The validity and reliability of the modified forgotten joint score.

We aim to validate the "Modified Forgotten Joint Score" (MFJS) as a new patient-reported outcome measure (PROM) in hip and knee arthroplasty, against the UK's gold standard Oxford Hip and Knee Scores (OHS/OKS). The original Forgotten Joint Score (FJS) (12 items) was created to assess post-arthroplasty joint awareness. We modified the FJS to 10-items to improve its reliability. Postal questionnaires were sent out to 400 total hip or knee replacement (THR/TKR) patients who were 1-2 years' post-op, along with the OHS/OKS. Data, collected from the 212 returned questionnaires (53% response rate), was analysed in relation to construct and content validity. A sub-cohort of 77 patients took part in a test-retest repeatability study, to assess reliability of the MFJS. The MFJS proved to have an increased discriminatory power in high-performing patients in comparison to the OHS and OKS. 30.8% of TKR patients (n = 131) scored highly (87.5% or more) in the OKS compared to just 7.69% in the MFJS TKR patients. The MFJS proved to have increased test-retest repeatability, based upon its intra-class correlation coefficient of 0.968 compared to the Oxford's 0.845, p < 0.001. The MFJS is a more relevant tool, compared to the FJS, with greater discrimination in the assessment of well performing hip and knee arthroplasties in comparison to the OHS/OKS.

The virtual fracture clinic: Reducing unnecessary review of clavicle fractures.

INTRODUCTION: We re-designed the outpatient management of trauma at our institution to eliminate appointments if there would be no change in management or information provision. All cases referred by the Emergency Department (ED) were reviewed at a Virtual Fracture Clinic (VFC) by an orthopaedic consultant and telephoned afterwards by a senior nurse. If face-to-face review was required, it was arranged at a specialist shoulder clinic. AIMS: The primary aim of this study was to evaluate the proportion of clavicle fractures that could be discharged without physical review. The secondary aim was to assess the patient reported functional outcome and satisfaction among patients who were discharged without further review. PATIENTS AND METHODS: A retrospective review was performed of patients who attended the ED with a clavicle fracture between October 2011 and September 2012. 138 patients were included. The number of patients who were discharged without a physical review was analysed. All radiographs were classified according to the Robinson classification. We recorded the number of undisplaced/minimally-displaced fractures that were discharged virtually. The number of patients with a displaced midshaft fracture who were seen at a specialist clinic was also recorded. A questionnaire was sent to all patients at one year post-injury to evaluate their outcome (QuickDASH and EQ-5D) and satisfaction with the new service. RESULTS: 62/138 (45%) were directly discharged from the VFC. The majority of virtual discharges occurred in the undisplaced fracture types (84% versus 13%, RR 6.4, 95% CI 3.5-11.5). 78% patients responded to the questionnaires. 91% of patients were satisfied with their recovery from the injury. 86.4% patients were satisfied with the information provided regarding their treatment. In the virtually discharged group the mean EQ-5D VAS was 78.1 (EQ5D range 0.06-1, SD 0.248). The mean Quick DASH score was 16.1(SD 25.2). CONCLUSIONS: Virtual discharge of undisplaced clavicle fractures is appropriate and results in acceptable clinical outcomes and patient satisfaction. This redesigned process has significant benefits for patients as there were far fewer hospital visits by avoiding unnecessary appointments. The orthopaedic service also benefited by having more time available for the management of complex cases.

Femoro Patella Vialla patellofemoral arthroplasty: An independent assessment of outcomes at minimum 2-year follow-up.

