Antiproliferative Activity Against MCF‐7 Breast Cancer Cells by Diamino‐Triazaspirodiene Antifolates

Two triazaspirodienes, having similar phenoxy propyloxy side chain, were identified as potent mammalian dihydrofolate reductase inhibitors; one having a 6,5‐spiro bicyclic ring system (IC₅₀ = 2.3 nm ) and the other a 6,6‐spiro bicyclic system (IC₅₀ = 6.9 nm ). They also showed more than 50% antiproliferative activity against the MCF‐7 breast cancer cells at 20 μm . This study demonstrated the potential lead of the diamino‐triazaspirodienes in anticancer chemotherapeutical agents’ discovery.     

A systematic review of resident‐as‐teacher programmes

Context Residents in all disciplines serve as clinical teachers for medical students. Since the 1970s, there has been increasing evidence to demonstrate that residents wish to teach and that they respond positively to formal teacher training. Effective resident‐as‐teacher (RaT) programmes have resulted in improved resident teaching skills. Current evidence, however, is not clear about the specific features of an effective RaT programme. Objectives This study was performed in order to investigate the effectiveness of RaT programmes on resident teaching abilities and to identify the features that ensure success. Methods of assessment used to ascertain the effectiveness of RaT programmes are also explored. Methods The literature search covered the period between 1971 and 2008. Articles focusing on improving resident teaching skills were included. Each study was reviewed by two reviewers and data were collected using a standard abstraction summary sheet. Study outcomes were graded according to a modified Kirkpatrick's model of educational outcomes. Results Twenty‐nine studies met review inclusion criteria. Interventions included workshops, seminars, lectures and teaching retreats. Twenty‐six studies used a pre‐ and post‐intervention outcome comparison method. Subjective outcome measures included resident self‐evaluation of teaching skills or evaluation by medical students, peers and faculty members. Objective outcome measures included written tests, evaluation of teaching performance by independent raters and utilisation of objective structured teaching examinations. One study objectively measured learning outcomes at the level of medical students, utilising the results of an objective structured clinical examination. Overall resident satisfaction with RaT programmes was high. Participants reported positive changes in attitudes towards teaching. Participant knowledge of educational principles improved. Study methodologies allowed for significant risks of bias. Conclusions More rigorous study designs and the use of objective outcome measures are needed to ascertain the true effectiveness of RaT programmes. Future research should focus on determining the impact of RaT programmes on learning achievement at the level of medical students.     

Serum IgA and IgG functional antibodies and their subclasses to Streptococcus pneumoniae capsular antigen found in two aged‐matched cohorts of children with and without otitis media with effusion

Serum IgA and IgG functional antibodies and their subclasses to Streptococcus pneumoniae capsular antigen found in two aged‐matched cohorts of children with and without otitis media with effusion The relationship between acute otitis media and otitis media with effusion (OME) is uncertain and the aetiology of OME is multifactorial. Otitis media with effusion may be an inflammatory condition; both bacteria and viral infections could play a part in this inflammation. The four bacteria Streptococcus pneumoniae, Haemophilus influenza, Staphylococcus aureus and Branhamella catarrhalis cause 60% of the infections whereas S. pneumoniae accounts for up to 35%. IgA provides the dominant surface response to polysaccharide and lipopolysaccharide antigens, of which IgA₂ is the main subclass. Once the mucosa has been breached, most protection is provided by IgG. IgG₂ acts mainly against bacterial capsular antigens. This study looked at two groups of 50 children with and without OME who were aged between 3 and 10 years. The aims were to determine if, firstly, the levels of the serum immunoglobulins were different in the two groups, secondly whether these children made the appropriate antibody response to the capsular antigen to S. pneumoniae (PCP), and finally if there was a delay in the maturity of the IgA response. The total IgG, IgA and all subclass levels were measured using radial immunodiffusion. Levels of functional IgA and IgG were measured using ELISAs (25 patients in each group). The results were analysed with non‐parametric tests. The immunoglobulin levels were within the normal levels for both groups. There were very good correlations between the IgG total anti‐PCP and the IgG₂ anti‐PCP (R > 0.9, p = 0.001). There was a good correlation between the levels of both IgG total and IgG₂ anti‐PCP against IgA total anti‐PCP in both groups (R > 0.85, p > 0.01). This confirms a normal antibody response between both groups of patients. The ages of the controls and patients (50 samples) were correlated with increasing titres of circulating functional antibodies (P = 0.001). This is highly suggestive of a normal age‐related response. In conclusion, the findings were contradictory to our original hypothesis that there is a subtle difference in surface protection between children with and without OME. We believe that a previous history of recurrent acute otitis media is unrelated to the development of OME after 3 years of age.     

Changes to osteoporosis prevalence according to method of risk assessment.

