A randomized controlled trial investigating the value of patient-specific instrumentation for total knee arthroplasty in the Canadian healthcare system.

AIMS: The purpose of the present study was to compare patient-specific instrumentation (PSI) and conventional surgical instrumentation (CSI) for total knee arthroplasty (TKA) in terms of early implant migration, alignment, surgical resources, patient outcomes, and costs. PATIENTS AND METHODS: The study was a prospective, randomized controlled trial of 50 patients undergoing TKA. There were 25 patients in each of the PSI and CSI groups. There were 12 male patients in the PSI group and seven male patients in the CSI group. The patients had a mean age of 69.0 years (sd 8.4) in the PSI group and 69.4 years (sd 8.4) in the CSI group. All patients received the same TKA implant. Intraoperative surgical resources and any surgical waste generated were recorded. Patients underwent radiostereometric analysis (RSA) studies to measure femoral and tibial component migration over two years. Outcome measures were recorded pre- and postoperatively. Overall costs were calculated for each group. RESULTS: There were no differences (p > 0.05) in any measurement of migration at two years for either the tibial or femoral components. Movement between one and two years was < 0.2 mm, indicating stable fixation. There were no differences in coronal or sagittal alignment between the two groups. The PSI group took a mean 6.1 minutes longer (p = 0.04) and used a mean 3.4 less trays (p < 0.0001). Total waste generated was similar (10 kg) between the two groups. The PSI group cost a mean CAD$1787 more per case (p < 0.01). CONCLUSION: RSA criteria suggest that both groups will have revision rates of approximately 3% at five years. The advantages of PSI were minimal or absent for surgical resources used and waste eliminated, and for meeting target alignment, yet had significantly greater costs. Therefore, we conclude that PSI may not offer any advantage over CSI for routine primary TKA cases. Cite this article: Bone Joint J 2019;101-B:565-572.

Ureteroarterial fistulas after radical pelvic surgery: pathogenesis, diagnosis, and therapeutic modalities.

Ureteroarterial fistulas (UAF) are a rare but potentially life-threatening complication of intra-abdominal malignancy, typically occurring after vascular or pelvic surgery. Patients with a history of radical pelvic surgery, chronic indwelling ureteral stents, and prior pelvic radiation appear to be at increased risk. The predisposing risk factors suggest that gynecological oncologists are the likely specialty to face this problem and should be familiar with the clinical presentation and etiology of UAF. We present two such cases to illustrate these salient points of clinical diagnosis and management.

Highly crosslinked polyethylene wear rates and acetabular component orientation: a minimum ten-year follow-up.

Aims: The aim of this study was to determine whether there is a difference in the rate of wear between acetabular components positioned within and outside the 'safe zones' of anteversion and inclination angle. Patients and Methods: We reviewed 100 hips in 94 patients who had undergone primary total hip arthroplasty (THA) at least ten years previously. Patients all had the same type of acetabular component with a bearing couple which consisted of a 28 mm cobalt-chromium head on a highly crosslinked polyethylene (HXLPE) liner. A supine radiostereometric analysis (RSA) examination was carried out which acquired anteroposterior (AP) and lateral paired images. Acetabular component anteversion and inclination angles were measured as well as total femoral head penetration, which was divided by the length of implantation to determine the rate of polyethylene wear. Results: The mean anteversion angle was 19.4° (-15.2° to 48°, sd 11.4°), the mean inclination angle 43.4° (27.3° to 60.5°, sd 6.6°), and the mean wear rate 0.055 mm/year (sd 0.060). Exactly half of the hips were positioned inside the 'safe zone'. There was no difference (median difference, 0.012 mm/year; p = 0.091) in the rate of wear between acetabular components located within or outside the 'safe zone'. When compared to acetabular components located inside the 'safe zone', the wear rate was no different for acetabular components that only achieved the target anteversion angle (median difference, 0.012 mm/year; p = 0.138), target inclination angle (median difference, 0.013 mm/year; p = 0.354), or neither target (median difference, 0.012 mm/year; p = 0.322). Conclusion: Placing the acetabular component within or outside the 'safe zone' did not alter the wear rate of HXLPE at long-term follow-up to a level that risked osteolysis. HXLPE appears to be a forgiving bearing material in terms of articular surface wear, but care must still be taken to position the acetabular component correctly so that the implant is stable. Cite this article: Bone Joint J 2018;100-B:891-7.