AIM: To determine outcomes using the Femoro-Patella Vialla (FPV) arthroplasty and if there is an ideal patient for this implant. METHODS: A total of 41 FPV patellofemoral joint replacements were performed in 31 patients (22 females, 9 males, mean age 65 years). Mean follow-up was 3.2 years (minimum 2 years). Radiographs were reviewed preoperatively and postoperatively. We assessed whether gender, age, previous surgery, patella atla or trochlear dysplasia influenced patient satisfaction or patient functional outcome. RESULTS: The median Oxford Knee Score was 40 and the median Melbourne Patellofemoral Score was 21 postoperatively. Seventy-six percent of patients were satisfied, 10% unsure and 14% dissatisfied postoperatively. There was no radiological progression of tibiofemoral joint arthritis, using the Ahlback grading, in any patient. One patient, who was diagnosed with rheumatoid arthritis postoperatively, underwent revision to total knee replacement. There were no intraoperative lateral releases and no implant failures. Gender, age, the presence of trochlear dysplasia, patella alta or bilateral surgery did not influence patient outcome. Previous surgery did not correlate with outcome. CONCLUSION: In contrast to the current literature, the FPV shows promising early results. However, we cannot identify a subgroup of patients with superior outcomes.

Improved Accuracy of Component Positioning with Robotic-Assisted Unicompartmental Knee Arthroplasty: Data from a Prospective, Randomized Controlled Study.

BACKGROUND: Higher revision rates have been reported in patients who have undergone unicompartmental knee arthroplasty compared with patients who have undergone total knee arthroplasty, with poor component positioning identified as a factor in implant failure. A robotic-assisted surgical procedure has been proposed as a method of improving the accuracy of component implantation in arthroplasty. The aim of this prospective, randomized, single-blinded, controlled trial was to evaluate the accuracy of component positioning in unicompartmental knee arthroplasty comparing robotic-assisted and conventional implantation techniques. METHODS: One hundred and thirty-nine patients were randomly assigned to treatment with either a robotic-assisted surgical procedure using the MAKO Robotic Interactive Orthopaedic Arm (RIO) system or a conventional surgical procedure using the Oxford Phase-3 unicompartmental knee replacement with traditional instrumentation. A postoperative computed tomographic scan was performed at three months to assess the accuracy of the axial, coronal, and sagittal component positioning. RESULTS: Data were available for 120 patients, sixty-two who had undergone robotic-assisted unicompartmental knee arthroplasty and fifty-eight who had undergone conventional unicompartmental knee arthroplasty. Intraobserver agreement was good for all measured component parameters. The accuracy of component positioning was improved with the use of the robotic-assisted surgical procedure, with lower root mean square errors and significantly lower median errors in all component parameters (p < 0.01). The proportion of patients with component implantation within 2° of the target position was significantly greater in the group who underwent robotic-assisted unicompartmental knee arthroplasty compared with the group who underwent conventional unicompartmental knee arthroscopy with regard to the femoral component sagittal position (57% compared with 26%, p = 0.0008), femoral component coronal position (70% compared with 28%, p = 0.0001), femoral component axial position (53% compared with 31%, p = 0.0163), tibial component sagittal position (80% compared with 22%, p = 0.0001), and tibial component axial position (48% compared with 19%, p = 0.0009). CONCLUSIONS: Robotic-assisted surgical procedures with the use of the MAKO RIO lead to improved accuracy of implant positioning compared with conventional unicompartmental knee arthroplasty surgical techniques. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Satisfaction and functional outcome with "self-care" for the management of fifth metacarpal fractures.

BACKGROUND: Fifth metacarpal fractures are common and comprise a significant proportion of traditional orthopaedic fracture clinic workload. We reviewed the functional outcome and the satisfaction of patients managed with a new protocol that promoted "self-care" and resulted in the discharge of most of these patients from the emergency department with no further follow-up. METHODS: A retrospective study was performed of patients discharged with a fifth metacarpal fracture between April 2012 to October 2012. A postal questionnaire was sent to each patient, followed by a telephone call. Patient-reported outcome measures (EQ-5D, QuickDASH) and patient satisfaction were assessed. Of the 167 patients eligible for the study, 5 were excluded. Of the remaining 162, 64 were uncontactable or declined to participate. The mean follow-up time was 21.6 months (SD 1.9, range 18.1 to 24.7). RESULTS: The median EQ-5D health index score was 0.87 (IQR 0.74 to 1.00), and the median QuickDASH score was 2.3 (IQR 0 to 6.8). Seventy-nine (80.6 %) patients were satisfied with the outcome of their injury, while 83 (84.9 %) reported being satisfied with the process. There was no difference between those with a fracture or those without a fracture in EQ-5D (p = 0.307) or QuickDASH (p = 0.820). CONCLUSION: Fifth metacarpal fractures can be managed effectively through an Emergency Department protocol without any formal orthopaedic follow-up. This pathway lead to excellent patient-reported outcome measures and patient satisfaction. This protocol has reduced unnecessary hospital attendances for patients and increased the time available for clinicians to deal with more challenging injuries.

