Early Results in Total Replacement of the Distal Radioulnar Joint.

BACKGROUND: Pathology of the distal radioulnar joint (DRUJ) including instability and arthritis presents a challenge for hand and upper extremity surgeons. Surgical options include a Darrach procedure and similar resections, soft tissue interposition arthroplasty, and a one-bone forearm. In 2005, a prosthesis for DRUJ arthroplasty was approved for use in the United States. The authors hypothesize that DRUJ arthroplasty will lead to improved pain and range of motion (ROM) with a moderate, but manageable, complication rate. METHODS: A retrospective review of 46 patients who underwent DRUJ arthroplasty by a single private group of hand surgeons was performed. Demographics, complications, postoperative visual analog scale (VAS), and postoperative ROM were obtained and analyzed. RESULTS: The patients were followed up for a mean of 60 weeks. The implant was used both as primary surgical treatment for DRUJ pathology and as salvage for previous failed procedures. Twenty-two percent of patients experienced complications: 15% required revision surgery. No patients were converted to another type of implant, including those who underwent revision surgery. Prominent hardware was the most common indication requiring revision. Patients achieved an improvement in supination of 17° and extension of 5°. They additionally achieved a decrease in average VAS score from 7.1 to 2.3. CONCLUSIONS: Distal radioulnar joint arthroplasty reduces pain and improves ROM in patients with DRUJ pathology with a 22% complication rate. This cohort demonstrates improved pain, modest improvement in ROM, but a 22% complication rate for this implant. Further long-term studies are encouraged.

Return to Sports and Recreational Activities Following Arthroplasty of the Basal Joint of the Thumb: A Retrospective Review.

Purpose: Arthroplasty of the basal, or carpometacarpal, joint of the thumb has been shown to decrease pain, improve strength, improve range of motion, and allow return to work. This study sought to assess whether basal joint arthroplasty also allows for a return to sports and recreational activities. Methods: A survey assessing participation in sports and recreational activities, timing of return to play after surgery, enjoyment, and the presence of pain and limitations was mailed to patients who had undergone an arthroplasty of the basal joint of the thumb over a 3-year period. Results: Of the 333 patients who underwent thumb carpometacarpal arthroplasty, met the criteria, and responded, 73% were able to successfully return to sports and recreational activities, with decreased pain and at the same or increased level of play, frequency of participation, and level of enjoyment for their sport or recreational activity. Patients were more likely to successfully return to sports and recreational activities if they had undergone surgery on their nondominant hand, did not stop their sport or recreational activity before surgery, were able to return within 9 months of surgery, and reported no postoperative limitations. Successful return to sports and recreational activities was not related to age, sex, surgeon, level of play, or the type of sport or recreational activity. Conclusions: Most patients who replied to our survey reported successful return to sports and recreational activities after arthroplasty of the basal joint of the thumb. Type of study/level of evidence: Prognostic IV.

Multiligamentous Knee Injuries: Acute Management, Associated Injuries, and Anticipated Return to Activity.

Multiligamentous knee injuries (MLKIs) are devastating injuries. The energy and severity of these injuries encompass a wide range from low-energy single-joint mechanisms to high-energy polytrauma settings. Currently, there is no consensus on surgical treatment approach, surgical timing, or the return to preinjury activity levels after injury. There does appear to be a difference in the rate of return to activity and level of activity based on whether the injury was sustained during sport, in a trauma setting, or while on active military duty. The purpose of this descriptive review was to summarize current concepts related to (1) the acute management of MLKIs; (2) the effect of concomitant neurovascular, meniscal, and chondral injury on MLKI outcomes; (3) the effect of surgical versus nonsurgical treatment of MLKI on outcomes; and (4) rates and predictors of return to sport, work, and active military service after an MLKI.

Combining aspirin with cholecalciferol (vitamin D3)--a potential new tool for controlling possum populations.