Taperosis: Does head length affect fretting and corrosion in total hip arthroplasty?

Tribocorrosion at the head-neck taper interface - so-called 'taperosis' - may be a source of metal ions and particulate debris in metal-on-polyethylene total hip arthroplasty (THA). We examined the effect of femoral head length on fretting and corrosion in retrieved head-neck tapers in vivo for a minimum of two years (mean 8.7 years; 2.6 to 15.9). A total of 56 femoral heads ranging from 28 mm to 3 mm to 28 mm + 8 mm, and 17 femoral stems featuring a single taper design were included in the study. Fretting and corrosion were scored in three horizontally oriented concentric zones of each taper by stereomicroscopy. Head length was observed to affect fretting (p = 0.03), with 28 mm + 8 mm femoral heads showing greater total fretting scores than all other head lengths. The central zone of the femoral head bore taper was subject to increased fretting damage (p = 0.01), regardless of head length or stem offset. High-offset femoral stems were associated with greater total fretting of the bore taper (p = 0.04). Increased fretting damage is seen with longer head lengths and high-offset femoral stems, and occurs within a central concentric zone of the femoral head bore taper. Further investigation is required to determine the effect of increased head size, and variations in head-neck taper design.

Revision total hip arthroplasty in patients with extensive proximal femoral bone loss using a fluted tapered modular femoral component.

Revision total hip arthroplasty (THA) is challenging when there is severe loss of bone in the proximal femur. The purpose of this study was to evaluate the clinical and radiographic outcomes of revision THA in patients with severe proximal femoral bone loss treated with a fluted, tapered, modular femoral component. Between January 1998 and December 2004, 92 revision THAs were performed in 92 patients using a single fluted, tapered, modular femoral stem design. Pre-operative diagnoses included aseptic loosening, infection and peri-prosthetic fracture. Bone loss was categorised pre-operatively as Paprosky types III-IV, or Vancouver B3 in patients with a peri-prosthetic fracture. The mean clinical follow-up was 6.4 years (2 to 12). A total of 47 patients had peri-operative complications, 27 of whom required further surgery. However, most of these further operations involved retention of a well-fixed femoral stem, and 88/92 femoral components (97%) remained in situ. Of the four components requiring revision, three were revised for infection and were well fixed at the time of revision; only one (1%) was revised for aseptic loosening. The most common complications were post-operative instability (17 hips, 19%) and intra-operative femoral fracture during insertion of the stem (11 hips, 12%). Diaphyseal stress shielding was noted in 20 hips (22%). There were no fractures of the femoral component. At the final follow-up 78% of patients had minimal or no pain. Revision THA in patients with extensive proximal femoral bone loss using the Link MP fluted, tapered, modular stem led to a high rate of osseointegration of the stem at mid-term follow-up. Cite this article: Bone Joint J 2015; 97-B:312-17.

Knee manipulation under anaesthetic following total knee arthroplasty: a matched cohort design.

The purpose of this study was to compare clinical outcomes of total knee arthroplasty (TKA) after manipulation under anaesthesia (MUA) for post-operative stiffness with a matched cohort of TKA patients who did not requre MUA. In total 72 patients (mean age 59.8 years, 42 to 83) who underwent MUA following TKA were identified from our prospective database and compared with a matched cohort of patients who had undergone TKA without subsequent MUA. Patients were evaluated for range of movement (ROM) and clinical outcome scores (Western Ontario and McMaster Universities Arthritis Index, Short-Form Health Survey, and Knee Society Clinical Rating System) at a mean follow-up of 36.4 months (12 to 120). MUA took place at a mean of nine weeks (5 to 18) after TKA. In patients who required MUA, mean flexion deformity improved from 10° (0° to 25°) to 4.4° (0° to 15°) (p < 0.001), and mean range of flexion improved from 79.8° (65° to 95°) to 116° (80° to 130°) (p < 0.001). There were no statistically significant differences in ROM or functional outcome scores at three months, one year, or two years between those who required MUA and those who did not. There were no complications associated with manipulation. At most recent follow-up, patients requiring MUA achieved equivalent ROM and clinical outcome scores when compared with a matched control group. While other studies have focused on ROM after manipulation, the current study adds to current literature by supplementing this with functional outcome scores.

1192U90 in animal tests that predict antipsychotic efficacy, anxiolysis, and extrapyramidal side effects.

