A vector expressing feline mature IL-18 fused to IL-1beta antagonist protein signal sequence is an effective adjuvant to a DNA vaccine for feline leukaemia virus

DNA vaccination using vectors expressing the gag/pol and env genes of feline leukaemia virus (FeLV) and plasmids encoding feline interleukin-12 (IL-12) and IL-18 completely protected cats from viraemia following challenge [Hanlon L, Argyle D, Bain D, Nicolson L, Dunham S, Golder MC, et al. Feline leukaemia virus DNA vaccine efficacy is enhanced by coadministration with interleukin-12 (IL-12) and IL-18 expression vectors. J Virol 2001;75:8424-33]. However, the relative contribution of each cytokine gene towards protection is unknown. This study aimed to resolve this issue. IL-12 and IL-18 constructs were modified to ensure effective expression, and bioactivity was demonstrated using specific assays. Kittens were immunised intramuscularly with FeLV DNA and various cytokine constructs. Together with control kittens, these were challenged oronasally with FeLV and monitored for 15 weeks. All six kittens given FeLV, IL-12 and IL-18 were protected from the establishment of persistent viraemia and four from latent infection. Of six kittens immunised with FeLV DNA and IL-18, all were protected from viraemia and five from latent infection. In contrast, three of five kittens given FeLV DNA and IL-12 became persistently viraemic. Therefore, the adjuvant effect on the FeLV DNA vaccine appears to reside in the expression of IL-18.     

Infrequently occurring activities and contexts in time use data

In this paper we describe an approach to the study of time use data that focuses on relatively infrequent activities as well as the contexts in which the activities take place. To illustrate the method, we present several examples from a secondary analysis of the Multinational Comparative Time-Budget data, based on over 25,000, 24-hour, time use diaries collected in 12 countries during 1965 through 1966. Activities that represent a small fraction of the overall time budget of a population may nevertheless yield valuable insights into a culture or group. Analyses of such mundane events as doing the laundry, transporting children, and taking a walk indicate marked differences among the countries surveyed in terms of frequencies, durations, by whom, and with whom these activities were typically performed. In the future, time use studies can be expected to contribute to the understanding of mental disorders in natural contexts. In contrasting specific diagnostic groups with normal subjects, analyses of specific activities (e.g., personal care, social interaction) or contexts (e.g., alone vs. with others, at home vs. away) may be particularly relevant. Strategies that combine continuous recording (diary) with repeated, instantaneous experience-sampling methods are likely to be the most useful in such studies of mental disorders.     

Phase I study of the anthrapyrazole biantrazole: clinical results and pharmacology

Summary In a phase I study the anthrapyrazole biantrazole (Warner-Lambert Company) was given to 41 patients with tumour refractory to existing therapy. The drug was given i.v. weekly for 3 weeks, with a 3-week interval between courses. At the 1st week a full pharmacokinetic study was performed, and at weeks 2 and 3, blood samples were taken at 1 and 6 h following treatment to check for drug accumulation. Biantrazole pharmacokinetics were linear with respect to the AUC (r=0.924) over the full range of doses studied (4–36 mg/m²) but exhibited large inter-patient variations at each dose level. Elimination was triphasic, comprising two rapid early phases and a long terminal half-life (mean, 14.1±7.8 h). There was no evidence of drug accumulation over the 3-week treatment period. Approximately 12% of the parent drug was excreted unchanged in the urine together with two non-circulating, more water-soluble metabolites. Biantrazole was well tolerated but did cause moderate emesis at doses of >18 mg/m² and mild alopecia. The dose-limiting side effect was leucopenia, with no other major toxicity being observed. One patient developed biventricular failure that was not clearly related to biantrazole administration. On the present schedule, the recommended dose of biantrazole is 24 mg/m². No response were seen in this patient population. Authors: on behalf of the EORTC Early Clinical Trials Group and the CRC Phase I/II Trials Committee     

Mast cells and matrix degradation at sites of tumour invasion in rat mammary adenocarcinoma

