Cyclic vomiting syndrome and benign paroxysmal torticollis are associated with a high risk of developing primary headache: A longitudinal study.

BACKGROUND AND AIM: Episodic syndromes that may be associated with migraine are a group of disorders affecting patients with migraine or with an increased risk of presenting it, and likely represent an early life expression of migraine. Cyclic vomiting syndrome and benign paroxysmal torticollis are well characterized and represent a frequent cause of request for specialist consultations. The aim of this study is to longitudinally assess the rate of headache in patients presenting with cyclic vomiting syndrome and benign paroxysmal torticollis during infancy, and to define the main clinical features of the disorder. METHODS: We administered a questionnaire to the parents of all our pediatric patients with previous diagnosis of cyclic vomiting syndrome and/or benign paroxysmal torticollis according to ICHD-3; questions were focused on the main clinical features of the disorder as well as the prognosis, with particular emphasis on the development of headache. RESULTS: For the final analysis we considered 82 patients with cyclic vomiting syndrome and 33 with benign paroxysmal torticollis. Seventy-nine percent of patients with cyclic vomiting syndrome presented with headache during the follow-up, with a mean age at onset of 6 years; 67% of patients with benign paroxysmal torticollis suffered from headache during the follow-up, with a mean age at onset of 5 years. DISCUSSION: Cyclic vomiting syndrome and benign paroxysmal torticollis are associated with a very high risk of developing headache, mostly migraine, later in life. In both groups of patients, the vast majority presented with different episodic syndromes that may be associated with migraine at different ages, thus suggesting an age-dependent evolution of migraine-like symptoms before the onset of clear migrainous headache.

Position paper of the Italian Society of Internal Medicine (SIMI) on prophylaxis and treatment of venous thromboembolism in patients with cancer.

Cancer patients are at high risk of developing thrombotic events, including venous thromboembolism (VTE) [deep venous thrombosis (DVT) and pulmonary embolism (PE)], and arterial thrombosis. DVT and PE represent the second leading cause of death in cancer patients; moreover, the development of thromboembolic events in cancer patients is linked to a greater need of hospitalization and frequency of side effects during treatment, in particular bleeding, and to an increased risk of recurrence during and following antithrombotic therapy. The thromboembolic risk may be different in different subgroups of cancer population, being highest in patients with metastatic disease, patients with pancreas, stomach, kidney or primary brain cancer, or during therapeutic interventions or surgery. This document focuses on several relevant topics including the epidemiology and pathogenesis of cancer-associated VTE, the current and future strategies of primary prevention and anticoagulant treatment, and the management of bleeding complications. The main literature data are discussed in detail, including, when available, evidence from randomized clinical trials and meta-analyses, international guidelines statements, the results of recently published trials comparing direct oral anticoagulants to low molecular weight heparin, and the design and aims of ongoing trials on prevention/treatment of cancer-associated VTE.

Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome.

Rivaroxaban is an effective and safe alternative to warfarin in patients with atrial fibrillation and venous thromboembolism. We tested the efficacy and safety of rivaroxaban compared with warfarin in high-risk patients with thrombotic antiphospholipid syndrome. This is a randomized open-label multicenter noninferiority study with blinded end point adjudication. Rivaroxaban, 20 mg once daily (15 mg once daily based on kidney function) was compared with warfarin (international normalized ratio target 2.5) for the prevention of thromboembolic events, major bleeding, and vascular death in patients with antiphospholipid syndrome. Only high-risk patients triple positive for lupus anticoagulant, anti-cardiolipin, and anti-ß2-glycoprotein I antibodies of the same isotype (triple positivity) were included in the study. The trial was terminated prematurely after the enrollment of 120 patients (59 randomized to rivaroxaban and 61 to warfarin) because of an excess of events among patients in the rivaroxaban arm. Mean follow-up was 569 days. There were 11 (19%) events in the rivaroxaban group, and 2 (3%) events in the warfarin group. Thromboembolic events occurred in 7 (12%) patients randomized to rivaroxaban (4 ischemic stroke and 3 myocardial infarction), whereas no event was recorded in those randomized to warfarin. Major bleeding occurred in 6 patients: 4 (7%) in the rivaroxaban group and 2 (3%) in the warfarin group. No death was reported. The use of rivaroxaban in high-risk patients with antiphospholipid syndrome was associated with an increased rate of events compared with warfarin, thus showing no benefit and excess risk. This trial was registered at www.clinicaltrials.gov as #NCT02157272.