The introduced Australian brushtail possum is a major vertebrate pest in New Zealand, with impacts on conservation and agriculture being managed largely through poisoning operations. Cholecalciferol (vitamin D3) is registered for use in controlling possums and despite its many advantages it is expensive and relatively inhumane. Combination of a high proportion of aspirin with a low proportion of cholecalciferol was effective in killing high proportions of groups of acclimatised, caged possums: this is attributed to both an unexpectedly high toxicity of the type of cholecalciferol used, and a proposed synergistic mechanism between the two compounds. Death was caused by localised damage to heart ventricles by aspirin, and inhibition of tissue repair by both aspirin and cholecalciferol. The observed toxicosis had lower impact on the welfare of possums than either compound administered alone, particularly aspirin alone. Residue analyses of bait remains in the GI tract suggested a low risk of secondary poisoning by either compound. The combination of cholecalciferol and aspirin has the potential to meet key requirements of cost-effectiveness and humaneness in controlling possum populations, but the effect of the combination in non-target species has yet to be tested.

Diagnosis of von Willebrand disease in South Island, New Zealand.

New Zealand is a small country of two islands and 4 million people, of which 1 million reside in the South Island. Canterbury Health Laboratories provides laboratory services to the whole of South Island and lower parts of North Island. There are 155 Von Willebrand disease (VWD) patients in our South Island database, of which 17 have type 2 and 3 have type 3 VWD. A brief overview of diagnostic services for VWD being followed in our region is detailed in this article. We strive continually to advance the repertoire of diagnostic tests. We also present an analysis of our experience with a flow-based functional Von Willebrand factor assay. The VWD patients are managed by hemostasis team members, who also provide screening and educational input to affected families. The Haemophilia Foundation of New Zealand is an active patient support group providing education and support both directed individually and in the group setting, through residential educational camps.

Genotyping the factor VIII intron 22 inversion locus using fluorescent in situ hybridization.

The factor VIII intron 22 inversion is the most common cause of hemophilia A, accounting for approximately 40% of all severe cases of the disease. Southern hybridization and multiplex long distance PCR are the most commonly used techniques to detect the inversion in a diagnostic setting, although both have significant limitations. Here we describe our experience establishing a multicolor fluorescent in situ hybridization (FISH) based assay as an alternative to existing methods for genetic diagnosis of the inversion. Our assay was designed to apply three differentially labelled BAC DNA probes that when hybridized to interphase nuclei would exhibit signal patterns that are consistent with the normal or the inversion locus. When the FISH assay was applied to five normal and five inversion male samples, the correct genotype was assignable with p<0.001 for all samples. When applied to carrier female samples the assay could not assign a genotype to all female samples, probably due to a lower proportion of informative nuclei in female samples caused by the added complexity of a second X chromosome. Despite this complication, these pilot findings show that the assay performs favourably compared to the commonly used methods.

A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia.

We report the first identified mutation in the gene encoding human cytochrome c (CYCS). Glycine 41, invariant throughout eukaryotes, is substituted by serine in a family with autosomal dominant thrombocytopenia caused by dysregulated platelet formation. The mutation yields a cytochrome c variant with enhanced apoptotic activity in vitro. Notably, the family has no other phenotypic indication of abnormal apoptosis, implying that cytochrome c activity is not a critical regulator of most physiological apoptosis.

Written advice can provide a safe and acceptable alternative to new patient assessment for selected referrals to haematologists.

OBJECTIVE: To measure the safety and acceptability of providing written advice (WA) for selected patients referred to a haematology service, as an alternative to inpatient or outpatient assessment. DESIGN, SETTING AND PARTICIPANTS: Review of the initial management and subsequent course of patients newly referred to a tertiary referral hospital in Christchurch, New Zealand, between 16 October 2003 and 8 June 2006. Structured questionnaires were sent to all referring doctors and patients recently managed with WA. MAIN OUTCOME MEASURES: Numbers and diagnoses of patients managed with WA, early assessment or delayed assessment; re-referral and treatment details; characteristics of WA letters; and opinions of referring doctors and their patients on the WA process. RESULTS: 26% of new referrals (714/2785) were managed with prompt WA, while 16% (455/2785) received the alternative of delayed assessment. After a median follow-up of 23 months (range, 8-40 months), 13% of those managed with WA (91/714) were re-referred back to the same haematologists; 7% (52/714) were assessed in hospital and 2% (15/714) eventually required treatment. There were no deaths due to haematological causes. Over 90% of responding referring doctors said the WA process was rapid and effective, and 77% of recently managed patients were pleased to be treated by their own doctors. CONCLUSIONS: Using WA to manage a substantial minority of patients referred to haematologists can be rapid and safe. It is widely accepted by referring doctors.