The impact of clinical risk factor-based absolute risk methods on the prevalence of high risk for osteoporotic fracture is unknown. We applied absolute risk methods to 6646 subjects and found that the prevalence of elderly women deemed to be at high risk increased substantially, whereas the overall prevalence was highly dependent on the threshold used to designate high risk. INTRODUCTION: Many groups have advocated using absolute risk methods that incorporate clinical risk factors to target patients for osteoporosis therapy. We examined how the application of such absolute risk classification systems influences the prevalence of those considered to be at high risk for osteoporotic fracture and compared these systems to one based solely on BMD. MATERIALS AND METHODS: Using 6646 subjects from the Canadian Multicentre Osteoporosis Study (CaMos), a prospective, randomly selected, population-based cohort, we assessed three different systems for determining prevalence of high risk for osteoporotic fracture: a BMD-based system; a simplified risk factor system incorporating age, sex, BMD, and two clinical risk factors; and a comprehensive system, incorporating age, sex, BMD, and seven clinical risk factors. The 10-year absolute risks of incident fragility fracture were compared across systems using three different high-risk thresholds. RESULTS: The prevalence of a T score < or = -2.5 was 18.8% (95% CI: 17.7-19.9%) in women and 3.9% (95% CI: 3.0-4.7%) in men. Using a 15% 10-year risk of fracture threshold, the prevalence of women at high risk increased to 46.9% (95% CI: 45.4-48.4) and 42.5% (95% CI: 41.1-43.9) when the comprehensive and simplified risk factor classification systems were used, respectively. Using a 25% 10-year absolute risk threshold, the prevalence of high risk was similar to that of the BMD-based system, whereas the 20% threshold gave intermediate rates. All thresholds analyzed resulted in an increased prevalence of older women at high risk for fracture, whereas only the 15% 10-year risk of fracture threshold resulted in an increase in the prevalence of men at high risk. CONCLUSIONS: The application of risk factor-based systems results in an increased prevalence of older women at high risk. The prevalence of individuals at high risk may increase with changes to the methods used to determine those who are eligible for therapy. These data have important implications for the pattern of care and costs of treating osteoporotic fractures.     

Impaired modulation of motor cortex excitability by homonymous and heteronymous muscle afferents in focal hand dystonia.

A decrease of heteronymous median nerve-evoked inhibition of corticospinal projections to forearm extensor muscles was reported in a group of 10 dystonic patients by Bertolasi and colleagues in 2003. Here we tested the excitability of corticomotoneuronal connections to both wrist extensor (ECR) and flexor (FCR) muscles after conditioning stimulation of median and also radial nerve at rest in a group of 25 patients with focal hand dystonia compared to 20 healthy subjects. We also investigated the effect of the wrist dystonic posture, either in flexion or in extension, on the afferent modulation of ECR and FCR motor evolved potentials (MEPs). The heteronymous (median-induced) but also homonymous (radial-induced) inhibitions (interstimuli intervals 13-21 ms) of ECR MEP size observed in healthy subjects were decreased in patients. In addition, homonymous (median-induced) facilitation of FCR MEP size was also decreased in patients while heteronymous inhibition (radial-induced) was not. Neither the involvement of the target muscle in the dystonic posture nor the origin of the afferent volley (from a dystonic muscle) influenced the degree of impairment of afferent modulation of the MEP. These findings support the view that a global abnormal somatosensory coupling in focal hand dystonia may contribute to an inadequate motor command to wrist muscles.     

Prefrontal cortex dysfunction and depression in atypical parkinsonian syndromes.

Depressive symptoms are common in patients with neurodegenerative disorders. Imaging studies suggest that a disruption of frontal-subcortical pathways may underlie depression associated with basal ganglia disease. This pilot study tested the hypothesis that frontal dysfunction contributes to depression associated with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Depressed patients with MSA (n = 11), PSP (n = 9), and age-matched controls (n = 25) underwent measures of cerebral glucose metabolism applying positron emission tomography with (18)F-fluorodeoxyglucose. Regional metabolism in the patient groups was compared to the normal subjects using the voxel-based statistical parametric mapping. Depressive symptom severity (Hamilton Depression Rating) and degree of locomotor disability (Hoehn & Yahr) were assessed in the patient groups. The association between prefrontal metabolism and the occurrence of depressive symptoms and the degree of locomotor disability was investigated. When compared to controls, MSA patients revealed significant metabolic decreases in bilateral frontal, parietal, and cerebellar cortex and in the left putamen. In PSP patients, significant hypometabolism was demonstrated in bilateral frontal cortex, right thalamus, and midbrain. Depression severity but not the patients' functional condition was significantly associated with dorsolateral prefrontal glucose metabolism in both patient groups. The findings of this pilot study support the hypothesis that depressive symptoms in MSA and PSP are associated with prefrontal dysfunction.