Explore the vast range of titles available.

Congenital factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder characterized by prolonged prothrombin time (PT) and reduced FVII coagulant activity (FVII: C). Here, we present the case of a middle-aged male patient with gastrointestinal bleeding, who exhibited prolonged PT and decreased FVII: C levels. Gene sequencing analysis revealed compound heterozygous mutations in the F7 gene: c.64G > A (p.V22I) and c.506-1G > A. Based on the laboratory results and gene sequencing, the patient was diagnosed as FVII deficiency. After adding recombinant activated FVII (rFVIIa) for several days, the laboratory indicators returned to normal and the bleeding symptoms were relieved. In subsequent validation studies, we also identified the c.506-1G > A mutation in his older sister and daughter. Importantly, this represents the first documented case where both mutations coexist concurrently. Additionally, our literature review reveals that approximately 50% of mutation types associated with congenital FVII deficiency are located on exon 9; however, there is no significant correlation between the reduction in FVII: C levels and severity of clinical symptoms based on EAHAD database analysis.

Factor XIII (FXIII) is a protein involved in blood clot stabilisation which also plays an important role in processes including trauma, wound healing, tissue repair, pregnancy, and even bone metabolism. Following surgery, low FXIII levels have been observed in patients with peri-operative blood loss and FXIII administration in those patients was associated with reduced blood transfusions. Furthermore, in patients with low FXIII levels, FXIII supplementation reduced the incidence of post-operative complications including disturbed wound healing. Increasing awareness of potentially low FXIII levels in specific patient populations could help identify patients with acquired FXIII deficiency; although opinions and protocols vary, a cut-off for FXIII activity of ~ 60–70% may be appropriate to diagnose acquired FXIII deficiency and guide supplementation. This narrative review discusses altered FXIII levels in trauma, surgery and wound healing, diagnostic approaches to detect FXIII deficiency and clinical guidance for the treatment of acquired FXIII deficiency.

Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by widespread intravascular activation of coagulation that can be caused by infectious insults (such as sepsis) and non-infectious insults (such as trauma). The main pathophysiological mechanisms of DIC are inflammatory cytokine-initiated activation of tissue factor-dependent coagulation, insufficient control of anticoagulant pathways and plasminogen activator inhibitor 1-mediated suppression of fibrinolysis. Together, these changes give rise to endothelial dysfunction and microvascular thrombosis, which can cause organ dysfunction and seriously affect patient prognosis. Recent observations have pointed to an important role for extracellular DNA and DNA-binding proteins, such as histones, in the pathogenesis of DIC. The International Society on Thrombosis and Haemostasis (ISTH) established a DIC diagnostic scoring system consisting of global haemostatic test parameters. This scoring system has now been well validated in diverse clinical settings. The theoretical cornerstone of DIC management is the specific and vigorous treatment of the underlying conditions, and DIC should be simultaneously managed to improve patient outcomes. The ISTH guidance for the treatment of DIC recommends treatment strategies that are based on current evidence. In this Primer, we provide an updated overview of the pathophysiology, diagnosis and management of DIC and discuss the future directions of basic and clinical research in this field. Disseminated intravascular coagulation can be caused by various infectious and non-infectious insults, such as sepsis and trauma, respectively. It is characterized by the widespread activation of coagulation and, depending on the underlying condition, can manifest as bleeding and/or thrombosis.

