[Therapeutic strategies in advanced ALK positive non-small cell lung cancer]. / Stratégies thérapeutiques dans le cancer bronchique non à petites cellules ALK positif de stade IV.

Anaplastic lymphoma kinase (ALK) rearrangement is a therapeutically targetable oncogenic driver found in 5% of patients with non-small-cell lung cancer (NSCLC). The objective of this paper is to synthesise current knowledge on ALK rearrangement and its impact on the management of advanced NSCLC. Several inhibitors of the tyrosine kinase of ALK (crizotinib, ceritinib, alectinib) have been approved as first line therapies in patients with advanced ALK positive NSCLC, which are associated with a better median progression-free survival than conventional chemotherapy. Unfortunately, the emergence of drug resistance leads to tumor progression. In patients with oligoprogressive disease if local ablative therapy can be effected, continuing with the same ALK tyrosine kinase inhibitor is one option. In patients with progression, clinicians may consider switching to another therapy. Rebiopsy of the tumor or liquid biopsy could be attempted to identify the mechanisms of resistance and to customize ALK-target therapy. The emergence of crizotinib drug resistance has prompted the development of next generation drugs including ceritinb, alectinib, brigatinib and lorlatinib. The ability to quickly develop targeted therapies against specific oncogenic drivers will require close co-operation between pathologists, pulmonologists and oncologists in the future to keep pace with drug discoveries and to define optimal therapeutic strategies.

[Malignant rhabdoid tumor of the lung]. / Tumeur pulmonaire maligne de type rhabdoïde.

INTRODUCTION: Rhabdoid tumours usually develop in brain and spinal cord or kidney; they are highly malignant neoplasms that typically arise in infancy and early childhood. However, rare cases of pulmonary localization have been described, particularly among young adults. CASE REPORT: A 26-year-old man, smoker, had a right apical lung mass associated with a Pancoast syndrome leading to haemoptysis. There was also a tumour of the left thigh and scalp. Histological samples taken at these three locations were in favour of an undifferentiated carcinoma. The lack of nuclear integrase interactor 1 expression, and immunohistochemical appearance supported the diagnosis of rhabdoid tumour. Despite treatment, unfavourable progression confirmed this hypothesis, doubling time was less than six weeks with development of multiple metastases resulted in death within only three months after diagnosis. CONCLUSION: The lack of expression of integrase interactor 1 should suggest the diagnosis of rhabdoid tumour, especially when there is quick progression. The prognosis of these tumours remains poor and therapeutic options are limited.

[AA-type amyloidosis secondary to multidrug resistant pulmonary tuberculosis: implications for therapy]. / Amylose AA secondaire à une tuberculose pulmonaire multi-résistante: implications thérapeutiques.

Multidrug resistant pulmonary tuberculosis was diagnosed to a 32-year-old man. An AA-amyloidosis was subsequently diagnosed on the renal biopsy performed for nephrotic syndrome and macroscopic hematuria. A 6-drug antibiotic treatment was delivered quickly after first results of genotypic antibiogram given the renal failure, and was secondarily adapted to the phenotypic antibiogram. Multidrug therapy was fairly well tolerated. Clinical and biological improving were slow. Although tuberculosis is a classic cause of amyloidosis, this is the first case reporting an association between a multidrug resistant case and an amyloidosis in adults. This case also raises the question of MDR probabilistic treatments in situations whether a vital organ prognosis is engaged.

Negative-pressure wound therapy for the treatment of pharyngocutaneous fistula.

INTRODUCTION: Pharyngocutaneous fistula is a well-known complication of head and neck cancer surgery.The purpose of this study was to determine the value of negative-pressure wound therapy (NPWT) for the treatment of these fistulas. NPWT is used in many fields of medicine, but its use in otorhinolaryngology has been rarely reported. NPWT is a cost-effective means to accelerate wound healing. PATIENTS AND METHODS: A single-centre retrospective study was conducted on 7 patients with pharyngo-cutaneous fistula following surgery for squamous cell carcinoma between January 2011 and April 2013.These fistulas were treated by negative-pressure wound therapy (NPWT). RESULTS: This series comprised seven male patients with a mean age of 65 years and 9 months. The mean duration of treatment was 23 days (range: 11 to 42 days). Two patients had a history of radiotherapy for pharyngolaryngeal cancer. Negative-pressure wound therapy achieved cure of the fistula in all patients with satisfactory acceptability. Mean follow-up was 10 months (range: 6 months to 2 years). CONCLUSION: Negative-pressure wound therapy represents a valuable treatment option in certain settings for the management of pharyngocutaneous fistula following head and neck cancer surgery.

