Allometry in the corpus callosum in neonates: Sexual dimorphism

The corpus callosum (CC) is the largest fiber tract in the human brain, allowing interhemispheric communication by connecting homologous areas of the two cerebral hemispheres. In adults, CC size shows a robust allometric relationship with brain size, with larger brains having larger callosa, but smaller brains having larger callosa relative to brain size. Such an allometric relationship has been shown in both males and females, with no significant difference between the sexes. But there is some evidence that there are alterations in these allometric relationships during development. However, it is currently not known whether there is sexual dimorphism in these allometric relationships from birth, or if it only develops later. We study this in neonate data. Our results indicate that there are already sex differences in these allometric relationships in neonates: male neonates show the adult‐like allometric relationship between CC size and brain size; however female neonates show a significantly more positive allometry between CC size and brain size than either male neonates or female adults. The underlying cause of this sexual dimorphism is unclear; but the existence of this sexual dimorphism in neonates suggests that sex‐differences in lateralization have prenatal origins.     

Direct derivatization of drugs in untreated biological samples for gas chromatographic analysis

The possibilities to derivatize an analyte directly in the biological sample are reviewed with examples from our own experiences and from the literature. Techniques, such as extractive acylation, alkylation and benzoylation, are frequently used. Improvement of the extractability of the drug from the matrix is a common feature, especially with hydrophilic compounds, where sometimes cyclizing reactions can be employed. Several analytes are reactive or labile in the sample and can be trapped in derivatization reactions in situ. In many cases, two-phase reactions lead to milder derivatization conditions (e.g. dealkylation of tertiary amines), which is favourable from a clean-up point of view.     

Potent antitumoral effects of targeted promoter-driven oncolytic adenovirus armed with Dm-dNK for breast cancer in vitro and in vivo

Currently, no curative treatments are available for late-stage metastatic or recurrent breast cancer, because the cancer tolerates both chemotherapy and endocrine therapy. In this study, we investigated the feasibility of a dual-regulated oncolytic adenoviral vector with a novel suicide gene to treat breast cancer. Following targeted gene virotherapy of conditionally replicating adenoviruses (CRAds), the novel suicide gene of multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster (Dm-DNK) was inserted into the double-regulated oncolytic adenovirus SG500 to ensure more safety and enhanced antitumor activity against breast cancer both in vitro and in vivo. Selective replication, cell-killing efficacy, and cytotoxicity, combined with chemotherapeutics were investigated in several breast cell lines (MDA-MB-231 and MCF-7), normal cells (WI-38 and MRC-5), and human (MDA-MB-231) tumor models in vivo. The double-regulated SG500-dNK had high cell-killing activity in breast cancer. Replication was similar to wild-type in breast cells and was attenuated in normal cells. SG500-dNK combined with the chemotherapeutics (E)-5-(2-bromovinyl)-2′-deoxyuridine (Bvdu) and 2′,2′-difluoro-deoxycytidine (dFdC) resulted in synergistically enhanced cell killing and greatly improved antitumor efficacy in vitro or in breast xenografts in vivo. These data suggest that the novel oncolytic variant SG500-dNK is a promising candidate for targeting breast tumors specifically when combined with chemotherapeutics.     

Relationship between serum IgE levels and anaphylactic histamine release from isolated rat mast cells.

Inbred Hooded Lister rats were immunized with egg albumin with B. pertussis vaccine used as an adjuvant. The serum levels of total IgE and IgE antibody (egg albumin specific) were determined by radioimmunoassay techniques before and after immunization. The basic level of total IgE in serum was 560 +/- 110 ng/ml. After immunization a maximal peak at day 11 of 1940 +/- 160 ng/ml was registered. Anti-egg albumin IgE antibody showed a maximum around day 13 of 75 +/- 11 units/ml. Pleural mast cells were isolated on Ficoll between day 14 and 20 after immunization. A significant negative correlation between the basic total IgE level and histamine release by antigen (egg albumin) was found and also a significant positive correlation of specific IgE antibody (determined at day 11) and histamine release. The correlation between IgE level and histamine release was slightly improved if instead the ratio of specific IgE antibody over total IgE was used.     

Contact allergy and hand eczema in Swedish dentists

Hand eczema and contact allergy in Swedish dentists were studied in a multidisciplinary project. The aims of the study were to establish diagnoses, to investigate the occurrence of contact allergy, in particular to (meth)acrylates, and to evaluate certain consequences of hand eczema. A postal questionnaire on skin symptoms, atopy and occupational experience was mailed to 3,500 dentists aged <65 years, and licensed 1965-1995. The response rate was 88%. Among dentists living in 3 major cities, 14.9% (n= 191) reported hand eczema during the previous year. They were invited to a clinical examination, including patch testing with a standard and a dental series. 158/191 (83%) dentists attended, and hand eczema diagnosis was confirmed in 149/158 (94%). Irritant contact dermatitis was diagnosed in 67% and allergic contact dermatitis in 28%. On patch testing, 50% presented at least 1 positive reaction. The most frequent allergens were nickel sulfate, fragrance mix, gold sodium thiosulfate and thiuram mix. 7 (5%) had positive reactions to (meth)acrylates, all to 2-hydroxyethyl methacrylate and 6 also to ethyleneglycol dimethacrylate. 38% had consulted a physician, 4% had been on sick-leave and 1% had changed occupational tasks due to hand eczema. No dentist with allergy to acrylates had been on sick-leave or changed occupation. It is concluded that dentistry is a high-risk occupation for hand eczema, and that irritant contact dermatitis is most common. The prevalence of contact allergy to acrylates was below 1% in the population of responding dentists, and in most cases did not have serious medical, social or occupational consequences.     