E2f transcription factors The in vivo function of E2f transcription factors has been a matter of debate. Here it is shown that E2f1–3 contribute to the activation of cell cycle genes in dividing progenitor cells during mouse development but are dispensable for cell division. However, in differentiating cells, E2f1–3 act as repressors to facilitate cell cycle exit. The in vivo function of E2f transcription factors has been a matter of debate. The effects of E2f1 , E2f2 and E2f3 triple deficiency are now examined in murine embryonic stem cells, embryos and small intestines. E2f1–3 are shown to function as transcriptional activators in normal dividing progenitor cells; however, contrary to the current view, they are dispensable for cell division but are necessary for cell survival. In the established model of mammalian cell cycle control, the retinoblastoma protein (Rb) functions to restrict cells from entering S phase by binding and sequestering E2f activators ( E2f1 , E2f2 and E2f3 ), which are invariably portrayed as the ultimate effectors of a transcriptional program that commit cells to enter and progress through S phase 1 , 2 . Using a panel of tissue-specific cre -transgenic mice and conditional E2f alleles we examined the effects of E2f1 , E2f2 and E2f3 triple deficiency in murine embryonic stem cells, embryos and small intestines. We show that in normal dividing progenitor cells E2f1–3 function as transcriptional activators, but contrary to the current view, are dispensable for cell division and instead are necessary for cell survival. In differentiating cells E2f1–3 function in a complex with Rb as repressors to silence E2f targets and facilitate exit from the cell cycle. The inactivation of Rb in differentiating cells resulted in a switch of E2f1–3 from repressors to activators, leading to the superactivation of E2f responsive targets and ectopic cell divisions. Loss of E2f1–3 completely suppressed these phenotypes caused by Rb deficiency. This work contextualizes the activator versus repressor functions of E2f1–3 in vivo, revealing distinct roles in dividing versus differentiating cells and in normal versus cancer-like cell cycles.

Homozygous mutation of the Csf1r locus ( Csf1rko ) in mice, rats and humans leads to multiple postnatal developmental abnormalities. To enable analysis of the mechanisms underlying the phenotypic impacts of Csf1r mutation, we bred a rat Csf1rko allele to the inbred dark agouti (DA) genetic background and to a Csf1r -mApple reporter transgene. The Csf1rko led to almost complete loss of embryonic macrophages and ablation of most adult tissue macrophage populations. We extended previous analysis of the Csf1rko phenotype to early postnatal development to reveal impacts on musculoskeletal development and proliferation and morphogenesis in multiple organs. Expression profiling of 3-week old wild-type (WT) and Csf1rko livers identified 2760 differentially expressed genes associated with the loss of macrophages, severe hypoplasia, delayed hepatocyte maturation, disrupted lipid metabolism and the IGF1/IGF binding protein system. Older Csf1rko rats developed severe hepatic steatosis. Consistent with the developmental delay in the liver Csf1rko rats had greatly-reduced circulating IGF1. Transfer of WT bone marrow (BM) cells at weaning without conditioning repopulated resident macrophages in all organs, including microglia in the brain, and reversed the mutant phenotypes enabling long term survival and fertility. WT BM transfer restored osteoclasts, eliminated osteopetrosis, restored bone marrow cellularity and architecture and reversed granulocytosis and B cell deficiency. Csf1rko rats had an elevated circulating CSF1 concentration which was rapidly reduced to WT levels following BM transfer. However, CD43 hi non-classical monocytes, absent in the Csf1rko , were not rescued and bone marrow progenitors remained unresponsive to CSF1. The results demonstrate that the Csf1rko phenotype is autonomous to BM-derived cells and indicate that BM contains a progenitor of tissue macrophages distinct from hematopoietic stem cells. The model provides a unique system in which to define the pathways of development of resident tissue macrophages and their local and systemic roles in growth and organ maturation.

BackgroundFactor VII deficiency is considered a contraindication to neuraxial anesthesia due to the risk of an epidural hematoma.Case ReportA 32 year old G1P0 parturient with severe factor VII deficiency presented for an anesthesiology consultation at 32 weeks gestation. Initial coagulation studies were significant for an elevated INR (2.0) and a low factor VII level of 6%. After interdisciplinary discussion, it was decided that neuraxial analgesia could be offered if her coagulation studies corrected after administration of recombinant activated factor VII (rFVIIa). The patient presented at 36 weeks gestation for a rFVIIa challenge. She received 22 mcg/kg rFVIIa and coagulation studies were analyzed 20 minutes later which showed complete correction of the coagulopathy. The patient presented to the hospital at 39 weeks and 3 days for delivery, received 2 mg rFVIIa and 20 minutes later, successfully received an epidural catheter. Her INR was monitored every 3 hours during her labor course and rFVIIa was given if the INR was 1.3 or greater. She required three additional doses over 22 hours. No bleeding or thrombotic events occurred, and the patient was discharged home without complications.ConclusionThis case highlights the safe management of an epidural catheter in a parturient with severe factor VII deficiency.