Detection of factor VIII gene mutations by high-resolution melting analysis.

BACKGROUND: Single base-pair substitution mutations in the gene for coagulation factor VIII, procoagulant component (hemophilia A) (F8) account for approximately 50% of severe cases of hemophilia A (HA), and almost all moderate or mild cases. Because F8 is a large gene, mutation screening using denaturing HPLC or DNA sequencing is time-consuming and expensive. METHODS: We evaluated high-resolution melting analysis as an option for screening for F8 gene mutations. The melting curves of amplicons heterozygous for known F8 gene mutations were compared with melting curves of the corresponding normal amplicons to assess whether melting analysis could detect these variants. We examined 2 platforms, the Roche LightCycler 480 (LC480) and the Idaho Technology LightScanner. RESULTS: On both instruments, 18 (90%) of the 20 F8 gene variants we examined were resolved by melting analysis. For the other 2 mutations, the melting curves of the heterozygous amplicons were similar to the corresponding normal amplicons, suggesting these variants may not be detected by this approach in a mutation-scanning screen. CONCLUSION: High-resolution melting analysis is an appealing technology for F8 gene screening. It is rapid and quickly identifies mutations in the majority of HA patients; samples in which no mutation is detected require further testing by DNA sequencing. The LC480 and LightScanner platforms performed similarly.

Double complex mutations involving F8 and FUNDC2 caused by distinct break-induced replication.

Genomic rearrangements are a well-recognized cause of genetic disease and can be formed by a variety of mechanisms. We report a complex rearrangement causing severe hemophilia A, identified and further characterized using a range of PCR-based methods, and confirmed using array-comparative genomic hybridization (array-CGH). This rearrangement consists of a 15.5-kb deletion/16-bp insertion located 0.6 kb from a 28.1-kb deletion/263-kb insertion at Xq28 and is one of the most complex rearrangements described at a DNA sequence level. We propose that the rearrangement was generated by distinct but linked cellular responses to double strand breakage, namely break-induced replication (BIR) and a novel model of break-induced serial replication slippage (SRS). The copy number of several genes is affected by this rearrangement, with deletion of part of the Factor VIII gene (F8, causing hemophilia A) and the FUNDC2 gene, and duplication of the TMEM185A, HSFX1, MAGEA9, and MAGEA11 genes. As the patient exhibits no clinically detectable phenotype other than hemophilia A, it appears that the biological effects of the other genes involved are not dosage-dependent. This investigation has provided novel insights into processes of DNA repair including BIR and the first description of SRS during repair in a pathological context.

Low molecular weight heparin (tinzaparin) therapy for moderate risk thromboprophylaxis during pregnancy. A pharmacokinetic study.

