Developmental trajectories of spatial-sequential and spatial-simultaneous working memory in Down syndrome.

BACKGROUND: Working memory (WM) is generally considered an area of weakness in the cognitive profile associated with Down syndrome (DS). The great majority of studies explored WM in this population through a comparison with typical development (TD) on the basis of mental age or developmental level. However, it is also relevant to understand how these skills develop and whether such development could be more related to chronological or developmental level. In the present study, we explored cross-sectional developmental trajectories of spatial-sequential and spatial-simultaneous WM in individuals with DS across chronological age and developmental level. Typically developing children (TD) of similar mental age were also included as a comparison group. METHODS: Eighty-four individuals with DS (aged between 7 and 30 years) and 327 children with TD (aged between 4 and 8 years) were administered with tasks to assess spatial-sequential and spatial-simultaneous WM, together with tasks to assess both general verbal and spatial developmental levels. RESULTS AND CONCLUSION: Performance in spatial-simultaneous WM task was lower compared with spatial-sequential WM task in both groups. In the case of individuals with DS, the developmental trajectories of chronological age are better described through a segmented model showing increased performance until approximately 13 years of age, followed by a rather flat progress. In the case of TD children, developmental trajectories are better described through a linear model in the spatial-simultaneous WM task when chronological age is considered; in the spatial-sequential WM, the increase in performance with age was however characterised by a discontinuity at age 6. The increase in performance followed a linear pattern in both groups (DS and TD) without substantial differences between the types of measure used (verbal vs. spatial) when the developmental level is considered.

Environment learning from virtual exploration in individuals with down syndrome: the role of perspective and sketch maps.

BACKGROUND: Spatial knowledge about an environment is an important determinant of ability to move effectively within it and of personal autonomy. Individuals with Down's syndrome (DS) have difficulty managing configural visuospatial information. METHOD: Twenty-nine individuals with DS and 29 typically developing (TD) children, matched for mental age, learned about environments through virtual exploration using a route or survey view. A sketch map of the environment was or was not presented before exploration. Then the acquisition of configural knowledge (landmark locations) and route retracing were tested. RESULTS: Individuals with DS were able to acquire configural knowledge through virtual exploration in all presentation conditions, and generally performed no worse than matched TD children. However, they were not able to benefit from the conditions that facilitated acquisition of configural knowledge in TD children, that is, seeing a sketch map before exploring and exploring in survey (rather than route) view. As regards route retracing, individuals with DS paused more often than controls and tended to travel longer paths, which made them slower overall. CONCLUSIONS: DS reduces children's ability to benefit from additional survey information and may be related to difficulty in elaborating configural/simultaneous information.

Altos níveis de fitase em rações para frangos de corte / High levels of phytase in diets for broilers

Avaliaram-se o desempenho, o coeficiente de digestibilidade da matéria seca (CDMS), da proteína bruta (CDPB), a retenção aparente de cálcio (Ca) e fósforo (P) e a energia metabolizável aparente corrigida para balanço de nitrogênio (EMAn) de dietas suplementadas com altos teores de fitase (FTU) para frangos, até 35 dias de idade. Foram utilizados 1848 pintos, distribuídos em delineamento inteiramente ao acaso, com sete tratamentos e oito repetições de 35 aves. Os tratamentos foram: T1: dieta-controle; T2: dieta com inclusão de 1.500FTU/kg; T3: 3.000FTU/kg; T4: 4.500FTU/kg; T5: 6.000FTU/kg; T6: 8.000FTU/kg e T7: 10.000FTU/kg de ração. No 10º e 28º dias de experimento, quatro e três aves, respectivamente, foram transferidas para gaiolas de metabolismo. A partir da inclusão de 4.500FTU/kg, o desempenho das aves de 1 a 35 dias foi semelhante ao das aves do grupo-controle (P>0,05). Não houve diferença (P>0,05) entre os tratamentos nos CDPB e nos valores de EMAn, porém, na fase inicial, observou-se maior aproveitamento da MS com os altos níveis de fitase (P<0,05). Em relação à retenção de Ca e P, houve efeito positivo da suplementação enzimática, com aumento significativo do uso desses minerais pelas aves. Concluiu-se que é possível suplementar altos teores de fitase valorando adequadamente os nutrientes da dieta.