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1 – 4 . Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5 – 8 . By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9 , 10 . However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3 , 4 . Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2 , CBFA2T3 , PRDM6 , UTX and OTX2 . CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens , and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES + KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB. Derailed differentiation of human-specific progenitors of the developing cerebellar rhombic lip is the cause of group 4 medulloblastoma, the most common childhood brain tumour. 

Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration.

Perineural invasion (PNI) is thought to be one of the factors responsible for the high rate of tumor recurrence after surgery and the pain generation associated with pancreatic cancer. Signaling via the nerve growth factor (NGF) pathway between pancreatic cancer cells and the surrounding nerves has been implicated in PNI, and increased levels of these proteins have been correlated to poor prognosis. In this study, we examine the molecular mechanism of the NGF signaling pathway in PNI in pancreatic cancer. We show that knocking down NGF or its receptors, TRKA and p75NTR, or treatment with GW441756, a TRKA kinase inhibitor, reduces the proliferation and migration of pancreatic cancer cells in vitro. Furthermore, pancreatic cancer cells migrate towards dorsal root ganglia (DRG) in a co-culture assay, indicating a paracrine NGF signaling between the DRGs and pancreatic cancer cells. Knocking down the expression of NGF pathway proteins or inhibiting the activity of TRKA by GW441756 reduced the migratory ability of Mia PaCa2 towards the DRGs. Finally, blocking NGF signaling by NGF neutralizing antibodies or GW441756 inhibited the neurite formation in PC-12 cells in response to conditioned media from pancreatic cancer cells, indicating a reciprocal signaling pathway between the pancreatic cancer cells and nerves. Our results indicate that NGF signaling pathway provides a potential target for developing molecularly targeted therapies to decrease PNI and reduce pain generation. Since there are several TRKA antagonists currently in early clinical trials they could now be tested in the clinical situation of pancreatic cancer induced pain.

Idiopathic retroperitoneal fibrosis is an IgG4-related disease where pathological role and clinical significance of IgG4 antibodies remain largely unknown. This report shows a rare case of retroperitoneal fibrosis in presence of Autoimmune coagulation factor XIII deficiency, in which an acute life-threatening hemorrhage was successfully managed with effective treatment strategies. Following this, we investigated the molecular mechanisms underlying the patient's pathology using experimental translational approach. The patient was a 60-year-old Asian man with a retroperitoneal mass. A laparoscopic biopsy confirmed that the lesion was retroperitoneal fibrosis with IgG4-expressing plasma cell infiltration. Though biopsy was completed without complications, the patient experienced repeated life-threatening intraperitoneal bleeding starting the next day. Despite performing one emergency laparotomy and three series of emergency transcatheter arterial embolization along with massive transfusions, achieving hemostasis was difficult. Suspecting a humoral autoimmune hemorrhagic disorder, we performed plasma exchange, which achieved complete hemostasis. Later, an abnormal decrease in the activity of coagulation Factor XIII was observed, leading to the diagnosis of Autoimmune coagulation Factor XIII deficiency. Subsequent treatment with steroids and coagulation Factor XIII concentrates prevented further bleeding. We investigated the potential involvement of IgG4-related disease and the effects of IgG4 on coagulation Factor XIII using an system, and it was demonstrated that both IgG1 and IgG4 recognized the A subunit of coagulation Factor XIII. The purified IgG antibody samples containing IgG1 and IgG4 were shown to significantly reduce the function of coagulation Factor XIII derived from healthy individuals. The patient experienced recurrent life-threatening bleeding due to Autoimmune coagulation Factor XIII deficiency, which was successfully controlled through plasma exchange therapy. This is the first reported case of concurrent retroperitoneal fibrosis and Autoimmune coagulation Factor XIII deficiency. Based on the results of our research, it is suggested IgG4 may play a role in the pathology of both disorders. It was hypothesized that this hematological disorder could be a part of the spectrum of IgG4 autoimmune diseases.