Load-induced deformation of the tibia and its effect on implant loosening detection.

CT imaging under external valgus and varus loading conditions and consecutive image analysis can be used to detect tibial implant loosening after total knee arthroplasty. However, the applied load causes the tibia to deform, which could result in an overestimation of implant displacement. This research evaluates the extent of tibia deformation and its effect on measuring implant displacement. Ten cadaver specimen with TKA were CT-scanned under valgus/varus loading (20 Nm), first implanted without bone cement fixation (mimicking a loose implant) and subsequently with bone cement fixation (mimicking a fixed implant). By means of image analysis, three relative displacements were assessed: (1) between the proximal and distal tibia (measure of deformation), (2) between the implant and the whole tibia (including potential deformation effect) and (3) between the implant and the proximal tibia (reduced deformation effect). Relative displacements were quantified in terms of translations along, and rotations about the axes of a local coordinate system. As a measure of deformation, the proximal tibia moved relative to the distal tibia by, on average 1.27 mm (± 0.50 mm) and 0.64° (± 0.25°). Deformation caused an overestimation of implant displacement in the cemented implant. The implant displaced with respect to the whole tibia by 0.45 mm (± 0.22 mm) and 0.79° (± 0.38°). Relative to the proximal tibia, the implant moved by 0.23 mm (± 0.10 mm) and 0.62° (± 0.34°). The differentiation between loose and fixed implants improved when tibia deformation was compensated for by using the proximal tibia rather than the whole tibia.

Does Consulting an Occupational Medicine Specialist Decrease Time to Return to Work Among Total Knee Arthroplasty Patients? A 12-Month Prospective Multicenter Cohort Study.

PURPOSE: The aim of this study is to investigate whether total knee arthroplasty (TKA) patients who consulted an occupational medicine specialist (OMS) within 3 months after surgery, return to work (RTW) earlier than patients who did not consult an OMS. METHODS: A multi-center prospective cohort study was performed among working TKA patients, aged 18 to 65 years and intending to RTW. Time to RTW was analyzed using Kaplan Meier and Mann Whitney U (MWU), and multiple linear regression analysis was used to adjust for effect modification and confounding. RESULTS: One hundred and eighty-two (182) patients were included with a median age of 59 years [IQR 54-62], including 95 women (52%). Patients who consulted an OMS were less often self-employed but did not differ on other patient and work-related characteristics. TKA patients who consulted an OMS returned to work later than those who did not (median 78 versus 62 days, MWU p < 0.01). The effect of consulting an OMS on time to RTW was modified by patients' expectations in linear regression analysis (p = 0.05). A median decrease in time of 24 days was found in TKA patients with preoperative high expectations not consulting an OMS (p = 0.03), not in patients with low expectations. CONCLUSIONS: Consulting an OMS within 3 months after surgery did not result in a decrease in time to RTW in TKA patients. TKA patients with high expectations did RTW earlier without consulting an OMS. Intervention studies on how OMSs can positively influence a timely RTW, incorporating patients' preoperative expectations, are needed.

Deciphering the natural history of SCA7 in children.

BACKGROUND AND PURPOSE: Childhood-onset autosomal dominant cerebellar ataxia type 7 (SCA7) is a severe disease which leads to premature loss of ambulation and death. Early diagnosis of SCA7 is of major importance for genetic counselling and still relies on specific genetic testing, driven by clinical expertise. However, the precise phenotype and natural history of paediatric SCA7 has not yet been fully described. Our aims were to describe the natural history of SCA7 in a large multicentric series of children of all ages, and to find correlates to variables defining this natural history. METHODS: We collected and analysed clinical data from 28 children with proven SCA7. All had clinical manifestations of SCA7 and either a definite number of CAG repeats in ATXN7 or a long expansion > 100 CAG. RESULTS: We identified four clinical presentation patterns related to age at onset. Children of all age groups had cerebellar atrophy and retinal dystrophy. Our data, combined with those in the literature, suggest that definite ranges of CAG repeats determine paediatric SCA7 subtypes. The number of CAG repeats inversely correlated to all variables of the natural history. Age at gait ataxia onset correlated accurately to age at loss of walking ability and to age at death. CONCLUSION: SCA7 in children has four presentation patterns that are roughly correlated to the number of CAG repeats. Our depiction of the natural history of SCA7 in children may help in monitoring the effect of future therapeutic trials.

Predicted osteotomy planes are accurate when using patient-specific instrumentation for total knee arthroplasty in cadavers: a descriptive analysis.

