Lack of association between MDM2 SNP309 and TP53 Arg72Pro polymorphisms with clinical outcomes in myelodysplastic syndrome.

MDM2/p53 pathway plays an important role in the control of apoptotic and proliferation mechanisms, and alterations in this pathway have been described in myelodysplastic syndromes (MDS). We investigated the frequency of MDM2 SNP309, TP53 Arg72Pro polymorphisms in de novo MDS and the association of these polymorphisms with clinical characteristics. Our results showed that the frequencies of genotypes for MDM2 SNP309 and TP53 Arg72Pro did not differ between MDS and healthy controls and that these polymorphisms were not associated with clinical and laboratory parameters, disease progression and overall survival, suggesting that MDM2 and TP53 polymorphisms are not involved in risk for MDS, or in the clinical and laboratory characteristics of the disease.

Association between Degree of Anaplasia and Degree of Inflammation with the Expression of COX-2 in Feline Injection Site Sarcomas.

Feline injection site sarcomas (FISSs) are mesenchymal neoplasms that develop at the sites of delivery of vaccines or other injectable products. Vaccine adjuvants can trigger an intense and persistent inflammatory response that may lead to neoplastic transformation. The proinflammatory role of cyclo-oxygenase (COX)-2 is well known and its overexpression has prognostic value in multiple neoplastic processes. One hundred and seventeen FISSs were evaluated for the degree of inflammation and anaplasia. Immunohistochemistry was used to determine the expression of COX-2 in these sarcomas. There was a significant association between the degree of inflammation and the expression of COX-2 by neoplastic cells. COX-2 expression was lower in tumours with higher degrees of anaplasia. These findings may be useful in predicting the sensitivity of FISSs to treatment with COX-2 inhibitors. The potential therapeutic use of such agents could then be restricted to tumours with lower degrees of anaplasia.

Improved outcome in young adults with de novo acute myeloid leukemia in first remission, undergoing an allogeneic bone marrow transplant.

We assessed the outcome of 170 patients with AML in first complete remission, aged 1-47 years (median 29), who had undergone an allogeneic BMT before or after 1990 (n=80 and n=90, respectively); all patients were prepared with cyclophosphamide and TBI; the median follow-up for surviving patients was 13 years. The donor was an HLA-identical sibling in 164 patients. Transplant-related mortality (TRM) was 30% before and 7% after 1990 (P<0.001); relapse-related death (RRD) was 26 and 11% (P=0.002); and actuarial 10-year survival was 42 and 79% (P<0.00001). Patients transplanted after 1990 were older, had a shorter interval diagnosis-BMT, had less FAB-M3 cases, received a higher dose of TBI, a higher marrow cell dose and combined (cyclosporine+methotrexate) GVHD prophylaxis. Patients relapsing after transplant had an actuarial survival of 0 vs 31% if grafted before or after 1990 (P=0.01), and their median follow-up exceeds 10 years. In conclusion, the overall survival of first remission AML undergoing an allogeneic BMT has almost doubled in the past two decades, despite older age and fewer M3 cases. Improvement has come not only from changes in transplant procedures, but also from effective rescue of patients relapsing after transplant.

Impacto de la Terapia de Alto Flujo de Oxigeno (TAFO) en un Hospital Pediátrico de la Provincia de Buenos Aires / Impact of High Flow Oxygen Therapy (TAFO) in a Pediatric Hospital of the Province of Buenos Aires

