Unique overlap in the prerequisites for thrombin inhibition and oral bioavailability resulting in potent oral antithrombotics

Despite intense research over the last 10 years, aided by the availability of X-ray structures of enzyme-inhibitor complexes, only very few truly orally active thrombin inhibitors have been found. We conducted a comprehensive study starting with peptide transition state analogues (TSA). Both hydrophobic nonpeptide analogues as well as hydrophilic peptidic analogues were synthesized. The bioavailability in rats and dogs could be drastically altered depending on the overall charge distribution in the molecule. Compound 27, a tripeptide TSA inhibitor of thrombin, showed an oral bioavailability of 32% in rats and 71% in dogs, elimination half-lives being 58 and 108 min, respectively. The thrombin inhibition constant of compound 27 was 1.1 nM, and in an in vivo arterial flow model, the ED(50) was 5.4 nmol/kg.min, comparable to known non-TSA inhibitors. A molecular design was found that combines antithrombotic efficiency with oral bioavailability at low dosages.     

Dutch–Flemish translation of nine pediatric item banks from the Patient-Reported Outcomes Measurement Information System (PROMIS)®

Quality of Life Research - The Patient-Reported Outcomes Measurement Information System (PROMIS®) is a new, state-of-the-art assessment system for measuring patient-reported health and...     

Health-related quality of life, cognitive functioning and behaviour problems in children with Langerhans cell histiocytosis

Gastrointestinal malignancies are extremely rare in the pediatric population, and duodenal cancers represent an even more unusual entity. Intestinal cancers in young adults and children have been observed to be associated with functional deficiencies of the mismatch repair (MMR) system causing a cancer‐predisposition syndrome. We report the case of a 16‐year‐old female with duodenal adenocarcinoma and past history of medulloblastoma found to have a novel germline bialleleic truncating mutation (c.[949C>T]+[949C>T]) of the PMS2 gene. Pediatr Blood Cancer 2009;53:116–120. © 2009 Wiley‐Liss, Inc.     

The incidence of theilerial parasites in East African buffalo (Syncerus caffer).

245 buffalo from 13 areas of East Africa were examined for theilerial infections. The vast majority of buffalo (97.1%) examined had piroplasms in their erythrocytes. Theileria lawrencei was isolated from the buffalo by tick feeding and cell culture and was found to be common in most of these buffalo populations. Also over 50% of the buffalo had indirect fluorescent antibody (IFA) titres to T. lawrencei. T. mutans was only isolated from 3 buffalo populations but is probably common. Haematoxenus sp. was detected in the blood of 56% of the buffalo sampled. In the light of these results the role of buffalo as a reservoir of cattle pathogenic theilerioses in East Africa is discussed.     

Production and evaluation of specific antisera against sera of various vertebrate species for identification of bloodmeals of Glossina morsitans centralis

Specific antisera against sera of 46 species of vertebrates were prepared. The antisera to 21 Bovidae species were raised in goats except the antiserum to goat serum which was raised in sheep. The antisera to 3 Suidae species were produced either in domestic pigs or warthogs, while antisera to most of the other vertebrate species were raised in rabbits. The antisera were used in an enzyme-linked immunosorbent assay (ELISA) to identify the source of bloodmeals ingested by teneral and non-teneral tsetse at different time intervals after feeding. The bloodmeal donors were identifiable in 100% of the teneral tsetse up to 40 h post-feeding and in 87.5% in those tested up to 74 h post-feeding. Non-teneral tsetse digested the species-distinguishing bloodmeal components faster than the tenerals. Bloodmeals could be identified in 100% non-tenerals at 20 h post-feeding but only 67.5% and 50% of the bloodmeals could be identified 40 h and 74 h post-feeding, respectively. The antisera were also able to identify mixed bloodmeals from closely related species.     

