Factors associated with a clinically significant improvement in health-related quality of life after total knee arthroplasty.

BACKGROUND: The aim was to identify independent preoperative factors associated with changes in health-related quality of life (HRQoL) following total knee arthroplasty (TKA), and whether these could be used as indicators for surgery. METHODS: A retrospective study of 3127 TKA patients was undertaken that included 1194 (38.2%) male and 1933 (61.8%) female patients, with a mean age of 70.5 years (standard deviation 9.0). Patient demographics, body mass index and ASA grade, Oxford Knee Score (OKS) and EuroQol 5-dimension (EQ-5D) 3-level, which was used to assess HRQoL, were collected preoperatively and 2 years postoperatively. RESULTS: When adjusting for confounding factors, obesity grade II (p = 0.002), ASA grade 3 (p = 0.002), and a better preoperative OKS (p < 0.001) or EQ-5D score (p < 0.001) were associated with a decreased improvement in the HRQoL at 2-years. A preoperative EQ-5D of < 0.8 (95.7% specific, AUC ≥ 67.0%) or an OKS of < 36 (97.1% specific, AUC ≥ 58.1%) was associated with a clinically significant improvement HRQoL. Patella resurfacing (n = 1454, 46.5%) was not independently associated with a clinical or statistically significant improvement in HRQoL. According to preoperative factors, no subgroup of patients benefited more from patella resurfacing according to improvement in their HRQoL. CONCLUSION: ASA grade 3, grade II obesity, a better preoperative EQ-5D or OKS were independently associated with a lesser improvement in HRQoL. The thresholds identified in the EQ-5D or OKS for a clinically significant improvement in HRQoL may be used as potential indicators for referral for TKA. Patella resurfacing was not independently associated with a clinically important improvement in HRQoL. LEVEL OF EVIDENCE: Retrospective diagnostic study, Level III.

Effects of a six-week exercise intervention on function, pain and lumbar multifidus muscle cross-sectional area in chronic low back pain: A proof-of-concept study.

INTRODUCTION: Exercise with the Functional Re-adaptive Exercise Device (FRED) has previously been shown to activate the lumbar multifidus (LM) and transversus abdominis (TrA) muscles in non-symptomatic volunteers. This study aimed to determine the effects of a six-week FRED exercise intervention on pain intensity, patient-reported function and LM cross sectional area (CSA) in people with chronic non-specific low back pain (LBP). METHODS: Thirteen participants undertook six weeks of FRED exercise for up to 15 min, three times per week. At six weeks pre-, immediately pre-, immediately post-, and six and 15 weeks post-intervention, participants completed the Numeric Pain Rating Scale, Patient-Specific Functional Scale, and ultrasound imaging was used to assess the size of the LM muscles at L5 level. Changes in outcomes were assessed using effect size, confidence intervals and minimum clinically important difference (MCID). RESULTS: There was no improvement in pain intensity following the intervention. Patient-reported function improved by at least twice the MCID for all follow-up assessments compared to immediately pre-intervention (d = 4.20-6.58). Lumbar multifidus CSA showed a large effect size increase from immediately pre-intervention to immediately post-intervention (d = 0.8-1.1); this was maintained at six weeks post-intervention (not measured at 15 weeks post-intervention). CONCLUSION: Six weeks of FRED exercise improved physical function in all 13 participants with chronic non-specific LBP who took part in this study and most participants' lumbar multifidus muscle CSA. On this basis, it may be an effective intervention for people with chronic LBP and should now be tested in a randomised controlled trial.

Inter-observer variability of manual contour delineation of structures in CT.

