Youth justice reform and the rights of the child: a step forward or backward?

Our purpose is to examine Canada's new Youth Criminal Justice Act in light of Canada's obligations under the UN Convention on the Rights of the Child and in contrast to the Young Offenders Act. After reviewing the Convention and the Young Offenders Act, we examine the new act to determine its consistency with the Convention. We conclude that the new act is a step forward because of its greater focus on rehabilitation and social reintegration. However, it is an inadequate step because it does not fully ensure the protection, provision, and participation rights of the child as defined by the Convention.

Treatment of plasma refractory thrombotic thrombocytopenic purpura with protein A immunoabsorption.

The objective of this study was to assess the effect of protein A immunoabsorption in terms of response rate and toxicities in patients with classical thrombotic thrombocytopenic purpura (TTP) refractory to therapeutic plasma exchange. The study included nine females and one male with a diagnosis of classical TTP treated at multiple university hospital centers with protein A immunoabsorption (PAI) after having failed plasma exchange. The 10 patients had an age range 17-62 years. Prior to PAI, the patients had failed to respond to a mean of 15 (range 6-39) therapeutic plasma exchanges. Three patients had previous episodes of TTP. Evaluation for response to PAI included serial measurements of serum creatinine, lactate dehydrogenase (LDH), hemoglobin, hematocrit, and platelet count before, during, and up to 18 months post-PAI treatment. Seven of 10 study patients had resolution of their TTP. Six of the patients required six or fewer therapeutic PAIs and one required 12 treatments. All responding patients had evidence of improvement by the third PAI treatment. Three patients demonstrated no response to PAI, with two patients expiring from complications of TTP and one patient demonstrating a complete response to a subsequent therapy. No significant toxicity was noted with the use of PAI in this setting. Protein A immunoabsorption in patients with classical TTP refractory to plasma exchange can produce durable complete remissions and warrants comparative studies.

Protein A immunoadsorption treatment in hematology: an overview.

Staphylococcal protein A efficiently binds immunoglobulins and circulating immune complexes (CIC) and provides an effective medium to remove immunoglobulins and CICs from plasma while sparing albumin and most coagulation proteins. Although it activates the complement system its clinical use abrogates the need for plasma expanders necessitated by plasma exchange. Despite anecdotal reports of utility in several hematologic syndromes, publications of clinical trials are available only for autoimmune thrombocytopenic purpura (AITP) and refractoriness to platelet transfusions (RFT) associated with alloimmunization. In the former situation Snyder et al. (Blood 79:2237-2245, 1992) reported on 72 patients with AITP all of whom had failed at least two previous therapies including splenectomy in 68%. Forty-six percent achieved improved platelet counts following treatment. The response was durable (8-26 mo) in all but 10%. Spleen-intact patients could not be differentiated from those who had been splenectomized. Both responders and nonresponders showed significant decreases in CIC and platelet-directed immunoglobulin (PDIG), but responders achieved near-normal levels. The beneficial response of these factors, particularly in spleen-intact patients, warrants a prospective study. In our studies at the University of Minnesota twelve patients with thrombocytopenia secondary to bone marrow failure who were refractory to platelet transfusion were treated with protein A immunoadsorption. Ten had demonstrable antiplatelet Abs (Anti-HLA, HPA, ABO). Seven of 12 demonstrated improved platelet counts and post-transfusion corrected count increments after treatment. This was associated with decreased platelet utilization and clinical bleeding. A prospective controlled clinical trial is justified.

Treatment of refractoriness to platelet transfusion by protein A column therapy.

Ten thrombocytopenic patients (platelets < 10-24 x 10(9)/L) who were refractory to platelet transfusion were investigated for their responsiveness to staphylococcal protein A column therapy. Nine patients had previously been treated with steroids, intravenous immune globulin, and/or other forms of immunosuppressive therapy without improvement in their transfusion response. All patients were receiving multiple platelet transfusions without achieving 1-hour corrected count increments (CCIs) > or = 7500. Eight patients had antibodies that reacted with platelets and were directed against HLA class I antigens, ABO antigens, and/or platelet-specific alloantigens. Plasma (500-2000 mL) from each patient was passed over a protein A silica gel column and then returned to the patient. Patients received from 1 to 14 treatments. A positive response to protein A therapy was defined as at least a doubling of the pretreatment platelet count and/or two successive 10- to 120-minute posttransfusion CCIs > or = 7500. Following plasma treatments, 6 of 10 patients responded with daily platelet counts that averaged 48 +/- 11 x 10(9) per L as compared with counts of 16 +/- 7 x 10(9) per L (p < 0.0005) before treatment. Posttransfusion CCI values determined in four of these patients averaged 2480 +/- 810 and 10,010 +/- 3540 (p < 0.005) before and after treatment, respectively. In contrast, among the four unresponsive patients, platelet counts averaged 10 +/- 9 and 13 +/- 10 x 10(9) per L (p = NS), respectively, while posttransfusion CCIs were 700 +/- 1410 and 1520 +/- 2460 (p = NS), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Mathematical modeling of reproductive and developmental toxic effects for quantitative risk assessment.