Introducción: Las infecciones respiratorias agudas bajas (IRAB), representan la causa más frecuente de consulta e internación en los meses de invierno. La insuficiencia respiratoria aguda es la complicación que motiva la internación de los pacientes y la necesidad de Unidad Terapia Intensiva (UTI).El objetivo del trabajo fue describir los resultados de la implementación de la Terapia de Alto Flujo (TAFO) en pacientes con IRAB grave internados en Terapia Intermedia Métodos: Estudio prospectivo y descriptivo que incluyó pacientes de 1 a 36 meses internados en Terapia Intermedia en el Hospital Sor María Ludovica de la ciudad de La Plata, desde junio de 2018 a septiembre de 2019. Se ingresaron a TAFO pacientes sin respuesta al tratamiento con oxígeno a bajo flujo. El ingreso a UTI se consideró fracaso de la TAFO Resultados: De 760 pacientes internados con IRAB, 91(11,9%) ingresaron a TAFO de los cuales 59 (64,8 %) tuvieron respuesta favorable con disminución de la frecuencia respiratoria (FR), frecuencia cardiaca (FC) y mejoría de la mecánica respiratoria; el resto (35,2%) pasó a UTI por fracaso terapéutico. Presentaron complicaciones a la TAFO el 5,5% de los pacientes Conclusión: La TAFO fue una terapéutica segura, de fácil utilización que, a través de un aporte de oxígeno conocido, permitió la corrección de la hipoxemia, logrando la disminución de la FR, FC y mejoría de la mecánica respiratoria, dándole mayor comodidad al paciente durante su enfermedad

Introduction: Respiratory infections remain the major cause of outpatient consultation and hospital admissions during the winter season. Lower respiratory illness may cause severe acute respiratory insufficiency and hypoxemic respiratory failure, thus determining the need for hospitalization and eventual intensive care (ICU). The purpose of this paper is to describe the results of High Flow Oxygen Therapy (HFOT) implementation for patients with acute lower respiratory infections (ALRI) admitted to intermediate therapy unit. Methods: Prospective and descriptive study which included patients from age 1 to 36 months, hospitalized at intermediate therapy care unit at "Sor María Ludovica", Hospital, in La Plata, from June, 2018 to September, 2019. Patients who did not show any improvement to low flow oxygen therapy were the subjects of this study. Further submission to ICU was considered as HFOT failure Results: From 760 patients hospitalized with ALRI, 91 (11.9%) were admitted to TAFO. Fifty nine, (64.8%) had a favorable response with decreased respiratory and heart frequency rate, and an improvement of the work of breathing. The rest (35.1%) went to ICU due to therapeutic failure. Five point five percent of patients presented complications to TAFO. Conclusion: HFOT was a safe, easy to implement therapy treatment which improved the hypoxemic respiratory failure. This therapy reduced the respiratory and heart rate, and yielded a better and lower respiratory work, making patients more comfortable during illness

Lack of in vitro colony (CFUC) formation and myelosuppressive activity in patients with severe aplastic anemia after autologous hematologic reconstitution.

In vitro colony formation (CFUC) was studied in 8 patients with severe aplastic anemia (SAA) in complete hematologic remission following high dose pulse methylprednisolone (P/6-MPr) and/or antilymphocyte globulin (ALG). All patients except one were off maintenance treatment at the time of study, and follow-up ranged from 271 to 630 days. All patients showed marked reduction of colonies (2 +/- 3/2.5 x 10(5) cells; our normal 61 +/- 14) and clusters (77 +/- 45; our normal 179 +/- 83), which persisted for as long as 600 days after initial therapy. Incubation of patients' marrow with ALG did not enhance significantly colony formation. Co-culture of bone marrow from 6 patients with SAA in remission and normal marrow produced a marked inhibition of the expected colonies (84 +/- 16%) and clusters (29 +/- 23%). Incubation of patients' marrow with ALG prior to the co-culture experiments did not prevent suppression of colonies and clusters. Co-culture of patients' peripheral blood lymphocytes with normal marrow had no effect on colony formation. Therefore remission marrow from patients with SAA exhibits severely impaired in vitro growth (CFUC) and marked myelosuppressive activity against normal marrow cells. Incubation of patients' marrow with ALG has no significant effect on either assay.

Treatment of severe aplastic anemia with sequential immunosuppression.

