Аналіз ефективності використання потенціалу матеріальних ресурсів підприємства

Метою даного дослідження виступає пошук аналітичних можливостей комплексної оцінки та аналізу використання потенціалу матеріальних ресурсів та визначення шляхів підвищення ефективності використання матеріальних ресурсів підприємства

2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism.

OBJECTIVES: Central hypothyroidism (CeH) is a rare form of hypothyroidism characterized by insufficient thyroid stimulation due to disturbed pituitary and/or hypothalamic functioning. Due to its origin and the whole clinical context, CeH represents a challenging condition in clinical practice as it is characterized by suboptimal accuracy of clinical and biochemical parameters for diagnosis and management. Since no expert consensus or guidance for this condition is currently available, a task force of experts received the commitment from the European Thyroid Association (ETA) to prepare this document based on the principles of clinical evidence. STUDY DESIGN: The task force started to work in February 2017 and after a careful selection of appropriate references (cohort studies, case reports, expert opinions), a preliminary presentation and live discussion during the 2017 ETA meeting, and several revision rounds, has prepared a list of recommendations to support the diagnosis and management of patients with CeH. RESULTS: Due to the particular challenges of this rare condition in the different ages, the target users of this guidance are pediatric and adult endocrinologists. Experts agreed on the need to recognize and treat overt CeH at all ages, whereas treatment of milder forms may be dispensable in the elderly (> 75 years). CONCLUSIONS: Despite the lack of randomized controlled clinical trials, the experts provide 34 recommendations supported by variable levels of strength that should improve the quality of life of the affected patients and reduce the metabolic and hormonal consequences of inadequate management.This is a guidelines article so funding sources are not acknowledged. However, my personal grant is from the Wellcome Trus

Pasireotide treatment for severe congenital hyper-insulinism due to a homozygous ABCC8 mutation

ABCC8 and KCJN11 mutations cause the most severe diazoxide-resistant forms of congenital hyperinsulinism (CHI). Somatostatin analogues are considered as secondline treatment in diazoxide-unresponsive cases. Current treatment protocols include the first-generation somatostatin analogue octreotide, although pasireotide, a second-generation somatostatin analogue, might be more effective in reducing insulin secretion. Herein we report the first off-label use of pasireotide in a boy with a severe therapy-resistant form of CHI due to a homozygous ABCC8 mutation. After partial pancreatectomy, hyperinsulinism persisted; in an attempt to prevent further surgery, off-label treatment with pasireotide was initiated. Short-acting pasireotide treatment caused high blood glucose level shortly after injection. Long-acting pasireotide treatment resulted in more stable glycemic control. No side effects (e.g., central adrenal insufficiency) were noticed during a 2-month treatment period. Because of recurrent hypoglycemia despite a rather high carbohydrate intake, the boy underwent near-total pancreatectomy at the age of 11 months. In conclusion, pasireotide treatment slightly improved glycemic control without side effects in a boy with severe CHI. However, the effect of pasireotide was not sufficient to prevent near-total pancreatectomy in this case of severe CHI

The role of transducin β-like 1 X-linked receptor 1 (TBL1XR1) in thyroid hormone metabolism and action in mice

Transducin β-like 1 X-linked receptor 1 (TBL1XR1) is a WD40 repeat-containing protein and part of the corepressor complex SMRT/NCoR that binds to the thyroid hormone receptor (TR). We recently described a mutation in TBL1XR1 in patients with Pierpont syndrome. A mouse model bearing this Tbl1xr1 mutation (Tbl1xr1Y446C/Y446C) displays several aspects of the Pierpont phenotype. Although serum thyroid hormone (TH) concentrations were unremarkable in these mice, tissue TH action might be affected due to the role of TBL1XR1 in the SMRT/NCoR corepressor complex. The aim of the present study was to evaluate tissue TH metabolism and action in a variety of tissues of Tbl1xr1Y446C/Y446C mice. We studied the expression of genes involved in TH metabolism and action in tissues of naïve Tbl1xr1Y446C/Y446C mice and wild type (WT) mice. In addition, we measured deiodinase activity in liver (Dio1 and Dio3), kidney (Dio1 and Dio3) and BAT (Dio2). No striking differences were observed in the liver, hypothalamus, muscle and BAT between Tbl1xr1Y446C/Y446C and WT mice. Pituitary TRα1 mRNA expression was lower in Tbl1xr1Y446C/Y446C mice compared to WT, while the mRNA expression of Tshβ and the positively T3-regulated gene Nmb were significantly increased in mutant mice. Interestingly, Mct8 expression was markedly higher in WAT and kidney of mutants, resulting in (subtle) changes in T3-regulated gene expression in both WAT and kidney. In conclusion, mice harboring a mutation in TBL1XR1 display minor changes in cellular TH metabolism and action. TH transport via MCT8 might be affected as the expression is increased in WAT and kidney. The mechanisms involved need to be clarified