PURPOSE: To quantify the inter-observer variability of manual delineation of lesions and organ contours in CT to establish a reference standard for volumetric measurements for clinical decision making and for the evaluation of automatic segmentation algorithms. MATERIALS AND METHODS: Eleven radiologists manually delineated 3193 contours of liver tumours (896), lung tumours (1085), kidney contours (434) and brain hematomas (497) on 490 slices of clinical CT scans. A comparative analysis of the delineations was then performed to quantify the inter-observer delineation variability with standard volume metrics and with new group-wise metrics for delineations produced by groups of observers. RESULTS: The mean volume overlap variability values and ranges (in %) between the delineations of two observers were: liver tumours 17.8 [-5.8,+7.2]%, lung tumours 20.8 [-8.8,+10.2]%, kidney contours 8.8 [-0.8,+1.2]% and brain hematomas 18 [-6.0,+6.0] %. For any two randomly selected observers, the mean delineation volume overlap variability was 5-57%. The mean variability captured by groups of two, three and five observers was 37%, 53% and 72%; eight observers accounted for 75-94% of the total variability. For all cases, 38.5% of the delineation non-agreement was due to parts of the delineation of a single observer disagreeing with the others. No statistical difference was found for the delineation variability between the observers based on their expertise. CONCLUSION: The variability in manual delineations for different structures and observers is large and spans a wide range across a variety of structures and pathologies. Two and even three observers may not be sufficient to establish the full range of inter-observer variability. KEY POINTS: • This study quantifies the inter-observer variability of manual delineation of lesions and organ contours in CT. • The variability of manual delineations between two observers can be significant. Two and even three observers capture only a fraction of the full range of inter-observer variability observed in common practice. • Inter-observer manual delineation variability is necessary to establish a reference standard for radiologist training and evaluation and for the evaluation of automatic segmentation algorithms.

Automatic segmentation variability estimation with segmentation priors.

PURPOSE: Segmentations produced manually by experts or by algorithms are subject to variability, as they depend on many factors, e.g., the structure of interest, the resolution, contrast and quality of the images, and the expert experience or the algorithmic method. To properly assess the quality of these segmentations, it is thus essential to quantify their variability. However, obtaining reference variability ground truth requires several observers to manually delineate structures, which is time-consuming and impractical. METHODS: We describe a new comprehensive formal framework for segmentation evaluation and variability estimation without ground truth and a generic method for automatic segmentation variability estimation based on segmentation priors and multivariate sensitivity analysis. The method inputs the image scan and a user-validated segmentation of the structure of interest and uses predefined segmentation priors to compute a variability estimation around the given segmentation. The segmentation priors are combined with an integrator function whose sensitivity around the given segmentation is the segmentation variability. RESULTS: We validate our methods with two studies. The first study establishes the reference manual delineation variability. Eleven radiologists with varying levels of expertise manually delineated the contours of liver tumors, lung tumors, kidneys, and brain hematomas on 2,835 delineations from 18 CT scans. The relative delineation volume variability ranges are 51 [-24,+27]% for liver tumors, 56 [-25,+31]% for lung tumors, 25 [-12,+13]% for kidney contours, and 53 [-24,+29]% brain hematomas. The second study compares the estimated segmentation variability results to this reference data. The mean volume variability difference of the delineation is <6%, with a Dice similarity coefficient of >70% with respect to the mean manual delineation variability data. CONCLUSIONS: Reliable segmentation variability estimation with no ground truth enables the establishment of a proper observer variability reference. The segmentation variability should be taken into account when setting reference standards for clinical decisions based on volumetric measurements and when evaluating segmentation algorithms.

Changes in health-related quality of life (EQ-5D) dimensions associated with community-based musculoskeletal physiotherapy: a multi-centre analysis.

