Project description:Recombinant blood clotting factor VIII is one of the most complex proteins for industrial manufacturing due to the low efficiency of its gene transcription, massive intracellular loss of its proprotein during post-translational processing, and the instability of the secreted protein. Improvement in hemophilia A therapy requires a steady increase in the production of factor VIII drugs despite tightening standards of product quality and viral safety. More efficient systems for heterologous expression of factor VIII can be created on the basis of the discovered properties of its gene transcription, post-translational processing, and behavior in the bloodstream. The present review describes the deletion variants of factor VIII protein with increased secretion efficiency and the prospects for the pharmaceutical development of longer acting variants and derivatives of factor VIII.
Project description:Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and ischemic end organ injury due to microvascular platelet-rich thrombi. TTP results from a severe deficiency of the specific von Willebrand factor (VWF)-cleaving protease, ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13). ADAMTS13 deficiency is most commonly acquired due to anti-ADAMTS13 autoantibodies. It can also be inherited in the congenital form as a result of biallelic mutations in the ADAMTS13 gene. In adults, the condition is most often immune-mediated (iTTP) whereas congenital TTP (cTTP) is often detected in childhood or during pregnancy. iTTP occurs more often in women and is potentially lethal without prompt recognition and treatment. Front-line therapy includes daily plasma exchange with fresh frozen plasma replacement and immunosuppression with corticosteroids. Immunosuppression targeting ADAMTS13 autoantibodies with the humanized anti-CD20 monoclonal antibody rituximab is frequently added to the initial therapy. If available, anti-VWF therapy with caplacizumab is also added to the front-line setting. While it is hypothesized that refractory TTP will be less common in the era of caplacizumab, in relapsed or refractory cases cyclosporine A, N-acetylcysteine, bortezomib, cyclophosphamide, vincristine, or splenectomy can be considered. Novel agents, such as recombinant ADAMTS13, are also currently under investigation and show promise for the treatment of TTP. Long-term follow-up after the acute episode is critical to monitor for relapse and to diagnose and manage chronic sequelae of this disease.
Project description:Acquired haemophilia A (AHA) is a rare haemorrhagic disease characterized by spontaneous extensive subcutaneous haemorrhage and soft tissue haematoma. The activated partial thromboplastin time is significantly prolonged and cannot be corrected by normal plasma. Approximately 50% of AHA patients lack a specific aetiology, so this can easily result in a misdiagnosis. This current case report describes a 27-year-old male that presented with gingival bleeding, haematuria and haematochezia with no obvious cause. At first, it was thought that he might have experienced anticoagulant rodenticide poisoning, but the subsequent anticoagulant rodenticide test was negative. At the same time, the patient was screened for mutations associated with bleeding and coagulation diseases. Two mutations were identified: a p.Y471H mutation the plasminogen activator, tissue type (PLAT) gene; and a p.Y244Y mutation the serpin family E member 1 (SERPINE1) gene. It should be noted that patient had no previous history of thrombosis or haemorrhagic disease, which confused the diagnosis. A professional haemophilia research centre provided clarification of the diagnosis when anti-factor VIII antibodies were detected. The patient was treated with 30 mg/day prednisone orally. Multiple follow-up examinations showed continuous complete remission. No factor VIII antibodies were detected in his blood and coagulation factor VIII increased significantly.
Project description:Chylothorax is a rare condition characterized by the accumulation of chyle in the pleural space. While it accounts for a small percentage of pleural effusions, chylothorax can lead to significant morbidity and mortality. This article provides a comprehensive overview of chylothorax, covering its relevant anatomy, aetiology, pathophysiology, clinical features, diagnosis, and management. Injury or disruption to the thoracic duct (which is responsible for chyle transport) leads to the development of chylothorax. This may result from trauma, such as iatrogenic injury during surgery, or non-traumatic causes, including malignancy, lymphatic disorders, and heart failure. Recognition of the underlying cause is essential to tailor management. Clinical presentation varies, with symptoms linked to rate of chyle accumulation and the causative condition. Diagnosis relies on pleural fluid analysis, with demonstration of elevated triglyceride levels (>110 mg/dL) and reduced cholesterol levels (<200 mg/dL) being the key diagnostic criteria employed in clinical practice. Various imaging modalities, including computed tomography (CT) scans and lymphatic-specific investigations, may be utilised to aid identification of the site of chyle leak, as well as determine the likely underlying cause. Chylothorax management is multifaceted, with conservative approaches such as dietary modification and pharmacological interventions often initiated as first-line treatment. Drainage of chylous effusion may be necessary for symptom relief. When conservative methods fail, interventional procedures like thoracic duct ligation or embolization can be considered. Due to the diverse aetiological factors and patient characteristics associated with chylothorax, individualized management strategies are recommended. Nonetheless, management of chylothorax is an evolving field with a paucity of high-quality evidence or standardized guidelines, highlighting the importance of ongoing research and a multidisciplinary approach to optimize individual patient care.
Project description:Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency that exemplifies the broad clinical features of primary immunodeficiencies (PIDs), extending beyond recurrent infections to include atopy, autoimmunity and cancer. It is caused by loss of function mutations in DOCK8, encoding a guanine nucleotide exchange factor highly expressed in lymphocytes that regulates the actin cytoskeleton. Additional roles of DOCK8 have also emerged, including regulating MyD88-dependent Toll-like receptor signaling and the activation of the transcription factor STAT3. DOCK8 deficiency impairs immune cell migration, function and survival, and it impacts both innate and adaptive immune responses. Clinically, DOCK8 deficiency is characterized by allergic inflammation as well as susceptibility towards infections, autoimmunity and malignancy. This review details the pathophysiology, clinical features and management of DOCK8 deficiency. It also surveys the recently discovered combined immunodeficiency due to DOCK2 deficiency, highlighting in the process the emerging spectrum of PIDs resulting from DOCK protein family abnormalities.