Opposite Incidence Trends for Differentiated and Medullary Thyroid Cancer in Young Dutch Patients over a 30-Year Time Span (vol 13, 5104, 2021)

Error in Figure In the original article [1], there was a mistake in Figure 1 as published. In this figure, two years are missing (2000 and 2001). The AAPC values as previously published are correct. The corrected Figure 1 appears below. In addition, in the original article, there was a mistake in Figure 2A–C as published. In these figures, two years are missing (2000 and 2001). The AAPC values were correct and do not require adjustment. The corrected Figure 2A–C appears below. The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original article has been updated. (figure presented)

Identification of a Novel CYP11B2 Variant in a Family with Varying Degrees of Aldosterone Synthase Deficiency

Isolated aldosterone synthase deficiency is a rare autosomal recessive disorder caused by pathogenic variants in CYP11B2, resulting in impaired aldosterone synthesis. We report on a neonate with isolated aldosterone synthase deficiency caused by a novel homozygous CYP11B2 variant Chr8: NM_000498.3: c.400G>A p.(Gly134Arg). The patient presented shortly after birth with severe signs of aldosterone deficiency. Interestingly, segregation analysis revealed that the patient's asymptomatic father was also homozygous for the CYP11B2 variant. Biochemical evaluation of the father indicated subclinical enzyme impairment, characterized by elevated aldosterone precursors. Apparently, this homozygous variant led to different clinical phenotypes in two affected relatives. In this manuscript we elaborate on the biochemical and genetic work-up performed and describe potential pitfalls in CYP11B2 sequencing due to its homology to CYP11B1

Mutations in IRS4 are associated with central hypothyroidism

Background: Four genetic causes of isolated congenital central hypothyroidism (CeH) have been identified, but many cases remain unexplained. We hypothesised the existence of other genetic causes of CeH with a Mendelian inheritance pattern. Methods: We performed exome sequencing in two families with unexplained isolated CeH and subsequently Sanger sequenced unrelated idiopathic CeH cases. We performed clinical and biochemical characterisation of the probands and carriers identified by family screening. We investigated IRS4 mRNA expression in human hypothalamus and pituitary tissue, and measured serum thyroid hormones and Trh and Tshb mRNA expression in hypothalamus and pituitary tissue of Irs4 knockout mice. Results: We found mutations in the insulin receptor substrate 4 (IRS4) gene in two pairs of brothers with CeH (one nonsense, one frameshift). Sequencing of IRS4 in 12 unrelated CeH cases negative for variants in known genes yielded three frameshift mutatio

Molecular mechanisms involved in pulmonary arterial hypertension development

Pulmonary arterial hypertension (PAH) is an elevation in pulmonary arterial pressure, characterized by symptoms of dyspnea, chest pain, decrease in exercise tolerance-fatigue, syncope and, if untreated, PAH leads to right heart failure. In PAH, there is an imbalance between mediators of vasodilation and vasoconstriction (e.g. nitric oxide and prostacycline – potent vasodilators, platelet inhibitor and antimitogens are decreased in PAH, while thromboxane, vasoconstrictor and platelet activator is increased in PAH, resulting in smooth muscle hypertrophy of small vessels, adventitial and intimal proliferation, and plexiform vascular lesions with vascular thrombosis). Standard diagnostic procedures for PAH include physical examination, pulmonary function testing, radiographic imaging, transthoracic echocardiography, right heart catheterization. Current drugs include synthet c prostanoids (iloprost, epoprostenil, beraprost, treprostinil) – vasodilators and antiplatelet agents. Phosphodiesterase-5 inhibitors decrease the breakdown of cGMP, increasing its intracellular levels, leukotriene receptor antagonist, – zafirlukast, decreases pulmonary arterial and venous pressure. Endothelin receptor blockers, bosentan, decrease pulmonary vascular resistance and improve results of functional tests. Other treatments are: anticoagulants, calcium-channel blockers, positive airway pressure therapy for obstructive sleep apnea, or oxygen for hypoxemia, and surgery. In conclusion, although there are some promising drugs in therapy of PAH, there is a need to develop new ones, together with surgical approaches, in order to increase the survival of patients with PAH. Gene and cell therapy could be expected as future perspectives