PURPOSE: To determine the changes in each of the five dimensions of the EuroQol 5-dimension index associated with community-based physiotherapy. METHODS: Four thousand one hundred and thirty-six patients that received community-based musculoskeletal physiotherapy across five NHS centres completed the EQ-5D on entry into the service and upon discharge. Patients were categorised on symptom location and response to treatment based on their EQ-5D index improving by at least 0.1 ("EQ-5D responders"). For each symptom location, and for responders and non-responders to treatment, the mean (± SD) were calculated for each dimension pre- and post-treatment as well as the size of effect. RESULTS: The mobility dimension improved (p < 0.05) in all symptom locations for EQ-5D responders (d = 0.26-1.58) and in ankle, knee, hip and lumbar symptoms for EQ-5D non-responders (d = 0.17-0.45). The self-care dimension improved (p < 0.05) in all symptom locations for EQ-5D responders (d = 0.49-1.16). The usual activities dimension improved (p < 0.05) across all symptom locations for EQ-5D responders (d = 1.00-1.75) and EQ-5D non-responders (d = 0.14-0.60). Despite the pain/discomfort dimension improving (p < 0.05) across all symptom locations for both EQ-5D responders (d = 1.07-1.43) and EQ-5D non-responders (d = 0.29-0.66), the anxiety/depression dimension improved (p < 0.05) from higher starting levels in EQ-5D responders (d = 0.76-1.05) with no change seen for EQ-5D non-responders (d = - 0.16 to 0.06). CONCLUSIONS: Clinicians should not assume that a patient presenting with pain but expressing high anxiety/depression is unlikely to respond to treatment, as they may show the best HRQoL outcomes. For patients presenting with pain/discomfort and low levels of anxiety/depression, the EQ-5D index is perhaps not a suitable tool for sole use in patient management and service evaluation.

A fully automatic end-to-end method for content-based image retrieval of CT scans with similar liver lesion annotations.

PURPOSE: The goal of medical content-based image retrieval (M-CBIR) is to assist radiologists in the decision-making process by retrieving medical cases similar to a given image. One of the key interests of radiologists is lesions and their annotations, since the patient treatment depends on the lesion diagnosis. Therefore, a key feature of M-CBIR systems is the retrieval of scans with the most similar lesion annotations. To be of value, M-CBIR systems should be fully automatic to handle large case databases. METHODS: We present a fully automatic end-to-end method for the retrieval of CT scans with similar liver lesion annotations. The input is a database of abdominal CT scans labeled with liver lesions, a query CT scan, and optionally one radiologist-specified lesion annotation of interest. The output is an ordered list of the database CT scans with the most similar liver lesion annotations. The method starts by automatically segmenting the liver in the scan. It then extracts a histogram-based features vector from the segmented region, learns the features' relative importance, and ranks the database scans according to the relative importance measure. The main advantages of our method are that it fully automates the end-to-end querying process, that it uses simple and efficient techniques that are scalable to large datasets, and that it produces quality retrieval results using an unannotated CT scan. RESULTS: Our experimental results on 9 CT queries on a dataset of 41 volumetric CT scans from the 2014 Image CLEF Liver Annotation Task yield an average retrieval accuracy (Normalized Discounted Cumulative Gain index) of 0.77 and 0.84 without/with annotation, respectively. CONCLUSIONS: Fully automatic end-to-end retrieval of similar cases based on image information alone, rather that on disease diagnosis, may help radiologists to better diagnose liver lesions.

The prevalence and significance of renal perfusion defects in early kidney transplants quantified using 3D contrast enhanced ultrasound (CEUS).

OBJECTIVES: Vascular complications are one of the most common causes of early kidney transplant dysfunction. Contrast enhanced ultrasound increases sensitivity to vascular changes. The aim of this study was to assess the prevalence and size of vascular abnormalities in early renal transplants using 3D CEUS and the significance of perfusion defects on renal function. METHODS: Ninety-nine renal transplant patients underwent 3D CEUS after surgery to quantify perfusion defects as percentage total renal volume (TRV). Serum creatinine and estimated glomerular filtration rate (eGFR) were recorded up to 3 months post-surgery. RESULTS: Twenty participants had focal perfusion defects (0.2-43%TRV). There was a meaningful difference in patients with perfusion defects in eGFR at 1 month (90% CI 2.7-19.2 mL/min/1.73 m2) and 3 months (90% CI 1.9-19.6 mL/min/1.73 m2) and creatinine at 3 months (90% CI -56 - -8 µmol/L) using a predetermined clinical threshold. Perfusion defect size correlated well with both serum creatinine and eGFR at 3 months (R = 0.80, p ≤ 0.000 and 0.58, p = 0.038). No correlation was seen prior to 3 months. CONCLUSIONS: Perfusion defects in kidney transplants were more common than expected and were highly likely to reduce renal function at 1-3 months, and the size of the defect affected the degree of functional change at 3 months. KEY POINTS: • Perfusion defects were more common than previously thought. • Perfusion defects could be quantified using 3D CEUS. • The presence of even small perfusion defects may affect kidney function. • Size of perfusion defects correlated with subsequent kidney function at 3 months. • Potentially useful in informing clinician expectations of kidney function post-surgery.

