Multiple antigenic peptides facilitate generation of anti-prion antibodies

Recent reports have demonstrated the ability of anti-prion antibodies to inhibit PrPSc propagation. Due to the relatively poor immunogenic properties of both PrPC and PrPSc, the generation of anti-prion antibodies still causes a significant problem in the development of immunotherapeutic strategies. This study examines the potential of multiple antigenic peptides (MAPs) to raise an antibody response to prion derived sequences in mice. The MAP was constructed of a four spiked ring. Two spikes containing human or mouse derived prion amino acid sequences and two spikes containing the universally promiscuous tetanus toxoid sequence (aa 830-844) which was used to assist T-cell-dependent B-cell antibody production. Following vaccinations with the MAP or MAP plus adjuvant, sera were taken and antibody titres assessed. The MAP containing only the mouse sequence failed to elicit a significant antibody response. MAPs containing human prion sequences elicited antibody production to the corresponding prion sequence. Further analysis also demonstrated that these peptides were able to generate antibody responses that recognize conserved human and mouse sequences. These homologous sequences contain the heralded PrPSc specific sequence 'Tyr-Tyr-Arg' and therefore these MAPs may have some therapeutic potential.     

Exploring the utility of whole‐exome sequencing as a diagnostic tool in a child with atypical episodic muscle weakness

The advent of whole‐exome next‐generation sequencing (WES) has been pivotal for the molecular characterization of Mendelian disease; however, the clinical applicability of WES has remained relatively unexplored. We describe our exploration of WES as a diagnostic tool in a 3½‐year old female patient with a 2‐year history of episodic muscle weakness and paroxysmal dystonia who presented following a previous extensive but unrevealing diagnostic work‐up. WES was performed on the proband and her two parents. Parental exome data was used to filter potential de novo genomic events in the proband and suspected variants were confirmed using di‐deoxy sequencing. WES revealed a de novo non‐synonymous mutation in exon 21 of the calcium channel gene CACNA1S that has been previously reported in a single patient as a rare cause of atypical hypokalemic periodic paralysis. This was unexpected, as the proband's original differential diagnosis had included hypokalemic periodic paralysis, but clinical and laboratory features were equivocal, and standard clinical molecular testing for hypokalemic periodic paralysis and related disorders was negative. This report highlights the potential diagnostic utility of WES in clinical practice, with implications for the approach to similar diagnostic dilemmas in the future.     

Serum concentrations of oestradiol-17beta, progesterone, relaxin and chorionic gonadotrophin during blastocyst implantation in natural pregnancy cycle and in embryo transfer cycle in the rhesus monkey

The present study was undertaken to assess the temporal association between the profiles of serum concentrations of oestradiol-17beta, progesterone, chorionic gonadotrophin (CG) and relaxin in pregnancies established naturally, and after embryo transfer, as well as in failed pregnancies in rhesus monkeys. In naturally mated cycles (group 1) a conception rate of 75% was obtained. In group 1, the mean day of CG detection in serum was 11.5 +/- 1.9 day post-ovulation, and for relaxin, 9.0 +/- 2.5 day post-ovulation. In group 2, embryo transfer to synchronous, non-mated surrogate recipients was performed; seven embryo transfer cycles yielded three pregnancies which were allowed to continue to term and normal infants were delivered. In embryo transfer cycles the mean day of CG detection was 14.8 +/- 1.8 day post- ovulation, and for relaxin, 11.4 +/- 2.6 day post-ovulation. A delay of about 3 days was observed in the appearance in circulation of CG (P < 0.05) and also of relaxin (P < 0.05) between natural mated and embryo transfer conception cycles. Significant differences (P < 0.05 for progesterone and P < 0.03 for oestradiol) were obtained for the areas under the curves for progesterone and oestradiol between days 12 and 16 in conception cycles compared with failed pregnancies. These data provide the first observation of the normal hormonal signals associated with maternal recognition of transferred embryos during the peri- implantation period, and suggest that the use of such an experimental primate embryo transfer model may help to elucidate components of maternal and embryonic signal-response mechanisms during embryo implantation.      

Assessment of a daily online implanted fiducial marker‐guided prostate radiotherapy process

The aims of this study were to investigate whether intrafraction prostate motion can affect the accuracy of online prostate positioning using implanted fiducial markers and to determine the effect of prostate rotations on the accuracy of the software‐predicted set‐up correction shifts. Eleven patients were treated with implanted prostate fiducial markers and online set‐up corrections. Orthogonal electronic portal images were acquired to determine couch shifts before treatment. Verification images were also acquired during treatment to assess whether intrafraction motion had occurred. A limitation of the online image registration software is that it does not allow for in‐plane prostate rotations (evident on lateral portal images) when aligning marker positions. The accuracy of couch shifts was assessed by repeating the registration measurements with separate software that incorporates full in‐plane prostate rotations. Additional treatment time required for online positioning was also measured. For the patient group, the overall postalignment systematic prostate errors were less than 1.5 mm (1 standard deviation) in all directions (range 0.2–3.9 mm). The random prostate errors ranged from 0.8 to 3.3 mm (1 standard deviation). One patient exhibited intrafraction prostate motion, resulting in a postalignment prostate set‐up error of more than 10 mm for one fraction. In 14 of 35 fractions, the postalignment prostate set‐up error was greater than 5 mm in the anterior–posterior direction for this patient. Maximum prostate rotations measured from the lateral images varied from 2° to 20° for the patients. The differences between set‐up shifts determined by the online software without in‐plane rotations to align markers, and with rotations applied, was less than 1 mm (root mean square), with a maximum difference of 4.1 mm. Intrafraction prostate motion was found to reduce the effectiveness of the online set‐up for one of the patients. A larger study is required to determine the magnitude of this problem for the patient population. The inability in the current software to incorporate in‐plane prostate rotations is a limitation that should not introduce large errors, provided that the treatment isocentre is positioned near the centre of the prostate.     