Diagnostic accuracy of the Thessaly test, standardised clinical history and other clinical examination tests (Apley's, McMurray's and joint line tenderness) for meniscal tears in comparison with magnetic resonance imaging diagnosis.

BACKGROUND: Reliable non-invasive diagnosis of meniscal tears is difficult. Magnetic resonance imaging (MRI) is often used but is expensive and incidental findings are problematic. There are a number of physical examination tests for the diagnosis of meniscal tears that are simple, cheap and non-invasive. OBJECTIVES: To determine the diagnostic accuracy of the Thessaly test and to determine if the Thessaly test (alone or in combination with other physical tests) can obviate the need for further investigation by MRI or arthroscopy for patients with a suspected meniscal tear. DESIGN: Single-centre prospective diagnostic accuracy study. SETTING: Although the study was performed in a secondary care setting, it was designed to replicate the results that would have been achieved in a primary care setting. PARTICIPANTS: Two cohorts of patients were recruited: patients with knee pathology (n = 292) and a control cohort with no knee pathology (n = 75). MAIN OUTCOME MEASURES: Sensitivity, specificity and diagnostic accuracy of the Thessaly test in determining the presence of meniscal tears. METHODS: Participants were assessed by both a primary care clinician and a musculoskeletal clinician. Both clinicians performed the Thessaly test, McMurray's test, Apley's test, joint line tenderness test and took a standardised clinical history from the patient. RESULTS: The Thessaly test had a sensitivity of 0.66, a specificity of 0.39 and a diagnostic accuracy of 54% when utilised by primary care clinicians. This compared with a sensitivity of 0.62, a specificity of 0.55 and diagnostic accuracy of 59% when used by musculoskeletal clinicians. The diagnostics accuracy of the other tests when used by primary care clinicians was 54% for McMurray's test, 53% for Apley's test, 54% for the joint line tenderness test and 55% for clinical history. For primary care clinicians, age and past history of osteoarthritis were both significant predictors of MRI diagnosis of meniscal tears. For musculoskeletal clinicians age and a positive diagnosis of meniscal tears on clinical history taking were significant predictors of MRI diagnosis. No physical tests were significant predictors of MRI diagnosis in our multivariate models. The specificity of MRI diagnosis was tested in subgroup of patients who went on to have a knee arthroscopy and was found to be low [0.53 (95% confidence interval 0.28 to 0.77)], although the sensitivity was 1.0. CONCLUSIONS: The Thessaly test was no better at diagnosing meniscal tears than other established physical tests. The sensitivity, specificity and diagnostic accuracy of all physical tests was too low to be of routine clinical value as an alternative to MRI. Caution needs to be exercised in the indiscriminate use of MRI scanning in the identification of meniscal tears in the diagnosis of the painful knee, due to the low specificity seen in the presence of concomitant knee pathology. Further research is required to determine the true diagnostic accuracy and cost-effectiveness of MRI for the detection of meniscal tears. TRIAL REGISTRATION: Current Controlled Trial ISRCTN43527822. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

A review of ligament augmentation with the InternalBrace™: the surgical principle is described for the lateral ankle ligament and ACL repair in particular, and a comprehensive review of other surgical applications and techniques is presented.