The digestibility of dry matter (DMD), and of crude protein (CPD), the apparent retention of calcium (Ca) and phosphorus (P) and apparent metabolizable energy corrected by nitrogen balance (AME) of diets supplemented with high levels of phytase (FTU) for broilers, 35 days old were evaluated. A total of 1848 chicks were distributed in a completely randomized experiment with seven treatments and eight repetitions. The treatments were: T1: control diet, T2: inclusion of 1,500FTU/kg; T3: 3,000FTU/kg; T4: 4,500FTU/kg; T5: 6,000FTU/kg; T6:8,000FTU/kg; and T7: 10,000FTU/kg feed. On the 10th and 28th days of the experiment, four and three birds, respectively, were transferred to metabolism cages. An addition of 4,500FTU/kg from 1 to 35 days resulted in a performance similar to the control group (P>0.05). There was no difference (P>0.05) among treatments for DMD and AME, however, during the initial phase there was a higher use of MS with high levels of phytase (P<0.05). Regarding the retention of Ca and P, a positive effect of enzyme supplementation significantly increased the use of these minerals by birds. It is possible that high levels of supplemental phytase adequate valuing the nutrients.

Avaliação do equilíbrio estático de crianças e adolescentes com síndrome de Down / Static balance assessment among children and adolescents with Down syndrome

OBJETIVOS: Avaliar o equilíbrio estático de crianças e adolescentes com Síndrome de Down (SD) pela Biofotogrametria Computadorizada e verificar a influência da visão nesta situação. MÉTODOS: Participaram 11 crianças e adolescentes com SD e 14 crianças e adolescentes de ambos os gêneros, neurologicamente normais que compuseram o grupo controle. Durante as filmagens, os participantes se mantiveram na posição ortostática com os braços posicionados ao lado do corpo e com os pés paralelos sobre uma superfície plana. As crianças de ambos os grupos foram filmadas na vista anterior (plano frontal) e na vista de perfil direito (plano sagital) nas condições com visão e sem visão. Nas filmagens na condição de olhos fechados, foram utilizados óculos de natação totalmente vedados, com a finalidade do participante não ter nenhuma informação visual. O instrumento utilizado foi a Biofotogrametria Computadorizada, que serviu como referência angular para verificar as oscilações do corpo em equilíbrio estático. RESULTADOS:As crianças e adolescentes com SD oscilaram mais (p<0,05) que as do grupo controle e, quando a informação visual foi manipulada, as oscilações ântero-posterior e latero-lateral mostraram a existência de diferenças significativas no equilíbrio nas crianças e adolescentes com SD quando comparadas com as crianças do grupo controle (p<0,01). CONCLUSÃO:O presente estudo mostrou que as crianças e adolescentes com SD oscilaram mais que as crianças do grupo controle com e sem a informação visual nos planos ântero-posterior e latero-lateral.

OBJECTIVES: To evaluate static balance and the influence of visual information among children and adolescents with Down Syndrome (DS) by means of computerized biophotogrammetry. METHODS: Eleven children and adolescents with DS took part in the study and 14 neurologically normal children and adolescents comprised the control group (both genders). During filming, the subjects remained in the orthostatic position with arms to the side of the body and feet parallel on a flat surface. Both groups were filmed in anterior view (frontal plane) and right lateral view (sagittal plane) with and without the eyes covered. While being filmed with eyes covered, the subjects wore fully blacked-out swimming goggles to eliminate all visual information. The instrument used was computerized biophotogrammetry, which served as an angular reference for verifying body sway in static stance. RESULTS:The subjects with DS swayed more (p<0.05) than the control group. When the visual information was eliminated, the anterior-posterior and lateral sway showed significant differences in the balance of the subjects with DS, compared with the subjects of the control group (p<0.01). CONCLUSION: The present study showed that children and adolescents with DS swayed more than the children in the control group with and without visual information and in both the anterior-posterior and lateral planes.

Effects of carvedilol in heart failure due to dilated cardiomyopathy. Results of a double-blind randomized placebo-controlled study (CARIBE study).

OBJECTIVE: To assess the effects of carvedilol in patients with idiopathic dilated cardiomyopathy. METHODS: In a double-blind randomized placebo-controlled study, 30 patients (7 women) with functional class II and III heart failure were assessed. Their ages ranged from 28 to 66 years (mean of 43 +/- 9 years), and their left ventricular ejection fraction varied from 8% to 35%. Carvedilol was added to the usual therapy of 20 patients; placebo was added to the usual therapy of 10 patients. The initial dose of carvedilol was 12.5 mg, which was increased weekly until it reached 75 mg/day, according to the patient's tolerance. Clinical assessment, electrocardiogram, echocardiogram, and radionuclide ventriculography were performed in the pretreatment phase, being repeated after 2 and 6 months of medication use. RESULTS: A reduction in heart rate (p = 0.016) as well as an increase in left ventricular shortening fraction (p = 0.02) and in left ventricular ejection fraction (p = 0.017) occurred in the group using carvedilol as compared with that using placebo. CONCLUSION: Carvedilol added to the usual therapy for heart failure resulted in better heart function.

