[Current design and cement mantle thickness in hip arthroplasty : Theory and analysis of register data]. / Aktuelles Design und Zementmanteldicke in der Hüftendoprothetik : Theorie und Analyse der Registerdaten.

BACKGROUND: In this article, an overview and comparison of the most commonly used cemented hip stems, grouped into different stem types and cement mantle thickness, is given to see which combination performs well. METHODOLOGY: Revision rates of cemented stem types were categorized from the Endoprosthesis Register-Germany, and 3­ and 5­year revision rates were reported and analyzed. For the research, the focus was on the Exeter, C­Stem, MS-30, Excia, Bicontact, Charnley, Müller straight stem, Twinsys, Corail, Avenir, Quadra, and the Lubinus SP II stems. An important aspect was which stem is preferred to be implanted and which cementing technique is used with regard to the planned cement mantle thickness. In order to identify a trend in cemented hip arthroplasty, data from the Danish, Swedish, Norwegian, Swiss, New Zealand, English and Australian arthroplasty registers were also compared. RESULTS AND CONCLUSION: Most countries use cemented prostheses according to the taper slip principle (Exeter, MS30, C­Stem etc) or the composite beam (Charnley, Excia, Bicontact), which are implanted with a cement mantle thickness of 2-4 mm. However, a trend has emerged in Germany and Switzerland towards the line-to-line technique, with a planned cement mantle thickness of 1 mm (Twinsys, Corail, Avenir, Quadra), following the principle of the Müller straight stem prosthesis and the Kerboul-Charnley prosthesis, even though these are postulated to be "French paradoxes" in themselves. In the EPRD 5­year results, the newer line-to-line prostheses seem to perform slightly worse. The best results are achieved by the "MS 30" in Germany and the "Exeter" in England. These are polished straight stems with centralizer and subsidence space at the apex with a 2-4 mm cement mantle in good cementing technique.

Socket versus bone-anchored trans-femoral prostheses: hip range of motion and sitting comfort.

This is the first study to report on hip range of motion (ROM) among active prosthesis users, when wearing and not wearing a trans-femoral socket prosthesis and to compare with individuals rehabilitated with an osseointegrated bone-anchored prosthesis. In addition, discomfort when sitting with the prosthesis is reported in both groups. The study group all had a non-vascular amputation and were divided into those supplied with a socket prosthesis (S group) (n = 43, mean age 51 years, 74% men) or a bone-anchored prosthesis (OI group) (n = 20, mean age 46 years, 75% men). Active hip ROM was measured with a goniometer, and self-reported problems with discomfort when sitting were recorded. The hip motion decreased in all directions when wearing the socket prosthesis compared to without it (P < 0.001 for all directions), and 37% of the subjects had less than 90 degrees of hip flexion when wearing their prosthesis. Discomfort when sitting was reported among 44% (n = 19) in the S group and was more common among individuals with less than 90 degrees of hip flexion motion (P= 0.025). In the OI group, no restriction in hip motion was measured with the prosthesis, and no subject had less than 90 degrees of flexion and 5% (n = 1) reported discomfort when sitting. This study shows that a trans-femoral prosthetic socket significantly reduces the ROM of the hip and that discomfort when sitting is common among individuals wearing such prostheses. Further, the study confirms that individuals using a bone-anchored prosthesis have no restricted hip motion with the prosthesis and report very few problems with discomfort when sitting.

Rehabilitation of the trans-femoral amputee with an osseointegrated prosthesis: the United Kingdom experience.

Osseointegration for the trans-femoral amputee has been used in the United Kingdom since 1997. To date, 11 candidates have undergone the procedure. The rehabilitation programme for the osseointegration candidate is a long and intensive programme following two surgical operations. This paper outlines the importance of a pre-osseointegration assessment to explore candidates' suitability and expectations for the procedure. The physical and prosthetic advantages of direct skeletal attachment have led to improvements in candidates' comfort, function and quality of life. However, some aspects of this promising developmental procedure for the management of the trans-femoral amputee need to be critically evaluated before it becomes a routine clinical procedure in the United Kingdom.