Significant numbers of mast cells have been demonstrated histologically around the periphery of the invasive rat mammary adenocarcinoma 13672NF. The number of mast cells at microfoci along the tumour:host tissue junction was significantly greater than that found in normal mammary tissues, and few mast cells were detected within the tumour itself. Mast cell degranulation, often associated with disruption and lysis of the connective tissue matrix, was a common feature in later stages of tumour proliferation. When soluble products derived from purified rat peritoneal mast cells were added to monolayer cultures of rat stromal fibroblasts or tumour cells they stimulated a significant increase in total collagenase production, and the mast cell products were also capable of activating the latent collagenases thus produced. Histological examination indicated that degradation of local collagenous matrix was a common feature of mast cell degranulation, an observation possibly explained by the release of mast cell enzymes and/or the potential of this cell to modulate the expression of collagenolytic activity by surrounding cells. These observations suggest that, at least in some tumours, mast cells contribute to the connective tissue breakdown commonly associated with tumour invasiveness and metastatic spread.     

Postoperative course in the cardiac intensive care unit following the first stage of Norwood reconstruction

The medical records of all patients born between 1 September, 2000, and 31 August, 2002, and undergoing the first stage of Norwood reconstruction, were retrospectively reviewed for details of the perioperative course. We found 99 consecutive patients who met the criterions for inclusion. Hospital mortality for the entire cohort was 15.2%, but was 7.3%, with 4 of 55 dying, in the setting of a "standard" risk profile, as opposed to 25.0% for those with a "high" risk profile, 11 of 44 patients dying in this group. Extracorporeal membrane oxygenation was utilized in 7 patients, with 6 deaths. Median postoperative length of stay in the hospital was 14 days, with a range from 2 to 85 days, and stay in the cardiac intensive care unit was 11 days, with a range from 2 to 85 days. Delayed sternal closure was performed in 18.2%, with a median of 1 day until closure, with a range from zero to 5 days. Excluding isolated delayed sternal closure, and cannulation and decannulation for extracorporeal support, 24 patients underwent 33 cardiothoracic reoperations, including exploration for bleeding in 12, diaphragmatic plication in 4; shunt revision in 4, and other procedures in 13. The median duration of total mechanical ventilation was 4.0 days, with a range from 0.7 to 80.5 days. Excluding those who died, the median total duration of mechanical ventilation was 3.8 days, with a range from 0.9 to 46.3 days. Reintubation for cardiorespiratory failure or upper airway obstruction was performed in 31 patients. Postoperative electroencephalographic and/or clinical seizures occurred in 13 patients, with 7 discharged on anti-convulsant medications. Postoperative renal failure, defined as a level of creatinine greater than 1.5 mg/dl, was present in 13 patients. Eleven had significant thrombocytopenia, with fewer than 20,000 platelets per microl, and injury to the vocal cords was identified in eight patients. Risk factors for longer length of stay included lower Apgar scores, preoperative intubation, early reoperations, reintubation and sepsis, but not weight at birth, genetic syndromes, the specific surgeon, or the duration of surgery.Although mortality rates after the first stage of reconstruction continue to fall, the course in the intensive care unit is remarkable for significant morbidity, especially involving the cardiac, pulmonary and central nervous systems. These patients utilize significant resources during the first hospitalization. Further studies are necessary to stratify the risks faced by patients with hypoplasia of the left heart in whom the first stage of Norwood reconstruction is planned, to determine methods to reduce perioperative morbidity, and to determine the long-term implications of short-term complications, such as diaphragmatic paresis, injury to the vocal cords, prolonged mechanical ventilation, and postoperative seizures.     

Prisms throw light on developmental disorders

Prism adaptation, in which the participant adapts to prismatic glasses that deflect vision laterally, is a specific test of cerebellar function. Fourteen dyslexic children (mean age 13.5 years); 14 children with developmental coordination disorder (DCD): 6 of whom had comorbid dyslexia; and 12 control children matched for age and IQ underwent prism adaptation (assessed by clay throwing accuracy to a 16.7 degrees visual displacement). All 8 DCD children, 5 of the 6 children with comorbid DCD and dyslexia and 10 of the 14 dyslexic children showed an impaired rate of adaptation, thereby providing strong evidence of impaired cerebellar function in DCD and developmental dyslexia. Taken together with other emerging evidence of overlap between developmental disorders, these findings highlight the importance of complementing research on the individual disorders with research on the commonalities between the disorders.