[Postoperative course of left ventricular function in aortic insufficiency]. / Evolução pós-operatória da função ventricular esquerda na insuficiência aórtica.

PURPOSE: To analyze the follow-up of left ventricular function (LVF) after surgical correction of severe chronic aortic insufficiency (AI). METHODS: Twenty-one out of 68 patients with AI, initially asymptomatic and that developed symptoms during the follow-up period of 24-36 months, were studied. Relationship between symptoms and LVF by echocardiogram and radioisotopic ventriculography at rest and in isotonic exercise were studied. Three clinical moments (CM) were assumed: CM-0- at the beginning of the study, when all patients were asymptomatic; CM-1- manifestation of the symptoms during 24-36 months; CM-2- corresponding to the late post-operative period of 8 months of 20 out of 21 patients (one refused the surgery). The analysis did not show any significant differences between the mean values of all echocardiographic variables (diastolic and systolic diameters, shortening fraction, final systolic stress, volume-mass ratio, contractility index) and the ejection fraction of the left ventricle (EF) obtained by the radioisotope ventriculography at rest and, including exercise, between clinical moments 0 and 1. RESULTS: In the CM-2, involution was verified for functional class I/II in all cases and absence of expressive complications or immediate or late postoperative mortality. Comparison between CM-2 and 0 showed expressive regression of the diameters at rest in the postoperative period and with significant improvement in the means mainly the percentual variation of the EF and total time of effort. CONCLUSION: Symptoms assembled patients with more advanced eccentric hypertrophy and did not coincide with any immediate change in findings studied at rest and at exercise. It represented a point of reference for surgical indication compatible with late postoperative involution of chronic adaptation of AI.

A quantitative analysis of transcapillary refill in severe hemorrhagic hypotension in dogs.

In pressure-driven hemorrhage (PDH), where the rate of bleeding is a function of prevailing arterial pressure, survival time, arterial pressure, cardiac output, oxygen consumption, and base excess are functions of initial bleeding rate. The quantitative rate of transcapillary refill (TR) throughout PDH leading to death was determined in splenectomized dogs, through serial analysis of Cr51-tagged red cell dilution. Mild, moderate, and severe levels of PDH were produced by varying initial bleeding rate (10, 25, and 50 ml/min, respectively). The rate of TR is a function of the severity of PDH, but does not correlate with arterial pressure, cardiac output, or systemic resistance. The volume of transferred fluid represents an ever increasing fraction of total plasma volume, and accounts for more than 75% of plasma volume in preterminal stages of shock. TR sustains a relatively fixed level of plasma volume, equivalent to two-third of the initial plasma volume, irrespective of the rate of bleeding. Hypertonic NaCl (7.5%) enhances TR, while isotonic NaCl reverses it.

Targeting the EGF receptor in breast cancer treatment.

Immunotoxins are a relatively new class of cytotoxic agents consisting of a catalytic toxin linked to an appropriate targeting ligand. The ligand directs the toxin to the surface of a tumor cell, whereupon the toxin enters the cell and catalytically inactivates the ribosome, thus disrupting protein synthesis and effecting cell death. Monoclonal antibodies (or their fragments) have been most commonly used to carry chemically conjugated toxins to proteins or antigens overexposed on the tumor cell surface, but specific ligands for tumor cell surface receptors could also provide effective targeting. The receptor for epidermal growth factor (EGFR) is overexpressed primarily in poor prognosis breast cancers that do not respond well to traditional therapies. Because EGFR is frequently overexpressed in breast cancer tissue and is associated with a poor prognosis, it is an attractive target for antitumor therapy. DAB389EGF is an EGFR specific fusion toxin produced with recombinant DNA techniques consisting of sequences for the enzymatically active and membrane translocation domains of diphtheria toxin plus sequences for human epidermal growth factor. DAB389EGF is a potent, EGFR specific, cytotoxic agent which rapidly inhibits protein synthesis by a mechanism of action similar to that of diphtheria itself. Preclinical studies in the laboratory and in animals now suggest the feasibility of investigating such an agent in the targeted therapy of patients with human breast cancer.

Phase I trial of a 90-minute infusion of the fusion toxin DAB486IL-2 in hematological cancers.