Direct retroviral delivery of human cytochrome P450 2B6 for gene-directed enzyme prodrug therapy of cancer.

Human cytochrome P450 2B6 (CYP2B6) metabolizes the prodrug cyclophosphamide (CPA) to produce phosphoramide mustard that cross-links DNA leading to cell death. We have constructed a novel retroviral vector encoding CYP2B6 (designated "MetXia-P450") and used it to transduce the human tumor cell lines HT29 and T47D. MetXia-P450 transduction sensitised these cells to the cytotoxic effects of the prodrug CPA. Results from in vitro experiments demonstrated adverse effects on the clonogenic survival of cyclophosphamide-treated cells transduced with MetXia-P450. Cytotoxic activity accompanied by bystander effect was particularly evident in 3-D multicellular spheroid models suggesting that this in vitro system may be a more appropriate model for assessing the efficacy of gene directed-enzyme prodrug therapy (GDEPT). We have applied this approach in a clinically relevant gene therapy protocol on established subcutaneous tumor xenografts. These studies show for the first time the efficacy of a P450-based GDEPT strategy mediated by a direct retroviral gene transfer in vivo.

Use of intron-disrupted polyadenylation sites to enhance expression and safety of retroviral vectors.

Normal mRNA polyadenylation signals are composed of an AAUAAA motif and G/U box spaced 20 to 30 bp apart. If this spacing is increased further, then polyadenylation is disrupted. Previously it has been demonstrated that insertion of an intron will similarly disrupt this signal even though such introns are removed during a nuclear splicing reaction (X. Liu and J. Mertz, Nucleic Acids Res. 21:5256-5263, 1993). This observation has led to the suggestion that polyadenylation site selection is undertaken prior to intron excision. We now present results that both support and extend these observations and in doing so create a novel class of retroviral expression vector with improved qualities. We found that when an intron-disrupted polyadenylation signal is inserted within a retroviral expression vector, such a signal, although reformed in the producer cell, remains benign until transduction, where it is then preferentially used. Thus, we demonstrate that upon transduction these vectors now produce a majority of shortened subgenomic species and as a consequence have a reduced tendency for subsequent mobilization from transduced cells. In addition, we demonstrate that the use of this internal signal leads to enhanced expression from such vectors and that this is achieved without any loss in titer. Therefore, split polyadenylation signals confer enhanced performance and improved safety upon retroviral expression vectors into which they are inserted. Such split signals may prove useful for the future optimization of retroviral vectors in gene therapy.

Split-intron retroviral vectors: enhanced expression with improved safety.

The inclusion of retrovirus-derived introns within retrovirus-based expression vectors leads to a fraction of the resulting transcripts being spliced. Such splicing has been shown to markedly improve expression (W. J. Krall et al., Gene Ther. 3:37-48, 1996). One way to improve upon this still further might involve the use of more efficient introns instead of those from the provirus. Currently, however, incorporation of such introns remains self-defeating since they are removed in the nucleus of the producer cell. In the past, elaborate ways to overcome this problem have included the use of alphaviruses to make the vector transcripts within the cytoplasm, thus avoiding the nuclear splicing machinery during vector production (K. J. Li and H. Garoff, Proc. Natl. Acad. Sci. USA 95:3650-3654, 1998). We now present a novel design for the inclusion of introns within a retroviral vector. In essence, this is achieved by exploiting the retroviral replication process to copy not only the U3 promoter but also a synthetic splice donor to the 5'-long-terminal-repeat position during reverse transcription. Once copied, synthesized transcripts then contain a splice donor at their 5' end capable of interacting with a consensus splice acceptor engineered downstream of the packaging signal. Upon transduction, we demonstrate these vectors to produce enhanced expression from near fully spliced (and thus packaging signal minus) transcripts. The unique design of these high titer and high-expression retroviral vectors may be of use in a number of gene therapy applications.

Reduced heart rate variability in ischemic heart disease is only partially caused by ischemia. An HRV study before and after PTCA.

