Project description:Several excellent guidelines and expert opinions on congenital hypothyroidism (CH) are currently available. Nonetheless, these guidelines do not address several issues related to CH in detail. In this review, the authors chose the following seven clinical issues that they felt were especially deserving of closer scrutiny in the hope that drawing attention to them through discussion would help pediatric endocrinologists and promote further interest in the treatment of CH. 1. How high should the levothyroxine (L-T4) dose be for initial treatment of severe and permanent CH? 2. What is the optimal method for monitoring treatment of severe CH? 3. At what level does maternal iodine intake during pregnancy affect fetal and neonatal thyroid function? 4. Does serum thyroglobulin differ between patients with a dual oxidase 2 (DUOX2) variants and those with excess iodine? 5. Who qualifies for a genetic diagnosis? 6. What is the best index for distinguishing transient and permanent CH? 7. Is there any cancer risk associated with CH? The authors discussed these topics and jointly edited the manuscript to improve the understanding of CH and related issues.
Project description:Patients with certain types of fibrosing interstitial lung disease (ILD) are at risk of developing a progressive phenotype characterised by self-sustaining fibrosis, decline in lung function, worsening quality of life, and early mortality. It has been proposed that such progressive fibrosing ILDs, which show commonalities in clinical behaviour and in the pathogenetic mechanisms that drive progressive fibrosis, may be "lumped" together for the purposes of clinical research and, potentially, for treatment. At present, no drugs are approved for the treatment of ILDs other than nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis. For other progressive fibrosing ILDs, the mainstay of drug therapy is immunosuppression. However, it is postulated that, once the response to lung injury in fibrosing ILDs has reached the stage at which fibrosis has become progressive and self-sustaining, targeted antifibrotic therapy would be required to slow disease progression. Nintedanib, an intracellular inhibitor of tyrosine kinases, has shown antifibrotic, anti-inflammatory and vascular remodelling effects in several non-clinical models of fibrosis, irrespective of the trigger for the injury. Ongoing clinical trials will provide insight into the role of antifibrotic treatment with nintedanib or pirfenidone in the management of fibrosing ILDs with a progressive phenotype.
Project description:Hypothyroidism is common throughout the world and readily diagnosed with thyroid function tests. Management should be straightforward but appears not to be the case. Thyroid hormone replacement with levothyroxine monotherapy is the standard treatment which is effective in the majority of cases. However, 10-15% of patients established on levothyroxine do not feel their health is entirely restored and some patients prefer the addition of liothyronine. Proponents of liothyronine argue that the ratio of T3 and T4 hormones is substantially altered on T4 monotherapy and therefore both hormones may be needed for optimal health. This remains controversial as clinical trials have not demonstrated superiority of combination therapy (levothyroxine and liothyronine) over levothyroxine monotherapy. There is now a pressing need for further studies and in particular randomized controlled trials in this area. To help design and facilitate dedicated trials and better understand thyroid hormone replacement, this review summarizes the evidence where there is established knowledge and agreement (knowns) and areas where research is lacking (unknowns). Agreements include the extent of dissatisfaction with levothyroxine monotherapy, biases in testing for hypothyroidism and prescribing levothyroxine, as well as variable thresholds for prescribing levothyroxine and challenges in liothyronine dosing. The review will also highlight and summarize the unknowns including the long-term safety profile of liothyronine, and potential biomarkers to identify individuals who might benefit most from combination therapy.
Project description:Adiponectin is an adipokine associated with the healthy obese phenotype. Adiponectin increases insulin sensitivity and has cardio and vascular protection actions. Studies related to adiponectin, a modulator of the innate and acquired immunity response, have suggested a role of this molecule in asthma. Studies based on various asthma animal models and on the key cells involved in the allergic response have provided important insights about this relation. Some of them indicated protection and others reversed the balance towards negative effects. Many of them described the cellular pathways activated by adiponectin, which are potentially beneficial for asthma prevention or for reduction in the risk of exacerbations. However, conclusive proofs about their efficiency still need to be provided. In this article, we will, briefly, present the general actions of adiponectin and the epidemiological studies supporting the relation with asthma. The main focus of the current review is on the mechanisms of adiponectin and the impact on the pathobiology of asthma. From this perspective, we will provide arguments for and against the positive influence of this molecule in asthma, also indicating the controversies and sketching out the potential directions of research to complete the picture.
Project description:Tuberculosis (TB), one of the deadliest threats to human health, is mainly caused by 2 highly related and human-adapted bacteria broadly known as Mycobacterium tuberculosis and Mycobacterium africanum. Whereas M. tuberculosis is widely spread, M. africanum is restricted to West Africa, where it remains a significant cause of tuberculosis. Although several differences have been identified between these 2 pathogens, M. africanum remains a lot less studied than M. tuberculosis. Here, we discuss the genetic, phenotypic, and clinical similarities and differences between strains of M. tuberculosis and M. africanum. We also discuss our current knowledge on the immune response to M. africanum and how it possibly articulates with distinct disease progression and with the geographical restriction attributed to this pathogen. Understanding the functional impact of the diversity existing in TB-causing bacteria, as well as incorporating this diversity in TB research, will contribute to the development of better, more specific approaches to tackle TB.