PURPOSE: Malalignment of implants is a major source of failure during total knee arthroplasty. To achieve more accurate 3D planning and execution of the osteotomy cuts during surgery, the Signature (Biomet, Warsaw) patient-specific instrumentation (PSI) was used to produce pin guides for the positioning of the osteotomy blocks by means of computer-aided manufacture based on CT scan images. The research question of this study is: what is the transfer accuracy of osteotomy planes predicted by the Signature PSI system for preoperative 3D planning and intraoperative block-guided pin placement to perform total knee arthroplasty procedures? METHODS: The transfer accuracy achieved by using the Signature PSI system was evaluated by comparing the osteotomy planes predicted preoperatively with the osteotomy planes seen intraoperatively in human cadaveric legs. Outcomes were measured in terms of translational and rotational errors (varus, valgus, flexion, extension and axial rotation) for both tibia and femur osteotomies. RESULTS: Average translational errors between the osteotomy planes predicted using the Signature system and the actual osteotomy planes achieved was 0.8 mm (± 0.5 mm) for the tibia and 0.7 mm (± 4.0 mm) for the femur. Average rotational errors in relation to predicted and achieved osteotomy planes were 0.1° (± 1.2°) of varus and 0.4° (± 1.7°) of anterior slope (extension) for the tibia, and 2.8° (± 2.0°) of varus and 0.9° (± 2.7°) of flexion and 1.4° (± 2.2°) of external rotation for the femur. CONCLUSION: The similarity between osteotomy planes predicted using the Signature system and osteotomy planes actually achieved was excellent for the tibia although some discrepancies were seen for the femur. The use of 3D system techniques in TKA surgery can provide accurate intraoperative guidance, especially for patients with deformed bone, tailored to individual patients and ensure better placement of the implant.

[Psychodynamic consequences of a family history with psychiatric disorders]. / Psychodynamische gevolgen van een psychiatrisch belaste familiegeschiedenis.

BACKGROUND: A positive family history for psychiatric disorders is the most important risk indicator for developing psychopathology. Often, the psychological consequences of a positive family history are insufficiently acknowledged.
AIM: To provide insight into the psychodynamics of children who grow up in a family with psychopathology, such as psychosis, to demonstrate how these effects can last a lifetime, and to suggest ways in which such effects might be prevented.
METHOD: We review the relevant literature, discuss theoretical concepts, and make clinical recommendations.
RESULTS: Parental psychopathology, including psychosis, can have a strong and lasting influence on the child's identity and sense of self.
CONCLUSION: A positive family history for psychiatric disorders has the potential to seriously disrupt the normal development of identity and sense of self. Various types of psychosocial interventions might be able to reduce these harmful effects.

The influence of corticosteroids on hemostasis in healthy subjects.

BACKGROUND: Corticosteroids have been associated with an increased risk of venous thromboembolism in patients treated for inflammatory diseases. It is unclear whether the thrombotic risk is induced by the inflammation of the underlying inflammatory diseases or whether corticosteroids are prothrombotic as well. Considering the widespread use of corticosteroids in clinical practise, it is critical to know whether corticosteroids enhance coagulation. OBJECTIVE: To investigate whether a 10-day prednisolone burst therapy activates hemostasis in healthy individuals. METHODS: Healthy subjects received either 0.5 mg kg(-1) day(-1) of oral prednisolone or placebo. Venous blood was collected at baseline, day 1 and day 10 and tested for thrombin-antithrombin complexes (TATc), D-dimer, plasmin-alpha2-antiplasmin complexes (PAPc), plasminogen-activator inhibitor type-1 (PAI-1), von Willebrand factor (VWF) and thrombin generation (peak thrombin, velocity index and endogenous thrombin potential [ETP]). RESULTS: Fifteen subjects received prednisolone and 16 placebo (median age 29 vs. 22 years, female subjects 33% vs. 56%, respectively). Peak thrombin and velocity index were higher in the placebo group at baseline. After 10 days of treatment, peak thrombin, velocity index, PAI-1 and VWF increased in the oral prednisolone group as compared with the placebo group (15.8 [SD 16.3] vs. -0.1 [SD 16.1], 41.2 [SD 41.3] vs. -2.3 [SD 42.7], 18.0 [IQR 8.0-37.0] vs. 0.5 [IQR -18.5-13.0], 4.0 [IQR -1.0-12.0] vs. 0.0 [IQR -2.5-1.5], respectively). No changes were observed for TATc, ETP, PAPc and D-dimer. CONCLUSIONS: Oral prednisolone induces a procoagulant state in healthy subjects, suggesting that corticosteroid treatment may increase the thromboembolic risk in patients with inflammatory diseases.

Evaluation of a CT-based technique to measure the transfer accuracy of a virtually planned osteotomy.