Forty-two patients with severe aplastic anemia (SAA) were treated with immunosuppressive therapy (IS) consisting of one or more courses of the following regimens: a) high dose bolus 6 methylprednisolone (BMPr); b) horse antilymphocytic globulin (HALG); c) rabbit ALG (RALG); d) ALG followed by the infusion of haploidentical marrow (ALG +/- BM); e) BMPr in combination with HALG; f) ALG in combination with androgens. All patients received one initial course of IS: 16 (38%) showed hematologic reconstitution and required no further transfusions, of 26 refractory patients 4 died, and 22 received a second course of IS 60 days after the first course. Of these 22, 6 (27%) responded, and of the 16 refractory patients, 9 died, and 7 received a third course of IS 60 days after the second course. Two of these responded (28%), 3 died and 2 are alive but pancytopenic. The overall response rate is 24/42 patients (57%): all of these patients are transfusion independent 6-60 months post-treatment, and 17 are off maintenance therapy with low dose steroids. The actuarial 5 year survival is currently 60%; 13/26 surviving patients have been followed for more than 3 years. The present study confirms that over 50% of patients with SAA can recover from their aplasia following IS treatment, and this is of relevance for patients who can not be offered a bone marrow transplant.

Limited proteolysis of porcine pancreatic lipase. Lability of the Phe 335-Ala 336 bond towards chymotrypsin.

Mild chymotrypsin digestion of native lipase (449 amino acids) preferentially cleaved the Phe 335-Ala 336 bond. On SDS-gel electrophoresis, 3 major bands were observed: band 1 (52 kDa) representing native lipase, bands 2 and 3 (40 and 12 kDa) representing the two lipase fragments A and B. Fragment A does not retain lipase activity but maintains its ability to adsorb to interfaces. Fragment B was identified with the lipase C-terminal region (336-449). It does not exhibit any activity towards tributyrylglycerol emulsions and any ability to adsorb to interfaces.

1,2,5-Oxadiazole N-oxide derivatives and related compounds as potential antitrypanosomal drugs: structure-activity relationships.

The syntheses of a new series of derivatives of 1,2,5-oxadiazole N-oxide, benzo[1,2-c]1,2,5-oxadiazole N-oxide, and quinoxaline di-N-oxide are described. In vitro antitrypanosomal activity of these compounds was tested against epimastigote forms of Trypanosoma cruzi. For the most effective drugs, derivatives IIIe and IIIf, the 50% inhibitory dose (ID50) was determined as well as their cytotoxicity against mammalian fibroblasts. Electrochemical studies and ESR spectroscopy show that the highest activities observed are associated with the facile monoelectronation of the N-oxide moiety. Lipophilic-hydrophilic balance of the compounds could also play an important role in their effectiveness as antichagasic drugs.

Acute myelomonocytic leukemia. Demonstration of pulmonary involvement by bronchoalveolar lavage.

Massive pulmonary infiltration by leukemic cells resulting in respiratory symptoms is a rare complication of acute leukemia. We report the findings in a patient with acute myelomonocytic leukemia presenting with acute onset of fever, dyspnea, and nonproductive cough, in whom the diagnosis of pulmonary invasion by leukemic cells was made by cytochemical analysis of bronchoalveolar cells recovered by lavage.

Autologous Unpurged Bone Marrow Transplantation for Acute Non Lymphoblastic Leukemia in First Remission.

Forty consecutive adult patients under the age of 50 with acute non-lymphoblastic leukemia (ANLL) in first complete remission, underwent autologous bone marrow transplantation (ABMT) between March 1984 and April 1990. The conditioning regimen employed included cyclophosphamide and total body irradiation, followed by the administration of unpurged ABMT. The median time from diagnosis to transplant was 7 months (3-15 months), and the median time from complete remission to ABMT was 4 months (range 3-9 months). Twenty-two (51%) patients remain in complete remission 6-81 months (median 24 months) after ABMT. The causes of death were, recurrent leukemia (11 patients), parenchymal toxicities such as acute respiratory distress syndrome and veno-occlusive disease (3 patients), hemorrhage (2 patients) and infection (2 patients). Eleven patients relapsed after 3-12 months (median 5 months). This study has produced survival data comparable to those of other institutions employing TBI for either allo or autotransplants.