1192U90 was developed on the assumption that antagonism of 5-HT2 receptors efficacy yields more potently than D2 receptors against positive and negative symptoms of schizophrenia with minimal liability for extrapyramidal side effects (EPSs), and that 5-HT1A agonism further reduces EPSs and provides anxiolytic and antidepressant activity. 1192U90 was submitted to four tests that predict antipsychotic efficacy (antagonism of apomorphine-induced climbing in mouse, antagonism of apomorphine-induced circling in rats with unilateral 6-OHDA lesions, antagonism of amphetamine-induced hyperlocomotion in rat, and inhibition of conditioned avoidance in rat), two tests of 5-HT2 function (antagonism of 5-MeODMT-induced head twitches in mouse and antagonism of 5-HTP-induced wet dog shakes in rat), and three tests that predict EPS liability (antagonism of apomorphine-induced stereotypy in mouse and rat and induction of catalepsy in mouse). ED50s (mg/kg PO) were as follows: climbing 10.1, circling 7.9, hyperlocomotion 6.6, and avoidance 5.7; head twitches 5 and wet dog shakes 4.6; stereotypy in mouse 91.1, stereotypy in rat 133.4, and catalepsy 192.4. The ratio of ED50 for stereotypy antagonism to ED50 for climbing antagonism was 9 (compared to 4, 3, and 4 for clozapine, risperidone, and haloperidol). The ratio of ED50 for catalepsy induction to ED50 for climbing antagonism was 19 (compared to 7, 2, and 17 for clozapine, risperidone, and haloperidol). 1192U90 was also submitted to three tests that predict anxiolysis: It produced only a small increase in punished lever pressing for food in rat (Geller-Seifter conflict test), which is specific for rapid-onset efficacy, but produced large increases in punished key pecking for food in pigeon and cork gnawing in rat, which identify the delayed onset 5-HT1A agonists such as buspirone. The results suggest that 1192U90 would be effective for positive and negative symptoms of schizophrenia, with minimal liability for EPSs, and may also have anxiolytic properties.

Benzodiazepine receptor binding activity of 9-(1-phenylethyl)purines.

Several alpha-methyl analogues of the 9-benzylpurines that bind to the benzodiazepine receptor (BZR) were synthesized and tested for BZR-binding activity. Although introduction of a m-amino group and an 8-bromo substituent gave an additive increase in BZR affinity with 9-(3-aminobenzyl)-8-bromo-6-(dimethylamino)-9H-purine (4), addition of an alpha-methyl group to 4 resulted in a loss in BZR affinity. This loss in affinity is apparently due to repulsive, steric interactions between the 8-bromo and 9-(1-phenylethyl) substituents, which results in a conformation that is not optimal for interaction with the BZR. Several compounds were tested on a modified Geller-Seifter conflict schedule, but none exhibited significant anxiolytic activity.

Benzodiazepine receptor binding activity of 6,9-disubstituted purines.

A series of 6,9-disubstituted purines were tested for their ability to bind to the benzodiazepine receptor in rat brain tissue. One of the most active compounds was 9-(3-aminobenzyl)-6-(dimethylamino)-9H-purine (44) with an IC50 = 0.9 microM, which was only 4.5-fold higher than the IC50 for chlordiazepoxide. Substitution of a 3-aminobenzyl or 3-hydroxybenzyl group at the 9-position of 6-(dimethylamino)purine led to over a 50-fold increase in receptor affinity. Compound 44 did not exhibit significant anxiolytic activity, nor did anticonvulsant activity correlate with relative receptor binding affinity.

Benzodiazepine receptor binding activity of 8-substituted-9-(3-substituted-benzyl)-6-(dimethylamino)-9H-purines.

A series of 8-substituted analogues of 9-(3-aminobenzyl)-6-(dimethylamino)-9H-purine (8) were synthesized and tested for their ability to bind to the benzodiazepine receptor (BZR) in rat brain tissue. The most active compound was the 8-bromo-9-(3-formamidobenzyl) analogue 16 (IC50 = 0.011 microM), which was 1000-fold more active than the parent 9-benzyl-6-(dimethylamino)-9H-purine (1) and nearly as active as diazepam. Although substitution of a m-formamido group and an 8-bromo substituent on 1 imparted potent BZR binding activity, neither 16 nor 11 analogues exhibited significant anxiolytic activity on a modified Geller-Seifter conflict schedule.

