A comparative multi-laboratory assessment of three factor VIII/von Willebrand factor concentrates

Five expert laboratories have participated in a cross-laboratory study to co-evaluate and compare three commercial Factor VIII/von Willebrand factor (VWF) concentrates. A total of nine factor concentrate lots were evaluated, comprising AHF (High Purity) (AHF HP; x3), Biostate (x3) and Humate/Haemate (x3). All laboratories blind tested for FVIII: C, VWF: Ag and VWF: CB, four tested for VWF: RCo, and one performed VWF: Multimers. The study yielded inter-laboratory CVs for VWF: Ag and FVIII:C around 10-15%, and for VWF:CB and VWF:RCo around 20%, significantly lower than those of previous multi-laboratory surveys. All three lots of AHF HP contained in the vicinity of 25 U/ml FVIII:C, around 60-75 U/ml of VWF:Ag, but only 30-45 U/ml of VWF:CB and 40-50 U/ml of VWF:RCo (thus, CB/Ag ratio around 0.5-0.6 and RCo/Ag ratio around 0.6-0.7). Study determined that FVIII: C and VWF: RCo levels were similar to manufacturer assigned levels. Some loss of the high molecular weight (HMW) multimers was observed, together with an intense low molecular weight (LMW) VWF band consistent with some reduction or proteolysis of HMW VWF. All three lots of Humate/Haemate contained in the vicinity of 23-32 U/ml of FVIII:C, 70-105 U/ml of VWF: Ag, 50-90 U/ml of VWF: CB and VWF: RCo (i.e. CB/Ag ratio around 0.6-0.9 and RCo/Ag ratio around 0.6-1.1). Study-determined FVIII: C and VWF: RCo levels were similar to manufacturer-assigned levels. The LMW multimer band seen with AHF HP was also observed with Humate/Haemate. All three lots of Biostate contained in the vicinity of 40-55 U/ml of FVIII:C, 105-170 U/ml of VWF:Ag, 90-150 U/ml of VWF:CB, and 90-135 U/ml of VWF:RCo (i.e. CB/Ag and RCo/Ag ratios around 0.7-1.0). Study-determined FVIII:C levels were similar to manufacturer-assigned levels. The LMW multimer band seen with AHF HP was not observed with Biostate. The defined pattern of increasing CB/ Ag from AHF HP to Humate/Haemate and Biostate was consistently observed in study data from each of the five laboratories. In conclusion, study findings indicate some differences in the retention of functional/ HMW VWF between factor concentrates, and this is expected to have significant implications in terms of clinical efficacy for therapy in VWD.     

Neuropsychiatric effects of guanfacine in children with mild tourette syndrome: a pilot study

The objective of this study was to evaluate the neuropsychiatric effects of the alpha-2a adrenergic agonist guanfacine in children with Tourette syndrome (TS). Twenty-four children with TS participated in a 4-week, double-blind, placebo-controlled study of guanfacine. Tic severity, neuropsychologic functioning, and parent ratings of behavior were evaluated pre- and post-treatment. The sample had mild tic severity and subtle neuropsychologic dysfunction pretreatment. Post-treatment, patients receiving guanfacine were rated by parents as significantly improved (compared to placebo) on one measure of executive function (parent-rated metacognition). Improvement on tic severity, performance-based neuropsychologic measures, and all other parent ratings were not significantly better than placebo. At a moderate dose and short-term treatment duration, guanfacine did not provide significant neuropsychiatric benefits in this group of children with mild TS.     

IGF-I and microglia/macrophage proliferation in the ischemic mouse brain

We have used a model of hypoxic-ischemic brain injury in adult male C57BL/6 mice to study insulin-like growth factor-I (IGF-I) and IGF-binding protein (IGFBP) expression in response to cerebral hypoxia-ischemia (H/I) in the adult mouse. A period of 20 min of H/I that resulted in histopathology in cortex, striatum, and thalamus was correlated with induction of mRNA for IGF-I, IGFBP-2, IGFBP-3, IGFBP-5, and glial fibrillary acidic protein (GFAP) by 4 days of recovery. Increased IGF-I mRNA was located within damaged regions and was surrounded by IGFBP-2 mRNA expression. The results of combined immunostaining/in situ hybridzation showed that the cells expressing IGFBP-2 mRNA were also GFAP-positive and comprised a subset of activated astrocytes immediately surrounding areas of damage. In contrast, staining within damaged regions showed high numbers of cells immunopositive for F4/80 and lectin B(4) indicative of microglia and macrophages but no cells immunopositive for the astrocytic proteins GFAP or S-100beta. Microglia/macrophages within the damaged areas expressed IGF-I mRNA and were also immunopositive for the proliferating cell nuclear antigen. To determine whether expression of IGF-I could contribute to proliferation of microglia, we treated purified cultures of adult brain microglia with IGF-I in the presence of (3)H-thymidine. IGF-I stimulated a twofold increase in DNA synthesis in cultures of adult brain microglia. Taken together with previous data demonstrating that IGF-I promotes proliferation of peripheral macrophages, these data support the hypothesis that IGF-I is an autocrine/paracrine mitogen for microglia/macrophages after H/I.     