Project description:Objective An acquired uterine arteriovenous malformation (AVM) is a rare cause of vaginal bleeding and, although hysterectomy is the definitive therapy, transcatheter embolization (TCE) provides an alternative treatment option. This systematic review presents the indications, technique, and outcomes for transcatheter treatment of the acquired uterine AVMs. Study Design Literature databases were searched from 2003 to 2013 for eligible clinical studies, including the patient characteristics, procedural indication, results, complications, as well as descriptions on laterality and embolic agents utilized. Results A total of 40 studies were included comprising of 54 patients (average age of 33.4 years). TCE had a primary success rate with symptomatic control of 61% (31 patients) and secondary success rate of 91% after repeated embolization. When combined with medical therapy, symptom resolution was noted in 48 (85%) patients without more invasive surgical procedures. Conclusion Low-level evidence supports the role of TCE, including in the event of persistent bleeding following initial embolization, for the treatment of acquired uterine AVMs. The variety of embolic agents and laterality of approach delineate the importance of refining procedural protocols in the treatment of the acquired uterine AVM. Condensation A review on the management of patients with acquired uterine AVMs.
Project description:Restless legs syndrome (RLS), a common neurological sensorimotor disorder in western countries, has gained more and more attention in Asian countries. The prevalence of RLS is higher in older people and females. RLS is most commonly related to iron deficiency, pregnancy and uremia. The RLS symptoms show a significant circadian rhythm and a close relationship to periodic limb movements (PLMs) in clinical observations, while the pathophysiological pathways are still unknown. The diagnostic criteria have been revised in 2012 to improve the validity of RLS diagnosis. Recent studies have suggested an important role of iron decrease of brain in RLS pathophysiology. Dopaminergic (DA) system dysfunction in A11 cell groups has been recognized long ago from clinical treatment and autopsy. Nowadays, it is believed that iron dysfunction can affect DA system from different pathways and opioids have a protective effect on DA system. Several susceptible single nucleotide polymorphisms such as BTBD9 and MEIS1, which are thought to be involved in embryonic neuronal development, have been reported to be associated with RLS. Several pharmacological and non-pharmacological treatment are discussed in this review. First-line treatments of RLS include DA agents and α2δ agonists. Augmentation is very common in long-term treatment of RLS which makes prevention and management of augmentation very important for RLS patients. A combination of different types of medication is effective in preventing and treating augmentation. The knowledge on RLS is still limited, the pathophysiology and better management of RLS remain to be discovered.
Project description:Herpetic infections have plagued humanity for thousands of years, but only recently have advances in antiviral medications and supportive treatments equipped physicians to combat the most severe manifestations of disease. Prompt recognition and treatment can be life-saving in the care of patients with herpes simplex-1 virus encephalitis, the most commonly identified cause of sporadic encephalitis worldwide. Clinicians should be able to recognize the clinical signs and symptoms of the infection and familiarize themselves with a rational diagnostic approach and therapeutic modalities, as early recognition and treatment are key to improving outcomes. Clinicians should also be vigilant for the development of acute complications, including cerebral edema and status epilepticus, as well as chronic complications, including the development of autoimmune encephalitis associated with antibodies to the N-methyl-D-aspartate receptor and other neuronal cell surface and synaptic epitopes. Herein, we review the pathophysiology, differential diagnosis, and clinical and radiological features of herpes simplex virus-1 encephalitis in adults, including a discussion of the most common complications and their treatment. While great progress has been made in the treatment of this life-threatening infection, a majority of patients will not return to their previous neurologic baseline, indicating the need for further research efforts aimed at improving the long-term sequelae.
Project description:Nearly 40% of patients presenting to the catheter laboratory with angina have non-obstructed coronary arteries (ANOCA), an umbrella term that encompasses distinct pathophysiological entities, such as coronary artery spasm. Coronary artery spasm leads to sudden reversible coronary flow attenuation, which clinically manifests as vasospastic angina (VSA). VSA is associated with poor quality of life and an increased risk of major adverse cardiac events. However, the pathophysiological mechanisms underlying this phenomenon are incompletely understood, which has resulted in limited therapeutic options for patients afflicted with this condition. The past decade has seen a surge in new research being conducted in the field of ANOCA and VSA. This review article provides a comprehensive summary of the underlying pathophysiological mechanisms of VSA and the current therapeutic options. We also appraise the current diagnostic approach in patients with suspected VSA.
Project description:BackgroundAcquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that usually mimics type 1 or 2A von Willebrand disease (VWD).Key clinical questionCan AVWS mimic the phenotype of type 2B VWD?Clinical approachA 64-year-old male patient presented with thrombocytopenia, normal routine hemostasis results, and normal VWF antigen and factor VIII levels but reduced von Willebrand factor (VWF) activity (31 IU/dL). The ristocetin-induced platelet aggregation test showed paradoxical aggregation at low doses of ristocetin, suggesting type 2B VWD, but no deleterious sequence variation was found in either the VWF or GP1BA genes, compatible with AVWS. Serum protein electrophoresis revealed a monoclonal immunoglobulin G antibody.ConclusionThis AVWS with a 2B phenotype VWD was probably related to a monoclonal immunoglobulin G antibody causing a VWF conformational change, resulting in increased affinity to platelet glycoprotein-Ib. In the event of surgery or bleeding, treatment with vonicog alfa seems to be the best option for this patient.