Obstetrical history of women with cerebral vein thrombosis: outcome of the pregnancies before and after the thrombotic event.

Cerebral vein thrombosis (CVT) is a rare disease usually affecting young people, especially women, with a high prevalence of thrombophilic defects. It is known that thrombophilia is associated with pregnancy complications; therefore, a high rate of complications could be expected in women with the previous CVT who become pregnant. This study examined the whole obstetric history of women who suffered from CVT to evaluate the incidence of pregnancy complications during their entire lifespan. We prospectively followed consecutive patients with CVT, limiting the analysis to females and their obstetrical history. We studied 123 pregnancies in 99 consecutive women who had a CVT; 71 women had 91 pregnancies before the CVT; 19 women had 23 pregnancies after the CVT; and nine women had a CVT related to pregnancy. All women with CVT before pregnancy were treated with LMWH at prophylactic dosage during pregnancy. No recurrent CVT, venous thromboembolic events, or death was recorded during the observed pregnancies. Ten miscarriages were recorded (rate 8.1%), with a rate similar to that expected in the general population. We confirm the favorable outcome of pregnancies in women who suffered from CVT during their entire lifespan, whether they have occurred before and after or in relation to CVT.

Thrombosis in Autoimmune Diseases: A Role for Immunosuppressive Treatments?

Autoimmune diseases are not infrequently associated with arterial or venous thrombotic events. Chronic inflammation and immune system impairment are considered the main pathogenetic mechanisms. Some of the drugs used in the treatment of such diseases have been associated with an increased risk of thrombosis. On the contrary, their anti-inflammatory and immune modulator activity could correct some mechanisms leading to thrombosis. In this review, recent evidence available on this topic is examined. There is a lack of adequate studies, but available evidence suggests that glucocorticoids and high-dose immunoglobulins are associated with an increased incidence of venous thromboembolism. Although available data do not allow drawing definite conclusions and more data are needed from future studies and registries, physicians should be aware of these associations.

Novel oral anticoagulants in atrial fibrillation: which novel oral anticoagulant for which patient?

Atrial fibrillation is the most common rhythm disorder and represents a major public health problem because it carries an increased risk of arterial thromboembolism and ischemic stroke. Current european society of cardiology guidelines recommend to stratify atrial fibrillation patients according to the CHA2DS2-VASc score and to administer anticoagulation, preferably with novel oral anticoagulants, that is, dabigatran, rivaroxaban, or apixaban, if the CHA2DS2-VASc score is at least 1. All novel anticoagulants have shown the same, if not greater, efficacy and safety as warfarin, with some advantages. The choice among the novel oral anticoagulants depends on their different pharmacokinetic profile, patients' stroke and bleeding risk, comorbidities, drug tolerability and costs and, finally, patients' preferences.

Residual perfusion defects in patients with pulmonary embolism are related to impaired fibrinolytic capacity.

BACKGROUND: Few studies investigated the relationship between fibrinolysis abnormalities and residual pulmonary perfusion defects after acute pulmonary embolism (PE). OBJECTIVE: To assess the fibrinolytic profile in patients with prior PE in relation to the extent of scintigraphically detectable residual perfusion abnormalities. PATIENTS AND METHODS: We studied 71 consecutive patients with a prior episode of PE, who were examined after one year of the incident embolic event, and at least one month after anticoagulation withdrawal. They underwent lung scintigraphy to assess the recovery of pulmonary perfusion, echocardiography and chest radiography to look for signs of pulmonary hypertension. Clot formation and lysis were evaluated by two turbidimetric methods: Clot and Lysis Assay and Clot Lysis Time. We also measured the in vitro plasmin-mediated lysis of fibrin from purified fibrinogen, and the circulating levels of fibrinolytic inhibitors. The sample was split in two categories based on the extent of residual perfusion defects: <10% (n=53), ≥ 10% (n=18). RESULTS: Patients with perfusion defects >10% had significantly longer lysis time (p<0.05), and higher levels of plasminogen activator inhibitor-1 (p<0.01) than those with perfusion defects <10%. The time interval between symptoms onset and PE diagnosis (time-to-diagnosis) was significantly longer in patients with perfusion defects >10% than in the others (p=0.005). In multivariate logistic regression, both lysis time and time-to-diagnosis were independently associated with perfusion defects >10% (p<0.001). None of the sampled patients had echocardiographic or radiologic signs of pulmonary hypertension. CONCLUSION: Prolonged time-to-diagnosis and fibrinolysis imbalance are independent predictors of incomplete perfusion recovery after acute PE.

