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Mechanical complications post ST elevation myocardial infarction (STEMI) are life-threating events, that require rapid recognition and appropriate management. Clinical diagnosis, considering high index of suspicion and bedside echocardiography should be considered in all STEMI patients Despite the overall decrease of the incidence of cardiac rupture (CR) secondary to STEMI in context of early revascularization and the wide availability of primary PCI, CR has still an unacceptable high mortality. Purpose To provide demographic, clinical, management and prognostic data associated to cardiac rupture from a tertiary centre of cardiology in Romania and to better describe in-hospital trajectory. The primary endpoint was defined as the incidence of CR and secondary endpoints were rate of surgical interventions, in-hospital mortality rate at 24 hours and after 24 hours during index hospitalization. Methods The analysis of the electronic medical records retrospectively identified 7703 patients admitted for STEMI between 01 Jan 2011 and 31 Dec 2020. A database consisting of demographic data, medical history, cv and non-cv comorbidities, in-hospital management were recorded using an UiPath robotic process automation (RPA) technology. Characteristics of the patients +/− CR were compared, and data analysis was performed using SPSS 26 Ed. Results Of a total number of 7703 consecutive STEMI patients, CR has been identified in 185 patients (mean incidence of 2.4%). The annual rates for CR incidence remained stable during the past decade (Figure 1). Patients with CR were older compared with non-CR (71.6±10.2 vs 61.47±12.8 years; p The CR patients had more comorbidities and CV risk factors – HTN, smoker status, DLP, more AF, CKD, obesity and chronic cognitive deficit (p Among the CR group patients, anterior MI was the frequent localisation (52%), followed by inferior MI (17%), infero-lateral (23%) and RV involvement MI (6.4%). According to the type of the mechanical complication, patients developed free wall rupture (50% of cases), 39% IVS rupture and 11% papillary muscle was involved; A number of 50 patients (27%), benefited from emergent cardiac surgery and 31.3% of CR patients received mechanical circulatory support. The overall STEMI mortality in the first 24-hours was 1.84% and in most of these patients the main cause of death was related to CR (31%). Overall total in-hospital mortality was 8.08% (6.5% non-CR group vs. 70.8% the CR group – Figure 1). Conclusions The study presents the epidemiological characteristics of CR complicating STEMI in the largest tertiary cardiovascular hospital in Romania. We have identified a stable trend for the incidence of CR incidence among patients with STEMI. In spite of the high rate of cardiac surgery and MCS, in-hospital mortality remains very high, particularly in the first 24 h since admission Funding Acknowledgement Type of funding sources: None.

Introduction A psychotic episode might stem from various psychiatric disorders, such as Major Depressive Disorder, Mania, Autism Spectrum Disorder, it might lead to Schizophrenia, or it might be a single event. Objectives The study aimed to assess the main comorbidities encountered in the onset of psychotic episodes in children and adolescents, who were hospitalized in a pediatric psychiatry department for at least one night. Furthermore, another objective was to establish whether a family history of mental illness or a poor socio-economic status have bigger impact on the evolution of these patients. Methods To analyze the objectives, it was used an observational study, based on patients with the onset of a psychotic episode and associated diagnosis according to ICD-10, evaluated in Child and Adolescent Psychiatric Department of “Prof. Dr. Al. Obregia” Hospital, between 2015-2019. Patients with psychotic episodes with onset related to Major Depressive Disorder and Mania or a personal history of Schizophrenia were excluded. Results The most frequent associated comorbidity was Autism Spectrum Disorder. In terms of long-term evolution, patients with comorbidities have poorer outcomes, more relapses and hospitalizations. Family history of mental illness, low socio-economic status, the age of onset were found to be prognostic factors and have an important impact on the outcome. Conclusions This study compared patients with psychotic episodes with and without comorbid conditions associated, considering the length of hospitalization period, the evolution and the number of relapses. The presence and the type of comorbidities are important factors of evolution and prognostic for these patients. Disclosure No significant relationships.

Despite the advanced therapeutic arsenal in Heart Failure (HF), this progressive disease, symptomatic in many clinical aspects and potentially fatal when compared to oncologic diseases, remains a public health issue, involving both the patient, the clinician and also the health system. By the nature of its’ prolonged evolution, HF affects the quality of life more pronounced compared to other chronic diseases [1]...

Introduction Splenic abcess represents a rare complication of left-sided infective endocarditis. Unlike splenic infarction, which is a more benign condition, splenic abcess requires rapid diagnosis and treatment as its course can be fatal. We present the case of a 52- year old male, with diabetes and hypertension, admitted for shortness of breath and fever in the past two months. Clinical examination revealed respiratory distress, tachypnea, diastolic murmur on the left sternal border. Baseline laboratory investigations showed elevated inflammation markers, leukocytosis and thrombocytosis. Enterococcus faecalis was isolated from the hemocultures. Transthoracic echocardiography revealed a dilated left ventricle (LV), with preserved LV ejection fraction, with severe aortic regurgitation due to valve destruction. A large (11mm diameter) vegetation-like structure attached to the ventricular side of the right coronary cusp, protruding into the left ventricular outflow tract was identified. Further evaluation by transoesopahgeal echocardiography did not identify other lesions, except for secondary moderate mitral regurgitation, with intact mitral leaflets. Dual antibiotic therapy with Ampicilin and Gentamycin was initiated. Surgery was planned after infection control. The first three days were uneventful, with rapid resolution of fever and inflammatory markers, but on the fourth day, the patient developed severe abdominal pain, with its focal point in the left hypochondrium. Contrast abdominal CT was performed and large multiple subcapsular lesions were identified. These findings, correlated with the symptomatology, suggested embolic splenic abcess and infarction. The patient successfully underwent laparoscopic splenectomy, but soon after he developed sepsis with respiratory failure and neurological deterioration (with normal CT scan) and was admitted to the intensive care unit, where he was intubated and mechanically ventilated. Consensus after discussions between cardiology, cardiac surgery and neurology services was to immediately replace the aortic valve, given the inability to otherwise control the infection. Intraoperative images were consistent with perforation of the right coronary cusp. During hospitalization in the ICU following cardiac surgery, the patient was extubated and his neurological function markedly improved. Repeated TTE and TEE showed normal prosthetic valve function and resolution of mitral regurgitation. The patient continued to improve clinically until his discharge. Conclusions We presented a case of a rare pathogenic entity- splenic abscess and infarction- due to systemic embolization from infective aortic valve endocarditis. Multidisciplinary teamwork was required between cardiologist, intensive care specialist, neurologist, infectionist, general surgeon and cardiac surgeon. Splenectomy was performed before valve replacement, a treatment-course characteristic in the occurrence of these rare cases.