A new mathematical dose-response model for reproductive and developmental risk assessment is proposed. The model includes the possibility of an exposure threshold as well as a litter-size effect. Correlation of responses of offspring from the same litter is taken into account through the use of the beta-binomial distribution. Confidence limits for low-dose extrapolation are based on the asymptotic distribution of the likelihood ratio. An empirical comparison of the proposed procedure to that of Rai and Van Ryzin demonstrates the improvement that can be achieved with the new procedure.

Analysis of trinomial responses from reproductive and developmental toxicity experiments.

This paper presents a Dirichlet-trinomial distribution for modelling data obtained from reproductive and developmental studies. The common endpoints for the evaluation of reproductive and developmental toxic effects are the number of dead fetuses, the number of malformed fetuses, and the number of normal fetuses for each litter. With current statistical methods for the evaluation of reproductive and developmental effects, the effect on the number of deaths and the effect on the number of malformations are analyzed separately. The Dirichlet-trinomial model provides a procedure for the analysis of multiple endpoints simultaneously. This proposed Dirichlet-trinomial model is a generalization of the beta-binomial model that has been used for handling the litter effect in reproductive and developmental experiments. Likelihood ratio tests for differences in the number of deaths, the number of malformations, and the number of normals among dosed and control groups are derived. The proposed test procedure based on the Dirichlet-trinomial model is compared with that based on the beta-binomial model with an application to a real data set.

Reversible pancytopenia following OKT3. Use in the context of multidrug immunosuppression for kidney allografting.

We present two instances of pancytopenia in kidney transplant patients associated with a course of OKT3 therapy. In one case, OKT3 was used prophylactically, in the other therapeutically to treat biopsy-proved rejection. They both occurred in the setting of multi-drug immunosuppression, including Minnesota anti-lymphocyte globulin, and recovered with supportive therapy. Previous antihypertensive medication, antibiotics, and azathioprine were restarted without hematologic sequelae. Evidence implicating OKT3, and resultant gamma-interferon-induced marrow suppression is discussed.

The response of erythropoietin to dietary protein in human renal disease.

The response of erythropoietin to dietary protein was examined in nine subjects with a variety of glomerular diseases. They were randomly assigned by using a crossover design to two 11-day periods, one on a high-protein diet (2 gm/kg/day) and the other on a low-protein diet (0.55 gm/kg/day). The high-protein diet was associated with increased urinary erythropoietin excretion (4.28 +/- 0.84 U/24 hr vs 1.28 +/- 0.16 U/24/hr; p less than 0.05), increased serum erythropoietin concentration (22 +/- 2 mU/ml vs 10 +/- 2 mU/ml; p less than 0.05), and increased reticulocyte count (3.0 +/- 0.8 vs 1.6 +/- 0.4; p less than 0.05), demonstrating that erythropoietin production by the diseased kidney was still responsive to dietary protein manipulation. To examine whether changes in erythrocyte survival could be responsible for the differences in erythropoietin production, red cell survival was measured in two groups of subtotally nephrectomized rats, one group ingesting a high-protein diet (30%) and the other a low-protein diet (6%). No difference in erythrocyte survival rate was found. Reticulocyte counts were, however, elevated on the high-protein diet. We conclude that in the diseased kidney, a high-protein diet, perhaps by increasing renal O2 consumption, directly stimulates erythropoietin production.

Time-related factors in quantitative risk assessment.

In regulatory or decision-making contexts related to carcinogenic hazards, one would like to know the extra risks associated with various levels, durations, and ages of exposure to a carcinogen. To supply that information, quantitative risk assessments are required that make extrapolations on variables related to dose levels, timing of exposure, and age. Quantitative models that express age-specific mortality rates as functions of the exposure pattern and that allow such extrapolations to be made are presented. The uncertainty inherently associated with those extrapolations is discussed and is found to be exacerbated by small data sets and inadequate data availability. Specific examples are provided that involve asbestos-induced mesothelioma and leukemia caused by benzene exposure.

High-resolution chromosomes as an independent prognostic indicator in adult acute nonlymphocytic leukemia.

