Failure of recombinant human interleukin-3 therapy to induce erythropoiesis in patients with refractory Diamond-Blackfan anemia [see comments]

In two previous studies, we observed that recombinant human interleukin- 3 (IL-3) induced an increase in marrow burst-forming unit-erythroid- derived colonies in vitro in some patients with Diamond-Blackfan anemia (DBA). To determine whether a similar erythropoietic response could be induced in vivo, we treated 13 patients with DBA (aged 4 to 19 years) with two preparations of IL-3. All patients had absent absolute reticulocyte counts and markedly reduced to absent recognizable bone marrow erythroid elements; patients with circulating reticulocytes in the previous 12 months were excluded from study. All patients except 1 had failed steroid therapy and had been transfusion-dependent since infancy; 1 patient was maintained on high-dose prednisone at the time of enrollment. On the first arm of the study, IL-3 (Immunex Corp, Seattle, WA) was administered subcutaneously using a dose escalation regimen of 125 to 500 micrograms/m2/day in divided dosage at 12-hour intervals, coadministered with 1.5 mg/kg/d of oral ferrous sulphate. Of the 13 patients that entered the trial, 4 stopped prematurely because of adverse side effects. In the other 9 evaluable cases, reticulocytes increased transiently in 1 patient from 0 to 65 x 10(9)/L after 35 days of IL-3 therapy at 250 micrograms/m2, but transfusion dependency persisted. One transient peak in absolute reticulocyte count was noted in 6 other patients, but no erythroid response was observed after completion of a full course of IL-3. Oral prednisone at 0.5 mg/kg/d was then coadministered with IL-3 at 500 micrograms/m2 to 5 of the patients without effect, and treatment was stopped. In 2 patients, a second preparation of IL-3 (Sandoz Canada Inc, Dorval, Quebec, Canada) was initiated in a dose escalation regimen of 2.5 to 10 micrograms/kg and was coadministered with ferrous sulphate. No erythroid response was observed in either patient, and in one of the two, alternate-day subcutaneous recombinant erythropoietin at 300 U/kg was administered for 3 weeks in combination with daily IL-3 at 10 micrograms/kg, but no increased erythropoiesis was seen. Significant increases in white blood cell and eosinophil counts during administration of both preparations of IL-3 were observed in all patients. These data show that the response of DBA patients to IL-3 in vivo is heterogeneous and cannot be predicted from in vitro studies. The absence of a corrective effect of IL-3 in these patients with DBA indicates that a deficiency of the cytokine is not central in the pathogenesis of the disorder.     

Active tuberculosis in inflammatory bowel disease patients under treatment from an endemic area in Latin America

BACKGROUNDThere has been an increase in cases of inflammatory bowel disease (IBD) in recent years. There is also greater access and availability of immunosuppressive and biological agents, which increase the risk of opportunistic infection despite improving the quality of life and promoting mucosal healing. Tuberculosis (TB) remains a public health problem, and it has a high incidence in several countries. Therefore, knowledge of the risk of developing TB in patients with IBD is important.AIMTo evaluate the risk of active TB in patients with IBD under treatment from an endemic area in Latin America.METHODSA standard questionnaire included demographic variables, clinical aspects of IBD disease, history of active TB during treatment, active TB characteristics and evolution, initial screening and results and time from the start of anti-tumor necrosis factor alpha (TNFα) to TB development.RESULTSAzathioprine, anti-TNFα and the combination of these two drugs were associated with a higher risk of active TB incidence. The TNFα blockers increased the relative risk of developing active TB compared to other treatments. All four multivariable models showed that the use of TNFα blockers alone or in combination with azathioprine was an important risk factor for the incidence of active TB. After adjustment for sex, age, type of IBD and latent TB, anti-TNFα with azathioprine increased the relative risk to 17.8 times more than conventional treatment. Late TB, which was diagnosed 3 mo after the start of anti-TNFα, was the most frequent.CONCLUSIONTreatment with anti-TNFα increased the risk of active TB in IBD patients from an endemic area in Latin America. This risk was increased when anti-TNFα was combined with azathioprine. The time from the beginning of the treatment to the active TB diagnosis suggests a new TB infection.     