Effect of central catecholamine alterations on the hypothermic response to 6-hydroxydopamine in desipramine treated rats.

The hypothermia observed in rats kept in a cold environment after the intracisternal administration of 6-hydroxydopamine was enhanced by desipramine. Since pretreatment with 6-hydroxydopamine virtually eliminated the temperature fall in response to a subsequent dose of 6-hydroxydopamine, brain catecholamines were implicated in the response. Preferential reduction of brain noradrenaline antagonized the hypothermia after 6-hydroxydopamine in desipramine-treated rats to a greater extent than did the preferential reduction of dopamine. The results indicate the importance of noradrenergic fibres in this hypothermic response, but do not exclude an involvement of brain dopaminergic pathways.

Effect of 6-hydroxydopamine on electrical self stimulation of the brain.

In rats, after a single intracisternal injection of 6-hydroxydopamine (6-OHDA) electrical self stimulation was reduced by approximately 50%. The concentrations of noradrenaline and dopamine in the brain were reduced by 83%. A second injection of 6-OHDA reduced the concentration of these amines to 7% of control values and virtually eliminated self stimulation.

Effect of ovarian hormones on conflict behavior.

We injected ovariectomized female rats with estrogen and progesterone. Some of the injection regimens used are known to induce estrus, while other do not. The effects of these treatments on operant behavior were evaluated. Operant behavior was maintained under a reinforcement schedule, one segment of which involved experimentally induced conflict. Such behaviors previously have been shown to be modified by anti-anxiety drugs. Those hormone treatments effective in inducing estrus had behavioral effects similar to the effects observed for established anti-anxiety agents. Hormone-injection regimens not capable of inducing estrus were without effect on operant behavior. Our findings suggest that the reproductive cycles of female rats are associated with behavioral changes which may be indicative of changing anxiety levels mediated in part by changing titers of ovarian hormones. We suggest that the evaluation of hormonal influences on operant behaviors sensitive to tranquilizers should be a useful model system for studying possible mechanisms underlying emotional changes associated with reproductive cycles.

Animal models used in prediction of antidepressant effects in man.

The discovery of bupropion's potential antidepressant activity resulted from studies of its behavioral effects in a number of animal models of depression. These animal models and data pertaining to their selectivity for other standard antidepressant drugs are reviewed.

Cue properties of oral and transdermal nicotine in the rat.

In a standard two-lever drug discrimination paradigm, rats were trained to discriminate nicotine 0.5 mg/kg PO from saline. Injections occurred 15 min before the session. Subjects reached the training criterion in a mean of 38 sessions. Nicotine PO, SC, and IP generated similar dose-effect curves (ED50 = 0.073 mg/kg PO, 0.076 mg/kg SC, 0.090 mg/kg IP); the dose-effect curve for transdermal (TD) administration fell approximately 1 log unit to the right (ED50 = 1.34 mg/kg). The percentage of rats choosing the nicotine-appropriate lever peaked at 15 min and gradually decreased to 50% or less by 180 min for nicotine PO and TD, a time-decay function similar to that previously shown for SC administration. The nicotinic cholinergic agonist cytisine (0.5-8.0 mg/kg) PO and TD produced up to 56% nicotine-appropriate responding, while the muscarinic cholinergic agonist arecoline (1.0-4.0 mg/kg) PO and TD produced only saline-appropriate responding. The nicotine cue did not generalize to the cholinergic antagonist mecamylamine (0.125-0.5 mg/kg) PO or TD; mecamylamine 0.5 mg/kg PO but not TD completely blocked the PO and TD nicotine cues. These results show that an approximately equal cue occurs with PO, IP, and SC administration, and that the TD cue is considerably weaker. The significance of the procedure as an animal analog of human transdermal nicotine intake is discussed.

Effects of chlordiazepoxide, pentobarbital, buspirone, chlorpromazine, and morphine in the stretched attend posture (SAP) test.

The stretched attend posture (SAP) in the mouse is an investigatory forward elongation of the body in a novel environment. In a previous study, the anxiolytics diazepam, clobazam, and phenobarbital reduced SAP, and low doses of the non-anxiolytics imipramine and chlorpromazine were ineffective, results which prompted the investigator to propose the SAP test as a screening method for anxiolytics. However, diazepam and clobazam also increased immobility. In the present study, the anxiolytics chlordiazepoxide, pentobarbital, and buspirone and behaviorally active doses of the non-anxiolytics chlorpromazine and morphine reduced SAP and tended to increase immobility. We concluded that therapeutic-class specificity has not been demonstrated for the SAP test.