The immediate effects of exercise using the Functional Re-adaptive Exercise Device on lumbopelvic kinematics in people with and without low back pain.

BACKGROUND: Dysfunction of the lumbar multifidus (LM) and transversus abdominis (TrA) muscles is associated with low back pain (LBP). The Functional Re-adaptive Exercise Device (FRED) has shown potential as a non-specific LBP intervention by automatically recruiting LM and TrA. Loss or lordosis and altered lumbopelvic positioning has also been linked to LBP and is often trained within LM and TrA interventions. The effect that FRED exercise has on lumbopelvic positioning and lumbar lordosis is unknown. OBJECTIVES: To assess the effect of FRED exercise on lumbopelvic kinematics and alignment to establish whether FRED exercise promotes a favourable lumbopelvic posture for training LM and TrA. DESIGN: Within and between-group comparison study. METHOD: One hundred and thirty participants, 74 experiencing LBP, had lumbopelvic kinematic data measured during over-ground walking and FRED exercise. Magnitude-based inferences were used to compare walking with FRED exercise within participants and between the asymptomatic and LBP groups, to establish the effects of FRED exercise on lumbopelvic kinematics, compared to walking, in each group. RESULTS: FRED exercise promotes an immediate change in anterior pelvic tilt by 8.7° compared to walking in the no-LBP and LBP groups. Sagittal-plane spinal extension increased during FRED exercise at all spinal levels by 0.9° in the no-LBP group, and by 1.2° in the LBP group. CONCLUSIONS: FRED exercise promotes a lumbopelvic position more conducive to LM and TrA training than walking in both asymptomatic people and those with LBP.

The accuracy of magnetic resonance imaging (MRI) in detecting meniscal pathology.

AIMS: The purpose of this study was to determine the accuracy of Magnetic Resonance Imaging (MRI) scanning in the detection of meniscal pathology in a district general hospital. METHODS: We retrospectively analysed a single-surgeon series of 240 knee arthroscopic investigations for all indications. The arthroscopic reports included an outline diagram of the meniscus upon which the surgeon could record his operative findings. 112 of these patients had also had a recent MRI scan. We compared the MRI findings with the arthroscopy findings. RESULTS: 66 patients had a positive MRI scan. 64 of these were found to have a meniscal tear at surgery. 37 MRI scans were reported as "no tear", of which four were found to have a meniscal tear at surgery. Nine MRI scans were descriptive, e.g. "signal change, possible tear", or "tear cannot be ruled out." These tended to correspond with equivocal arthroscopic findings of "degeneration" or "fibrillation". In our series of 112 patients with meniscal pathology, MRI scanning was 90.5% sensitive, 89.5% specific and 90.1% accurate. CONCLUSIONS: False positive MRI scans may lead to unnecessary surgery. Patients with negative MRI scans had a mean delay to surgery of 33 weeks compared to 18 weeks for patients with positive MRI scans. Patients with false negative MRI results may wait longer for their surgery. Two of the false negative MRI scan reports clearly showed meniscus tears, which were not identified by the reporting radiologist. In our series, the MRI scan itself was more accurate than the reporting. It is important to have an experienced musculoskeletal radiologist to minimise the number of missed meniscal tears. It is also important for the surgeon to review the MRI scan itself, as well as the report.