Low molecular weight heparin (LMWH) is used increasingly for prophylaxis and treatment of venous thromboembolism during pregnancy. However, the prophylactic dose for patients at moderate risk varies between centers, and the recommended LMWH dose for the non pregnant patient is frequently used in pregnant women. The aim of this study was to investigate the effects of pregnancy on the pharmacokinetics of anti-Xa levels during moderate risk thromboprophylaxis with the LMWH, tinzaparin. In 24 pregnant women, one of three doses of tinzaparin (50, 75 or 100 IU/kg) were given according to the treating physician's assessment of their risk profile. Four-hour peak anti-Xa levels were measured throughout pregnancy and 24-hour profiles were measured at 28 and 36 weeks gestation. Doses were adjusted when peak anti-Xa levels fell below 0.1 IU/ml and, in some cases, when levels at 10 and 18 hours post injection were undetectable (<0.05 IU/ml). Our results showed that women receiving tinzaparin (50 IU/kg) frequently had peak (4 hour) anti-Xa levels below 0.1IU/ml and that 46% of these patients required dose adjustment. Similarly anti-Xa levels were also found to be low over the 24-hour period. A starting dose of 75 IU/kg, once daily, gave greater anti-Xa cover over the 24-hour period and may avoid the need for dose adjustment. The results suggest that the pharmacokinetics of tinzaparin are affected by pregnancy. Larger studies are required to determine whether an increased tinzaparin dose (75 IU/kg) would be more effective in the prevention of thrombosis during pregnancy than 50 IU/kg.

Germline mosaicism resulting in the transmission of severe hemophilia B from a grandfather with a mild deficiency.

We report a family in which the normal pattern of X-linked inheritance of hemophilia B (Factor IX deficiency) is complicated by mosaicism in the proband's maternal grandfather. The proband, an infant with severe Factor IX deficiency, was initially thought to be a sporadic case. Testing of other family members identified his mother as a carrier of the disorder, and his asymptomatic maternal grandfather as having very mild FIX deficiency. The causative familial mutation was identified as a two base pair deletion (AG within codons 134-135) in the Factor IX gene. The grandfather was shown to be "heterozygous" for the deletion. Karyotype analysis confirmed him to be 46XY thereby ruling out Klinefelter syndrome. The proband's aunt, who as the daughter of a man with hemophilia is theoretically an obligate carrier, was found not to carry this familial mutation, and thus not to be a carrier of hemophilia B. The grandfather must therefore be an X chromosome somatic and germline mosaic, with consequent segregation of the affected and non-affected Factor IX genes. This observation underlines the importance of confirming carrier status even in those individuals assumed to be obligate carriers, and has implications for genetic counseling.

Tinzaparin sodium for thrombosis treatment and prevention during pregnancy.

OBJECTIVE: This study was undertaken to assess the pharmacodynamic profile, safety, and efficacy of tinzaparin during pregnancy. STUDY DESIGN: Fifty-four pregnant women, 12 for treatment of thrombosis and 42 for thromboprophylaxis, received tinzaparin by once daily injection. Four-hour postdose anti-Xa results were analyzed by use of repeated measures statistical methods. RESULTS: One woman (3.4%) on the 175 anti-Xa U/kg dose and three women (20%) on the 50 anti-Xa U/kg dose required a dose increase during the initial dose titration phase to achieve target anti-Xa activity. No thrombotic events occurred. CONCLUSION: The 175 anti-Xa U/kg dose is appropriate for treatment and for high-risk thromboprophylaxis throughout pregnancy. In pregnant women at moderate risk of thrombosis, a higher tinzaparin dose is required than in the nonpregnant state and 75 anti-Xa U/kg appears to be appropriate. The majority of women do not need a dose increase with advancing gestation.

The Ecarin time is an improved confirmatory test for the Taipan snake venom time in warfarinized patients with lupus anticoagulants.

The Taipan snake venom time using dilute phospholipid as a screening test with a platelet neutralization procedure as a confirmatory test has been shown to be a sensitive and specific approach to detection of lupus anticoagulants. Taipan venom is largely insensitive to the effects of ongoing warfarin anticoagulation and this can be useful in detection of lupus anticoagulants in patients receiving this treatment. This study compared the use of the platelet neutralization procedure with the Ecarin time as confirmatory tests for the Taipan snake venom time, the Ecarin venom fraction being insensitive to both lupus anticoagulants and the effects of oral anticoagulants. Screening and confirmatory test data were assessed for phospholipid dependence by three different mathematical methods and there was no advantage in using the Ecarin time in detection of 'uncomplicated' lupus anticoagulants. In lupus anticoagulant-positive warfarinized patients, the Ecarin time achieved higher detection rates than the platelet neutralization procedure irrespective of the method used to assess correction. The Ecarin time confirmed lupus anticoagulants in all of those samples that generated elevated Taipan snake venom time ratios whereas the platelet neutralization procedure identified only 33%. Taipan snake venom time plus Ecarin time offers good diagnostic precision for lupus anticoagulant detection in a group of patients where lupus anticoagulant identification is difficult due to ongoing anticoagulation.