A New Combination of Idarubicin, Etoposide and Cytarabine in Untreated Acute Non-Lymphoblastic Leukemia.

Sixty-seven unselected adult patients with untreated acute non lymphotblastic leukemia (ANLL) ranging in age from 15 to 80 years received a new induction regimen consisting of Idarubicin, Etoposide and Cytarabine. Patients who entered complete remission (CR) were then allocated to 4 courses of post remission intensification. After this, patients under 50 years of age with a compatible donor were given allogeneic bone marrow transplantation (BMT) or autologous BMT (ABMT) in those without an HLA-compatible donor; the remainder, older than 50, did not receive further therapy. Fifty-six of 67 patients (83.5%) achieved CR (02.5% in young and 70.3% in old patients) and 40 (71 %) after the first course. Seven patients (of whom, 6 were > 50 years) died in aplasia during the induction phase and four additional patients (all elderly) died during post-remission intensification without recurrent disease. Subsequently, the younger patients received transplants (BMT: 4 pts; ABMT: 10 pts). Twelve: of the 52 (23%) who survived post remission intensification (BMT: 1; ABMT: 4; others: 7) are disease free survivors 9-67 months (median, 32 months) after achieving CR. In conclusion, this intensive chemotherapy regimen is highly effective both in young and odder patients but the post-remission intensification may be too aggressive for elderly patients.

Effect of aflatoxin B1 on resistance induced by Bordetella bronchiseptica vaccine in rabbits.

The effects of aflatoxin B1 on the development of the immune response to oil-adjuvanted Bordetella bronchiseptica vaccine and on acquired resistance to bacterial challenge were studied in rabbits. The doses of aflatoxin used were insufficient to produce clinical intoxication. Rabbits were randomly assigned to three groups, each having six animals: control (T), vaccinated (V), and vaccinated plus aflatoxin (VA) at 0.05 mg/kg daily per os. Groups V and VA were vaccinated twice, and the three groups were subsequently challenged with virulent B. bronchiseptica. The average weight gain at weekly intervals was significantly reduced in group VA, and no statistically significant differences were found in the titers of agglutinating antibodies between groups V and VA. There were significant differences between groups V and VA in the extent and severity of the pneumonic process, group VA being most affected. Results indicated that agglutinating antibody titers were not related to the level of protection in the latter group. Other mechanisms, such as alveolar macrophage activity and cell-mediated immunity, were implicated in the impairment of the acquired resistance in rabbits subclinically intoxicated with aflatoxin.

1,2,5-Oxadiazole N-oxide derivatives as potential anti-cancer agents: synthesis and biological evaluation. Part IV.

Several new 1,2,5-oxadiazole N-oxide derivatives and some deoxygenated analogues were synthesized to be tested as potential selective hypoxic cell cytotoxins. Compounds prepared were designed in order to gain insight into the mechanism of action of this kind of cytotoxin. Compounds were tested in oxia and hypoxia and they proved to be non-selective. 3-Cyano-N(2)-oxide-4-phenyl-1,2,5-oxadiazole showed the best cytotoxic activity in oxia. The cytotoxicity observed for these derivatives could be explained in terms of the electronic characteristics of the 1,2,5-oxadiazole substituents. Electrochemical and ESR studies were performed on the more cytotoxic derivative.

Synthesis and antitrypanosomal evaluation of E-isomers of 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives. structure-activity relationships.

Several novel semicarbazone derivatives were prepared from 5-nitro-2-furaldehyde or 5-nitrothiophene-2-carboxaldehyde and semicarbazides bearing a spermidine-mimetic moiety. All derivatives presented the E-configuration, as determined by NMR-NOE experiments. These compounds were tested in vitro as potential antitrypanosomal agents, and some of them, together with the parent compounds, 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives, were also evaluated in vivo using infected mice. Structure-activity relationship studies were carried out using voltammetric response and lipophilic-hydrophilic balance as parameters. Two of the compounds (1 and 3) displayed the highest in vivo activity. A correlation was found between lipophilic-hydrophilic properties and trypanocidal activity, high R(M) values being associated with low in vivo effects.

