Role of oestrogen therapy in the management of short stature in Turner syndrome

It is now clear that parenteral growth hormone (GH) therapy stimulates growth and increases the adult stature of girls with Turner syndrome. In addition, oestrogens are given to almost all girls with this syndrome because of primary hypogonadism. Oestrogens influence both growth and maturation of the epiphyseal growth plates. Therefore, the form and timing of oestrogen therapy may have an important impact on the outcome of other growth-promoting therapies. To examine the impact of the timing of oestrogen initiation on growth, a randomized trial was conducted in patients with Turner syndrome who were receiving GH. Some patients received oestrogen at 12 years of age, while in others this treatment was not started until 15 years of age. Those girls that received oestrogen later were significantly taller as adults. The single most important factor in determining height gain appeared to be the number of years of GH therapy prior to the initiation of oestrogen treatment.     

Effects of phonemic awareness instruction on the encoding skills of children with severe speech impairment

Purpose: To examine the effects of phoneme-grapheme correspondence and phonemic awareness instruction on the encoding abilities of three pre-reading children with severe speech impairment (SSI). Method: Using a single subject multiple baseline design across behaviours and participants, children received phoneme-grapheme awareness instruction followed by instruction in segmenting, manipulating, and encoding consonant-vowel-consonant (CVC) pseudowords. Results: Generalization occurred to encoding of novel CVC pseudo- and real words for two of the three participants. Conclusions: Results suggest that phoneme-grapheme correspondence and phonemic awareness instruction is effective in developing encoding skills in children with SSI. Findings are consistent with those for other at-risk children.     

氯仿重结晶棉酚的质量研究

报道了氯仿重结晶的棉酚的化学性质,样品在不同温度下干燥恒重后,经熔点、薄层层析、紫外光谱、红外光谱、X-射线衍射、热重量分析、元素(C,H,Cl)分析及棉酚合量测定等一系列的分析,确证了在60℃以下棉酚与氯仿成溶剂化物(solvate)。随着干燥温度的升高或在室温长时间的贮存,此现象逐渐消失,100℃真空干燥恒重后成为纯棉酚。     

Prediction of the effect of erythromycin, diltiazem, and their metabolites, alone and in combination, on CYP3A4 inhibition

Predictive models of complex drug-drug interactions between multiple inhibitors and their metabolites have not been evaluated. The purpose of this study was to evaluate an interaction model for cytochrome P450 3A4 (CYP3A4) that incorporated the simultaneous reversible and irreversible inhibition by multiple inhibitors. Erythromycin (ERY) and diltiazem (DTZ), and their major metabolites, N-desmethylerythromycin (nd-ERY) and N-desmethyldiltiazem (nd-DTZ), were chosen to evaluate the model. k(inact) (rate constant for maximal inactivation), K(I) (inhibitor concentration at 50% maximal inactivation), and K(i) (reversible inhibition constant) were estimated for ERY, DTZ, nd-ERY, and nd-DTZ, respectively, using cDNA-expressed CYP3A4 and human liver microsomes under optimal experimental conditions. To evaluate the interaction model, combinations of inhibitors and metabolites were incubated at concentrations equal to K(I), (1/2)K(I), and 2K(I) of each inhibitor for specified durations in both enzyme systems. The models were further evaluated by the incubation of combinations of inhibitors with the substrate testosterone for 10 min. CYP3A4 inhibition in the presence of drug mixtures was predicted from the inhibition parameters determined for each drug or metabolite alone. The CYP3A4 activity in the presence of multiple inhibitors was well predicted by the model incorporating additive irreversible inhibition as modified by mutual competitive inhibition (percent mean error and percent mean absolute error ranged from -0.06 to 0.04 and from 0.03 to 0.09, respectively). In conclusion, the additive model predicted the combined effect of multiple inhibitors on CYP3A inhibition in vitro. However, simultaneous reversible and irreversible inhibition effects should be taken into account in a reaction mixture of substrate and multiple inhibitors of CYP3A4.     

Irbesartan-mediated reduction of renal and cardiac damage in insulin resistant JCR : LA-cp rats

Background and purpose:

Angiotensin II receptor antagonists (ARBs), originally developed for antihypertensive properties, have pleiotropic effects including direct vascular actions. We tested the hypothesis that the ARB irbesartan would be effective against micro- and macrovascular complications of the prediabetic metabolic syndrome using the obese, insulin-resistant JCR : LA-cp rat that exhibits micro- and macrovascular disease with ischaemic myocardial lesions and renal disease.

Experimental approach:

Obese male rats were treated with irbesartan (30 mg·kg⁻¹·day⁻¹, incorporated into chow) from 12 to 25 weeks of age.

Key results:

Irbesartan treatment caused no change in food intake or body weight. Fasting glycaemic control of the JCR : LA-cp rats was marginally improved, at the expense of increased plasma insulin levels (∼50%). Fasting plasma triglycerides were marginally reduced (∼25%), while cholesterol concentrations were unchanged. Elevated concentrations of adiponectin, monocyte chemotactic protein-1 and plasminogen activator inhibitor-1 were reduced along with severity of glomerular sclerosis. Macrovascular dysfunction (aortic hypercontractile response to noradrenergic stimulus and reduced endothelium-dependent relaxation) was improved and frequency of ischaemic myocardial lesions reduced (62%).

Conclusions and implications:

Irbesartan reduces markers of inflammation and prothombotic status, improves macrovascular function and reduces glomerular sclerosis and myocardial lesions in a model of the metabolic syndrome. Unlike pharmaceutical agents targeted on metabolic dysfunction, irbesartan reduced end-stage disease without major reduction of plasma lipids or insulin. The protective effects appear to be secondary to unknown intracellular mechanisms, probably involving signal transduction pathways. Understanding these would offer novel pharmaceutical approaches to protection against cardiovascular disease.     

Alloimmunization to platelet-specific antigens on glycoproteins IIb- IIIa and Ib/IX in multiply transfused thrombocytopenic patients

The rate of alloimmunization to platelet-specific antigens associated with platelet glycoproteins (GPs) IIb-IIIa and Ib/IX was studied in 293 multiply transfused thrombocytopenic patients. Antibodies to platelet-specific antigens were measured with a solid-phase assay using platelet GP IIb-IIIa or Ib/IX as the antigenic targets. Nine patients were found to have antibodies to platelet GP IIb-IIIa, and no patients had antibodies to platelet GP Ib/IX. In six of these nine patients, the specificity of the antibody was shown by using GP IIb-IIIa from donors with different platelet-specific antigen phenotypes. In the remaining three patients with antibodies to platelet GP IIb-IIIa, no specificity could be identified. These patients had autoimmune thrombocytopenia in association with lymphoma. The alloimmunization rate to platelet-specific antigens associated with GP IIb-IIIa was 2 percent, whereas the rate of alloimmunization to HLA antigens was 23 percent. Of the patients alloimmunized to HLA antigens, 9 percent also had antibodies to platelet-specific antigens. A poor response to HLA-identical platelet transfusions was observed only in those patients with positive assays in the solid-phase test. These results suggest that the incidence of antibodies to platelet-specific antigens carried on GP IIb-IIIa is low. Platelet-specific antibodies may be found more frequently in patients alloimmunized to HLA antigens than in those not so alloimmunized.