Similar effects of antidepressant and non-antidepressant drugs on behavior under an interresponse-time greater than 72-s schedule.

Antidepressant drugs were reported to decrease responses and increase reinforcements in water-deprived male albino rats pressing a lever for water on a schedule requiring a pause of at least 72 s between responses (IRT greater than 72). Subsequently other investigators, using food-deprived ovariectomized hooded rats pressing a lever for food, showed that antipsychotic drugs produced the same effect as antidepressants. Because methodologies differed somewhat, the present study was designed to replicate closely the experimental conditions of the original studies, e.g., same strain and sex, same reinforcer, similar baseline behavior. In this study the antidepressant imipramine, the antipsychotics chlorpromazine and haloperidol, and to some extent the anxiolytic buspirone produced qualitatively similar effects - decreased responses and increased reinforcements - although there were some quantitative differences. This result, and other results showing that some antidepressants increase responses and decrease reinforcements, suggest that the IRT greater than 72-s task lacks specificity as a screening method for antidepressants.

The Geller-Seifter conflict paradigm with incremental shock.

The typical Geller-Seifter conflict paradigm for predicting clinical efficacy of anxiolytics is a mult VI/CRF schedule in which response rates in the CRF (conflict) portion are depressed by response-contingent electric shock. In 1-h sessions, anxiolytics raise the depressed conflict rates. Recently it was shown that replacing the single shock level with an arrangement whereby shock begins at zero and is increased with each response in the conflict portion produced more orderly data and facilitated training and maintenance of experimental subjects; chlordiazepoxide was the test drug. In the present study, those results are replicated in 30-min sessions, and the incremental paradigm is demonstrated to be as specific for anxiolytics as the standard Geller-Seifter paradigm. The possibility of very short sessions is suggested.

The staircase test: some evidence of nonspecificity for anxiolytics.

In the staircase test, a naive mouse is placed in a Plexiglas chamber containing a five-step staircase, and the number of rearings and steps climbed are recorded for 3 min. A claim for drug-class specificity has been made because conventional anxiolytics reduced rearings at doses that did not reduce steps climbed, while non-anxiolytics affected both measures in parallel. In the present study chlordiazepoxide, meprobamate, and ethanol registered the expected true positive effect by reducing rearings at doses that did not reduce steps climbed. Nicotine, which has some clinical anxiolytic action, registered a small true positive. The benzodiazepine anxiolytic alprazolam reduced both measures, a false negative, although it reduced rearings more than steps climbed. The putative novel anxiolytics CGS 9896, ketanserine, and tracazolate registered negatives, as did the known clinical anxiolytic buspirone. The non-anxiolytics phencyclidine and phenacetin registered true negatives, but morphine registered a clear false positive. The anxiogenics FG 7142 and pentylenetetrazol produced no significant effects. Because of the equivocal false negative for alprazolam, the clear false negative for buspirone, and the clear false positive for morphine, we concluded that the test lacks the degree of therapeutic-class specificity previously proposed but may still be useful in basic research.

Stimulus properties of antidepressants in the rat.

Various doses of bupropion HCl (Wellbatrin) (5, 10, and 20 mg/kg), a new phenylaminoketone antidepressant, were employed as cues in a two-lever operant discrimination from saline control injections in rats on an FR10 schedule of food reinforcement. Subjects reached and maintained a high level of discrimination in the O vs 20 mg/kg bupropion stimulus condition but not at the lower doses. In generalization testing, the following compounds produced dose-related responding on the bupropion lever: viloxazine, nomifensine, caffeine, d-amphetamine, cocaine, methylphenidate, and benzylpiperazine. Drugs that failed to show dose-related generalization included phenethylamine, thyrotropin-releasing hormone, imipramine, nortriptyline, amitriptyline, desipramine, mianserin, chlordiazepoxide, diazepam, scopolamine, phenobarbital, and morphine. With the important exception of viloxazine, the generalization profile of bupropion seems to reflect its previously reported locomotor stimulant effects in the rat rather than its antidepressant activity and suggests that species differences exist between man and rat with regard to the pharmacologic activity of this new antidepressant.