Jaundice in neonates with sickle cell disease. A case-control study

This matched, case-control study was conducted on 68 neonates with sickle cell disease (SCD) to test the hypothesis that SCD contributes to neonatal jaundice. Previous uncontrolled studies have suggested that SCD leads to a high rate of neonatal jaundice. After matching, two neonates without SCD born in the same year were selected for each patient with SCD by use of random numbers. Matching factors were gestational age, sex, birth weight, and race. Serum bilirubin concentrations and the presence or absence of clinical jaundice were recorded. Information on factors potentially influencing the rate of neonatal jaundice was obtained for the first three days of life: maternal drug, alcohol, and tobacco usage, intrauterine infection, Apgar scores, highest infant hematocrit, culture-proved sepsis, blood group incompatibilities, hemorrhages, and presence of red blood cell sickling. We found no increase in the rate of clinical jaundice and no increase in the bilirubin concentration in either the entire group of patients with SCD, or in the subgroups with either homozygous or S-hemoglobin C disease, compared with their respective controls. We conclude that SCD probably is not a significant factor predisposing to neonatal jaundice.     

移植肾功能延迟恢复的护理体会

1临床资料我院1997-11/2004-11共行肾移植562(男386,女176)例,期中87例患者出现移植肾功能延迟恢复(DGF),男性58例,女性29例,年龄16～62(平均38.5)岁.术后常规服免疫抑制剂:环孢素,强的松,骁悉.发生DGF最早术后第4日,最晚20 d,均采用综合治疗措施,纠正水、电解质紊乱,控制血压,预防感染等,同时对不同原因引起的DGF采用相应的治疗、护理.85例患者均在术后3wk左右肾功能恢复,2例因并发症死亡.     

Metabolic effects of growth hormone treatment: an early predictor of growth response?

Fourteen children receiving one year of recombinant human growth hormone (rhGH) treatment underwent measurement of serial changes in body composition (measured by skinfold thickness, bioelectrical impedance, and H2(18)O dilution), resting energy expenditure (REE, estimated by ventilated hood indirect calorimetry), and total free living daily energy expenditure (TEE, measured by the doubly labelled water technique). Mean height velocity increased from 4.9 to 8.6 cm/year after six months of treatment. Fat free mass (FFM) increased more during the first six weeks (24.4 g/day) than from six to 26 weeks of treatment (6.8 g/day); fat mass decreased by 7.2 g/day and 1.1 g/day respectively. The six week increase in REE (kJ/day) was maintained after six months of treatment, though expressed per kilogram FFM (kJ/kgFFM/day), returned to pretreatment values by three months. Height velocity increases at six months correlated with six week changes in fat mass measured by skinfold thickness and REE, though use of this relationship to predict growth response in individuals is limited by the wide 95% prediction intervals. No significant changes in growth, body composition, or energy expenditure were observed between six and 12 months of treatment, in either patients who had initially responded well to treatment or those who were poor initial responders to treatment and who had their dose of rhGH doubled after six months.     

Some practical issues in the design, monitoring and analysis of a sequential randomized trial in pressure sore prevention

A sequential double blind (assessor and patient) triangular design was used to compare the incidence of pressure sores following elective major surgery among patients lying on a standard foam mattress with those on a dry visco-elastic polymer pad during their operation. A total of 446 patients were recruited into the trial between 1994 and 1996. Interim analyses were carried out after 181 patients were entered into the trial and then subsequently after approximately every 100 patients recruited. The trial unexpectedly reached a stopping boundary at the first interim analysis, however the Independent Data Monitoring Committee recommended continuation of the trial. They were concerned that there was a need for a larger definitive trial and about an apparent treatment by centre interaction. They required a substudy to be undertaken to further validate the subjective endpoint, and that further sensitivity analyses of the main trail endpoint should be carried out in the second interim analysis. The trial was stopped at the third interim analysis when again a stopping boundary was crossed indicating that the gel pad was associated with significantly fewer pressure sores than the standard mattress (log odds ratio -0.7, (95 per cent confidence interval (CI), -1.28, -0.11), p=0.02) (estimate CI, p-value adjusted for group sequential conduct). The design, monitoring and analysis of this trial will be presented as an example of the practical problems or non-problems encountered for the local hospitals, for the trials unit, for the data monitoring committee and for the funding committee.