Background The presence of small mobile masses on the ventricular side of the aortic valves in the absence of valvular regurgitation and signs of systemic inflammation has been previously described as marantic endocarditis and is now referred to as nonbacterial thrombotic endocarditis (NBTE). It is thought to be associated with endothelial dysfunction and procoagulative status, as is the case of acute decompensated heart failure (HF). Case description We present a series of three male patients, with similar clinical characteristics, who were admitted for acute decompensated HF. All three patients had chronic HF, due to non-ischemic dilated cardiomyopathy with severe biventricular dysfunction, with resynchronization therapy, with elevated natriuretic peptides and previous HF hospitalizations in the past year requiring prolonged intravenous treatments. Other clinical, biological criteria for the definition of advanced HF were also met. All patients were under chronic anticoagulation treatment using a direct oral anticoagulant because of persistent atrial fibrillation. Thorough echocardiographic evaluation (both transthoracic and transoesophageal ultrasound) identified small mobile masses on the ventricular side of the aortic valves, centrally, on the line of cusp coaptation, with only minor central regurgitation. The lack of progression of valve lesion and the absence of gross signs of inflammation (no fever, normal hemoleucogram, normal CRP, repeated negative blood cultures) on serial examinations during several weeks follow-up allowed for the exclusion of infective endocarditis. In one case we also identified a left atrial appendage thrombus and presumably thrombotic masses attached to right side pacing leads. No clinically systemic embolic events were identified. Conclusion We consider this to be an incidental finding in the given subclinical prothrombotic and inflammatory predisposing milieu of advanced chronic HF and the increasing high quality echocardiography imaging. Its clinical significance is still unknown, while differential diagnosis from subacute or chronic endocarditis relies largely on clinical judgment.

Background Transcatheter valve replacement (TAVR ) is currently the optimal treatment for patients with severe aortic stenosis who are considered to have an intermediate to high operative risk for surgical intervention. Intramural hematoma secondary to balloon-expandable TAVR is a poorly reported complication with unknown outcome. Among the risk factors associated with this complication are advanced age, female gender, bulky calcifications, significant basal hypertrophy and severe prothesis oversizing. Case report We report the case of a 84 year old woman with a history of permanent atrial fibrillation, who was diagnosed with severe aortic stenosis symptomatic with heart failure NYHA class III. An important comorbidity was liver cirrhosis of viral etiology (hepatitis C virus) with secondary thrombocytopenia. Transthoracic and transoesophageal echocardiography (TEE) showed severe aortic stenosis with asymmetric calcifications, with preserved gradient (a peak velocity of 4.7 m/s, mean gradient of 63.3mmHg), mild left ventricular disfunction (ejection fraction 45%), and calculated aortic valve area of 0,9 cm2. As a frail, high risk patient, the heart team recommended transcatheter aortic valve implantation. After complete computer tomographic evaluation, a 26 mm Edwards Sapien 3 valve was implanted through a femoral approach. Intraprocedural transesophageal echocardiography showed the developement of an intramural hematoma in the aortic root (right coronary and noncoronary sinuses), associated with a small pericardial effusion. After administration of Protamine, betablockers and strict blood pressure control, no extension of the hematoma was noted. Serial TEE showed significant regression of the hematoma and of the pericardial effusion, with normal parametres of the prothesis, with a transprothetic gradient of 23 mmHg, no aortic leak, no other complications.The patient was discharged 12 days after the procedure, clinically stable. Conclusion Aortic intramural hematoma may occur during intra-TAVR procedure. Although it may have a benign course, timely recognition and adequate imaging follow-up are mandatory in order to limit the extent and prevent life-threatening complications.

Introduction Left ventricular non-compaction is a rare form of cardiomyopathy charactherized by the presence of a two layered ventricular wall- a thinner epicardial layer and an inner, non-compacted layer with prominent trabeculations associated with deep, intratrabecular recesses that communicate with left ventricle cavity. Clinical manifestations vary in severity, including symptoms of heart failure, thromboembolic events or arrhythmias. Left ventricular (LV) dysfunction leads to tethering of the mitral apparatus and is a cause for secondary significant mitral regurgitation. Case presentation We report the case of a 57 year-old female patient, diagnosed with severe mitral regurgitation one year before presentation, with severe heart failure (HF) symptoms, referred to our clinic for the surgical replacement of the mitral valve. Clinical examination revealed no signs of pulmonary or systemic congestion and systolic apical murmur. Blood tests were normal, except for the elevated BNP (552 pg/ml). Electrocardiogram showed sinus rhythm and left ventricular hypertrophy. Coronary angiogram did not identify any coronary artery lesions. Echocardiography revealed mildly dilated left ventricle, but wih proeminent trabeculations and two distinct myocardial layers with a non-compacted/compacted ratio of 2:1 in the anterior and lateral walls, diagnostic for left ventricular non-compaction cardiomyopathy. LV ejection fraction was 40% , with severe secondary mitral regurgitation due to significant antero-posterior dilation of the mitral ring, with intact mitral leaflets; mild pulmonary hypertension was present. Magnetic resonance imaging (MRI) identified a two layer antero-lateral myocardium and confirmed the echo diagnosis; there was no evidence of scarring as there was absent late gadolinium enhacement. In the absence of fibrosis on MRI or any arrhythmic events on repeated Holter ECG monitoring, the implantation of a cardiac defibrillator was deferred. Given the secondary cause for mitral regurgitation (LV dysfunction), specific HF medication with beta blocker and renin-angiotensin-aldosterone blockade was initiated and titrated to optimal doses. With medical treatment the evolution was favourable. Currently, 3 years after the initial diagnosis, 6 minutes walk test revealed good functional capacity (510 m), a BNP value of 104 pg/l, without any worsening of LV systolic function nor progression of pulmonary hypertension. Conclusion Left ventricular non-compaction cardiomyopathy is a rare cause of heart failure, but due to advances in imaging modalities and increasing awareness, its prevalence is growing. Its pathogenesis and prognosis largely remain unknown, but early and adequate initiation of neurohormonal medication may be just as essential in order to prevent complications and improve long term prognosis, as for other forms of cardiomiopathy, even in the presence of severe secondary mitral regurgitation.

