encephalopathy, with a poor prognosis during childhood. The latter, Celia’s encephalopathy, which may or may not be associated with generalized lipodystrophy, is caused by the c.985C >T variant. This cytosine to thymine transition creates a cryptic splicing zone that leads to intronization of exon 7, resulting in an aberrant form of seipin, Celia seipin. It has been proposed that the accumulation of this protein, both in the endoplasmic reticulum and in the nucleus of neurons, might be the pathogenetic mechanism of this neurodegenerative condition. In recent years, other variants in BSCL2 associated with generalized lipodystrophy and progressive epileptic encephalopathy have been reported. Interestingly, most of these variants could also lead to the loss of exon 7. In this review, we analyzed the molecular bases of Celia’s encephalopathy and its pathogenic mechanisms, the clinical features of the different variants, and a therapeutic approach in order to slow down the progression of this fatal neurological disorderThis work was supported by the Instituto de Salud Carlos III and the European Regional Development Fund, FEDER (grant numbers PI10/02873 and PI13/00314), by the Consellería de Industria, Xunta de Galicia (grant numbers 10PXIB208013PR, ED341b 2017/19 and ED431B 2020/37), and by Fundación Mutua Madrileña (Call 2015). S.S.I. was awarded a Research Fellowship, granted by the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP)S

Identification of a Novel Variant in EARS2 Associated with a Severe Clinical Phenotype Expands the Clinical Spectrum of LTBL

The EARS2 nuclear gene encodes mitochondrial glutamyl-tRNA synthetase, a member of the class I family of aminoacyl-tRNA synthetases (aaRSs) that plays a crucial role in mitochondrial protein biosynthesis by catalyzing the charging of glutamate to mitochondrial tRNA(Glu). Pathogenic EARS2 variants have been associated with a rare mitochondrial disorder known as leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). The targeted sequencing of 150 nuclear genes encoding respiratory chain complex subunits and proteins implicated in the oxidative phosphorylation (OXPHOS) function was performed. The oxygen consumption rate (OCR), and the extracellular acidification rate (ECAR), were measured. The enzymatic activities of Complexes I-V were analyzed spectrophotometrically. We describe a patient carrying two heterozygous EARS2 variants, c.376C>T (p.Gln126*) and c.670G>A (p.Gly224Ser), with infantile-onset disease and a severe clinical presentation. We demonstrate a clear defect in mitochondrial function in the patient’s fibroblasts, suggesting the molecular mechanism underlying the pathogenicity of these EARS2 variants. Experimental validation using patient-derived fibroblasts allowed an accurate characterization of the disease-causing variants, and by comparing our patient’s clinical presentation with that of previously reported cases, new clinical and radiological features of LTBL were identified, expanding the clinical spectrum of this diseaseThis study was supported with a competitive PhD grant from a pre-Doctoral scholarship for research groups of the Health Research Institute of Santiago (IDIS)S

LipoDDx: a mobile application for identification of rare lipodystrophy syndromes

Background: Lipodystrophy syndromes are a group of disorders characterized by a loss of adipose tissue once other situations of nutritional deprivation or exacerbated catabolism have been ruled out. With the exception of the HIV-associated lipodystrophy, they have a very low prevalence, which together with their large phenotypic heterogeneity makes their identification difficult, even for endocrinologists and pediatricians. This leads to significant delays in diagnosis or even to misdiagnosis. Our group has developed an algorithm that identifies the more than 40 rare lipodystrophy subtypes described to date. This algorithm has been implemented in a free mobile application, LipoDDx®. Our aim was to establish the effectiveness of LipoDDx®. Forty clinical records of patients with a diagnosis of certainty of most lipodystrophy subtypes were analyzed, including subjects without lipodystrophy. The medical records, blinded for diagnosis, were evaluated by 13 physicians, 1 biochemist and 1 dentist. Each evaluator first gave his/her results based on his/her own criteria. Then, a second diagnosis was given using LipoDDx®. The results were analysed based on a score table according to the complexity of each case and the prevalence of the disease. Results: LipoDDx® provides a user-friendly environment, based on usually dichotomous questions or choice of clinical signs from drop-down menus. The final result provided by this app for a particular case can be a low/high probability of suffering a particular lipodystrophy subtype. Without using LipoDDx® the success rate was 17 ± 20%, while with LipoDDx® the success rate was 79 ± 20% (p < 0.01).Project financed with an intramural grant from the Xunta de Galicia, ED341b 2017/19. S.S-I was awarded a Research Fellowship, granted by the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP).S