Accurate transfer of a preoperatively planned osteotomy plane to the bone is of significance for corrective surgery, tumor resection, implant positioning and evaluation of new osteotomy techniques. Methods for comparing a preoperatively planned osteotomy plane with a surgical cut exist but the accuracy of these techniques are either limited or unknown. This paper proposes and evaluates a CT-based technique that enables comparing virtual with actual osteotomy planes. The methodological accuracy and reproducibility of the technique is evaluated using CT-derived volume data of a cadaver limb, which serves to plan TKA osteotomies in 3-D space and to simulate perfect osteotomies not hampered by surgical errors. The methodological variability of the technique is further investigated with repeated CT scans after actual osteotomy surgery of the same cadaver specimen. Plane displacement (derr) and angulation errors in the sagittal and coronal plane (ßerr, γerr) are measured with high accuracy and reproducibility (derr=-0.11±0.06mm; ßerr=0.08±0.04°, γerr=-0.03±0.03°). The proposed method for evaluating an osteotomy plane position and orientation has a high intrinsic accuracy and reproducibility. The method can be of great value for measuring the transfer accuracy of new techniques for positioning and orienting a surgical cut in 3-D space.

Functional characterization of the TSC2 c.3598C>T (p.R1200W) missense mutation that co-segregates with tuberous sclerosis complex in mildly affected kindreds.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by a combination of neurological symptoms and hamartomatous growths, and caused by mutations in the TSC1 and TSC2 genes. Overall, TSC2 mutations are associated with a more severe disease phenotype. We identified the c.3598C>T (R1200W) change in the TSC2 gene in seven different families. The clinical phenotypes in the families were mild, characterized by mild skin lesions, remitting epilepsy and a lack of severe mental retardation or major organ involvement. Functional analysis of the TSC2 R1200W variant, and four other TSC2 missense variants associated with a mild TSC phenotype, confirmed that the changes disrupted the TSC1-TSC2 function. Interestingly however, in each case, the TSC1-TSC2 interaction was not affected by the amino acid substitution.

Outcome of total parathyroidectomy and autotransplantation as treatment of secondary and tertiary hyperparathyroidism in children and adults.

BACKGROUND: Treatment safety and effectiveness of total parathyroidectomy and autotransplantation for secondary and tertiary hyperparathyroidism have been extensively proven in adults; the evidence for children, however, is scarce. Children and adolescents cannot simply be seen as young adults in the case of chronic kidney disease and hyperparathyroidism. The aim of this retrospective study was therefore, to evaluate whether parathyroidectomy with forearm autograft is as effective and safe in children and adolescents as in adults. METHODS: A group of 64 adults and 8 children and adolescents treated for secondary or tertiary hyperparathyroidism were retrieved from our database. The outcomes were compared on patient demographics, operation results, and blood parameters consisting of parathyroid hormone (PTH) and calcium levels. Our results were compared with all currently available articles on parathyroidectomy in children with secondary or tertiary hyperparathyroidism (n = 11). RESULTS: For adults, preoperative mean serum calcium was 2.67 +/- 0.29 mmol/l and mean parathyroid hormone (PTH) level was 120 +/- 86 pmol/l. For children, preoperative mean serum calcium was 2.62 +/- 0.20 mmol/l and mean parathyroid hormone (PTH) level was 80 +/- 38 pmol/l. Postoperative calcium and parathyroid hormone levels for adults dropped to 2.39 +/- 0.23 mmol/l and 30 +/- 53 pmol/l, respectively. Postoperative calcium and parathyroid hormone levels for children dropped to 2.41 +/- 0.16 mmol/l and 26 +/- 33 pmol/l, respectively. The effectiveness of parathyroidectomy with autotransplantation was 75% in children and 72% in adults. Thus, effectiveness did not differ significantly between children and adults. CONCLUSIONS: Combining the results of our own study with a literature review on pediatric parathyroidectomy, we conclude that parathyroidectomy and forearm autograft is as effective a treatment for secondary and tertiary hyperparathyroidism in children and adolescents as it is in adults.

A MELAS-associated ND1 mutation causing leber hereditary optic neuropathy and spastic dystonia.

OBJECTIVE: To report a novel mutation that is associated with Leber hereditary optic neuropathy (LHON) within the same family affected by spastic dystonia. DESIGN: Leber hereditary optic neuropathy is a mitochondrial disorder characterized by isolated central visual loss. Of patients with LHON, 95% carry a mutation in 1 of 3 mitochondrial DNA-encoded complex I genes. The complete mitochondrial DNA was screened for mutations in a patient with LHON without 1 of these 3 primary mutations. The heteroplasmy level and biochemical consequence of the mutation were determined. RESULTS: A pathogenic 3697G>A/ND1 mutation was detected and seemed associated with an isolated complex I deficiency. This family has similar clinical characteristics as the previously described families with LHON and dystonia with an ND6 mutation. CONCLUSIONS: The 3697G>A/ND1 mitochondrial DNA mutation causes the LHON and spastic dystonia phenotype in the same family. This mutation can also cause MELAS syndrome (which encompasses mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke), and other genetic factors may contribute to the clinical expression.