Cardiovascular oncology: a new discipline inside internal medicine?

Cardiovascular disease and cancer incidence and prevalence have risen over the past few decades to become the leading causes of death. On the one hand, cancer patients will be treated with cardiotoxic chemotherapies; on the other, cardiovascular patients will receive a new diagnosis of cancer and will have to face treatments that may worsen their disease. Moreover, venous thromboembolism can commonly complicate the natural course of patients with cancer in an apparently spontaneous manner or can be triggered by a clinical event such as surgery, invasive procedures, a course of chemotherapy or radiotherapy and is known to be the second cause of death in these patients who also may need to be treated for pre-existing medical conditions or comorbidities. Thus, we introduce the concept of cardiovascular oncology (in the place of cardiooncology) to underline that the problems in this field are not limited to cardiotoxicity of chemotherapies and to the interaction between cardiologists and oncologists, and we focus on the role of the Internist, the only health care giver able to face the multiple problems that cancer patients may undergo.

Hyperhomocysteinemia in patients with pulmonary embolism is associated with impaired plasma fibrinolytic capacity.

Hyperhomocysteinemia (HHcy) affects haemostasis and shifts its balance in favour of thrombosis. In vitro and in vivo studies suggested that HHcy may impair fibrinolysis either by influencing the plasma levels of fibrinolytic factors or by altering the fibrinogen structure. We investigated the influence of mild HHcy levels on plasma fibrinolytic potential by using clot lysis time (CLT) and fibrin susceptibility to plasmin-induced lysis in 94 patients with previous pulmonary embolism and no pulmonary hypertension. CLT was measured as lysis time of tissue factor induced clots exposed to exogenous tissue plasminogen activator (t-PA). The rate of in vitro plasmin-mediated cleavage of fibrin ß-chain was assessed over a 6-h period on fibrin clots, which were obtained by exposition to thrombin of purified fibrinogen. Homocysteine plasma levels were measured by Abbott Imx immunoassay and we considered as altered the values above 15 µmol/L according to the literature. In 68 patients homocysteine levels were below 15 µmol/L (NHcy) and in 26 they were above (HHcy). Significant differences were observed between the two groups regarding plasma fibrinolytic potential (p = 0.016), TAFIact (expressed as clot lysis ratio) (p = 0.02), t-PA (0.008) and PLG (0.037), but not for the other assessed components. The HHcy-patients had a threefold higher risk to have an impaired fibrinolysis. Instead, a multivariate logistic regression analysis adjusted for significances of univariate showed that HHcy (OR 5.2 95% CI 1.7-15.9; p = 0.003) and BMI (OR 5.0 95% CI 1.6-15.9; p = 0.006) resulted independently associated with impaired fibrinolytic activity. HHcy affects TAFI-mediated hypofibrinolysis but not fibrin(ogen) structure or function as documented by fibrin degradation analysis.

Pharmacological prevention of venous thromboembolism in orthopaedic surgery.

The prophylaxis of venous thromboembolism (VTE) with anticoagulant drugs is a long-established practice in hip and knee replacement surgery, as well as in the treatment of femoral neck fractures, while there are few data regarding the prevention of VTE in other fields of orthopaedic surgery and traumatology. In order to provide practical recommendations for daily management of VTE prophylaxis in orthopaedic patients, recently the Italian Societies of Thrombosis and Haemostasis, Orthopaedics and Traumatology and Anaesthesia have drawn up a first Intersociety Consensus on antithrombotic prophylaxis in total hip and knee replacement surgery, and in the treatment of femoral neck fracture, then updated in 2013, and a subsequent Intersocietary Consensus, in cooperation also with the Society of general practitioners, concerning antithrombotic prophylaxis in other types of orthopaedic surgery and traumatology. Before starting any prophylactic treatment it is of crucial importance the assessment of both thrombotic and bleeding risk of patients undergoing surgery. Thromboembolic prophylaxis is recommended with low molecular weight heparins (LMWH), fondaparinux (FON) or with the new oral anticoagulants (NOA) in patients undergoing hip and knee replacement surgery while patients undergoing treatment of femoral neck fracture should be treated with LMWH or FON. Regarding the non-prosthetic orthopaedic surgery and traumatology, it is recommended prophylaxis with LMWH or FON in situations of high thromboembolic risk or in the case of interventions or trauma involving pelvis, acetabulum or knee.

Staphylococcus aureus infections and factors associated with resistance to methicillin in a hospital emergency department.