Optokinetic stimulation rehabilitation in preventing seasickness.

OBJECTIVES: Seasickness occurs when traveling on a boat: symptoms such as vomiting are very disturbing and may be responsible for discontinuing travel or occupation and can become life-threatening. The failure of classical treatment to prevent seasickness has motivated this retrospective study exploring optokinetic stimulation in reducing these symptoms. PATIENTS AND METHODS: Experimental training of 75 sailors with optokinetic stimulation attempted to reduce seasickness manifestations and determine the factors that could predict accommodation problems. RESULTS: Eighty percent of the trained subjects were able to return on board. No predictive factors such as sex, occupation, degree of illness, number of treatment sessions, time to follow-up, and age were found to influence training efficacy. CONCLUSION: Optokinetic stimulation appears to be promising in the treatment of seasickness. Nevertheless, statistically significant results have yet to demonstrate its efficacy.

[Pregnancies occurring during oral contraception: lessons from the GRECO study]. / Grossesses survenant sous contraception orale: les leçons de l'étude GRECO.

OBJECTIVES: The GRECO study has collected data on pregnancies, regardless of their outcome, that occurred in women taking an oral contraceptive. PATIENTS AND METHODS: The analysis concerned 551 women prospectively recruited in services of gynaecology or obstetrics, termination of pregnancy centres, family planning centres or consultations of gynaecology in France throughout 2002 and who were 12 weeks pregnant or less. RESULTS: Contraception used during the cycle of conception was an estroprogestative combination in 88% of cases, a microprogestative in 8.7%, a macroprogestative in 0.9% or another type of pill in 2.4%. Progestatives were levonorgestrel 59.0%, gestoden 17.2%, desogestrel 4.7%, norethisterone acetate 2.9%, norgestimate 1.8%, cyproterone acetate 2.0%, norgestrel 1.6%. When asked about the potential cause of the oral contraceptive failure, 76.9% of women reported events such as missed pills which were the most frequent cause of failure (60.8% of failures and 80.1% of events, 2.7+/-2.7 missed pills), followed by vomiting and diarrhoea. 81.5% of women chose to terminate their pregnancy. DISCUSSION AND CONCLUSION: The GRECO study, despite its limitations (retrospective collection of missed pills data, declaratory data) showed that missed pills, even once, were the most common reason for oral contraceptive failure. The most frequent decision was the termination of pregnancy.

Evidence of bacterial biofilm in tubing from hydraulic pathway of hemodialysis system.

Biofilms consist of microorganisms immobilized at a substratum surface embedded in an organic polymer matrix of bacterial origin. Tubing drawn from the fluid pathways within dialysis machines of various models were investigated for biofilm. Scanning electron microscopy (SEM), performed on approximately 2 cm2 samples of the tubing inner surfaces revealed that the inner surfaces of the tubing were covered with biofilms consisting of numerous deposits and glycocalix at different stages of formation with components containing bacteria and algae. Evaluations of biomass were performed from tubing sections of various lengths and inner diameters put in tubes containing water for injection and immersed in an ultrasound washtub for 1 h to ensure sloughing of the biofilm. Living bacteria were identified by plating on nutrient agar media and incubation for 48 h at 37 degrees C. Epifluorescent stains were used for the total bacteria count. Lipopolysaccharide levels were determined by the endotoxin activity measurements. Polyoside contents were determined by the colometric method, and the chemical oxygen demand was measured to evaluate the amount of organic substance. Biofilms detached from tubing samples drawn from the water path, bicarbonate path, and fresh dialysate path within dialysis machines contained approximately 1.10(3)-1.10(6) total bacteria/cm2, yet only some living bacteria were found. Endotoxin levels ranged from 1 to 12 EU/cm2. In contrast in the dialysate fluid, no bacteria were found, and the endotoxin content was under the detection level of the method. The polyoside content and chemical oxygen demand of the biomass ranged from 11 to 83 microg/cm2 and from 53 to 234 mg/cm2, respectively. It is concluded that a germ- and endotoxin-free dialysate does not exclude the risks and hazards of bacteria and endotoxin discharge from biofilm developed on the fluid pathway tubing, acting as a reservoir for continuous contamination, and efforts in the optimization of cleaning and disinfection procedures used for hemodialysis systems should aim to detach and neutralize biofilm when necessary.