Project description:Acute myeloid leukemia (AML) is a heterogeneous disease characterized by malignant proliferation of myeloid hematopoietic stem/progenitor cells. NPM1 represents the most frequently mutated gene in AML and approximately 30% of AML cases carry NPM1 mutations. Mutated NPM1 result in the cytoplasmic localization of NPM1 (NPM1c). NPM1c interacts with other proteins to block myeloid differentiation, promote cell proliferation and impair DNA damage repair. NPM1 is a good prognostic marker, but some patients ultimately relapse or fail to respond to therapy. It is urgent for us to find optimal therapies for NPM1-mutated AML. Efficacy of multiple drugs is under investigation in NPM1-mutated AML, and several clinical trials have been registered. In this review, we summarize the present knowledge of therapy and focus on the possible therapeutic interventions for NPM1-mutated AML.
Project description:Photosynthesis is the process that harnesses, converts and stores light energy in the form of chemical energy in bonds of organic compounds. Oxygenic photosynthetic organisms (i.e., plants, algae and cyanobacteria) employ an efficient apparatus to split water and transport electrons to high-energy electron acceptors. The photosynthetic system must be finely balanced between energy harvesting and energy utilisation, in order to limit generation of dangerous compounds that can damage the integrity of cells. Insight into how the photosynthetic components are protected, regulated, damaged, and repaired during changing environmental conditions is crucial for improving photosynthetic efficiency in crop species. Photosystem I (PSI) is an integral component of the photosynthetic system located at the juncture between energy-harnessing and energy consumption through metabolism. Although the main site of photoinhibition is the photosystem II (PSII), PSI is also known to be inactivated by photosynthetic energy imbalance, with slower reactivation compared to PSII; however, several outstanding questions remain about the mechanisms of damage and repair, and about the impact of PSI photoinhibition on signalling and metabolism. In this review, we address the knowns and unknowns about PSI activity, inhibition, protection, and repair in plants. We also discuss the role of PSI in retrograde signalling pathways and highlight putative signals triggered by the functional status of the PSI pool.
Project description:Alcoholic hepatitis is an acute, inflammatory liver disease associated with high morbidity and mortality both in the short term and long term. Alcoholic hepatitis often arises in patients with a background of chronic liver disease and it is characterised by the rapid onset of jaundice and the development of myriad complications. Medical therapy for severe alcoholic hepatitis relies on corticosteroids, which have modest effectiveness. Abstinence from alcohol is critically important in patients with alcoholic hepatitis, but recidivism is high. Because of the absence of effective medical treatments for alcoholic hepatitis and alcohol dependency, there is a pressing need to develop new and effective therapeutics. Supported by promising preliminary and preclinical studies, many ongoing clinical trials of new therapies for alcoholic hepatitis are currently underway and are discussed further in this Series paper.
Project description:Vitamin B6 is an ensemble of six interconvertible vitamers: pyridoxine (PN), pyridoxamine (PM), pyridoxal (PL), and their 5'-phosphate derivatives, PNP, PMP, and PLP. Pyridoxal 5'-phosphate is a coenzyme in a variety of enzyme reactions concerning transformations of amino and amino acid compounds. This review summarizes all known and putative PLP-binding proteins found in the Escherichia coli MG1655 proteome. PLP can have toxic effects since it contains a very reactive aldehyde group at its 4' position that easily forms aldimines with primary and secondary amines and reacts with thiols. Most PLP is bound either to the enzymes that use it as a cofactor or to PLP carrier proteins, protected from the cellular environment but at the same time readily transferable to PLP-dependent apoenzymes. E. coli and its relatives synthesize PLP through the seven-step deoxyxylulose-5-phosphate (DXP)-dependent pathway. Other bacteria synthesize PLP in a single step, through a so-called DXP-independent pathway. Although the DXP-dependent pathway was the first to be revealed, the discovery of the widespread DXP-independent pathway determined a decline of interest in E. coli vitamin B6 metabolism. In E. coli, as in most organisms, PLP can also be obtained from PL, PN, and PM, imported from the environment or recycled from protein turnover, via a salvage pathway. Our review deals with all aspects of vitamin B6 metabolism in E. coli, from transcriptional to posttranslational regulation. A critical interpretation of results is presented, in particular, concerning the most obscure aspects of PLP homeostasis and delivery to PLP-dependent enzymes.
Project description:The biogenic monoamine serotonin (5-hydroxytryptamine, 5-HT) is a chemical messenger widely distributed in the brain and various other organs. Its homeostasis is maintained by the coordinated activity of a variety of proteins, including enzymes of serotonin metabolism, transmembrane transporters of serotonin, and serotonin receptors. The serotonin system has been identified also in the placenta in rodent models as a key component of placental physiology. However, serotonin pathways in the human placenta are far from well understood. Their alterations may have long-lasting consequences for the fetus that can manifest later in life. In this review, we summarize information on the location of the components of the serotonin system in the human placenta, their regulation, function, and alterations in pathological pregnancies. We highlight current controversies and discuss important topics for future research.