IntroductionPsychiatric symptoms related with menstrual cycle vary from dysphoria to psychosis. There are only a few cases of menstrual psychosis reported, all characterized by acute onset, against a background of normality, brief duration, with full recovery and a circa-mensual periodicity.ObjectivesWe report a case of dissociative disorder, in a teenage girl, with atypical presentation and an unusual periodicity of symptoms and recoveries.MethodsPresentation of a case of dissociative disorder, followed by a review of the similar cases described in the literature.ResultsWe are presenting a case of a 15 years old female, who presented in our Emergency Department for confusion, anxiety, negativism in verbal and non-verbal response, bradylalia and bradypsychia, insomnia for over 48 hours. The symptoms suddenly began two days before arrival in our clinic. From the patient’s personal history, we retain the following: menarche at 14 years old, irregular periods, hypermenorrhea. Patient was born premature, G=1200g, spastic diplegia, periventricular leukomalacia (MRI – 2018). Three similar episodes happened a year ago, with one month periodicity, with spontaneous remission after 5-6 days. Patient was treated with antipsychotics and benzodiazepines for the second and the third episode, but the treatment was stopped six month ago. The investigations results were normal, except for a high level of plasmatic cortisol. Patient fully recovered in the day the menses stopped.ConclusionsWe considered this case to be atypical due to the sudden debut and recovery and there are still some remaining questions. Is it hormonal related, menstrual related or is it exclusively a psychiatric condition?DisclosureNo significant relationships.

Nowadays, urinary bladder cancer represents a major health problem, due to very high medical and social costs. This disease affects mainly the elderly. We performed a study on 1073 patients admitted to the Urology Clinic within the Emergency Clinical Hospital of Craiova, between 2013-2015 with bladder cancer. Of the 1073 cases, 741(69.06%) were diagnosed in men, and 332 (30.94%) were found in women, the men/ women ratio being of 2.23/1. The highest incidence of bladder tumors was recorded in individuals aged between 60 and 79 years old. In this age group, there were admitted 734 patients with bladder cancer, representing 68.44%. Regarding the tumor recurrence, out of 1073 bladder tumors, a number of 608 (56.66%) patients were diagnosed with primary tumors, while a number of 465 (43.34%) patients presented recurrent tumors. Of the symptoms presented by the patients, the most frequent were haematuria (present in about 87% of the patients), pollakiuria (present in 64% of the patients), dysuria (present in 55% of the patients) and urinary infections (present in about 23% of the patients).

We classify the finite dimensional irreducible representations of the double affine Hecke algebra (DAHA) of type C ∨ C 1 in the case when q is not a root of unity.

The purpose of this study was the clinical and histo-immunohistochemical analysis of two cases: a cutaneous pigmented facial malignant melanoma and a lumbar congenital nevus with malignant transformation. A series of clinical elements raised the suspicion of some malignant melanocytic lesions and the histopathological analysis through the paraffin embedding technique confirmed the clinical suspicion. The immunohistochemical analysis using the streptavidin-biotin-peroxydase method of the facial malignant melanoma showed: S100 protein intense and diffuse positive, Tyrosinase diffuse positive, HMB45 strong and focal positive, Cyclin D1 positive in approximately 40% and Ki-67 positive in almost 70% of the tumor cells. The malignant melanoma developed on the nevocellular nevus displayed: S100 protein intense and diffuse positive, both in the nevus cells and in the malignant melanocytes as well, Tyrosinase intense and diffuse positive in the malignant melanocytes, poor and focal positive in the nevus cells and HMB45 intense and focal positive in the malignant cells and positive in the isolated nevus cells. Cyclin D1 was positive in about 70% of the malignant cells, but negative in the nevus area and Ki-67 was found positive in relatively 30% of the malignant melanocytes, also in less than 1% of the nevus cells. The pattern and the intensity of the Tyrosinase and HMB45 immunoexpression are important in the differentiation of the nevus cells from the malignant melanocytic cells. The immunoexpression of Cyclin D1 does not correlate directly with the proliferating activity of the malignant melanocytic cells in all types of malignant melanomas.

Anaplastic lymphoma kinase (ALK) is a transmembrane receptor tyrosine kinase in the insulin receptor superfamily. We recently demonstrated that the growth factors pleiotrophin (PTN) and midkine (MK) are ligands for ALK and that upon ALK activation, insulin receptor substrate-1 (IRS-1) and other substrates are phosphorylated. Here, the role of IRS-1 in ligand-mediated ALK signaling is investigated in interleukin-3 (IL-3)-dependent 32D murine myeloid cells. These cells do not express ALK and IRS family members, and do not respond to exogenously added PTN or MK. We show that expression of ALK plus IRS-1 renders these cells independent of IL-3 owing to the activation of ALK by endogenous MK. Mutational analysis reveals that this transformed phenotype of 32D cells requires kinase-active ALK as well as the interaction of ALK with IRS-1. Furthermore, 32D/IRS-1/ALK cells display an enhanced activation of mitogen-activated protein kinase and PI3-kinase pathways, and a selective transcriptional activation of nuclear factor (NF)-kappaB. Small interfering RNA-mediated knockdown of the endogenous MK or p65/NF-kappaB revealed that both these are rate limiting for the transformed phenotype induced by ALK plus IRS-1. We conclude that the recruitment of IRS-1 to activated ALK and the activation of NF-kappaB are essential for the autocrine growth and survival signaling of MK.

Epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), and heregulin-beta1 (HRG-beta1), can modulate the expression and activity of the estrogen receptor-alpha (ER-alpha) via the phosphatidylinositol 3-kinase (PI 3-K)/Akt pathway in the ER-alpha-positive breast cancer cell line, MCF-7. Estradiol can also rapidly activate PI 3-K/Akt in these cells (nongenomic effect). The recent study examines whether Akt is involved in the ER-alpha regulation by estradiol (genomic effect). Stable transfection of parental MCF-7 cells with a dominant-negative Akt mutant, as well as the PI 3-K inhibitors wortmannin and LY 294,002, blocked the effect of estradiol on ER-alpha expression and activity by 70-80 and 55-63%, respectively. Stable transfection of MCF-7 cells with a constitutively active Akt mimicked the effect of estradiol. The changes in ER-alpha expression and activity were abrogated in response to estradiol by an arginine to cysteine mutation in the pleckstrin homology (PH) domain of Akt (R25C), suggesting the involvement of this amino acid in the interaction between Akt and ER-alpha. Experiments employing selective ErbB inhibitors demonstrate that the effect of estradiol on ER-alpha expression and activity is mediated by ErbB2 and not by EGFR. Moreover, anchorage-dependent and -independent growth assays, cell cycle and membrane ruffling analyses showed that Akt exerts estrogen-like activity on cell growth and membrane ruffling and that a selective ErbB2 inhibitor, but not anti-ErbB2 antibodies directed to the extracellular domain, can block these effects. In the presence of constitutively active Akt, tamoxifen only partially inhibits cell growth. In contrast, in cells stably transfected with either a dominant-negative Akt or with R25C-Akt, as well as in parental cells in the presence of a selective ErbB2 inhibitor, the effect of estradiol on anchorage-dependent and -independent cell growth was inhibited by 50-75 and 100%, respectively. Dominant-negative Akt inhibited membrane ruffling by 54%; however, R25C-Akt did not have any effect, suggesting that kinase activity plays an important role in this process. Scatchard analysis demonstrated a 67% reduction in estrogen-binding capacity in cells transfected with constitutively active Akt. No change in binding affinity of estradiol to the receptor was observed upon transfection with either Akt mutant. Taken together, our results suggest that estradiol treatment results in binding to membrane ER-alpha and interaction with a heterodimer containing ErbB2, leading to tyrosine phosphorylation. This results in the activation of PI 3-K and Akt. Akt, in turn, may interact with nuclear ER-alpha, altering its expression and activity.

Previously, we have demonstrated that the two mitogenic growth factors epidermal growth factor and IGF-I can activate Akt and estrogen receptor-alpha (ERalpha) in the hormone-dependent breast cancer cell line, MCF-7. In this report we now show that estradiol can also rapidly activate phosphatidylinositol 3-kinase (PI 3-K)/Akt and that this effect is mediated by the ErbB2 signaling pathway. Treatment of cells with estradiol resulted in phosphorylation of Akt and a 9-fold increase in Akt activity in 10 min. Akt activation was blocked by wortmannin and LY 294,002, two inhibitors of PI 3-K; by genistein, a protein tyrosine kinase inhibitor and an ER agonist; by AG825, a selective ErbB2 inhibitor; and by the antiestrogens ICI 182,780 and 4-hydroxy-tamoxifen; but not by rapamycin, an inhibitor of the ribosomal protein kinase p70S6K; nor by AG30, a selective epidermal growth factor receptor inhibitor. Akt activation by estradiol was abrogated by an arginine-to-cysteine mutation in the pleckstrin homology domain of Akt (R25C). Growth factors also activated Akt in the ER-negative variant of MCF-7, MCF-7/ADR, but estradiol did not induce Akt activity in these cells. Transient transfection of ERalpha into these cells restored Akt activation by estradiol, suggesting that estradiol activation of Akt requires the ERalpha. Estradiol did not activate Akt in MCF-7 cells stably transfected with an anti-ErbB2-targeted ribozyme, further confirming a role for ErbB2. In vitro kinase assays using immunoprecipitation and anti-Akt1, -Akt2, and -Akt3-specific antibodies demonstrated that Akt1 is activated by estradiol in MCF-7 cells whereas Akt3 is the activated isoform in ER-negative MDA-MB231 cells, implying that selective activation of Akt subtypes plays a role in the actions of estradiol. Taken together, our data suggest that estradiol, bound to membrane ERalpha, interacts with and activates an ErbB dimer containing ErbB2, inducing activation of PI 3-K/Akt.

Midkine (MK) is a developmentally regulated, secreted growth factor homologous to pleiotrophin (PTN). To investigate the potential role of MK in tumor growth, we expressed MK in human SW-13 cells and studied receptor binding, signal transduction, and activity of MK. The MK protein stimulates soft agar colony formation in vitro and tumor growth of SW-13 cells in athymic nude mice, as well as proliferation of human endothelial cells from brain microvasculature and umbilical vein (HUVEC) in the low ng/ml range. MK binds to anaplastic lymphoma kinase (ALK), the receptor for PTN, with an apparent K(d) of 170 pm in intact cells, and this receptor binding of MK is competed by PTN with an apparent K(d) of approximately 20 pm. Monoclonal antibodies raised against the extracellular ligand-binding domain of ALK inhibit ALK receptor binding of MK as well as MK-stimulated colony formation of SW-13 cells. Furthermore, MK stimulates ALK phosphorylation in WI-38 human fibroblasts and activates PI3-kinase and MAP kinase signal transduction in WI-38, HUVEC, neuroblastoma (SH SY-5Y) and glioblastoma (U87MG) cells that express the ALK protein. We conclude that MK can act as a growth, survival, and angiogenic factor during tumorigenesis and signals through the ALK receptor.

Glioblastoma multiforme is the most common highly aggressive human brain cancer, and receptor tyrosine kinases have been implicated in the progression of this malignancy. We have recently identified anaplastic lymphoma kinase (ALK) as a tyrosine kinase receptor for pleiotrophin, a secreted growth factor that is highly expressed during embryonic brain development and in tumors of the central nervous system. Here we report on the contribution of pleiotrophin-ALK signaling to glioblastoma growth. We found ALK overexpressed in human glioblastoma relative to normal brain and detected ALK mRNA in glioblastoma cell lines. We reduced the endogenous ALK in glioblastoma cells by ribozyme targeting and demonstrated that this prevents pleiotrophin-stimulated phosphorylation of the anti-apoptotic protein Akt. Furthermore, this depletion of ALK reduced tumor growth of xenografts in athymic nude mice and prolonged survival of the animals because of increased apoptosis in the tumors. These findings directly implicate ALK signaling as a rate-limiting factor in the growth of glioblastoma multiforme and suggest potential utility of therapeutic targeting of ALK.