Acute lung injury fibroblast migration and invasion of a fibrin matrix is mediated by CD44.

Fibrosis results when myofibroblasts invade the wound fibrin provisional matrix. Extracellular matrix receptors on the cell surface mediate cell adhesion, migration, and invasion. Recent work with transformed cells indicates that these cells use the cell surface matrix receptor CD44 for migration and invasion. In this study, we examine whether lung fibroblasts, isolated from patients dying with acute alveolar fibrosis, use CD44 to invade a fibrin matrix. Consistent with a role for CD44 in mediating fibroblast invasion and subsequent tissue fibrosis, immunohistochemical analysis of lung tissue from patients who died from acute alveolar fibrosis after lung injury reveals CD44-expressing mesenchymal cells throughout newly formed fibrotic tissue. PCR, Western, and immunoprecipitation analysis demonstrate that the 85-kD CD44 isoform is expressed by acute lung injury fibroblasts. Consistent with a role in mediating matrix adhesion and migration ultrastructurally, CD44 was found uniformly over the cell surface and was found densely labeling filopodia and lamellipodia, highly motile structures involved in cell migration. To determine if lung injury fibroblasts use CD44 to invade fibrin, a fibrin gel model of fibrosis was used. By blocking the function of CD44 with monoclonal antibodies, fibroblast invasion into a fibrin matrix was inhibited. To examine the mechanism by which CD44 mediates fibroblast invasion, the role of CD44 in fibroblast migration and adhesion was evaluated. Anti-CD44 antibody blocked fibroblast migration on the provisional matrix proteins fibronectin, fibrinogen, and hyaluronic acid. Additionally, fibroblast CD44 mediated adhesion to the provisional matrix proteins fibronectin, fibrin, and hyaluronic acid, but not to laminin, a component of the basement membrane. These findings support the hypothesis that fibroblast CD44 functions as an adhesion receptor for provisional matrix proteins and is capable of mediating fibroblast migration and invasion of the wound provisional matrix resulting in the formation of fibrotic tissue.

The role of cytokines in human lung fibrosis.

Fibrosis is a disorder characterized by a qualitative and quantitative alteration of the deposition of extracellular matrix with accumulation of mesenchymal cells in replacement of normal tissue. The sequence of events leading to fibrosis of an organ involves the subsequent processes of injury with inflammation and disruption of the normal tissue architecture, followed by tissue repair with accumulation of mesenchymal cells in this area. A similar sequence of events occurs in wound healing with formation of normal, limited and transient granulation tissue, while in fibrosis, a maladaptive repair leads to an extensive, exaggerated process with functional impairment. Inflammatory cells (mainly mononuclear phagocytes), platelets, endothelial cells, and type II pneumocytes play a direct and indirect role in tissue injury and repair. The evaluation of several human fibrotic lung diseases, five diffuse (idiopathic pulmonary fibrosis (IPF); adult respiratory distress syndrome (ARDS); coal workers' pneumoconiosis (CWP); Hermansky-Pudlak syndrome (HPS); systemic sclerosis (SS)) and two focal (tumour stroma in lung cancer; and obliterative bronchiolitis (OB) after lung transplantation), has shown that several cytokines participate in the local injury and inflammatory reaction (interleukin-1 (IL-1), interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), and tumour necrosis factor-alpha (TNF-alpha)), while other cytokines are involved in tissue repair and fibrosis (platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-beta), and basic-fibroblast growth factor (b-FGF)). A better understanding of the cytokines and cytokine networks involved in lung fibrosis leads to the possibility of new therapeutic approaches.

Validity in nulliparas of increased beta-human chorionic gonadotrophin at mid-term for predicting pregnancy-induced hypertension complicated with proteinuria and intrauterine growth retardation.