This article reviews the surgical decision-making considerations when preparing to undertake an anatomic ligament repair with augmentation using the InternalBrace™. Lateral ankle ligament stabilization of the Broström variety and ACL repair in particular are used to illustrate its application. The InternalBrace™ supports early mobilization of the repaired ligament and allows the natural tissues to progressively strengthen. The principle established by this experience has resulted in its successful application to other distal extremity ligaments including the deltoid, spring, and syndesmosis complex. Knee ligament augmentation with the InternalBrace™ has been successfully applied to all knee ligaments including anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), medial collateral ligament (MCL), lateral collateral ligament (LCL), anterolateral ligament (ALL), and patellofemoral ligament (PFL). The surgical technique and early results will be reviewed including multi-ligament presentations. Upper limb experience with acromioclavicular (AC) joint augmentation and ulnar collateral ligament (UCL) repair of the elbow with the InternalBrace™ will also be discussed. This article points to a change in orthopaedic practice positioning reconstruction as a salvage procedure that has additional surgical morbidity and should be indicated only if the tissues fail to heal adequately after augmentation and repair.

Influence of skin incision position on physiological and biochemical changes in tissue after primary total knee replacement - a prospective randomised controlled trial.

BACKGROUND: Influence of skin incision position on physiological and biochemical changes in tissue after primary total knee replacement. A prospective randomised controlled trial. The blood supply to the skin covering the anterior knee has been shown to arise predominantly from blood vessels on the medial side of the knee. Skin incisions for primary Total Knee Replacement (TKR) positioned medially therefore risk creating a large lateral skin flap that may be poorly perfused. Poorly perfused skin is likely to result in hypoxia at the wound edges and consequently may lead to delayed wound healing and complications. METHODS: We have carried out a randomised controlled trial (n = 20) to compare blood flow on both the medial and lateral sides of two commonly used skin incisions in TKR (midline and paramedian). We have also assessed interstitial biochemistry (glucose, pyruvate and lactate levels) in the presumed at risk lateral skin flap of both incision types. RESULTS: In both incision types tissue hyper-perfusion occurs post-operatively and is maintained for at least 3 days. We found no significant difference between blood flow between the two incision types on the medial side of the incision at either day 1 (p = 0.885) or day 3 post-op (p = 0.269), or, on the lateral side of the incision (p = 0.885 at day 1, p = 0.532 at day 3). Glucose levels are maintained post-operatively in the at risk lateral flap with only minimal changes. Lactate levels rise post-operatively and remain elevated for at least 24 hours. However, the levels did not reach levels suggestive of critical ischaemia in either incision group and no significant difference was observed between incision types. CONCLUSION: We conclude that the use of a paramedian incision results in only minimal biochemical changes, which are unlikely to alter wound healing. TRIAL REGISTRATIONS: ISRCTN06592799 .

Electromagnetic navigation in total knee arthroplasty-a single center, randomized, single-blind study comparing the results with conventional techniques.

We report on the results of a randomized study (n=200) to compare total knee arthroplasty performed using conventional instrumentation or electromagnetic computer assisted surgical technique. 92% of navigated and 85% of conventional knees were implanted within ±3° from neutral mechanical alignment; there was no statistically significant difference between these proportions. There was also no difference in femoral or tibial rotation assessed by CT scan. At 1year follow up there was no statistical difference between the two groups in American Knee Society Score, Oxford Knee Scores, patient satisfaction, quality of life, hospital length of stay, complication rates or other adverse events. Tourniquet time in the navigated group was longer. Proving value for navigation in total knee arthroplasty surgery remains a challenge.

Functional outcome and satisfaction with a "self-care" protocol for the management of mallet finger injuries: a case-series.

BACKGROUND: Mallet finger injuries are usually successfully treated non-operatively with a splint. Most patients are reviewed at least twice in a clinic after the initial presentation in A&E. A new protocol promoting "self-care" was introduced at our institution. Patients were provided with structured verbal and written information, and given access to a telephone helpline. METHODS: A prospective electronic patient record was used to identify all patients who presented to the emergency department with a mallet finger with a minimum six month follow-up. A satisfaction and patient reported outcome measure was administered via a postal questionnaire. The response rate was 36/47 (77%). RESULTS: The median QuickDASH score was 2.3 (IQR 0 to 4.6). All patients were satisfied with the treatment plan provided. Nine used the helpline and all were satisfied with information given. Although 13 patients reported some extensor lag, or bump, they had no functional limitation. Seven patients were reviewed by the general practitioner or other clinicians during their treatment period for issues such a skin care, splint size changes or sickness certification. Five were subsequently reviewed at the end of their treatment period in a clinic at their request, or their general practitioner, but did not require further surgical intervention. CONCLUSIONS: Self-care for mallet finger injuries, with adequate patient information and telephone back-up, leads to acceptable functional results and satisfaction. LEVEL OF EVIDENCE: III.