OBJECTIVE: Assessment of the characteristics of patients with Staphylococcus aureus (SA) infections, and factors associated with resistance to methicillin in a hospital emergency department (ED) in Spain. MATERIALS AND METHODS: All adult patients admitted between January 2007 and December 2010 with a SA infection confirmed by a positive culture in a sample obtained in the hospital emergency department were selected for enrolment. Epidemiological, clinical, therapeutic and microbiological variables were retrospectively collected from the patients' medical charts. The variable assessed within the primary outcome of the study was the isolation of methicillin resistant Staphylococcus aureus (MRSA). For the purpose of the analysis, the sample was divided in terms of the presence or not of the resistance to methicillin and a logistic regression analysis was performed to identify the factors associated with isolation and empirical antibiotic coverage of MRSA. RESULTS: A total of 207 patients with a confirmed SA infection were included in the study analysis, with a mean age of 64.7 (SD 20) years. MRSA was isolated in a total of 63 (30.4%) patients, and a linear incremental trend was observed over the course of the study (p=0,047). MRSA was empirically covered in the emergency department on an average rate of one in three patients. Independent factors associated with the isolation of MRSA were: age above 65 years [OR 2.97 (95% CI 1.24 to 7.1), P = 0.014], severe baseline functional dependence [OR 2.41 (95 % 1.02 to 5.69), P = 0.045], chronic obstructive pulmonary disease [OR 4.83 (95% CI 1.88 to 12.42), P = 0.001], history of antibiotic treatment within the previous 2 months [OR 4.94 (95% CI 2.27 to 10.76), P <0.001] and a confirmed urinary infection [OR 5.98 (95% CI 1.65 to 21.69) p = 0.007]. Independent factors associated with empiric coverage of MRSA in the ED were history of antibiotic treatment within the previous 2 months [OR 3.88 (95% CI 1.76 to 8.57), P <0.001] and the presence of a catheter device [OR 6.28 (95% CI 1.64 to 24.07), P = 0.007]. CONCLUSIONS: Resistance to methicillin appears to be increasingly frequent in patients infected with SA admitted in our emergency department and there appears to be a need for a more optimal empiric antibiotic treatment in these patients.

Risk of recurrence in patients with pulmonary embolism: predictive role of D-dimer and of residual perfusion defects on lung scintigraphy.

The stratification of recurrence risk after a first episode of venous thromboembolism (VTE) is an important topic of research, especially in patients with pulmonary embolism (PE). Elevated D-dimer levels and residual vein obstruction (RVO) at compression ultrasonography have been studied as predictors of recurrence after withdrawing oral anticoagulant treatment (OAT). It is still unknown if residual perfusion defects (PD) on lung scintigraphy are related to recurrent PE. In the present study, we evaluated the association of PD with PE recurrence. The relationship between PD, elevated D-dimer levels, and RVO was also investigated. We prospectively followed 236 consecutive patients who survived a first episode of objectively confirmed PE, with or without deep-vein thrombosis. After at least three months of OAT, treatment was withdrawn in 139 patients. D-dimer levels were evaluated at one month of OAT withdrawal, RVO was measured, and perfusion lung scan (P-scan) was performed to evaluate PD. During follow-up, 20 patients experienced a recurrent episode of VTE. Elevated D-dimer levels were significantly associated with VTE recurrence, (p=0.003). RVO was present in 22% of the patients with recurrence and in 7.5% of those without (p=0.07). No significant association was found between PD >10% and VTE recurrence, D-dimer, or RVO. In conclusion, we confirmed the positive predictive value of elevated D-dimer levels for recurrent VTE. Residual PD on lung scintigraphy are neither predictive of recurrence nor related to D-dimer levels or RVO.

Antiplatelets in acute coronary syndrome: personal perspectives.

High platelet reactivity (HPR) during dual-antiplatelet therapy is a marker of vascular risk, in particular stent thrombosis, in patients with acute coronary syndromes. Genetic determinants (CYP2C19*2 polymorphism), advanced age, female gender, diabetes and reduced ventricular function are related to a higher risk to develop HPR. In addition, inflammation and increased platelet turnover, as revealed by the elevated percentage of reticulate platelets in patients' blood, that characterize the acute phase of acute coronary syndrome are associated with HPR. To overcome the limitation of clopidogrel, new antiplatelet agents (prasugrel and ticagrelor) were developed and the demonstration of their superiority over clopidogrel was obtained in the two randomized trials, TRITON TIMI 38 and PLATO. Due to the current possibility not a choice between multiple antiplatelet strategies, the future prospect is to include, in addition to clinical data and classical risk factors, the definition of platelet function during treatment in order to set a tailored therapy.