The objective of the present study was to investigate whether increased beta-human chorionic gonadotrophin (beta HCG) plasma concentrations in an unselected population of nulliparas could predict the occurrence of complicated pregnancy-induced hypertension (PIH). The design was that of a prospective population study. It was conducted at the obstetric departments of Amiens University Hospital and Creil General Hospital on 434 consecutive nulliparas with singleton pregnancies after natural fertilization who accepted the systematic offer of trisomy 21 screening but for whom this disorder was finally estimated. Measurement of plasma concentration of beta HCG (ELISA method) was carried out between 14 and 20 weeks (mean: 17 weeks) of amenorrhea, and measurement of blood pressure and proteinuria (> 300 mg/24 h or Albustix +2) during the first, second and third term and 2-3 months after the delivery, as well as measurement of birth weight for determination of small for gestational age (SGA) babies, 37 women developed PIH, 10 without other complication, 16 with proteinuria (5 of which with SGA babies) and 11 with SGA babies. Furthermore 2 patients presented abruptio placentae without PIH. 395 women did not develop PIH including 389 normotensive women and 6 chronic hypertensive patients without superimposed toxemia. Only 1 was diabetic. None had chronic renal disease. Mean (+/- SD) levels of beta HCG were higher in PIH than in controls: 46,805 +/- 19,068 versus 23,479 +/- 13,463 IU. A pathologic threshold was chosen as the mean for the whole population + 1 SD: 25,613 + 15,479 = 41,082 IU. Elevated levels (above this value) were significantly associated with isolated PIH or PIH complicated with proteinuria and/or with SGA babies. The positive predictive value of this criterion was respectively 11, 15 and 12% for each of these complications. The relative risk (and 95% confidence limit) of women with elevated beta HCG for each of these complications was 20 (6-79), 11 (4-43) and 22 (7-93). Elevated plasma beta HCG found around 17 weeks of amenorrhea predicts PIH complicated with either proteinuria or SGA babies with a positive predictive value comparable to that of the best and earliest test proposed up to now to select nulliparas at high risk of preeclampsia, namely the abnormalities of the Doppler waveforms of the uterine arteries. Since this test is simpler to perform, it represents the most convenient method to screen a population of nulliparas for evaluation of the benefits of low-dose aspirin.

Cytokines in human lung fibrosis.

Fibrosis is a pathological process characterized by the replacement of normal tissue by mesenchymal cells and the extracellular matrix produced by these cells. The sequence of events leading to fibrosis of an organ involves the subsequent processes of injury with inflammation and disruption of the normal tissue architecture, followed by tissue repair with accumulation of mesenchymal cells in the area of derangement. The same sequence of events occurs in wound healing with normal granulation tissue and scar formation, but, while normal scar formation is very localized and transient, in contrast, in fibrosis, the repair process is exaggerated and usually widespread and can be chronic. Inflammatory cells (mainly mononuclear phagocytes), platelets, endothelial cells, and type II pneumocytes play a direct and indirect role in tissue injury and repair. The evaluation of three human fibrotic lung diseases, two diffuse [idiopathic pulmonary fibrosis (IPF), and the adult respiratory distress syndrome (ARDS)], and one focal (tumor stroma in lung cancer), has shown that several cytokines participate to the local injury and inflammatory reaction [interleukin-1 (IL-1), interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha)], while other cytokines are involved in tissue repair and fibrosis [platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-beta), and basic-fibroblast growth factor (b-FGF)]. A better understanding of the cytokines and cytokine networks involved in lung fibrosis leads to the possibility of new therapeutic approaches.

[Hypertension and pregnancy. Diagnosis, physiopathology and treatment]. / Hypertension et grossesse. Diagnostic, physiopathologie et traitement.