Using high-resolution chromosomes of bone-marrow specimens from 105 consecutive adult patients with de novo acute nonlymphocytic leukemia, we found an unusually high degree of complexity in this disorder, which may explain previous difficulties in identifying useful prognostic indicators. Specimens from 99 of the 105 patients were successfully analyzed, and 92 (93 per cent) had a chromosomal defect. Seventeen categories were identified, 12 representing a specific recurrent defect. Three of them have been found to have independent prognostic importance. Patients with an inversion 16 (9 per cent), diagnosed as having M2, M4, or M5b disease according to the morphologic classification of the French-American-British Acute Leukemia Cooperative Study Group, had a uniform and sustained complete remission and a median survival of 25 months. In contrast, 14 patients (14 per cent) with complex chromosomal abnormalities and a diagnosis of M1, M2, M4, M5a, or M6 disease had a very poor prognosis. In 12 of the 14 patients efforts to achieve induction of remission failed, and the group had a median survival of 2.5 months. A third group with a trisomy 8 as the single defect (11 per cent) had an intermediate prognosis and a median survival of 10 months. With the different types of treatment for acute nonlymphocytic leukemia that are now available, we suggest that high-resolution chromosome analysis will become an important tool in selecting specific types of therapy for groups of patients with differing prognoses.

Recurrent chromosomal defects are found in most patients with non-Hodgkin's-lymphoma.

Using methotrexate cell synchronization, we successfully analyzed chromosomal preparations of 40 lymph node biopsies and one bone marrow sample from 44 patients with non-Hodgkin's, non-Burkitt's lymphoma. All of the 41 patients successfully analyzed showed clonal chromosomal abnormalities. In 25 of the 41 (61%), the defects were found to be consistent with (A) a deletion 6q in five of seven patients with diffuse large cell lymphoma, (B) a t(11;14), a del 11q, or a + 12 in seven of nine patients with small cell lymphocytic lymphoma, and (C) a t(14;18) in 12 of 15 patients with follicular lymphoma (small cleaved and mixed small and large cleaved) and in a single case of diffuse large cell lymphoma. In three patients with small cell lymphocytic lymphoma whose biopsies exhibited a t(11;14), lymphocytes were cultured and chromosomes examined for the presence of fragile sites. In two, frequent breaks at band 11q13.3 were observed. Such findings suggest a possible relationship between a fragile site and a predisposition to a specific chromosomal rearrangement in human neoplasia.

Antithymocyte globulin treatment of severe aplastic anaemia.

Nineteen patients with severe aplastic anaemia were treated with antithymocyte globulin. Ten patients obtained remissions (transfusion independent, at least 45000 platelets and 2000 PMN/mm3) within 2-3 months and continue in remission 5-35 months after antithymocyte globulin. Ages of responders ranged from 17 to 71. Complications of antithymocyte globulin included arthralgias, rash, serum sickness, angioedema and fever. Two patients died during, two shortly after, and one 10 months after therapy. One patient with a previous remission following antithymocyte globulin relapsed and achieved a second remission with retreatment. Previous androgen therapy did not affect outcome since two of four patients with and eight of 15 patients without previous androgen therapy achieved remission with ATG. Treatment with antithymocyte globulin is a promising alternative to bone marrow transplantation in the treatment of severe aplastic anaemia.

Anemia in the elderly. Common causes and suggested diagnostic approach.

Anemia is a frequent finding in the elderly. Hypochromic microcytic anemia, usually secondary to iron deficiency, is the most common type. Macrocytic anemia, usually caused by folic acid or vitamin B12 deficiency, is the next most common. Both iron and vitamin B deficiencies are easy to treat with supplements, but the clinician must make a careful search for the cause of the deficiency. Normochromic normocytic anemia can be caused by a number of conditions. The only effective treatment is arrest or cure of the underlying disorder.

Effect of therapy on T cell subpopulations in patients with chronic lymphocytic leukemia.

We have previously demonstrated functional and quantitative imbalances in two human thymic (T) cell subpopulations, T gamma and T mu, in chronic lymphocytic leukemia (CLL) patients. Serial evaluations of the numbers of T gamma and T mu subsets in CLL were performed in order to delineate more completely the patterns of T cell abnormalities two groups of CLL patients were studied: (I) previously untreated (n = 3) and (II) stable CLL on chemotherapy (n = 12). In Group I, two of three patients had significantly increased percentages of T gamma cells (mean +/- S.E.M. = 57 +/- 5 vs 18 +/- 2 for controls). There was defective in vitro appearance of T mu cells in both groups. In Group II, repeated studies of T cell subsets revealed persistently elevated T gamma cells despite various modes of oral chemotherapy. In three CLL patients who required splenectomy a dramatic decrease in the percentages of T gamma cells was noted post-splenectomy (51 +/- 3 to 15 +/- 3). In all cases the spleen was diffusely involved with CLL. These findings indicate: (1) abnormalities of T cell subsets are present early in CLL, (2) chemotherapy does not affect the levels of T gamma cells in stable patients and (3) removal of infiltrated CLL spleens results in a dramatic decrease in the proportion of T gamma cells. This latter finding plus the increase in T gamma cells in progressive disease post-splenectomy suggest T gamma cells may be an important determinant of the course of CLL.