Pleiotrophin (PTN) is a secreted growth factor that induces neurite outgrowth and is mitogenic for fibroblasts, epithelial, and endothelial cells. During tumor growth PTN can serve as an angiogenic factor and drive tumor invasion and metastasis. To identify a receptor for PTN, we panned a phage display human cDNA library against immobilized PTN protein as a bait. From this we isolated a phage insert that was homologous to an amino acid sequence stretch in the extracellular domain (ECD) of the orphan receptor tyrosine kinase anaplastic lymphoma kinase (ALK). In parallel with PTN, ALK is highly expressed during perinatal development of the nervous system and down-modulated in the adult. Here we show in cell-free assays as well as in radioligand receptor binding studies in intact cells that PTN binds to the ALK ECD with an apparent Kd of 32 +/- 9 pm. This receptor binding is inhibited by an excess of PTN, by the ALK ECD, and by anti-PTN and anti-ECD antibodies. PTN added to ALK-expressing cells induces phosphorylation of both ALK and of the downstream effector molecules IRS-1, Shc, phospholipase C-gamma, and phosphatidylinositol 3-kinase. Furthermore, the growth stimulatory effect of PTN on different cell lines in culture coincides with the endogenous expression of ALK mRNA, and the effect of PTN is enhanced by ALK overexpression. From this we conclude that ALK is a receptor that transduces PTN-mediated signals and propose that the PTN-ALK axis can play a significant role during development and during disease processes.

This study examines whether the serine/threonine protein kinase, Akt, is involved in the cross-talk between epidermal growth factor (EGF) and insulin-related growth factor I (IGF-I) receptors and ER-α. Treatment of MCF-7 cells with either EGF or IGF-I resulted in a rapid phosphorylation of Akt and a 14- to 16-fold increase in Akt activity, respectively. Akt activation was blocked by inhibitors of phosphatidylinositol 3-kinase, but not by an inhibitor of the ribosomal protein kinase p70S6K. Stable transfection of cells with a dominant negative Akt mutant blocked the effects of EGF and IGF-I on ER-α expression and activity, whereas stable transfection of cells with a constitutively active Akt mutant mimicked the effects of EGF and IGF-I. In the latter cells, there was a decrease in the amount of ER-α protein and messenger RNA (70–80%) and an increase in the amount of progesterone receptor protein, messenger RNA (4- to 9- and by 3.5- to 7-fold, respectively) and pS2 (3- to 5-fold). Coexpression of wild-type ...

SUMMARY Through the integration of high speed computer networks and interactive multimedia workstations, the IRI (Interactive Remote Instruction) system creates a geographically dispersed virtual classroom. Each student participates in a lesson using a personal workstation which can be used to view multimedia lectures, to make presentations, to take notes in a multimedia notebook and to interact via audio/video and shared computer tools. We compare this approach with other modes of instruction and describe lessons learned from the instructor, student and technical perspectives.

This paper discusses the important role of multicasting in designing, implementing, and managing interactive multimedia distance learning systems. This is achieved in the context of IRI, an Interactive Remote Instruction system for distance learning built at Old Dominion University. IRI is an Internet-based system which integrates continuous multimedia, shared applications and a variety of multi-user collaborative utilities. In this paper, we concentrate on the process architecture and dynamic multicast group handling as they pertain to managing multimedia resources, and show how they support robustness and short response time to user actions. IRI uses raw IP multicasting for audio and video streams and reliable multicasting for resource management and data sharing. The system is scalable (uses multicast for inter-process communication) and expandable(partitioned into a setof autonomousbutcooperating components).

Many distance learning systems claim to be interactive, but few can offer two-way video, on-the-fly interaction and application sharing. To address these limitations, our research group built the Interactive Remote Instruction (IRI) system, which links sites over a high-speed intranet, allowing students at geographically dispersed satellite campuses and community colleges to take a class together. Access from home PCs through a Windows NT port is planned but not yet available. IRI improves on the Old Dominion University's Teletechnet system in five areas: video resolution, asymmetrical video presence, interaction, teacher support and computer simulations.

Cutaneous leiomyosarcoma (CLM) is a very rare smooth muscle tumor arising from the dermis or subcutaneous tissue in the skin. Superficial leiomyosarcoma originates in the superficial dermis or subcutaneous tissue and represents about 3% of the soft tissue sarcomas. CLM presents in persons of all ages but with a peak between 60-70 years old. It may also occur anywhere on the body; the existing cases reported it on the face and trunk. The clinic of leiomyosarcoma consists in a firm dermal nodule, which can be painful, pruritic or paresthestic. The tumor is of 1-3 cm in diameter and can often be seen as a solitary formation. We report one case of a cutaneous leiomyosarcoma arising in the chest region of a 79- year-old male. Leiomyosarcoma is a rare entity whose clinical presentation may appear nonspecific, making diagnosis difficult. Primary tumor excision with wide oncological safety margins is considered, when suitable case, the most appropriate method. Other therapeutic methods, such as radio- or chemotherapy are described as without significant benefits. Despite the claims of radical surgical treatment, due to recurrence rates, the prognosis remains poor. We recommend long-term follow-up of patients to capture a subsequent malignant disease progression.

This paper describes experiences with the use of the Interactive Remote Instruction (IRI) System which was used to teach a computer science graduate course at Old Dominion University during the Fall 1995 semester. Through the use of high-speed networks and high performance workstations, IRI creates a virtual classroom so that geographically dispersed students can fully participate in a class. Central to this system is the availability to each and every student a personal workstation through which the class is taken. Placing a workstation at each student''s disposal opens the opportunity for student interaction and group collaboration. We compare this approach with other educational settings and describe lessons learned from instructor, student and technical perspective. We also describe changes we are putting in place for an expanded usage in the coming fall semester using fiberoptic cable supporting a WAN internet protocol.