Large deletion at the TSC1 locus in a family with tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by seizures, mental retardation and the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene on chromosome 9q34, or the TSC2 gene on chromosome 16p13.3. Here we describe a deletion encompassing the TSC1 gene and two neighboring transcripts on chromosome 9q34 in six affected individuals from a family with TSC. To our knowledge, this is the first report of such a large deletion at the TSC1 locus and indicates that screening for similar mutations at the TSC1 locus is warranted in individuals with TSC.

The whole truth and nothing but the truth, but what is the truth?

The moral aspects of genetic counselling are explored in situations where the outcome of a DNA test does not lead to certain knowledge. The most frequent type of interaction between counsellor and counsellee is when factual information is given, but sometimes "factual" information is difficult to obtain. How do counsellors deal with "uncertain" knowledge in genetics? Arguments and assumptions are presented and the finding of a 27 CAG repeat in the Huntington gene is used as an example. However, the questions "how far does the duty to inform reach?" and "to what extent is the doctor responsible?" are important in the whole field of genetics, and will be even more important in the future. The aims of science and clinical practice are discussed; we conclude that counsellors run the risk of taking on an infinite responsibility.

Using a roster and haplotyping is useful in risk assessment for persons with intermediate and reduced penetrance alleles in Huntington disease.

The risk of a person having a child with an inherited disorder, caused by an unstable triplet repeat, such as Huntington disease (HD), depends on the expansion of the mutation in that person, which is connected both to the biological nature of the mutation and to the person's relation to the carrier of the full mutation. Once the mutation causing HD was identified, we were able to diagnose sporadic patients. A sporadic patient can sometimes be connected to a known HD pedigree by using a roster. By haplotyping and calculating the posterior identity-by-descent probability, we could establish whether a connection was coincidental or not. Furthermore, we describe the frequency of intermediate and reduced penetrance alleles detected. Using the family history and the roster to search for a connection, we examined whether these alleles were on the HD haplotype of a family. It is important to know the origin of an intermediate or reduced penetrance allele because if it comes from an HD branch of the family or from the non-HD affected side of the pedigree, different risks for relatives and penetrance ensue. In our study, most intermediate alleles came from the non-HD-affected side of the pedigree and had a repeat size in the lower range with a negligible risk for expansion. Intermediate alleles on the HD haplotypes were larger and found in predictive test applicants from known families or relatives from new mutations with a higher risk for expansion. Reduced penetrance alleles in the higher range were mainly found in symptomatic and predictive test applicants from known families, with a considerable risk for penetrance, although at older age. We conclude that a roster, a thorough family history, and haplotyping in persons with intermediate and reduced penetrance alleles are essential in considering the risk of a person having (a child with) HD.

Paradox of a better test for Huntington's disease.

OBJECTIVES: To describe the consequences of the identification of the Huntington's disease (HD) mutation on predictive and prenatal testing. METHODS: A retrospective study was performed considering the test applicants, procedures, and results before and after the identification of the mutation. 1032 people at risk for Huntington's disease in The Netherlands were included, of whom 741 applied for the predictive test in the period 1987 to 1997 in Leiden at the Department of Clinical Genetics, and after 1994, also in the other seven clinical genetics departments in The Netherlands. Uptake, sociodemographic variables, and test results, taken before and after the mutation was identified, are described. RESULTS: The uptake of the predictive test in the period studied was 24% and for the prenatal test 2%. No differences were noted in numbers and sociodemographic data between the period before and after the mutation was identified. After an initial increase in test applicants, a decrease was seen after 1995. After 1993 a significant increase of 25% at risk test applicants and a significant decrease of prenatal exclusion tests was noticed. Only 7% asked for reassessment by mutation analysis. New problems arose after the identification of the mutation, such as the option of reassessing the risk obtained by linkage analysis, direct mutation testing of 25% at risk persons with a parent who does not wish to know, new choices regarding reproduction, and new uncertainties for carriers of intermediate and reduced penetrance alleles and for their offspring and relatives. CONCLUSIONS: Although predictive testing has become reliable and available for every person at risk since the mutation has been identified, the uptake of predictive and prenatal tests fell short of expectation, no change in sociodemographic variables was seen, and a decrease in number of applicants was noted. Furthermore, new uncertainties, psychological problems, and questions arose.