A new "virtual" patient pathway for the management of radial head and neck fractures.

BACKGROUND: Minimally displaced radial head and neck fractures are common and the outcome with conservative treatment is generally excellent. A new protocol was introduced to manage patients with these suspected fractures at a major urban hospital. Simple, undisplaced fractures without other associated injuries or instability were discharged with structured advice but no further face-to-face review. Patients with more complex injuries were reviewed at a "virtual clinic." The aim of this study was to examine the outcome of this process in terms of patient flow, satisfaction, reattendance, and reintervention. METHODS: The 202 eligible patients, who presented during a 1-year period from October 2011 to October 2012, were identified retrospectively from a prospectively collected administrative database. Mason type III and IV fractures were excluded. A questionnaire was administered by mail or phone call to assess satisfaction with the process, information received, and function. RESULTS: Twenty (10%) patients required face-to-face review in a clinic, whereas 182 (90%) were managed with direct discharge; 155 patients responded to the survey (77%). The overall satisfaction rate was 96% in the suspected fracture group and 87% in the definite fracture group (P = .08). Satisfaction with the information provided was 95%. Two (1%) required late surgical intervention. CONCLUSION: In this study, patients with suspected Mason I or II fractures were managed with limited face-to-face follow-up with high satisfaction rates. The reintervention rate was extremely low. This process has significant benefits to patients, who have fewer hospital visits, and to orthopaedic departments, which have more time to devote to complex cases.

Component rotational alignment in unexplained painful primary total knee arthroplasty.

BACKGROUND: Rotational malalignment of the components in total knee arthroplasty (TKA) can be a factor in poor outcomes but has yet to be defined. This study compares the rotational alignment of components in a cohort of 56 patients with unexplained pain following total knee arthroplasty with a matched control cohort of 56 patients with cemented Nex Gen Legacy posterior stabilised (LPS) flex fixed bearing TKA between March 2006 and May 2010. The aim of the study was to define an acceptable limit of rotation in total knee replacement. METHODS: Rotational alignment was calculated using the Berger protocol with post operative computerised tomography scanning. The alignment parameters measured were tibial and femoral component rotations and the combined component rotations and the component rotational mismatch. RESULTS: The two cohorts were demographically matched. Excessive internal rotation of the components was defined using the tenth percentile of rotations in the control cohort. Values of excessive internal rotation were 5.8° of the tibial component, 3.9° of the femoral component, 8.7° of combined rotation and 5.6° of the component mismatch. No significant difference was identified in excessive external rotation in any of the parameters. A significant difference in the mean rotations between the two cohorts was identified with internal rotation of the components in the painful cohort and external rotation on the control cohort. CONCLUSIONS: We identified internal rotation malalignment of the tibial (p=0.0003) and femoral (p=0.014) components individually as well as the combined component rotation (p=0.0003) and component rotation mismatch (p=0.0001) to be a factor in pain following TKA. External rotation of any of the component parameters was not identified to be a factor in painful TKA. This study adds to the understanding of rotational alignment in TKA and suggests limits of internal rotation alignment associated with painful Nex Gen Legacy posterior stabilised (LPS) flex fixed bearing TKA. LEVEL OF EVIDENCE: Level III.

Eliciting health state utilities for Dupuytren's contracture using a discrete choice experiment.