The effects of antihistamines with varying anticholinergic properties on voluntary and involuntary movement

ObjectiveRecent evidence indicates that antihistamines can affect movement, which is most likely due to altered neurotransmission in cholinergic and histaminergic pathways. The purpose of this study was to determine if antihistamines with varying anticholinergic properties differentially affect voluntary and involuntary movement control.MethodsEleven healthy subjects were enlisted into a human double blind, placebo-controlled, five-way crossover study. Drowsiness, reaction time, and physiological tremor were examined 1-, 2-, and 3-hr post-ingestion of antihistamines with known anticholinergic profiles. These were the first-generation promethazine, and second-generation loratadine, desloratadine, and fexofenadine. Hyoscine butylbromide was used in an additional experiment to determine how a peripheral antimuscarinic drug influenced neuromotor function.ResultsPromethazine, desloratadine and fexofenadine increased drowsiness. Promethazine increased simple and choice reaction time and reduced tremor. Desloratadine increased choice reaction time and tremor, while loratadine slowed simple and choice reaction time.ConclusionCentral anticholinergic and antihistaminergic properties of antihistamines potentially contribute to movement dysfunction.SignificanceSecond-generation antihistamines have provided the consumer with a safer alternative to the first-generation sedating antihistamine. However, the results of this study suggest that loratadine and desloratadine have the potential to affect movement control, and further research is warranted to understand the clinical relevance of these findings.     

Parkinson’s disease: considerations for dental hygienists

Abstract: The prevalence of Parkinson’s disease (PD) is expected to double over the next 20 years owing to the increase in life expectancy. This progressive disease has several implications relating to oral health, and many are manageable with proper awareness and knowledge about the disease. This article reviews the epidemiology, pathophysiology, and characteristics of PD, as well as the treatments and oral health considerations to enable dental hygienists to undertake an informed approach to patient management strategies and provide optimal care.     

Platelet reactivity in type 2 diabetes mellitus: a comparative analysis with survivors of myocardial infarction and the role of glycaemic control

Patients with type 2 diabetes mellitus exhibit considerable platelet dysfunction, though this is poorly characterized in patients with diabetes taking aspirin for the primary prevention of cardiovascular events. We sought to compare platelet function in this patient population with that of a high-risk group of non-diabetic subjects with a history of previous myocardial infarction (MI), and to assess whether glycaemic control impacts on platelet function. Methods: Platelet aggregation was measured in response to incremental concentrations of five platelet agonists using light transmission aggregometry. All patients were taking aspirin, and aspirin insensitivity was defined as ≥ 20% arachidonic acid (AA) mediated aggregation. Patients with diabetes were divided according to glycaemic control (HbA(1c)): optimal ≤ 6.5, good 6.6-7.4 and suboptimal ≥ 7.5%. Results: In total, 85 patients with type 2 diabetes and 35 non-diabetic patients with previous MI were recruited. Compared to MI patients, diabetes patients had increased aggregation in response to multiple concentrations of epinephrine, collagen, adenosine diphosphate and AA. Aspirin insensitivity was more common in type 2 diabetes (15% vs. 0%, p=0.037). Platelet aggregation was increased in response to several agonists patients with suboptimal glycaemic control compared to patients with optimal control. Aspirin insensitivity was also more common in patients with suboptimal glycaemic control compared to those with good or optimal control (26.0% vs. 8.3% vs. 4%, p=0.04). Conclusion: Patients with type 2 diabetes mellitus, without proven vascular disease, exhibit platelet dysfunction and have increased platelet aggregation and aspirin insensitivity compared to non-diabetic patients with previous MI. Platelet dysfunction in diabetes is more severe in patients with suboptimal glycaemic control.