This review on hypertension in pregnancy focuses mainly on the pathophysiology and prevention of pregnancy induced hypertension which, when associated with proteinuria, is usually called preeclampsia. Rather than a genuine hypertensive disease, preeclampsia is mainly a systemic endothelial disease causing activation of platelets and diffuse ischemic disorders whose most obvious clinical manifestations involve the kidney (hence the proteinuria, edema and hyperuricemia), the liver (hence the hemolytic elevated liver enzymes and low platelets, or HELLP syndrome), and the brain (hence eclamptic convulsions). Hypertension is explained by increased vascular reactivity rather than by an imbalance between vasoconstrictive and vasodilating circulating hormones. This increased reactivity is due to endothelial dysfunction with imbalance between prostacyclin and thromboxane A2 and possibly dysfunction of NO and endothelin synthesis. The aggressive substances for endothelium are thought to be of placentar origin and the cause of their release is explained by placentar ischemia related to a defect of trophoblastic invasion of the spiral arteries. The etiology of this latter defect is unknown but involves immunologic mechanisms with genetic predisposition. The only effective treatment for PIH is extraction of the baby with the whole placenta. The decision for extraction is often a very delicate obstetric problem. Antihypertensive drugs are mainly indicated in severe hypertension (> 160-100 mm Hg), with the aim of preventing cerebral hemorrhage in the mother, but have not been shown to improve fetal morbidity or mortality. Eclamptic seizures can be prevented and treated more effectively with magnesium sulfate than with diazepam or phenytoin. Prevention of preeclampsia remains the main challenge. Whereas antihypertensive drugs are ineffective, calcium supplementation and low dose aspirin have proven effective but mainly in selected populations with a relatively high incidence of preeclampsia (> 8-10%). In multiparas the selection of such a high risk population is relatively easy when at least 2 (or 1?) previous pregnancies were complicated with early preeclampsia and/or intrauterine growth retardation. In nulliparas the selection of the high-risk population is still a subject of research. The 2 most promising criteria are abnormal Doppler velocimetry of the uterine arteries at around 20 weeks of amenorrhea, and abnormally high plasma levels of beta HCG at 17 weeks of amenorrhea.

Synergic in vitro effects of interleukin-2 and tau-interferon on the migration of blood monocytes from control subjects and patients with lung cancer.

BACKGROUND: Macrophages can play a major role against cancer by exerting their cytotoxic activity against tumor cells. The presence of macrophages in tumor stroma is related to the recruitment of circulating blood monocytes through the release of chemotactic factors by cancer cells. However, fewer blood monocytes from patients with cancer, such as lung cancer, migrate from in vivo and in vitro, compared with blood monocytes control subjects. METHODS: Two cytokines, interleukin-2 (IL-2) and tau-interferon (tau-INF), proposed in the treatment of cancer, were tested for their ability to modulate the migratory response in modified Boyden chemotactic chambers of blood monocytes obtained from control subjects and patients with lung cancer in the presence of two chemotactic factors: N-formylmethionyl-leucyl-phenylalanine and complement fraction C5a (C5a). RESULTS: Incubation with IL-2 and tau-INF resulted in a dose-dependent depression of the migration of blood monocytes from control subjects and patients with lung cancer. IL-2 depression was induced by IL-2 concentrations of 10(5) units/ml, and tau-IFN effects were measured for concentrations of 100 mu/ml. Furthermore, when low concentrations of IL-2 were tested in combination with low concentrations of tau-IFN, dose-dependent depression of blood monocyte migration occurred. CONCLUSIONS: Dose-dependent depression of blood monocyte migration may modulate the inflammatory component of tumor stroma in patients with lung cancer treated with these cytokines. It may also explain, in part, the high incidence of infections in patients treated with IL-2.

Platelet-derived growth factor AA and AB dimers are present in normal human epithelial lining fluid.

Normal lung architecture is related to the presence of mesenchymal cells (fibroblasts and smooth muscle cells), and to the production by these cells of extracellular matrix. The turnover of mesenchymal cells is under a fine regulation due, at least in part, to the local presence of different mediators acting on their cell cycle. Since normal human alveolar macrophages obtained by bronchoalveolar lavage (BAL) spontaneously release platelet-derived growth factor (PDGF), a cytokine with chemotactic and growth activity on mesenchymal cells, we evaluated normal human epithelial lining fluid (ELF) for the presence of PDGF. Active only as a dimer, PDGF is a glycoprotein composed of two chains (A and B) and, thus, can be present in three forms: AA, AB, and BB dimers. Interestingly, normal ELF contains PDGF AA dimers, and to a lesser extent AB dimers, while no significant level of BB dimers is detected. Furthermore, ELF PDGF is biologically active and responsible for a significant part of the chemotactic activity and the "competence" growth activity for mesenchymal cells present in normal ELF. These findings suggest that ELF PDGF has a role in normal lung structure maintenance and tissue repair.