The risk stratification in atrial fibrillation.

Atrial fibrillation (AF) is the most common rhythm disorder and represents a major public health problem because it carries an increased risk of arterial thromboembolism and ischemic stroke. Because the absolute benefit of antithrombotic therapy depends on the underlying risk of stroke, an accurate stratification of patients' risk is needed to choose the appropriate antithrombotic strategy. Over the years, several stroke risk stratification models (RSMs) were developed based on the 'classic' risk factors for stroke such as increasing age, hypertension, diabetes mellitus, and left ventricular dysfunction. Among all RSMs, the CHADS(2) score is the most popular and used one thanks to its simplicity and endorsement in several widely promulgated practice guidelines. Despite its validation in large datasets and specific population of AF patients, it has many limitations, especially due to the non-inclusion of several proven risk factors for stroke and to the classification of a large number of patients in the intermediate risk category, so creating ambiguity over the most appropriate antithrombotic therapy. Thus, the CHA(2)DS(2)-VASc score was introduced and was demonstrated to perform better than the CHADS(2), even in a "real world" population of elderly AF patients. Recently, in view of the availability of new oral anticoagulant drugs, that can overcome the limitations of warfarin and allow a more personalized therapy, many efforts are being made to identify other possibilities to assess the thromboembolic risk in AF patients. It has been demonstrated that an increase in C-reactive protein and interleukin-6 and the presence of G20210A factor II gene polymorphism and hyper-homocysteinemia are independent risk factors for ischemic complications in AF patients. Even the presence of chronic renal disease and the daily AF burden, registered with implantable monitors, are associated with an increase risk of stroke. Finally, the assessment of thromboembolic risk should go hand in hand with the consideration of the risk of bleeding. For this purpose, it has been recently developed a practical bleeding risk score, the HAS-BLED, which was included in the last ESC guidelines for the risk stratification of AF patients before starting anticoagulant therapy.

A hypercoagulable and hypofibrinolytic state is detectable by global methods in patients with retinal vein occlusion.

The pathogenesis of retinal vein occlusion (RVO), has not been well understood. Recent data have shown the efficacy of an anticoagulant therapy with LMWHs in the treatment of acute RVO suggesting the presence of a hypercoagulable state in these patients. New global tests for detection of hypercoagulability and hypofibrinolysis have become available and their application might improve the knowledge of the pathophysiology of RVO and, potentially, its treatment. The aim of our study was to evaluate coagulation and fibrinolytic alterations by two global tests in RVO patients: Endogenous Thrombin Potential (ETP) and Clot Lysis Time (CLT), respectively. We studied 81 RVO patients (40 males; median age 61 years) and a control group matched for age and sex. The ETP was measured by functional chromogenic assay and expressed as the time until thrombin burst (LagTime), Time to peak (T(max)), Peak amount of thrombin generation (C(max)) and ETP. CLT was determined by a plasma-based, tissue factor-induced clot lysis assay. C(max), ETP and CLT values were significantly higher in RVO patients than in controls (C(max)p = 0.010; ETP p < 0.001; CLT p < 0.001) and remained significantly associated with the disease at the multivariate analysis adjusted for cardiovascular risk factors. Our results indicate that -beyond the assay of different parameters associated with clotting activation and lysis- global methods might allow us to easily detect the presence of hypercoagulability and hypofibrinolysis in RVO patients. Further studies should assess the possible clinical value of our data in the management of RVO patients.

The thrombophilic pattern of different clinical manifestations of venous thromboembolism: a survey of 443 cases of venous thromboembolism.

Although pulmonary embolism (PE) and deep vein thrombosis (DVT) share many risk factors, it is uncertain whether thrombophilic abnormalities may impact differently on the development of these two clinical manifestations of venous thromboembolism (VTE). To give further insight into this issue, we estimated the association of PE with different types of thrombophilia and evaluated whether these abnormalities have a different prevalence in patients presenting with PE, alone or associated with DVT, as compared with those with isolated DVT. In this study 443 consecutive patients with a first episode of VTE and 304 matched healthy controls underwent laboratory screening for thrombophilia, including natural anticoagulants, factor V Leiden and prothrombin G20210A polymorphisms, antiphospholipid antibodies, homocysteine, factor VIII, and lipoprotein(a). Of the 443 patients, 224 patients had isolated DVT, 144 had combined DVT/PE, and 75 had isolated PE. At least one thrombophilic abnormality was detected in 72.8% of DVT, 66% of DVT/EP, and 60% of isolated PE patients. A high prevalence of hyperhomocysteinemia and elevated lipoprotein(a) levels was found in all patients with no significant differences among the three groups. The prevalence of prothrombin G20210A polymorphism and of elevated factor VIII levels was significantly higher in patients with DVT and DVT/PE than in controls, but not in those with isolated PE, whereas factor V Leiden polymorphism was associated with isolated DVT but not with DVT/PE or isolated PE. In conclusion, the thrombophilic burden seems different in isolated PE versus DVT with or without PE, suggesting that PE may encompass a different pathophysiological process of thrombosis to DVT.