Auditory deprivation affects processing of motion,but not color

Event-related potentials (ERPs) were recorded in response to color changes of isoluminant, high spatial frequency gratings and to motion of grayscale, low spatial frequency gratings in 11 normally hearing and 11 congenitally deaf adults. The stimuli were designed to activate preferentially the ventral and dorsal streams of visual processing, respectively. Color changes evoked prominent P1 and N1 components in the ERP; motion evoked an early, focal positivity (the P-INZ), a minimal P1, and a prominent N1. Color changes elicited similar ERP components in hearing and deaf participants. In contrast, motion elicited larger amplitude and more anteriorly distributed N1 components in deaf than hearing participants. These results suggest that early auditory deprivation may have more pronounced effects on the functions of the dorsal visual pathway than on functions of the ventral pathway.     

Executive control function: a review of its promise and challenges for clinical research. A report from the Committee on Research of the American Neuropsychiatric Association

This report reviews the state of the literature and opportunities for research related to "executive control function" (ECF). ECF has recently been separated from the specific cognitive domains (memory, language, and praxis) traditionally used to assess patients. ECF impairment has been associated with lesions to the frontal cortex and its basal ganglia-thalamic connections. No single putative ECF measure can yet serve as a "gold standard." This and other obstacles to assessment of ECF are reviewed. ECF impairment and related frontal system lesions and metabolic disturbances have been detected in many psychiatric and medical disorders and are strongly associated with functional outcomes, disability, and specific problem behaviors. The prevalence and severity of ECF deficits in many disorders remain to be determined, and treatment has been attempted in only a few disorders. Much more research in these areas is necessary.     

Breaking bones,breaking budgets: a clinical and economic evaluation of a prospective,randomized, practice controlled,intervention study in the prevention of accidents in primary care

OBJECTIVE: This longitudinal study was designed to assess the effect of an educational training package for primary health care teams in accident prevention for older people, with reference to the incidence of accidents and their associated economic consequence. METHODS: Nineteen general practices in the West Midlands serving a population of 138 397 were allocated randomly at the practice level either to receive training or continue normal practice. Study data was collated from the initial telephone call, reporting an accident, to the surgery, advice/treatment given at the practice and/or the community, casualty, inpatient care, written correspondence to the patient's GP and any subsequent follow-up visits for accidents to people aged 65 years or older. RESULTS: One thousand, six hundred and sixty-six (8.2%) patients aged 65 years or older registered with the participating practices experienced one accident or more, costing the NHS pound 1.4 million. Extrapolated nationally, annual costs to the NHS for accidents to older people amount to pound 568 million. The educational package had no significant impact on the incidence of accidents. A paucity of general safety advice was given [48 (1.8%) occasions]. CONCLUSIONS: Budgets are being eroded and patients are suffering unnecessarily due to lack of accident prevention advice. This should be considered a priority within the primary health care team. Educational packages alone do not appear to be a cost-effective approach to accident prevention in primary care.     

Management of hip dislocation with postural management

BACKGROUND: Hip dislocation in children with cerebral palsy has a well-documented history and morbidity. OBJECTIVE: This paper presents a retrospective study of children with bilateral cerebral palsy who had various postural management and its effect on hip deformity. The most widely accepted theoretical model of hip subluxation/dislocation is that an imbalance in muscle length and strength around the hip leads to acetabular dysplasia and consequent hip subluxation. Maintenance of muscle length and strength and loadbearing is therefore a logical prevention. Research on normal infants' postures has provided biomechanical data to form the theoretical basis of 24 h postural management equipment. METHODS: The notes and X-rays of 59 children with bilateral cerebral palsy from East and West Sussex and Oxfordshire were examined and measured to determine whether a relationship existed between postural management and the level of hip subluxation/dislocation. X-rays were measured using Reimers' hip migration percentage. Postural management support was divided into three groups for analysis. Category 1: use of a 24-h postural management approach using Chailey Adjustable Postural Support (CAPS) systems in lying, sitting and standing; category 2: two items of CAPS (either lying/sitting or sitting/standing supports); category 3: use of the CAPS seat only and/or any other postural supports. Hip status was recorded for analysis as both hips safe (under 33% migrated), or one/both hips subluxed. RESULTS: Children using 'All CAPS' before hip subluxation maintained significantly more hip integrity than other groups (chi2 P < 0.05). CONCLUSIONS: Postural management interventions have an important role in the prevention of hip dysplasia.     