The effect of total hip and hip resurfacing arthroplasty on vertical ground reaction force and impulse symmetry during a sit-to-stand task.

BACKGROUND: The aim of this study was to determine the influence of total hip arthroplasty and hip resurfacing arthroplasty on limb loading symmetry before, and after, hip reconstruction surgery during a sit-to-stand task. METHODS: Fourteen patients were recruited that were about to receive either a total hip prosthesis (n=7) or a hip resurfacing prosthesis (n=7), as well as matched controls. Patients performed a sit-to-stand movement before, 3 months after, and 12 months after surgery. Peak vertical ground reaction force and impulse were measured for each leg, from which ground reaction force and impulse symmetry ratios were calculated. FINDINGS: Before surgery, hip resurfacing patients showed a small asymmetry which was not different to normal for ground reaction force (0.88(0.28) vs. 1.00(0.11); p=0.311) or impulse (0.87(0.29) vs. 0.99(0.09); p=0.324) symmetry ratios. Total hip patients offloaded their affected hip by 30% in terms of impulse symmetry ratio (0.71(0.36) vs. 0.99(0.23); p=0.018). At 3 months following surgery asymmetries were seen that were different to normal in both hip resurfacing patients for ground reaction force (0.77(0.16); p=0.007), and total hip patients for ground reaction force (0.70(0.15); p=0.018) and impulse (0.72(0.16); p=0.011) symmetry ratios. By 12 months after surgery total hip patients regained a symmetrical loading pattern for both ground reaction force (0.95(0.06); p=0.676) and impulse (1.00(0.06); p=0.702) symmetry ratios. Hip resurfacing patients, however, performed the task by overloading their operated hip, with impulse symmetry ratio being larger than normal (1.16(0.16); p=0.035). INTERPRETATION: Physiotherapists should appreciate the need for early recovery of limb loading symmetry as well as subsequent differences in the responses observed with different prostheses.

Is tibial tuberosity-trochlear groove distance an appropriate measure for the identification of knees with patellar instability?

PURPOSE: Tibial tuberosity-trochlear groove distance (TT-TG) has been regarded as a useful tool for establishing therapeutic choices for patellar instability. Recently, it has been shown that TT-TG negatively correlated with the quadriceps angle, suggesting that if used individually, neither provide a valid measure of instability. This study aimed to compare TT-TG distance between both knees in patients with unilateral instability to assess whether this measurement is a decisive element in the management decisions for patellar instability. METHODS: Sixty-two patients (18 male and 44 female), reporting to a specialist patella clinic for recurrent unilateral patellar instability, were included in the study. Patients underwent bilateral long leg computed tomography scan to determine TT-TG distance in both knees. Tibial TT-TG in symptomatic and asymptomatic knees in the same individual was compared statistically. RESULTS: Mean TT-TG distance in the symptomatic knee was 16.9 (±4.9) mm, compared to 15.6 (±5.6) mm in the asymptomatic knee. Tibial TT-TG was not significantly different between stable and unstable knees (n.s.). CONCLUSIONS: The lack of difference in TT-TG distance between stable and unstable knees suggests that TT-TG distance alone may not be a decisive element in establishing therapeutic choices for patellar instability. It should, therefore, be interpreted with caution during clinical evaluations. LEVEL OF EVIDENCE: II.

Low impact weight-bearing exercise in an upright posture achieves greater lumbopelvic stability than overground walking.

The aim of this study was to determine the kinematic differences between movements on a new exercise device (EX) that promotes a stable trunk over a moving, unstable base of support, and overground walking (OW). Sixteen male participants performed EX and OW trials while their movements were tracked using a 3D motion capture system. Trunk and pelvis range of motion (ROM) were similar between EX and OW in the sagittal and frontal planes, and reduced for EX in the transverse plane. The pelvis was tilted anteriorly, on average, by about 16° in EX compared to OW. Hip and knee ROM were reduced in EX compared to OW. The exercise device appears to promote similar or reduced lumbopelvic motion, compared to walking, which could contribute to more tonic activity of the local lumbopelvic musculature.