Treatment of organophosphate poisoning in pigs: antidote administration by a new binary autoinjector

 The therapeutic effectiveness of a new binary autoinjector containing 500 mg HI-6 and 2 mg atropine sulphate was tested in anesthetized pigs poisoned by a lethal dose of soman i.v. (9 μg/kg per 20 min). Pharmacokinetics and pharmacodynamics of HI-6 were studied concomitantly on administration of HI-6 alone, together with atropine sulphate, or together with atropine sulphate during soman intoxication. Cardiopulmonary parameters were monitored and serum concentrations of oxime and acetylcholinesterase (AChE) were measured in blood samples taken at intervals over a 6-h period postinjection. Five minutes after the start of soman infusion, mean AChE activity was decreased to 27±4.3% of baseline and signs of poisoning appeared. The antidotes, HI-6 and atropine sulphate, were then administered i.m. One minute after this injection there was a transient significant increase in AChE activity of 76±8.2% of baseline (p<0.01). It then again decreased and remained suppressed throughout the experiment. Mean respiratory rate was significantly decreased (p<0.01) to 20±3.2% of baseline after 20 min of soman infusion and remained low during the rest of the experiment. The poisoning signs were counteracted 15–20 min after antidote therapy and all pigs survived soman intoxication without ventilatory assistance. Administration of either atropine or atropine and soman had no significant effect on the pharmacokinetics of HI-6 in anesthetized pigs. Received: 20 February 1995/Accepted: 3 May 1995     

Model-Based Adaptive Optimal Design (MBAOD) Improves Combination Dose Finding Designs: an Example in Oncology

Design of phase 1 combination therapy trials is complex compared to single therapy trials. In this work, model-based adaptive optimal design (MBAOD) was exemplified and evaluated for a combination of paclitaxel and a hypothetical new compound in a phase 1 study to determine the best dosing regimen for a phase 2 trial. Neutropenia was assumed as the main toxicity and the dose optimization process targeted a 33% probability of grade 4 neutropenia and maximal efficacy (based on preclinical studies) by changing the dose amount of both drugs and the dosing schedule for the new drug. Different starting conditions (e.g., initial dose), search paths (e.g., maximal change in dose intensity per step), and stopping criteria (e.g., “3?+?3 rule”) were explored. The MBAOD approach was successfully implemented allowing the possibility of flexible designs with the modification of doses and dosing schedule throughout the trial. The 3?+?3 rule was shown to be highly conservative (selection of a dosing regimen with at least 90% of the possible maximal efficacy in less than 21% of the cases) but also safer (selection of a toxic design in less than 2% of the cases). Without the 3?+?3 rule, better performance was observed (>67% of selected designs were associated with at least 90% of possible maximal efficacy) while the proportion of DLTs per trial was similar. Overall, MBAOD is a promising tool in the context of dose finding studies of combination treatments and was showed to be flexible enough to be associated with requirements imposed by clinical protocols.     

Immediately loaded implants supporting fixed prostheses in the edentulous maxilla: a preliminary clinical and radiologic report

PURPOSE: To evaluate the survival rate of immediately loaded ITI sand-blasted, large-grit, acid-etched (SLA) solid-screw dental implants in the edentulous maxilla after 8 months of loading. MATERIALS AND METHODS: Twenty-eight patients (mean age 63 years) with edentulous maxillae each received 6 implants and 1 implant-supported fixed provisional prosthesis within 24 hours after surgery. After a mean healing time of 15 weeks, the patient received a definitive, screw-retained, implant-supported fixed prosthesis. A total of 168 implants were placed. Clinical parameters were registered after 1 month of loading with the implant-supported fixed prostheses as well as 8 months after implant placement. Radiologic examinations and assessments were made at implant placement and after 8 months. RESULTS: The mean marginal bone level at implant placement was 1.6 mm (range 0 to 5.1; SD 1.1) apical of the reference point (the implant shoulder). The mean marginal bone level at the 8-month follow-up was 3.2 mm (range 0.4 to 5.9; SD 1.1) apical of the reference point. Three implants failed during the healing period. DISCUSSION: The improved results in the present study might be a result of the positive effect of splinting the implants immediately after placement. CONCLUSION: ITI SLA solid-screw implants immediately loaded (ie, loaded within 24 hours of placement) and supporting fixed prostheses had successful survival rates after 8 months. The present results constitute a solid baseline for future follow-up studies.     

Primary and secondary care clinicians’ views on self-treatment of COPD exacerbations: A multinational qualitative study

Objective

To explore clinicians’ views on antibiotic and/or steroid ‘rescue packs’ used as self-treatment for patients with exacerbations of COPD.

Methods

21 focus groups conducted in 7 countries – Netherlands, Russia, Norway, China (Hong Kong), Wales, Germany and Poland involving 142 primary care clinicians and pulmonologists.

Results

We found wide variation in reported use of and attitudes to self-treatment among GPs and pulmonologists in the participating countries. Clinicians highlighted the importance of identifying patients who were most likely to benefit (those with more severe disease) and most likely to use the treatment appropriately (demonstrated by previous behaviour), and the importance of adequate patient education and ongoing communication in regard to use of self-treatment packs. Clinicians recognised patient empowerment and facilitating prompt treatment as potential benefits of self-treatment. However, many felt they did not have the time or resources for appropriate patient selection and education.

Conclusion

Clinicians do not feel it is appropriate to offer self-treatment rescue packs to all patients routinely without careful consideration of patient understanding of their illness and their capacity for self-management.

Practice Implications

Adequate resources and continuity of patient care are required for clinicians to feel confident in the safe and effective implementation of this strategy.