DAB486IL-2, a recombinant fusion toxin in which the native receptor binding domain of diphtheria toxin has been replaced with interleukin-2 (IL-2), has displayed significant activity in patients with chemotherapy refractory hematological cancers. To further investigate the safety and antitumor effect of this agent, we conducted a single arm, dose escalation study of a 90-min infusion of DAB486IL-2 daily for 5 days. Patients with cancers of a histology previously reported to express the p55 component of the IL-2 receptor and who could not receive potentially more effective therapy were eligible for enrollment. Fifteen men and 8 women with a median age of 49 years were given a total of 51 courses of DAB486IL-2. The maximum tolerated dose was 0.3 mg/kg/day defined by renal insufficiency associated with hemolysis and thrombocytopenia. The clearance of DAB486IL-2 from serum fit a one-compartment model with a half-life of 11.5 +/- 4.3 (SD) min at the 0.2-mg/kg dose. Two patients sustained a partial response and 4 patients had tumor reduction not qualifying for an objective response. No tumors that were negative for expression of the p55 subunit of the receptor responded to DAB486IL-2 treatment. Reduction in size occurred in 2 tumors in which p55 expression was unknown and 4 patients with tumors that were known to be p55 positive. Dosing determined by specific activity rather than mass also appeared to be an important determinant of response. This study suggests that the presence of p55 expression on tumor cells is necessary, but alone may not be sufficient to achieve a tumor response. The correlation of additional variables such as specific activity of DAB486IL-2 and tumor expression of the p75 subunit of the IL-2 receptor and receptor function will also require further study.

Phase I trial of an interleukin-2 (IL-2) fusion toxin (DAB486IL-2) in hematologic malignancies expressing the IL-2 receptor.

DAB486IL-2 is a recombinant fusion toxin in which the native receptor binding domain of diphtheria toxin has been replaced with human interleukin-2 (IL-2). It selectively binds and intoxicates only cells that bear the high-affinity receptor for IL-2. In the first clinical trial of a genetically engineered ligand fusion-toxin, we have treated 18 patients with chemotherapy-resistant IL-2 receptor expressing hematologic malignancies with escalating doses of DAB486IL-2. The maximal tolerated dose of a daily intravenous bolus of DAB486IL-2 was 0.1 mg/kg per day for 10 doses, established by asymptomatic, reversible elevations of hepatic transaminases without changes in other tests of liver function. Other mild reversible side effects noted were rash, nausea, elevated creatinine, chest tightness, and fever. Pharmacokinetic analysis showed a monophasic clearance of 5.8 +/- 0.7 minutes with peak levels of 3,549 +/- 1,041 mg/mL at the 0.1 mg/kg dose. Approximately 50% of patients developed an antibody response to diphtheria toxin or DAB486IL-2. The presence of such antibodies did not preclude patients from experiencing an antitumor response as four of the six patients with antitumor effect had detectable antibody titers. Although this was a phase I trial designed to define the safety of DAB486IL-2, remissions were observed in three patients lasting from 5 to over 18 months. The ability to achieve significant tumor reductions in this group of heavily treated patients is encouraging and suggests additional trials are warranted in hematologic malignancies.

Prophylaxis of cytomegalovirus infection with ganciclovir in allogeneic marrow transplantation.

Cytomegalovirus (CMV) infection is one of the most common causes of morbidity and mortality after allogeneic marrow transplantation. We studied 14 consecutive CMV-seropositive patients adding ganciclovir (2.5 mg/kg i.v. every 8 hours for 7 days prior to transplant and 6 mg/kg three times a week after neutrophils became greater than 0.5 x 10(9)/l and the patients were platelet transfusion-independent until d 70) to our previous prophylaxis regimen which consisted of intravenous immunoglobulin and acyclovir. The result was compared with 30 consecutive patients whom we studied with our previous regimen. The addition of ganciclovir did not cause any extra toxicities. The incidence of interstitial pneumonitis and cumulative probability of CMV excretion in the first 100 d post-transplantation was significantly reduced (p = 0.038 and p = 0.035 respectively). The result shows that addition of ganciclovir significantly decreased the incidence of CMV infection in the early post-transplantation period.

Phase I trial of H65-RTA immunoconjugate in patients with cutaneous T-cell lymphoma.