Fludarabine, ARA-C, idarubicin and G-CSF (FLAG-Ida), high dose ARA-C and early stem cell transplant. A feasable and effective therapeutic strategy for de novo AML patients.

Forty-three consecutive patients with de novo and untreated non M3 AML aged 60 or less entered the study. The mean age of patients was 50 (range 15-60). The induction regimen (FLAG-Ida) included fludarabine (30 mg/sqm), Ara-C (2 g/sqm) on days 1-5, and idarubicin (10 mg/sqm) on days 1, 3, 5. G-CSF (300 mcg/day) was administered s.c. 12 hours before starting fludarabine and was continued for five days. HDT with stem cell rescue was planned for all patients in first CR after one course of high dose Ara-C (HDAC) consolidation and in good clinical conditions. Forty-two (98%) patients were evaluable for response. One patient died during induction (2%). CR was achieved in 35 patients (82%). Twenty-three patients, 66% of those achieving CR, underwent autologous (N = 17) or allogeneic (N = 6) transplantation. With a median follow up of 24 months, the average median duration of CR is 17 months (range 3-66) and the median survival is 20 months (range 1-83). Overall the 5 year projected disease free survival (DFS) and overall survival (OS) were 37% and 43%, respectively. Among patients who underwent stem cell transplantation DFS and OS were 53% and 69%, respectively. The median time to PMN recovery (> 0.5 x 10(9)/l) was 17 days (range 10-28) and 50 x 10(9)/l platelets were reached at a median of 17 days (12-38). In conclusion FLAG-Ida regimen is effective, low toxic and improves feasibility of stem cell transplant.

Mycotoxin T-2 and aflatoxin B1 as immunosuppressors in mice chronically infected with Toxoplasma gondii.

The aim of this study was to determine whether repeated ingestion of mycotoxin T-2 (T2) or aflatoxin B1 (AFL) at low doses could contribute to the activation of toxoplasmosis in experimentally infected mice. Mice were divided into two groups: Control (C) and Infected (I). The cyst-forming Beverley strain of Toxoplasma gondii was used to produce the infection one month before treatment with mycotoxins. Mycotoxins were given intragastrically for a 50-day period. The average weight gain was reduced in the groups treated with mycotoxins. Mice developed specific IgG to T. gondii. Histopathological studies showed severe encephalitis in all groups infected. The number of unruptured and ruptured cysts was established and the severity of the lesions was evaluated, the groups treated with mycotoxins being the most severely affected. Immunohistochemical studies of the brain showed free antigen in tissues surrounding ruptured cysts. It is suggested that low and repeated doses of mycotoxins, necessary to produce a subclinical intoxication, precipitate Toxoplasma cyst rupture and consequently the activation of chronic toxoplasmosis.

Five day intermittent vs seven day continuous 2-chlorodeoxyadenosine infusion for the treatment of hairy cell leukemia. A study by Italian Group for the Hairy Cell Leukemia.

The new purine-analogue 2-chlorodeoxyadenosine (2-CdA) has proved to induce an high CR rate and a long lasting disease free survival. In this study we compare the efficacy and toxicity of 2-CdA employed in two different schedules (A and B). Forty-one patients have been enrolled from 1994: 22 p. (group A) were treated with a single cycle of 2-CdA given as two hour i.v. infusion on 5 consecutive days (0.15 mg/kg/die); while 19 p. (group B) with continuous i.v. infusion for 7 consecutive days (0.10 mg/kg/die). Response criteria were those proposed by NCI. The Hairy Cell Index (HCI) was calculated using DBA44 MoAb. At three months, the responses in group A (19/22) were: 5 CR (26.3%), 6 GPR (31.5%), 5 PR and 3 NR.; in group B (17/19): 6 CR (35.3%), 3 GPR (17.6%), 4 PR and 4 NR. Overall response at six months was respectively 84.2% and 76.5%. At six months the responses were: in group A (18/22): 9 CR (50%), 4 GPR (22.2%), 3 PR, 2 NR; in group B (16/19): 4 CR (25%), 6 GPR (37.5%), 3 PR, 3 NR. Overall response at 6 months was respectively 88.8% (group A) and 81.2% (group B). The 5 day intermittent schedule appears efficient, well tolerated and suitable for out-patient treatment. DBA44 MoAb appears useful to better define the HCI and to distinguish CR from GPR.