The tumor suppressor gene Syk tyrosine kinase is absent or reduced in invasive breast cancer tissues and cell lines; its loss in breast tissues is linked to poor prognosis and metastasis. Also, evidence shows that in vitro Syk is involved in regulating proliferation. Here, we show by in situ hybridization on breast tissue sections that the loss of Syk expression is progressive during tumor development. Strikingly, Syk is already partially lost in normal epithelial tissue adjacent to the cancer lesion. In vivo, cell proliferation (as measured by the proliferative index Ki67) increased from normal to ductal carcinoma in situ to invasive, whereas Syk in situ staining in the same tissues decreased. In vitro, the presence of Syk was associated with reduced cell proliferation in an epidermal growth factor receptor-overexpressing breast cancer cell line, BT549, whereas changes in apoptosis were undetected. Concomitantly, the kinase activity of the proto-oncogene Src was reduced by ∼30%. A 5-fold increase in abnormal mitoses was observed in the Syk-transfected cells compared with vector control. We propose that Syk is involved in the regulation of cell proliferation, possibly by controlling mechanisms of mitosis and cytokinesis via Src signal transduction pathway(s). Because of its progressive and early loss during tumor onset and development, monitoring of Syk loss in breast epithelial cells by noninvasive techniques such as ductal lavage may be a powerful tool for screening purposes.

The growth factor plelotrophin is a positive regulator of tumor angiogenesis and is expressed in breast cancer cell lines and in primary tumor specimens and is one of the factors for the malignant phenotypes of human mammary carcinoma. The expression of PTN in normal and pathologic human breast tissue is mediated by co expression of the species specific transcript and the HERV-PTN fusion transcript. The transcription factor YYl strongly represses HERV-PTN fusion transcript in two breast cancer cell lines. In an effort to understand the biological and biochemical effects of PTN, we recently found that it exerts its action through an orphan membrane tyrosine kinase receptor, anaplastic lymphoma kinase (ALK). We present evidence that ALK is activated by PTN and, sequentially, activates an array of second messengers in various cell lines. Interestingly, human primary mammary fibroblasts express ALK, and Akt and MA%K are activated upon addition of PTN. ALK expression levels are important for the tumorigenicity of cell lines that expresses PTN also. Upregulated levels of ALK in HUVEC render these cells more susceptible to PTN and promote angiogenesis. We conclude that expression of PTN in human mammary cells leads to activation of ALK in stromal cells and promote tumor growth.

This study examines whether the serine/threonine protein kinase, Akt, is involved in the crosstalk between the ErbB2 and estrogen receptor-alpha (ER-alpha) pathways. Treatment of MCF-7 cells with 10(-9) M heregulin-beta1 (HRG-beta1) resulted in a rapid phosphorylation of Akt and a 15-fold increase in Akt activity. Akt phosphorylation was blocked by inhibitors of phosphatidylinositol 3-kinase (PI 3-K), by antiestrogens, the protein tyrosine kinase inhibitor, genistein, and by AG825, a selective ErbB2 inhibitor; but not by AG30, a selective EGFR inhibitor. Akt phosphorylation by HRG-beta1 was abrogated by an arginine to cysteine mutation (R25C) in the pleckstrin homology (PH) domain of Akt, and HRG-beta1 did not induce Akt phosphorylation in the ER-negative variant of MCF-7, MCF-7/ADR. Transient transfection of ER-alpha into these cells restored Akt phosphorylation by HRG-beta1, suggesting the requirement of ER-alpha. HRG-beta1 did not activate Akt in MCF-7 cells stably transfected with an anti-ErbB2-targeted ribozyme, further confirming a role for ErbB2. Stable transfection of the cells with a dominant negative Akt or with the R25C-Akt mutant, as well as PI 3-K inhibitors, blocked the effect of HRG-beta1 on ER-alpha expression and activity and on the growth of MCF-7 cells. Stable transfection of MCF-7 cells with a constitutively active Akt mimicked the effect of HRG-beta1. Experiments employing selective ErbB inhibitors demonstrate that the effect of HRG-beta1 on ER-alpha expression and activity is also mediated by ErbB2 and not by EGFR, demonstrating that ErbB2 is the primary mediator of the effects of HRG-beta1 on ER-alpha regulation. Taken together, our data suggest that HRG-beta1, bound to the ErbB2 ErbB3 heterodimer, in the presence of membrane ER-alpha, interacts with and activates PI 3-K/Akt. Akt leads to nuclear ER-alpha phosphorylation, thereby altering its expression and transcriptional activity.

The fibroblast growth factor-binding protein (FGF-BP) binds and activates fibroblast growth factors in the extracellular matrix, and can have a rate-limiting role in tumor angiogenesis. Here we demonstrate high levels of FGF-BP expression in invasive human breast cancer, relative to normal breast and in situ carcinoma, and in MDA-MB-468 human breast cancer cells. In these cells, FGF-BP was up-regulated by treatment with epidermal growth factor (EGF), dependent on protein kinase C and p38 mitogen-activated protein kinase signaling. Mutational analysis revealed that the activator protein 1 and CCAAT/enhancer binding protein (C/EBP) sites on the FGF-BP gene promoter were required for the EGF effect, whereas deletion of the C/EBP site resulted in a significant increase in promoter basal activity indicating a basal repressive control mechanism. These data suggest that the C/EBP site is a central regulatory element for the regulation of FGF-BP promoter activity in MDA-MB-468 cells. We found that MDA-MB-468 cells express high endogenous levels of both the activating (LAP) and repressive (LIP) isoforms of C/EBPbeta. Overexpression of C/EBPbeta-LAP in MDA-MB-468 cells resulted in a large 80-fold increase in FGF-BP promoter basal activity, which was reversed by coexpression of LIP. Gel-shift analysis revealed that four LIP- and LAP-containing complexes (a-d) bind to the C/EBP site. DNA binding of the LIP and LAP-containing c complex and the b complex in the presence of EGF was modulated by inhibition of p38 mitogen-activated protein kinase, suggesting a role for these complexes in the EGF induction of the FGF-BP promoter. This study suggests that along with its well-defined role in mammary gland development, C/EBPbeta may well play a role in the pathology of breast cancer, in particular in the control of angiogenesis in the invasive phenotype.

Discusses the software architecture, interprocess communication and the reference implementation of the Interactive Remote Instruction (IRI) system for distance learning. IRI is an Internet-based system which integrates continuous multimedia, shared applications and a variety of multi-user collaborative utilities. Internet multicasting is used by IRI for group management and data sharing, UDP (Unix domain protocol) multicasting is used for audio and video streams, while a reliable multicasting protocol (RMP) is used by XTV, the data sharing engine of IRI. The system is both scalable and expandable. It is scalable through the use of multicasting for interprocess communication. It is expandable due to its partitioning into a set of autonomous but cooperating components. The interaction among components is specified by a set of messages and the functions needed to send and receive these messages.