A prospective study of recombinant activated factor VII administered by continuous infusion to inhibitor patients undergoing elective major orthopaedic surgery: a pharmacokinetic and efficacy evaluation.

After surgery in haemophilia, haemostasis is difficult to maintain in the presence of an antifactor VIII antibody. This study assessed the pharmacokinetics of recombinant activated factor VII (rFVIIa) and its efficacy in securing post-operative haemostasis in haemophiliacs with inhibitors. Continuous infusion of rFVIIa was evaluated for elective major orthopaedic surgery in nine patients with neutralizing antibodies to FVIII and at high risk of bleeding. After an initial preoperative bolus of 90 micro g/kg, rFVIIa was infused at a fixed rate of 50 micro g/kg/h for a median of 20 d (range 7-20 d). The median plasma FVII coagulant activity (FVII:C) at 24 h, 72 h and 20 d after surgery was 38 IU/ml (range 22-169 IU/ml), 45 IU/ml (range 17-88 IU/ml) and 31 IU/ml (range 27-46 IU/ml) respectively. The median plasma FVIIa:C at the same time points was 51 (range 24-211), 63 (range 22-99) and 44 (range 28-76) IU/ml respectively. Median total rFVIIa clearance remained stable during the rFVIIa continuous infusion period and was 40 (range 9-70), 34 (range 17-86) and 48 (range 32-55)ml/kg/h at the end of 24 h, 72 h and 20 d infusion respectively. Post-operatively, there were bleeds in six patients, which settled readily after a single bolus of rFVIIa (60 micro g/kg). There was a good clinical outcome for all patients. These data indicate that rFVIIa infusion at 50 micro g/kg/h achieves continuous plasma FVII procoagulant activity in excess of 30 IU/ml (12-15 nmol/l) and provides adequate haemostatic control for inhibitor patients during major orthopaedic surgery.

Evidence for a role for Galphai1 in mediating weak agonist-induced platelet aggregation in human platelets: reduced Galphai1 expression and defective Gi signaling in the platelets of a patient with a chronic bleeding disorder.

We have examined platelet functional responses and characterized a novel signaling defect in the platelets of a patient suffering from a chronic bleeding disorder. Platelet aggregation responses stimulated by weak agonists such as adenosine diphosphate (ADP) and adrenaline were severely impaired. In comparison, both aggregation and dense granule secretion were normal following activation with high doses of collagen, thrombin, or phorbol-12 myristate-13 acetate (PMA). ADP, thrombin, or thromboxane A2 (TxA2) signaling through their respective Gq-coupled receptors was normal as assessed by measuring either mobilization of intracellular calcium, diacylglycerol (DAG) generation, or pleckstrin phosphorylation. In comparison, Gi-mediated signaling induced by either thrombin, ADP, or adrenaline, examined by suppression of forskolin-stimulated rise in cyclic AMP (cAMP) was impaired, indicating dysfunctional Galphai signaling. Immunoblot analysis of platelet membranes with specific antiserum against different Galpha subunits indicated normal levels of Galphai2,Galphai3,Galphaz, and Galphaq in patient platelets. However, the Galphai1level was reduced to 25% of that found in normal platelets. Analysis of platelet cDNA and gDNA revealed no abnormality in either the Galphai1 or Galphai2 gene sequences. Our studies implicate the minor expressed Galphai subtype Galphai1 as having an important role in regulating signaling pathways associated with the activation of alphaIIbbeta3 and subsequent platelet aggregation by weak agonists.