Clinically insignificant association between anterior knee pain and patellofemoral lesions which are found incidentally.

BACKGROUND: Patellofemoral chondral lesions are frequently identified incidentally during the arthroscopic treatment of other knee pathologies. A role has been described for arthroscopic debridement when symptoms are known to originate from pathology of the patellofemoral joint. However, it remains unclear how to manage lesions which are found incidentally whilst tackling other pathologies. The purpose of this study was to establish the strength of association between anterior knee pain and patellofemoral lesions identified incidentally in a typical arthroscopic population. METHODS: A consecutive series of patients undergoing arthroscopy for a range of standard indications formed the basis of this cross section study. We excluded those with patellofemoral conditions in order to identify patellofemoral lesions which were solely incidental. Pre-operative assessments were performed on 64 patients, where anterior knee pain was sought by three methods: an annotated photographic knee pain map (PKPM), patient indication with one finger and by palpated tenderness. A single blinded surgeon, performed standard arthroscopies and recorded patellofemoral lesions. Statistical correlations were performed to identify the association magnitude. RESULTS: Associations were identified between incidental patellofemoral lesions and tenderness palpated on the medial patella (P = 0.007, χ(2) = 0.32) and the quadriceps tendon (P = 0.029, χ(2) = 0.26), but these associations were at best fair, which could be interpreted as clinically insignificant. CONCLUSION: Incidental patellofemoral lesions are not necessarily associated with anterior knee pain, we suggest that they could be left alone. This recommendation is only applicable to patellofemoral lesions which are found incidentally whilst addressing other pathology.

Combined pubic rami and sacral osteoporotic fractures: a prospective study.

BACKGROUND: Pelvic osteoporotic fractures (POFs) are often associated with considerable morbidity and mortality mainly as a result of infections and cardiovascular events. Patients usually need prolonged institutionalization, rehabilitation, and follow-up, with a high rate of dependency and cost. The most common sites of POFs include the pubic rami, sacrum, ilium, and acetabulum. Combined pubic rami (PROFs) and sacral osteoporotic fractures (SOFs) have been reported, mostly in retrospective studies, describing the mechanism of injury and incidence. The aim of this study was to evaluate the association between PROFs and SOFs and to assess the effect of combined PROFs and SOFs on patients' mobility, discharge destination, and length of stay. MATERIALS AND METHODS: We prospectively studied 67 patients with low-impact PROFs and/or SOFs. There were 54 (80.4%) female and 13 (19.6%) male patients, and the average age was 87.5 (range 65-96) years. All patients were assessed by the fracture liaison service. Patients had magnetic resonance imaging or bone scan when there was history of low back pain following the injury or lumbosacral tenderness on clinical examination. RESULTS: The mean length of stay for all patients was 45 (± 35) days. Mortality rate was 10.4%. A significant relationship was found between low back pain and a positive finding of sacral fracture. Patients with combined PROFs and SOFs showed significantly longer length of stay than those with isolated PROFs. CONCLUSIONS: The presence of low back pain and tenderness in patients who had low-impact pelvic injuries was highly suggestive of the presence of an associated SOF. There was a high association between sacral and PROFs. The length of stay of patients with PROFs associated with sacral osteoporotic fractures was significantly longer than that of patients with PROFs only. Therefore, we recommend considering the high association between SOFs and PROFs in planning the management and rehabilitation of patients with POFs.

The relationship between quadriceps angle and tibial tuberosity-trochlear groove distance in patients with patellar instability.