Development of a Type 2 Diabetes Symptom Checklist: a Measure of Symptom Severity

The aim of the present study was to develop a Type 2 diabetes symptom checklist for use in clinical and epidemiological research, which can measure differences in symptom severity between patients and detect changes over time within patients. Face and content validity of items and dimension structure were based on literature and experiences of diabetologists. Two Likert scales were used to measure symptom frequency and perceived burden. Reliability, responsiveness and validity were studied in 185 Type 2 diabetic patients. Factor-analysis confirmed the predesigned dimension structure with 34 items, distributed over 6 dimensions. The internal consistency with Cronbach α coefficients between 0.76 and 0.95 and test-retest reliability with Pearson product-moment correlation coefficients between 0.79 and 0.94 were satisfactory. The ability to detect change over time (responsiveness) was estimated in stable subjects, using sample size calculations. A minimal detectable mean change of 0.07-0.58 points in total score on the 10-point scale within a group of 100 subjects suggests an impressive responsiveness. Significant differences in symptom severity score were found between patients with different co-morbidity status and treatment modes, indicating satisfactory construct validity of the dimension structure. The Type 2 Diabetes Symptom Checklist was found to be a useful diabetes-specific symptom severity assessment method for clinical and epidemiological studies.     

Quality of life in young adult survivors of childhood cancer

In recent years the necessity of measuring quality of life in childhood cancer survivors has been stressed. This paper gives an overview of the results of studies into the quality of life (QL) of young adult survivors of childhood cancer and suggest areas for future research. The review located 30 empirical studies published up to 2001. The results are described in terms of the following QL dimensions: physical functioning (QL, general health), psychological functioning (overall emotional functioning, depression and anxiety, self-esteem), social functioning (education, employment, insurance, living situation, marital status and family), and sexual functioning. Factors related to survivors' QL are reported: demographics and illness- and treatment related variables. Although the literature yields some inconsistent findings, a number of clear trends can be identified: (a) most survivors reported being in good health, with the exception of some bone tumour survivors; (b) most survivors function well psychologically; (c) survivors of CNS tumours and survivors of acute lymphoblastic leukaemia (ALL) are at risk for educational deficits; (d) job discrimination, difficulties in obtaining work and problems in obtaining health and life insurance were reported; (e) survivors have lower rates of marriage and parenthood; (f) survivors worry about their reproductive capacity and/or about future health problems their children might experience as a result of their cancer history. There is a need for methodological studies that measure QL among survivors of childhood cancer more precisely by taking into account the effects of the severity of the cancer and the long-term impact of different treatments. Additional data are needed to help us understand the needs of survivors and to identify those subgroups of survivors who are at greatest risk for the adverse sequelae of the disease and its treatment.     

Impaired cognition and schooling in adults with end stage renal disease since childhood.

AIMS: To determine cognitive and educational attainment in adults with end stage renal disease (ESRD) since childhood. METHODS: All Dutch patients with onset of ESRD at age 0-14 years between 1972 and 1992, who were born before 1979, were asked to perform the Wechsler Adult Intelligence Scale (WAIS) test. Educational attainment was assessed by a questionnaire. Determinants of cognitive performance were measured by reviewing medical charts in 37 hospitals. Data on cognition were compared to those of age matched controls who cooperated in the revision of the Dutch WAIS. National Dutch Statistics data were used to compare educational attainment. RESULTS: Data on intelligence and schooling were acquired in 126 of 187 patients (67%) and data on determinants of outcome in all patients. Clinical characteristics of participants and non-participants were comparable. Educational attainment of patients was low compared to the Dutch standard. Patient mean full scale IQ, performal IQ, and verbal IQ were 10.4, 9.2, and 9.7 points lower, respectively, compared to those of 36 controls. The lowest scores were observed in tasks which require concentration, memory, and general knowledge. Patients currently on dialysis and transplanted patients had similar IQ scores. Cumulative dialysis duration of more than four years was associated with a 3.4 times higher chance of having a full scale IQ of 1 SD below the mean. CONCLUSION: ESRD of childhood is associated with an impaired cognitive and educational attainment in adulthood. Long duration of dialysis may enhance intellectual impairment, which may not be reversible after renal transplantation.