Clinical presentation of acute pulmonary embolism: survey of 800 cases.

BACKGROUND: Pulmonary embolism (PE) is a common and potentially fatal disease that is still underdiagnosed. The objective of our study was to reappraise the clinical presentation of PE with emphasis on the identification of the symptoms and signs that prompt the patients to seek medical attention. METHODOLOGY/PRINCIPAL FINDINGS: We studied 800 patients with PE from two different clinical settings: 440 were recruited in Pisa (Italy) as part of the Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis (PISAPED); 360 were diagnosed with and treated for PE in seven hospitals of central Tuscany, and evaluated at the Atherothrombotic Disorders Unit, Firenze (Italy), shortly after hospital discharge. We interviewed the patients directly using a standardized, self-administered questionnaire originally utilized in the PISAPED. The two samples differed significantly as regards age, proportion of outpatients, prevalence of unprovoked PE, and of active cancer. Sudden onset dyspnea was the most frequent symptom in both samples (81 and 78%), followed by chest pain (56 and 39%), fainting or syncope (26 and 22%), and hemoptysis (7 and 5%). At least one of the above symptoms was reported by 756 (94%) of 800 patients. Isolated symptoms and signs of deep vein thrombosis occurred in 3% of the cases. Only 7 (1%) of 800 patients had no symptoms before PE was diagnosed. CONCLUSIONS/SIGNIFICANCE: Most patients with PE feature at least one of four symptoms which, in decreasing order of frequency, are sudden onset dyspnea, chest pain, fainting (or syncope), and hemoptysis. The occurrence of such symptoms, if not explained otherwise, should alert the clinicians to consider PE in differential diagnosis, and order the appropriate objective test.

Down-regulation of RNA editing in pediatric astrocytomas: ADAR2 editing activity inhibits cell migration and proliferation.

Since alterations in post-transcriptional events can contribute to the appearance and/or progression of cancer, we investigated whether RNA editing, catalyzed by the ADAR (adenosine deaminases that act on RNA) enzymes, is altered in pediatric astrocytomas. We find a decrease in ADAR2 editing activity that seems to correlate with the grade of malignancy in children. Despite the loss of ADAR2 editing activity in tumor tissues, the high grade astrocytomas do not exhibit alterations in ADAR2 expression when compared with their specific control tissues. However, high expression levels of ADAR1 and ADAR3 were found in tumors when compared with normal tissues dissected in the same area of the brain. We reintroduced either ADAR2 or the inactive version of ADAR2 in three astrocytoma cell lines (U118, A172, U87). The "reverted" editing status is necessary and sufficient for a significant decrease in cell malignant behavior as measured by proliferation, cell cycle, and migration assays. We show that elevated levels of ADAR1, as found in astrocytomas, do indeed interfere with ADAR2 specific editing activity. Furthermore, we show that the endogenous ADAR1 can form heterodimers with ADAR2 in astrocytes.

Drosophila Grainyhead specifies late programmes of neural proliferation by regulating the mitotic activity and Hox-dependent apoptosis of neuroblasts.

The Drosophila central nervous system is generated by stem-cell-like progenitors called neuroblasts. Early in development, neuroblasts switch through a temporal series of transcription factors modulating neuronal fate according to the time of birth. At later stages, it is known that neuroblasts switch on expression of Grainyhead (Grh) and maintain it through many subsequent divisions. We report that the function of this conserved transcription factor is to specify the regionalised patterns of neurogenesis that are characteristic of postembryonic stages. In the thorax, Grh prolongs neural proliferation by maintaining a mitotically active neuroblast. In the abdomen, Grh terminates neural proliferation by regulating the competence of neuroblasts to undergo apoptosis in response to Abdominal-A expression. This study shows how a factor specific to late-stage neural progenitors can regulate the time at which neural proliferation stops, and identifies mechanisms linking it to the Hox axial patterning system.