Predictive testing of 25 percent at-risk individuals for Huntington disease (1987-1997).

Before the mutation causing Huntington disease was identified, predictive testing of 25% at-risk persons with a 50% at-risk parent who did not wish to know his/her genetic status, was only possible by exclusion testing. The exclusion test, using linked markers, ensures the parent's wish not to know because the parent's risk is not changed. When mutation analysis became available in 1993, new testing options for 25% at-risk persons emerged: viz., the exclusion-definitive test and direct mutation analysis. These new tests not only disclose the risk of the test candidate, but may also change the risk of the at-risk parent and siblings. The testing options for 25% at-risk test applicants and their consequences are discussed and the testing procedures and results of testing 64 25% at-risk persons in the period 1987 to 1997 are described. Relatives received unsought information in 56% of the test procedures before and 34% after the mutation was identified. A decision tree and guidelines for predictive testing of 25% at-risk test applicants are proposed. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:662-668, 1999.

Experience in prenatal testing for Huntington's disease in The Netherlands: procedures, results and guidelines (1987-1997).

We have performed 31 exclusion tests (43 per cent) and 41 direct tests (57 per cent) in 43 couples at risk, in the period 1987 to 1997 in Leiden, The Netherlands. This resulted in termination of 28 pregnancies (39 per cent), with an increased risk. In 28 couples (65 per cent), the woman was at risk. Prenatal testing in consecutive pregnancies (mean number: 3) was performed in 15 couples (35 per cent), with a mean time interval of 15 months. Parents should make an independent choice for (every) pregnancy, although most (86 per cent) did not change their initial choice. It is important that the position of children in the same family, of whom some know their status as a result of prenatal testing, whereas others remain at risk, is taken into consideration in counselling. The relative number of exclusion tests when compared with direct tests has diminished since the mutation was identified. The prenatal exclusion-definitive test (Fig. 1) was rarely used (2/72, 3 per cent). Nowadays, direct mutation testing of the fetus only is simpler and faster and the risk of disclosure of the genetic status of the at-risk parent is only 25 per cent. This test should therefore be offered as another option and included in the international guidelines. The uptake for prenatal testing is low: for 2 per cent of the at-risk persons, 11 per cent of the tested carriers and a small group of at-risk persons wishing not to be tested themselves, prenatal testing seems an acceptable choice regarding reproduction.

Memory and learning are not impaired in presymptomatic individuals with an increased risk of Huntington's disease.

Retrieval from long-term memory in patients with brain injuries was investigated with a memory scanning paradigm (Conway & Engle, 1994), that allows dissociation of scanning processes within short-term memory and memory retrieval processes from long-term memory. The study focused on the influence of brain injury on memory retrieval processes that are assumed to be automatic. Thirteen patients with memory impairment and 13 healthy matched control subjects were tested. In general, patients showed increased reaction times, but they showed set size independent retrieval from long-term memory indicating preserved automatic retrieval processes. In a subgroup of patients with more severe memory deficits, however, automatic retrieval processes appeared not to be intact. Learning profiles of the patients were characterized by smaller item chunks, indicating differences in the process of information acquisition.

Early cognitive and motor symptoms in identified carriers of the gene for Huntington disease.

OBJECTIVE: To study early motor and cognitive symptoms in Huntington disease. DESIGN: A follow-up cohort study after a DNA test procedure in which gene carriers and noncarriers were identified among people genetically at risk for Huntington disease. SETTING: Leiden University Medical Center, Department of Neurology, Leiden, the Netherlands, in cooperation with the Clinical Genetics Center Leiden and the Department of Medical Psychology and Psychotherapy, Erasmus University Rotterdam, Rotterdam, the Netherlands. PARTICIPANTS: Thirty-three individuals: 9 unaffected gene carriers, 6 gene carriers with motor symptoms, and 18 noncarriers of the gene for Huntington disease. MAIN OUTCOME MEASURES: A neuropsychologic examination covering a broad area of cognitive functioning, reaction time procedures, and motor tasks. RESULTS: The neuropsychologic assessment showed no significant differences between presymptomatic gene carriers and noncarriers. Three motor tasks differentiated between these 2 groups on a liberal .05 P level (analysis of variance followed by the Student test). The affected gene carriers performed less well than the presymptomatic gene carriers and the noncarriers in 10 motor tasks and 7 cognitive tasks. These differences were significant at P < .05. CONCLUSION: Motor symptoms play a more prominent and unequivocal role than cognitive symptoms in early stages of Huntington disease.