BACKGROUND AND PURPOSE: An internet-based discrete choice experiment (DCE) was conducted to elicit preferences for a wide range of Dupuytren's contracture (DC)-related health states. An algorithm was subsequently developed to convert these preferences into health state utilities that can be used to assess DC's impact on quality of life and the value of its treatments. METHODS: Health state preferences for varying levels of DC hand severity were elicited via an internet survey from a sample of the UK adult population. Severity levels were defined using a combination of contractures (0, 45, or 90 degrees) in 8 proximal interphalangeal and metacarpophalangeal joints of the index, middle, ring, and little fingers. Right-handed, left-handed, and ambidextrous respondents indicated which hand was preferable in each of the 10 randomly-selected hand-pairings comparing different DC severity levels. For consistency across comparisons, anatomically precise digital hand drawings were used. To anchor preferences onto the traditional 0-1 utility scale used in health economic evaluations, unaffected hands were assigned a utility of 1.0 whereas the utility for a maximally affected hand (i.e., all 8 joints set at 90 degrees of contracture) was derived by asking respondents to indicate what combination of attributes and levels of the EQ-5D-5L profile most accurately reflects the impact of living with such hand. Conditional logistic models were used to estimate indirect utilities, then rescaled to the anchor points on the EQ-5D-5L. RESULTS: Estimated utilities based on the responses of 1,745 qualified respondents were 0.49, 0.57, and 0.63 for completely affected dominant hands, non-dominant hands, or ambidextrous hands, respectively. Utility for a dominant hand with 90-degree contracture in t h e metacarpophalangeal joints of the ring and little fingers was estimated to be 0.89. Separately, reducing the contracture of metacarpophalangeal joint for a little finger from 50 to 12 degrees would improve utility by 0.02. INTERPRETATION: DC is associated with substantial utility decrements. The algorithms presented herein provide a robust and flexible framework to assess utility for varying degrees of DC severity.

Predisposition to accelerated Alzheimer-related changes in the brains of human immunodeficiency virus negative opiate abusers.

Cognitive impairment is a recognized effect of drug misuse, including the use of opiates. The pathological basis for this is unknown but the temporal and frontal cortices have been implicated. We have shown previously that deposits of hyperphosphorylated tau in drug user brains exceed those seen in age-matched controls. The present quantitative study of hyperphosphorylated tau and beta amyloid in drug user brains allows comparison with the related pathology in Alzheimer's disease. Brains were obtained from the Edinburgh Medical Research Council Brain Banks, comprising 39 human immunodeficiency virus negative drug users, five subjects with Alzheimer's disease and 37 age-matched, cognitively normal controls, all legally and ethically approved for research. Hyperphosphorylated tau positive (AT8, AT100) neuropil threads were significantly increased in the frontal and temporal cortex, and in the locus coeruleus, of drug users aged > 30 years (all P = 0.04). Under the age of 30 years, drug users showed a similar increase in neuropil threads compared with controls, but this reached significance only in the frontal cortex (P = 0.03). Immunopositivity for both three- and four-repeat tau was present in drug user brains. There was a direct relationship between the numbers of neuropil threads and of neurofibrillary tangles: neurofibrillary tangles were sparse in brains that had neuropil thread counts below 200 cm(2). Hyperphosphorylated tau positive neuropil threads increased at a faster rate in drug users than in controls and the levels of the phosphorylating enzyme, GSK-3, was raised in drug user brains. Beta amyloid (AB4, AB42 and 4G8) was raised in drug user brains (mainly as shadow plaques) but not significantly different from controls and there was no correlation between high beta amyloid and hyperphosphorylated tau in individual cases. Hyperphosphorylated tau levels correlated significantly (P = 0.038) with microglial activation in drug users but not in controls. The levels of hyperphosphorylated tau in drug users fell far short of those seen in Alzheimer's disease but overlapped with those in elderly controls. We conclude that drug users show early Alzheimer's disease-related brain pathology that may be the basis for cognitive impairment and that neuroinflammation is an early accompanying feature. This provides an opportunity to study the pathogenesis of tau pathology in the human brain.

Reactivation and mutation of newly discovered WU, KI, and Merkel cell carcinoma polyomaviruses in immunosuppressed individuals.