BACKGROUND: Reduced heart rate variability (HRV) after acute myocardial infarction (AMI) indicates poor prognosis. HRV in patients with uncomplicated coronary artery disease is reduced, and an association with poor prognosis has been suggested. The mechanism of the HRV reduction is not known, but ischemia is a possibility. AIM: To evaluate, in angina patients with no prior AMI, no other disease and drug-free, if complete revascularization and thus important reduction of ischemia by means of PTCA influences HRV. PATIENTS AND METHODS: Twenty-four-hour Holter recordings were performed at baseline prior to PTCA in 48 patients with angina and in 41 age-matched healthy control subjects. The recording was repeated 1 and 6 months after complete revascularization. In addition, HRV was registered during controlled respiration in the supine and standing positions and during cold pressure test at baseline in all angina patients and controls and in 17 consecutive angina patients 6 months after PTCA. RESULTS: Compared to controls, angina patients had a significantly reduced mean RR interval (p = 0.02), SD (p = 0.003), rMSSD (p = 0.03), pNN50 (p = 0.03), total power (p = 0.003), low- (p = 0.004) and high-frequency peak (p = 0.04), but normal SDNN, SDANN and LF/HF. One and 6 months after PTCA, 42/46 and 32/40 follow-up patients, respectively, were free of angina. Six months after PTCA, there was a significant recovery of vagal modulation seen in the frequency domain during controlled respiration, but only nonsignificant trends in HRV parameters analyzed over 24 h. CONCLUSION: Patients with uncomplicated angina had reduced HRV, mainly affecting vagal activity, but normal low frequency variability associated with mortality. Complete revascularization caused a partial normalization of vagal modulation indicating that ischemia may be one of but not the only mechanism of the HRV reduction in uncomplicated chronic coronary artery disease.

Evidence that downregulation of the M-CSF receptor is not dependent upon receptor kinase activity.

The downregulation of tyrosine kinase receptors attenuates signalling and is thought to be dependent upon intrinsic receptor kinase activity, largely because down-regulation is inhibited by a kinase-inactivating mutation of an invariant lysine residue of the receptors for EGF, insulin, M-CSF and PDGF. We confirmed that this mutation inhibited the degradation of the M-CSF receptor. However, two different kinase inactivating mutations of the invariant amino acids Gly 591 and Glu 633 did not prevent M-CSF-induced receptor degradation, so demonstrating that receptor kinase activity is not essential for this process. Three other kinase-inactivating mutations were found to cause constitutive receptor degradation in the absence of M-CSF, most probably by disrupting the structure of the activating loop of the kinase domain. It is known that extensive movement of the A-loop is necessary for kinase activation and is normally induced by ligand-binding. It is therefore suggested that some aspect or consequence of the change in structure of the A-loop caused by ligand binding also activates receptor downregulation, so ensuring that downregulation is coupled to but is not necessarily dependent upon receptor kinase activity.

Cell specific transformation by c-fms activating loop mutations is attributable to constitutive receptor degradation.

Expression of a receptor for human macrophage-colony stimulating factor (M-CSF or CSF-1), containing a point mutation which changes an aspartate to a valine at position 802 of the activating loop of the kinase domain, potently transforms the haemopoietic cell line FDC-P1 yet prevents Rat-2 fibroblast transformation. In order to understand this apparent paradox, aspartate 802 was changed by cassette mutagenesis to each of the other 19 amino acids. All hydrophobic amino acid substitutions were transforming when tested in FDC-P1 cells yet inactivating when tested in Rat-2 fibroblasts. These same amino acid substitutions also activated receptor degradation, strongly suggesting a causal relationship between receptor degradation and inactivation in fibroblasts. Point mutations or small deletions of Y708 within the kinase insert region of the mutant D802V receptor partly inhibited receptor degradation. The more stable D802V receptor derivatives were able to transform both FDC-P1 cells and Rat-2 fibroblasts, so establishing that the cell specific effect of the c-fmsD802V activating loop mutation is attributable to receptor degradation which accompanies kinase activation and prevents the transformation of Rat-2 but not of FDC-P1 cells.

Reliability and validity of the Perinatal Grief Scale for women who experienced late pregnancy loss.