Possible transient adaptive response to mitomycin C in peripheral lymphocytes from thyroid cancer patients after iodine-131 therapy

Our study attempted to assess the possible induction and persistence of an adaptive response in lymphocytes of thyroidectomized thyroid cancer patients treated with 131I (2,590 MBq, corresponding to whole body doses in the range of 200-300 mGy), to a testing dose of mitomycin C (MMC) in vitro. The cytogenetic endpoint studied was the induction of micronuclei in cytokinesis-blocked peripheral blood lymphocytes, immediately before treatment and 1, 6 and 24 months after therapy. One month after therapy, induction of micronucleated cytokinesis-blocked lymphocytes ( per thousand ) by MMC was lower (34.6 +/- 7.7) than before therapy (52.1 +/- 5.0). In 7 of 11 patients this reduction was significant. However, at 6 months, induction of micronuclei was markedly higher (133.1 +/- 13.6). This significant increase was observed regardless of the decrease at 1 month. At 24 months, the frequency of micronucleated cells decreased (84.8 +/- 5.5), but remained higher than before treatment. The results obtained 1 month after therapy could reflect adaptation due to radiation, or a higher rate of early apoptosis or cell death, with bone marrow suppression, visible as a lower response in vitro towards MMC. At 6 months, recovery of the lymphocyte population may occur, and higher responses to MMC in vitro could reflect higher chromosomal instability in the previously irradiated stem cells with a concomitant disappearance of adaptation, whereas at 24 months the results show a tendency to return to pretherapy values.     

Activity of gemcitabine and carboplatin in advanced non-small cell lung cancer: a phase II trial

This phase II trial was designed to investigate the efficacy and tolerability of gemcitabine combined with carboplatin in patients with advanced or metastatic NSCLC. Patients were treated with gemcitabine 1000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle and carboplatin AUC 5 mg/ml/min on day 2 of each cycle. Fifty patients (Zubrod-ECOG-WHO performance status 0/1 in 70/30%, stage IV disease in 64%) entered the study and were evaluable for response and toxicity. There was 1 complete response and 24 partial responses among 50 evaluable patients, for a response rate of 50% (95% CI: 36.0-64.1%). The median survival time was 13 months (range: 6-22 months), and the 1-year survival rate was 54%. Hematologic toxicities included grades 3 and 4 neutropenia in 24 and 8% of patients, respectively, and grades 3 and 4 thrombocytopenia in 48 and 8% of patients, respectively. These were without clinical sequelae. Seven (14%) patients had grade 3 nausea and vomiting. The combination of gemcitabine and carboplatin is highly active and well tolerated in patients with advanced or metastatic NSCLC.     

Tumor cytosol carcinoembryonic antigen as prognostic parameter in non-small cell lung cancer

AIMS AND BACKGROUND: Carcinoembryonic antigen (CEA) belongs to a family of cell surface glycoproteins. Its level in serum has a significant value for the follow-up and treatment of patients with malignancies. The aim of this study was to correlate the concentration of tumor cytosol CEA (cCEA) with tumor size, patient age and sex, clinical stage, lymph node metastases, and overall survival rate in primary non-small cell lung carcinoma (NSCLC). METHODS AND STUDY DESIGN: The cCEA levels were determined in 76 NSCLC patients by luminescence assay (LIA) and radioimmunoassay (RIA). RESULTS: A strong correlation between LIA and RIA assay results was found (r = 0.992). No correlation was observed between serum CEA and cCEA levels. Tumors smaller than 3 cm had significantly higher cCEA levels than larger tumors, but when a logistic modeling process was applied this difference was not significant (P = 0.038). Histologically well-differentiated tumors also showed a significantly higher expression of cCEA (P <0.05). In addition, patients without lymph node involvement had higher cCEA levels than patients with tumor-positive lymph nodes (P < 0.05). Univariate statistical analysis revealed that the risk of lymph node metastases was 1.8-fold higher in patients with low cCEA levels than in patients with higher levels, taking the median value as cutoff (P = 0.04, Kruskal-Wallis test). CONCLUSIONS: According to the results of our study, patients with overexpression of cCEA may have a better prognosis than those with low cCEA expression. cCEA might therefore be considered a good prognostic parameter as well as a prognostic factor independent of the traditional parameters for lymph node metastases.