BACKGROUND: Infection with the human polyomaviruses BK (BKV) and JC (JCV) is almost ubiquitous, asymptomatic, and lifelong. However, reactivation during immunosuppression, associated with mutations in the transcriptional control region (TCR) that up-regulates viral replication, can cause life-threatening disease. In this study, we investigated whether the recently discovered WU and KI polyomaviruses (WUPyV and KIPyV) and Merkel cell polyomavirus (MCPyV) could, like BKV and JCV, persist, mutate, and reactivate in immunodeficient subjects. METHODS: Autopsy samples of lymphoid tissue from 42 AIDS-immunosuppressed subjects and 55 control samples were screened by polymerase chain reaction for all 5 polyomaviruses. TCR sequences from KIPyV and WUPyV recovered from both immunosuppressed and nonimmunosuppressed subjects were compared. RESULTS: Combined polyomavirus detection frequencies were much higher for the immunosuppressed group, compared with the nonimmunosuppressed group (35.7% vs. 3.6%), with viral loads in lymphoid tissues ranging from < or = 8.4 x 10(5) to > 1.5 x 10(5) viral genome copies per 10(6) cells. MCPyV was recovered from only 1 HIV-negative study subject. TCR sequences from reactivated WUPyV and KIPyV variants showed a number of point mutations and insertions that were absent in viruses recovered from respiratory tract specimens obtained from nonimmunosuppressed subjects. CONCLUSIONS: KIPyV and WUPyV show reactivation frequencies comparable to those of BKV and JCV during immunosuppression. TCR changes that potentially lead to transcriptional dysregulation may have pathogenic consequences equivalent in severity to those observed for JCV and BKV.

The effects of illicit drugs on the HIV infected brain.

Evidence accumulating from clinical observations, neuroimaging and neuropathological studies suggests that illicit drug abuse accentuates the adverse effects of HIV on the central nervous system (CNS). Experimental investigation in cell culture models supports this conclusion. Injecting drug abuse is also a risk factor for the acquisition of HIV infection, the incidence of which continues to rise in intravenous drug users (IVDU) even in countries with access to effective therapy. In order to understand the interactions of drug abuse and HIV infection, it is necessary to examine the effects of each insult in isolation before looking for their combined effects. This review traces progress in understanding the pathogenesis of HIV related CNS disorders before the introduction of effective therapy and compares the state of our knowledge now that effective therapy has significantly modified disease progression. The additional impact of intravenous drug abuse on HIV-associated brain disease, then and now, is also reviewed. Predictions for the future are discussed, based on what is known at present and on recently emerging data.

Impact of HIV on regional & cellular organisation of the brain.

There are many excellent reviews of HIV infection of the nervous system. However these all assume that the reader has a working knowledge of the structure and cellular architecture of the brain. It may be that specialised brain vocabulary represents an unwelcome hurdle for those scientists with expert knowledge of the effects of HIV in other cell systems and who wish to extend that interest to the brain. This review provides an introduction to the component structures and cells of the brain and an overview of their involvement in HIV/AIDS. HIV infection leads to death through its capacity to progressively devastate the immune system. Current anti-HIV therapy has achieved considerable success in halting and partially reversing this process. In the absence of treatment, the breakdown of immunity is marked by declining CD4 counts and increasing vulnerability to opportunistic infections. In parallel with these effects on the lymphoid system, the nervous system is frequently the site of an initially stealthy infection which leads ultimately to symptomatic disease in a significant proportion of HIV infected individuals. The most feared manifestation of central nervous system (CNS) involvement is dementia. Unfortunately, serial CD4 counts and measurement of blood viral load do not serve to identify or monitor early infection of brain tissue. Since effective anti-HIV therapy has not achieved eradication of virus from lymphoid tissues, and anti-HIV drugs do not enter the nervous system easily, it is hardly surprising that HIV infection of the nervous system continues to cause clinical problems. Even in treatment-compliant patients, a measurable degree of cognitive impairment may develop, signalling previous or present HIV-related brain injury. The cause of HIV associated dementia and cognitive disability remains poorly understood. Perhaps most significantly, the long-term consequences of clinically occult brain infection are unknown and will require further investigation.

Accelerated Tau deposition in the brains of individuals infected with human immunodeficiency virus-1 before and after the advent of highly active anti-retroviral therapy.