PURPOSE: The quadriceps angle (Q-angle) represents the angle between the vector of action of the quadriceps and the patellar tendon. An increased Q-angle has been associated with an increased risk of patellar instability, although there is disagreement on its reliability and validity as it is affected by the position of the limb and contraction of the quadriceps. Tibial tuberosity-trochlear groove distance (TT-TG) is ascertained by axial CT scanning, with an increased value associated with patellar instability. This study aimed to determine whether the Q-angle correlates with the TT-TG distance in patients with patellar instability. METHODS: Q-angles were measured in 34 knees that had previously undergone CT scanning for assessment of patellar instability. Measurements were made with the patient supine, the knee extended and the lower limbs in neutral rotation with the quadriceps relaxed and contracted. TT-TG distance was measured on CT scanning in an identical position. RESULTS: Of the 34 knees measured, 24 had symptoms of patellar instability, and 10 were normal. A significant negative correlation between relaxed Q-angle and TT-TG in all knees was demonstrated (p = 0.028). In symptomatic knees, contracted Q-angle also demonstrated a significant negative correlation with TT-TG (p = 0.037). CONCLUSIONS: If TT-TG distance is regarded as the gold standard measurement, Q-angle is not a reliable indicator of patellar instability. There is a clear need to develop methods to more fully characterise the knee and factors contributing to patellar instability. LEVEL OF EVIDENCE: II.

Interactions between severity and location of chondral lesions and meniscal tears found at arthroscopy.

PURPOSE: This study reports the specific interactions between the different grades and locations of chondral lesions found in symptomatic knees requiring arthroscopy. The associations between meniscal tears and chondral lesions were also investigated. METHODS: Data were analysed for 141 knee arthroscopies (87 males and 54 females), with a mean patient age of 45.9 years. Chondral lesions were defined according to the modified Outerbridge classification system by a single surgeon immediately following arthroscopic surgery. RESULTS: The most common clinical findings were medial meniscal tears (47%) and medial femoral condyle lesions (57%). Compared to other locations within the knee, the medial femoral condyle was the most commonly affected location for a chondral lesion and 75% of these lesions were graded as III (32%) or IV (43%). Similarly, 77% of knees with a trochlea lesion were affected by high-grade chondral lesions (grade III = 12%; grade IV = 65%). The trochlea presented with the greatest percentage of grade IV chondral lesions. Eighty percent of patients with a meniscal tear also had a chondral lesion. Medial meniscal tears were most commonly observed with medial femoral condyle lesion. Lateral meniscal tears were most commonly observed with lateral tibial plateau lesions. Twenty-nine percent of patients had corresponding lesions on the medial femoral condyle and medial tibial plateau, and this was the most commonly found interaction between chondral lesion locations. CONCLUSION: Patients with medial meniscal tears are likely to also have a chondral lesion on the same side of the knee. LEVEL OF EVIDENCE: II.

The photographic knee pain map: locating knee pain with an instrument developed for diagnostic, communication and research purposes.

Pain maps are used to determine the location of pain. Knee pain maps have previously been described, but only one study has reported on reliability and none report validity. The present study describes the generation of a photographic knee pain map (PKPM) together with its validity and reliability. A photographic representation of a pair of knees was chosen by 26 patients, (66.7%) from a group of 39. The selected photograph was modified and a template of anatomical zones was generated. The opinions of 25 independent subject matter experts were canvassed and validity ratios calculated for these zones, ranged from 0.28 to 0.84. Hypothetical comparisons were made between the PKPM and an alternative knee pain map, in a cross-sectional group of 26 patients (35 knees). Convergent patterns of validity were found where hypothesised. Reliability was determined using a different cohort of 44 patients (58 knees) who completed the PKPM before and after a sampling delay. Four of these patients were excluded with a short sampling delay. Calculated agreement of test-retest reproducibility was fair to good. All of the completed PKPM (151 knees) were then subject to further analysis where inter-rater reproducibility was good to very good and intra-rater reproducibility was very good. The PKPM is readily accessible to patients with low completion burden. It is both valid and reliable and we suggest it can be used in both clinical and research settings. Further studies are planned to explore its predictive ability as a diagnostic tool. The PKPM can be found at www.photographickneepainmap.com.