Human granulocyte- and granulocyte-macrophage-colony stimulating factors are chemotactic and "competence" growth factors for human mesenchymal cells.

Mesenchymal cell migration and replication are biological events regulated by cytokines released by several cell types. Human granulocyte-colony stimulating factor (G-CSF) and macrophage-granulocyte-CSF (GM-CSF) were evaluated for chemotactic and growth activity for mesenchymal cells, using modified Boyden chemotactic chambers and complementation tests with human mesenchymal cells as target cells. G-CSF and GM-CSF, at biological concentrations, were demonstrated to be chemotactic and "competence" growth factors for these cells. Furthermore, G-CSF chemotactic activity was truly chemotactic (as demonstrated by checkerboard analysis) and significantly more potent than GM-CSF', while GM-CSF "competence" activity was significantly higher than G-CSF'. These observations suggest the potential role of these cytokines in tissue repair and fibrosis.

[Pathological Doppler uterine readings when the placenta is laterally situated]. / Doppler utérin pathologique et latéralisation placentaire.

We carried out a retrospective study on 96 patients whose uterine waveforms were abnormal, in order to determine if a laterally located placenta further increased this risk. Our population was separated into 2 groups (75 women with a laterally located placenta, 21 with a centrally located placenta). We have found a significant difference between ipsi placental uterine blood flow velocity and contralateral placental blood flow velocity when the placenta is located laterally, where as the 2 arteries are similar when the placenta has a central location. The following factors were used to compare the two groups: the patient's previous obstetric record and the incidence of hypertensive disorders and fetal distress. In the group with laterally located placentas, the incidence of complications in previous pregnancies was higher, hypertension was more frequently serious or presented complications, fetal distress and cesarean sections were more frequent as was IUGR. All cases of intrauterine death were found in the group with laterally located placentas. In determining the predictive value of the "laterally located placenta" test, we found in the centrally located placenta group that hypertensive disorders were often less serious and less frequently complicated by albuminuria, that the outcome of pregnancy disorders was less serious for the fetus, and that the neonate was less hypotrophic. No incidence of intrauterine death was recorded for the centrally located group. Placental laterality significantly increases both the frequency and the seriousness of fetomaternal hypertensive disorders.

In vitro effects of pentoxifylline on smooth muscle cell migration and blood monocyte production of chemotactic activity for smooth muscle cells: potential therapeutic benefit in the adult respiratory distress syndrome.

The adult respiratory distress syndrome (ARDS) is a severe lung condition characterized by an acute lung injury leading to a massive intra-alveolar fibrosis with rapid lung failure. ARDS intra-alveolar fibrosis results from the migration of mesenchymal cells (mainly smooth muscle cells [SMC]) into the alveoli through alveolar epithelial basement membrane gaps resulting from the injury. SMC migration is followed by their replication and production of extracellular matrix, which leads to fibrosis. Thus, any pharmacologic agent able to prevent SMC migration should prevent, at least in part, intra-alveolar fibrosis. SMC migration is thought to be due to the presence, in the alveolar spaces, of chemotactic factors for mesenchymal cells, such as fibronectin and platelet-derived growth factor (PDGF). The local presence of these chemotactic factors can be due to plasmatic leakage, platelet degranulation, and mononuclear phagocyte activation. Pentoxifylline is a methylxanthine interacting with the biology of several types of cells, including red blood cells, neutrophils, blood monocytes, and endothelial cells. Pentoxifylline prescription has been suggested in ARDS with respect to its activity on neutrophils, its inhibition of tumor necrosis factor-alpha (TNF) release by mononuclear phagocytes, and its prevention of TNF-induced lung injury. Since pentoxifylline can modulate the migration of several cell types, we hypothesized that it could interfere with mesenchymal cell migration. SMC migratory response was measured in vitro with modified Boyden chemotactic chambers in the presence of PDGF, fibronectin, "platelet extract," and activated blood monocyte supernatants. Pentoxifylline, at therapeutic levels, significantly reduced SMC migration in response to the presence of these chemotactic activities.(ABSTRACT TRUNCATED AT 250 WORDS)