This study aims to investigate the influence of human immunodeficiency virus (HIV) infection on the neurodegenerative processes normally associated with ageing. We have looked for evidence of beta amyloid and hyperphosphorylated Tau deposition in HIV-infected subjects before and after the advent of highly active anti-retroviral therapy (HAART). In addition we have looked for evidence of axonal damage. We have compared these HIV-positive cases with age-matched controls and with older non-demented controls. We find no evidence of significant premature beta amyloid deposition in HIV-infected cases; however, we do observe elevated levels of hyperphosphorylated Tau in the hippocampus of many HIV-infected subjects, compared with age-matched controls. The greatest levels of hyperphosphorylated Tau are noted in HAART-treated subjects. Axonal damage marked by expression of beta amyloid pre-cursor protein (BAPP) was highly variable in all groups including control subjects. We surmise that HIV infection and/or the use of anti-retroviral therapy may predispose to accelerated neuroageing in the form of hyperphosphorylated Tau deposition in the hippocampus. Within the age groups studied these significant neuropathological changes remained subclinical and were not yet associated with cognitive impairment.

Neurobiology of multiple insults: HIV-1-associated brain disorders in those who use illicit drugs.

Despite two decades of research, certain aspects of HIV-related central nervous system (CNS) disease remain poorly understood. HIV targets microglia and macrophages within the CNS and enters the brain compartment early. However, HIV is there held in check apparently until the onset of significant immune compromise, when viral replication, microglial activation, neuronal damage, and cognitive impairment are likely to ensue. Illicit drug abuse continues to be a significant risk factor for HIV transmission worldwide. Whether HIV-related CNS disease is more prevalent or more severe in this risk group has long been debated. Drugs of abuse can of themselves cause immune suppression, blood-brain barrier breakdown, microglial activation, and neuronal injury. This review presents evidence that HIV associated CNS disorders are indeed accentuated in drug abusers. However, the advent of effective therapy has added a new dimension, which must be taken into consideration. Treated individuals are surviving much longer and HIV encephalitis and HIV-associated dementia have become much less common. However, more subtle forms of CNS damage are emerging. Examination of the brains of individuals who have been treated long term with highly active antiretroviral therapy (HAART) reveals a surprising degree of microglial activation, comparable at times to that seen formerly in milder cases of HIV encephalitis. In addition, these individuals show evidence of increased deposition of neurodegenerative proteins, particularly hyperphosphorylated tau. Similar observations have been made in young opiate abusers who are HIV negative. Taken together, these results suggest that neuroinflammation and neurodegeneration, which are clinically silent at present, may cause problems in the future in HAART-treated subjects.

Effects of human immunodeficiency virus encephalitis and drug abuse on the B lymphocyte population of the brain.

We aimed to assess the effects of human immunodeficiency virus (HIV) encephalitis (HIVE) on the B-lymphocyte population of the brain. We also tested the effects of intravenous opiate drug abuse because this is a major risk factor for infection, with known immunosuppressive properties. Immunohistochemistry was used to identify B lymphocytes in the brains of clinically well-characterized HIV-negative drug abusers, individuals with HIVE, and, for comparison, HIV-negative individuals with encephalitis. Perivascular and parenchymal B lymphocytes were studied in 11 regions of each brain. We found that despite a small apparent rise, the abuse of opiate drugs had no significant effect on the B-lymphocyte population of the brain. Individuals with HIVE were found to have a greater number of B lymphocytes in brain tissue than individuals with acquired immunodeficiency syndrome (AIDS) who had no central nervous system (CNS) pathology. However, in comparison to nonimmunocompromised individuals with encephalitis, the B-lymphocyte population of HIVE brains was greatly reduced. We suggest that this latter finding may be linked to declining CD4 T-lymphocyte levels in end-stage AIDS, and that CD4 T lymphocytes may be required for efficient entry of B lymphocytes to the CNS. The brain B-lymphocyte population correlated well with CD4 T-lymphocyte level in the blood, in cases with viral encephalitis. These findings suggest that systemic immune competence is required to mount a full B-lymphocyte response to viral CNS infections. Furthermore, we suggest that CD4 T lymphocytes may play a key role in the humoral immune response to viral infection of the brain.