A major feature that distinguishes multimedia applications from other traditional applications is the integration of various media streams that have to be presented in a synchronized fashion. We present a set of algorithms for achieving fine-grain synchronization in a best-effort distributed system. Our algorithms, based on numerical time stamps, take into account both the possible frame loss due to the device buffer overflow at the sender, and the display time of a video frame at the receiver. As a proof of concept, we have implemented a robust solution for lip-synchronization. Experimental results show that the skew between audio and video was between the acceptable values. We extended the solution to n continuous stream synchronization that has the same or different sources. A direct application of our research is the Interactive Remote Instruction (IRI) project, which requires synchronization algorithms in a distance learning environment where participants use best-effort operating systems and networks.

The secreted growth factor pleiotrophin (PTN) can induce mitogenesis in cells that express the receptor for this growth factor, anaplastic lymphoma kinase (ALK). Here we examine the ability of PTN to produce anti-apoptotic signals. We demonstrate that PTN is a survival factor for SW-13 epithelial cells and show that ribozyme-mediated depletion of ALK from SW-13 cells abolishes this effect of PTN. Furthermore, in serum-starved NIH3T3 fibroblasts PTN prevents apoptosis (measured by annexin V staining) with an EC(50) of 0.2 ng/ml and induces cell growth at higher concentrations of PTN. A polyclonal antibody against the PTN ligand-binding domain of the ALK receptor (alpha-LBD) was a partial agonist for ALK in NIH3T3 cells. This alpha-LBD antibody showed high agonist activity for anti-apoptosis (56 +/- 9% relative to PTN), low agonist activity for cell growth (21 +/- 1% relative to PTN), and was an antagonist of PTN-induced cell growth (61 +/- 2% inhibition). Both MAP kinase and phosphatidylinositol (PI) 3-kinase cascades in NIH3T3 cells were activated by PTN, and this effect persisted for up to 3 h. Surprisingly, the anti-apoptotic effect of PTN was completely blocked by the MAP kinase inhibitor UO126, but was not affected by the PI 3-kinase inhibitor LY294002. In contrast, PTN-dependent cell growth required both MAPK and PI 3-kinase activity. We conclude that anti-apoptotic signaling of PTN through ALK in NIH3T3 fibroblasts is via the MAP kinase pathway.

This study examines whether the serine/threonine protein kinase, Akt, is involved in the cross-talk between epidermal growth factor (EGF) and insulin-related growth factor I (IGF-I) receptors and ER-alpha. Treatment of MCF-7 cells with either EGF or IGF-I resulted in a rapid phosphorylation of Akt and a 14- to 16-fold increase in Akt activity, respectively. Akt activation was blocked by inhibitors of phosphatidylinositol 3-kinase, but not by an inhibitor of the ribosomal protein kinase p70S6K. Stable transfection of cells with a dominant negative Akt mutant blocked the effects of EGF and IGF-I on ER-alpha expression and activity, whereas stable transfection of cells with a constitutively active Akt mutant mimicked the effects of EGF and IGF-I. In the latter cells, there was a decrease in the amount of ER-alpha protein and messenger RNA (70-80%) and an increase in the amount of progesterone receptor protein, messenger RNA (4- to 9- and by 3.5- to 7-fold, respectively) and pS2 (3- to 5-fold). Coexpression of wild-type ER-alpha and the dominant negative Akt mutant in COS-1 cells also blocked the growth factor-stimulated activation of ER-alpha, but coexpression of the wild-type receptor with the constitutively active Akt mutant increased ER-alpha activity. Receptor activation was blocked by an antiestrogen. Studies using mutants of ER-alpha demonstrated that Akt increased estrogen receptor activity through the amino-terminal activation function-1 (AF-1). Serines S104 S106, S118, and S167 appear to play a role in the activation of ER-alpha by Akt.

The effect of forearm or calf ischemia on computerized EEG was studied in five patients with peripheral nervous system affections and five patients with cerebral infarction. Spatial analysis of power spectra in various frequency bands was performed in two 8-sec epochs, the former before ischemia and the latter after 5-min from the cessation of circulatory arrest which lasted 15 min. Transient peripheral ischemia resulted in consistent augmentation of alpha activity involving both the anterior and the posterior hemispheric areas, bilaterally. On the other hand, the slower frequency bands (theta, delta) underwent minor, nonsignificant alterations after ischemic stress. The rise of alpha amplitude induced by ischemic stress was ascribed to the activation of nonspecific thalamic system. The activation of this system might also be involved in the favourable effects exerted by ischemic stress on motor recovery of paretic limbs.

The catecholamine (CA) response to upright posture was studied in 30 brainstem infarct patients with orthostatic arterial hypotension; the investigation was made before and after 10 days propranolol therapy (in 15 cases) and before and after 10 days metoclopramide therapy (in other 15 cases). Before treatment almost all patients responded to posture by a rise in adrenaline (A) excretion and by a depression in noradrenaline (NA) excretion. Propranolol therapy prevented the excessive A release produced by standing and normalized their NA response to posture. Metoclopramide administration also prevented the post-orthostatic A discharge but had no significant influence on NA response to posture. Both drugs exerted a favourable influence on postural hypotension of investigated patients. As post-orthostatic A discharge observed in patients with postural hypotension is involved in the pathogeny of this syndrome and both metoclopramide and propranolol are able to correct this disorder one may maintain that the clinical favourable results obtained with these drugs are ascribable at least partly to their blocking effect on A release.

Catecholamine (CA) response to exercise was studied in patients with common (16 cases) or classic (7 cases) migraine as well as in subjects with lumbar disc disease (20 control cases). In migrainous patients exercise induced constantly a rise in epinephrine (E) urinary excretion and a depression in norepinephrine (NE) excretion; the post-exercise E excretion represented the double or the treble of basal E excretion. In controls the pattern of CA response to exercise was opposite to that noted in migraineurs: the exercise induced in almost all controls an augmentation in NE excretion and a depression in E excretion. The pattern of CA response to exercise of migrainous patients is similar to that noted in them after light exposure. As such patients responded by an E discharge to both exercise and light exposure, two conditions preceding quite often the onset of migraine attack, the data suggest the participation of this biochemical abnormality in the pathogeny of migraine. The interpretation is also supported by our previous data demonstrating that the antimigraine drugs are able to prevent the E discharge induced in migrainous patients by light exposure.