Novel bisphosphonate inhibitors of phosphoglycerate kinase.

A series of novel, conformationally-restrained bisphosphonate analogues of 1,3-bisphosphoglyceric acid 1 have been synthesised and evaluated as inhibitors of 3-PGK. They are competitive inhibitors of the human enzyme and, especially for certain alpha-halophosphonic acid analogues, both Ki and IC50 values extend into the submicromolar range.

Clinical pharmacology of doxazosin in patients with essential hypertension.

Doxazosin is a new quinazoline derivative that, like prazosin, has selectivity for alpha 1-receptors. A three-way crossover, randomized, open study in 18 patients with essential hypertension was conducted to investigate the clinical pharmacokinetics of 2, 4, and 8 mg doxazosin at steady state. The pharmacokinetics of the initial 2 mg dose was also studied. Doxazosin showed linear pharmacokinetics. Increases in doses from 2 to 8 mg (steady state) produced proportional increases in doxazosin serum levels (maximum plasma drug concentration [Cmax] minimum plasma drug concentration [C min], and O-24-hour area under the curve [AUC(p-24)], whereas half-life (t1/2) (19.4, 18.7, and 19.7 hours, respectively), volume of distribution (3.4, 3.4, and 3.6 L/kg, respectively), clearance from serum (2.2, 2.2, and 2.1 ml/min/kg, respectively), and degree of protein binding (1.2%, 1.0%, and 1.0% unbound, respectively) were dose independent. Similar t1/2 and time to reach peak concentration (tmax) were obtained with 2 mg initial dose and 2 mg steady state. alpha 1-Acid glycoprotein levels were unchanged during doxazosin treatment. Doxazosin lowered supine and standing systolic and diastolic blood pressure. The blood pressure reduction was associated with an increase in heart rate. Peak hypotensive and tachycardic effects occurred 5.7 +/- 0.1 hours after administration, whereas Cmax was achieved at 2.4 +/- 0.7 hours (tmax). Greater decreases in systolic blood pressure and increases in heart rate were seen in standing than in supine position. The reduction in standing systolic and diastolic blood pressure with 8 mg was greater than with 2 mg (P less than 0.05); however, the increases in heart rate were not different. Dizziness, headaches, and dry mouth were the most frequent side effects. This study indicates that doxazosin shows linear pharmacokinetics between 2 and 8 mg and that because of its long t1/2, once-a-day administration should be adequate for the treatment of hypertension.

Interaction between antidepressants and alpha 1-adrenergic receptor antagonists on the binding to alpha 1-acid glycoprotein.

alpha 1-Receptor antagonists and antidepressant agents are basic (cationic) drugs that are known to bind to alpha 1-acid glycoprotein (AAG). Since these drugs are frequently co-administered and since they bind to the same protein, this investigation was designed to evaluate the "in vitro" ability of antidepressants, alpha 1-receptor antagonists, and propranolol to displace [3H]imipramine and [3H]prazosin from the AAG binding site(s). Equilibrium dialysis was employed. Of the drugs studied, the following order of potency in displacing [3H]prazosin was found: trazodone greater than prazosin greater than doxazosin greater than propranolol greater than doxepin = amoxapine = trimazosin = amitriptyline greater than imipramine greater than nortriptyline = desipramine = nomifensine greater than bupropion = maprotiline. [3H]lmipramine binding from AAG was displaced with the following potency order: prazosin greater than imipramine greater than propranolol greater than doxazosin greater than nortriptyline greater than desipramine greater than trimazosin. Tricyclic antidepressants produced similar degrees of displacement of both [3H]imipramine and [3H]prazosin from AAG; whereas, alpha 1-receptor antagonists were more effective displacers of [3H]prazosin than of [3H]imipramine. Furthermore, the demethylated metabolites of imipramine and amitriptyline were less potent displacers than their parent compounds. These results suggest that more than a single binding site may be available for binding to AAG and that hydrophobic bonding is important in the binding of drugs to AAG.