STANDING, a four-step bedside algorithm for differential diagnosis of acute vertigo in the Emergency Department.

Vertigo is generally due to a benign disorder, but it is the most common symptom associated with misdiagnosis of stroke. In this pilot study, we preliminarily assessed the diagnostic performance of a structured bedside algorithm to differentiate central from non-central acute vertigo (AV). Adult patients presenting to a single Emergency Department with vertigo were evaluated with STANDING (SponTAneous Nystagmus, Direction, head Impulse test, standiNG) by one of five trained emergency physicians or evaluated ordinarily by the rest of the medical staff (control group). The gold standard was a complete audiologic evaluation by a clinicians who are experts in assessing dizzy patients and neuroimaging. Reliability, sensibility and specificity of STANDING were calculated. Moreover, to evaluate the potential clinical impact of STANDING, neuroimaging and hospitalisation rates were compared with control group. A total of 292 patients were included, and 48 (16.4%) had a diagnosis of central AV. Ninety-eight (33.4%) patients were evaluated with STANDING. The test had good interobserver agreement (k = 0.76), with very high sensitivity (100%, 95%CI 72.3-100%) and specificity (94.3%, 95%CI 90.7-94.3%). Furthermore, hospitalisation and neuroimaging test rates were lower in the STANDING than in the control group (27.6% vs. 50.5% and 31.6% vs. 71.1%, respectively). In conclusion, STANDING seems to be a promising simple structured bedside algorithm that in this preliminary study identified central AV with a very high sensitivity, and was associated with significant reduction of neuroimaging and hospitalisation rates.

Comparison of two prognostic models for acute pulmonary embolism: clinical vs. right ventricular dysfunction-guided approach.

BACKGROUND: Recently, some prognostic models for acute pulmonary embolism (PE) have been proposed. We investigated whether the Pulmonary Embolism Severity Index (PESI) and the European Society of Cardiology (ESC) prognostic approaches result in different prognoses. METHODS: Consecutive adult patients with acute PE were included. According to the ESC guidelines, high-risk patients were identified by the presence of shock/hypotension, intermediate-risk patients by elevated troponin I or right ventricular dysfunction as assessed by echocardiography, and low-risk patients by the absence of any of the above. In the PESI model, 11 clinical variables, easily accessible at the bedside, were used to generate three risk classes. The main outcomes were all-cause and PE-related in-hospital mortality. RESULTS: Forty-one patients (8%, 95% confidence interval [CI] 5.8-10.8) of 510 died. According to the ESC model, 40% were at low risk of short-term mortality, 54% at intermediate risk, and 6% at high risk. The distribution according to the PESI model was 31% (P < 0.05 vs. ESC), 49% and 20% (P < 0.05 vs. ESC), respectively. Mortality increased through the risk classes (P < 0.01), without significant differences between the models. The ESC model identified with higher accuracy than the PESI model both high-risk and low-risk patients (P < 0.05 for both). When patients with shock/hypotension were excluded, the PESI model stratified patients into classes with increasing PE-related mortality (0.7%, 4.3%, and 11.6%, P < 0.05). Troponin I and right ventricular dysfunction added incremental prognostic value to the PESI model, particularly in normotensive patients at intermediate risk. CONCLUSIONS: The ESC model showed higher accuracy than the PESI model in identifying high-risk and low-risk patients. In normotensive patients, the PESI model could guide clinical management as well as troponin I and echocardiography testing.