Transient ischemia of the extremities was applied in compression or traumatic neuropathies affecting radial nerve (17 cases), ulnar nerve (3 cases), upper brachial plexus (4 cases) or peroneal nerve (10 cases). The limb opposite to that displaying paresis was submitted repeatedly to a 15-minute-period of ischemia every other day for two weeks. The procedure induced in most patients (27 out of 34 cases) a motor improvement of variable degree. In some patients (13 cases) the motor recovery occurred two days or more after starting the procedures, while in others (14 cases) during the very day in which the initial session of ischemia was made or even during the first hour of procedure application. The most beneficial effects of peripheral ischemia were noted in compression neuropathy of peroneal nerve palsy, 9 out of 10 patients with such a disorder being improved by the procedure. We suppose that the method of therapy proposed by us restores promptly the motility of patients with compression neuropathy by inducing a long-lasting activation of some central neural mechanisms.

The effect of amitriptyline on catecholamine (CA) response to light of 20 migrainous patients was studied. The drug was given orally, 36 mg daily (12 mg x 3), for ten days. Before therapy, the migraineurs responded to light by an increase in epinephrine (E) excretion and not by the rise in norepinephrine (NE) excretion, noticed in controls. The NE excretion of migrainous subjects underwent very often a depression after photostimulation. Amitriptyline therapy prevented the post-photic rise in E excretion of migraineurs, without influencing significantly the variation in NE excretion produced in them by light. In other 8 migrainous subjects the effect of flunarizine, a selective calcium channel blocker, on CA response to light was tested. The dosage was of 5 mg daily, for ten days. Flunarizine had similar effects to those displayed by amitriptyline; the drug prevented the rise in E excretion produced by light without normalizing the NE response to light of migrainous subjects. The results suggest that the efficiency of these two drugs in migraine prophylaxis is connected with the ability of these substances to block the E discharge produced in migraineurs by light or by other stimuli. The interpretation is all the more likely as propranolol, another drug applied in migraine prophylaxis also blocks the post-photic E discharge of migraineurs.

The effects of centrophenoxine on catecholamine (CA) response to orthostasis and on postural blood pressure fall of 25 patients with orthostatic hypotension due to brainstem ischemia were studied. Before therapy, the patients responded to posture by a depression in norepinephrine (NE) excretion and a rise in epinephrine (E) excretion. After a 10-day treatment with centrophenoxine, 800 mg daily, the patients responded to posture like normals, i.e. by a rise in NE excretion and a reduction in E excretion. Although the orthostatic blood pressure fall was less marked after treatment, the favourable clinical effect of the drug could not be correlated significantly with the restoration of CA response to posture after treatment.

The influence of head down (HD) tilting on brain-stem auditory evoked responses (BAER) was studied in hypertensives with supine brain-stem disorders (occipital headache, vertigo, nausea, diplopia, blurred vision occurring after night recumbency), in hypertensives without such phenomena and in normotensives. In the latter two categories of subjects HD tilting had no effect on BAER. On the contrary, in hypertensives with supine brain-stem disorders the manoeuvre induced a constant prolongation of I-V and III-V intervals and a depression in the amplitude of wave V; the alterations of BAER produced by HD tilting reveal probably a dysfunction of the superior brain-stem area and might be due to the impaired cerebral venous draining subsequent to the manoeuvre. The study of BAER after HD tilting seems to be a proper means to attest the supine brain-stem disorders displayed by some hypertensives.

Reference to: Oncogene 2003; 22: 2073–2087. doi:10.1038/sj.onc.1206311 After careful examination of this paper, the authors have realized that they have inadvertently made a serious editorial error. While this error has no impact on the results or conclusions drawn in the study, the authors wish to withdraw this article.

The reactivity of the higher autonomic centers to hypoglycemia prior to and after the treatment with pyrithioxin or caffeine in patients with cerebral infarct was studied. Before treatment a hyporeact

SUMMARY 1 In 24 non-anaesthesized cats under the influence of curare studies were made of the effect of i.v.-administered quinidine on the cortical and thalamic post-discharges produced by focal electrical stimulation of the cortex and the thalamic nuclei, and on the discharges induced by local application of penicillin on the cerebral cortex. 2 Dosages lower than those which are necessary for the suppression of severe electro-convulsive crises, and which do not cause significant hypotensive effects (4–7 mg/kg) are sufficient for raising the threshold of the cortical and thalamic post-discharges up to 400%. These effects are long-lasting, persisting for several hours. 3 Dosages of 7–15 mg/kg suppress penicillin spikes during a short interval (5–10 minutes). Later on the spikes reappear and the development of general paroxysms cannot be avoided. Higher dosages (up to 30 mg/kg) lead to the disappearance of the electrical crises in the cortical leads. Only isolated spikes are observed, whereas the paroxysm continues to develop in the thalamic leads. RESUME 1 On a etudie sur 24 chats non-anesthesies et curarises l'effet de la quinidine administree par voie intraveineuse sur les post-decharges corticales et thalamiques, produites par la stimulation electrique focale du cortex et des noyaux thalamiques, ainsi que sur les decharges induites par l'application locale de la penicilline sur l'ecorce cerebrale. 2 Des doses plus faibles que celles necessaires pour la suppression des grandes crises electro-convulsives et qui n'entrainent pas des effets hypotensifs significatifs (4–7 mg/kg) sont efficientes pour elever le seuil des post-decharges corticales et thalamiques avec des valeurs qui vont jusqu'a 400%. Ces effets sont durables, persistant pour des heures. 3 Des doses de 7–15 mg/kg abolissent pour de courts intervalles (5–10 minutes) les pointes penicilliniques. Ulterieurement les pointes s'organisent de nouveau et ne peuvent pas etre empechees de determiner des paroxysmes generalises. Des plus fortes doses (allant jusqu'a 30 mg/kg) font disparaitre la crise electrique sur les derivations corticales et la remplacent par des pointes isoles, tandis que le paroxysme continue a se developper sur les derivations thalamiques.