The psychometric qualities of the Perinatal Grief Scale (PGS) were evaluated in a sample of 46 Dutch women in late pregnancy (> or = 24 weeks), who had been informed of the diagnosis 'lethal or severe fetal malformation'. The validity was assessed by comparing it to the Impact of Event Scale and to a clinical diagnosis of psychological instability. The PGS appeared to be internally consistent and particularly strongly related to psychological instability. It can therefore be considered as a valid assessment instrument, also for women who experience late pregnancy loss.

Emotional reactions in women in late pregnancy (24 weeks or longer) following the ultrasound diagnosis of a severe or lethal fetal malformation.

We studied the emotional reactions of 41 women in late pregnancy shortly after they had been informed of the diagnosis of 'severe or lethal fetal malformations' and 3 months after delivery. In addition, situational variables were explored as determinants of grieving. While grief did not diminish during the study period, psychological instability was less pronounced at 3 months after delivery. More grief reactions were evoked by self-reported easily versus self-reported not easily initiated pregnancy, gestational age between 24 and 34 weeks versus beyond 34 weeks, multiparity versus primiparity, and viewing versus not viewing the baby.

[Parents' reactions to the birth of a child with a congenital anatomical abnormality: an exploratory study]. / De reacties van ouders op de geboorte van een kind met een aangeboren anatomische afwijking: een oriënterend onderzoek.

In an exploratory study of 12 couples the emotional reactions to the birth of a child with extensive anatomical malformation were investigated retrospectively, using semistructured interviews (on average 18 months after the birth). The couples were selected from the group of parents of children admitted between January 1986 and August 1988 to the Paediatric Intensive Care Unit of the Sophia Hospital, Rotterdam. The couples were divided into three groups: those who had had no ultrasonography during the pregnancy (n = 4), those in whom ultrasonography during pregnancy had revealed a foetal abnormality (n = 4) and those in whose children no such diagnoses had been made at ultrasonography during pregnancy (n = 4). After the birth of a child with congenital abnormalities, most parental couples displayed a shock reaction, denial, anger and hurt. In general there was no difference in emotional reaction between the three groups. In all couples the mourning process appeared to have begun only after the birth. Parents of a child with clearly visible abnormalities appeared to have more problems. Two-thirds of the couples had accepted the child's anomaly after some time. Persistent anger, feelings of guilt and anxiety are probably due to uncertainty regarding complications in the child or another pregnancy. Teams treating a child with a congenital anomaly should be aware of the consequences for the parents and should regard support of the parents as an essential part of their task.

Work resumption and leisure activities after cardiac rehabilitation: the development of criteria to measure social recovery.

In a multicentered trial, the authors investigated 280 cardiac patients to determine the level of recovery of their social life after they had completed a physical training program. Data on work and leisure activities (sports, hobbies, social contacts, and odd jobs) were obtained immediately before and after rehabilitation and again 12 months later by means of semistructured interviews and an inventory of leisure activities. For the analysis of leisure variables, they developed a classification procedure to assign patients to one of five categories indicating an unchanged good outcome, significant recovery, nonparticipation, significant deterioration, or an unchanged poor outcome. The results after rehabilitation showed that some patients had benefited more than others. In addition, improvement or deterioration in one aspect of social recovery appeared to be independent from other aspects. Further systematic research is needed to determine which factors influence the amount of benefit derived from rehabilitation.

Medical, social and psychological recovery after cardiac rehabilitation.

A multidisciplinary study was undertaken to determine the number of patients that recovered, deteriorated or remained unchanged during a cardiac rehabilitation programme, as assessed in medical, social and psychological terms. In addition, the relationship between the medical, social and psychological aspects of recovery were investigated. Criteria for improvement, deterioration and an unchanged condition had been developed for the different aspects of recovery. These criteria were based on the degree of change during the rehabilitation programme (expressed in an effect size index) and the outcome at completion of the programme (expressed in terms of good, moderate or poor according to external standards). Although more patients improved than deteriorated, quite a few patients remained unchanged in medical, social or psychological condition. We conclude that cardiac rehabilitation might not be necessary for some patients and is not sufficient for others. Further, the relationship between the several aspects of recovery investigated was found to be weak.