H65-RTA is an immunoconjugate that consists of the A chain of ricin (RTA), a ribosomal-inhibiting protein, coupled to a murine monoclonal antibody (H65) directed against the pan-T-cell antigen CD5. The CD5 antigen is heterogeneously expressed on cutaneous T-cell lymphoma tumor cells, but is not expressed on normal cells except lymphocytes. A phase I trial was therefore conducted in which 14 patients with cutaneous T-cell lymphoma progressive on other therapies were treated with up to three cycles of H65-RTA. The maximal tolerated dose (MTD) of H65-RTA was 0.33 mg/kg/d administered intravenously for 10 days as defined by dyspnea at rest at higher doses. Other reversible side effects included myalgia, mild hypoalbuminemia with weight gain, pedal edema, fatigue, fevers, and chills. Six patients received more than one cycle of H65-RTA without increased side effects compared with the first cycle. Pharmacokinetic analysis showed that peak serum drug levels were dose-dependent, and ranged from 1.13 to 5.56 micrograms/mL, with a terminal half-life ranging from 1.0 to 2.9 hours. The development of antibodies against the immunoconjugate was associated with a lower peak drug level, but not with enhanced side effects. Partial responses lasting from 3 to 8 months were documented in four patients. Three of the responding patients received more than one cycle of H65-RTA in the presence of anti-immunoconjugate antibodies. The results from this phase I trial suggest that H65-RTA is an active drug in the treatment of cutaneous T-cell lymphoma. The immunoconjugate may be safely administered repeatedly, even in the presence of anti-immunoconjugate antibodies, with responses noted. Additional studies at the MTD are needed to define the response rate in this disease.

Therapeutic effects of genetically engineered toxin (DAB486IL-2) in patient with chronic lymphocytic leukaemia.

In DAB486IL-2 the receptor-binding domain of native diphtheria toxin is replaced by human IL-2 sequences. This recombinant fusion protein is selectively cytotoxic for cells bearing high-affinity IL-2 receptors--eg, leukaemic cells. A patient with chronic lymphocytic leukaemia who did not respond to gamma interferon and conventional antileukaemic drugs has responded to DAB486IL-2.

[Immunosuppressive drugs for the treatment of active myocarditis in children. Hemodynamic evaluation]. / Drogas imunossupressoras no tratamento da miocardite ativa na criança. Avaliação hemodinâmica.

PURPOSE: To analyse hemodynamic parameters (left ventricles ejection fraction, cardiac index, mean pulmonary wedge pressure and left ventricle diastolic diameter, in a group of children with active myocarditis (diagnosed by endomyocardial biopsy) pre and post treatment with conventional therapy and immunosuppressive drugs (isolated prednisone or prednisone associated with azathioprine or cyclosporine). PATIENTS AND METHODS: Forty-four pediatric patients with active myocarditis were studied. Twenty males and 24 females from 10 months to 15 years old (median = 1.3 years). All patients were submitted to hemodynamic study and endomyocardial biopsy. The hemodynamic parameters mentioned above were analysed before and after the proposed therapy. The patients were distributed in group according to the admission in the protocol, group I (9 pts)--conventional therapy (CT); group II (12 pts)--CT plus prednisone; group III (16 pts)--CT plus prednisone plus azathioprine; group IV (13 pts)--CT plus prednisone plus cyclosporine. RESULTS: Forty-four patients were submitted to four different groups of therapeutic protocol. The hemodynamic parameters were analysed in each of them. Left ventricle ejection fraction were no significantly different in the pre and post therapeutic scheme in group I and II, they were significantly higher (p less than 0.05) in group III and IV. The same happened with cardiac index. The mean pulmonary wedge pressure no presented statistical differences in group I and II before and after treatment but significantly lower lends were observed in group III and IV. The same behavior were noted in the left ventricle end diastolic diameter. CONCLUSION: The association of azathioprine or cyclosporine to prednisone presented better results in the left ventricle function, when compared with conventional drugs or isolated use of prednisone, based in the analysis of same hemodynamic parameters.

Methylprednisolone, cyclosporine and methotrexate for prophylaxis of acute graft-versus-host disease.

Twenty-four patients were given the combination of methylprednisolone 100 mg i.v. on day 0, cyclosporine 2 mg/kg i.v. every 12 h starting on day -3 and methotrexate 5 mg/m2 on days 1, 3, and 6, then 10 mg/m2 on days 11 and 18 after allogeneic bone marrow transplantation for hematological malignancies for the prophylaxis of acute graft-versus-host disease. (GVHD). Methylprednisolone was given prior to the marrow infusion for its lympholytic effect. The methotrexate dose on days 1, 3, and 6 was half of that given in other studies to decrease the early toxicities. The outcome of this group is compared with patients transplanted before 1988 and given methotrexate alone, methotrexate with prednisone, or cyclosporine alone. There is no difference in relapse and survival between the groups at this time. The rate of engraftment and incidence of mucositis with the combination is not significantly different from the cyclosporine group. No patient developed greater than grade II acute GVHD with the combination. The probability of grade II or higher acute GVHD with the combination (14%) is significantly less than methotrexate, with or without prednisone or cyclosporine alone.