Incidence Rates of Surgery After Knee MRI: Association According to Referring Physician Type and Patient's Age and Sex.

BACKGROUND: The utility of magnetic resonance imaging (MRI) in the primary care setting is uncertain, with a perception that there is less likelihood for surgery after MRI ordered by general practitioners (GPs) when compared with orthopaedic surgeons and sports medicine physicians. Additionally, the influence of patient age and sex on subsequent surgical intervention is currently unknown. PURPOSE/HYPOTHESIS: The purpose of this study was to compare surgical incidence after MRI referrals by orthopaedic surgeons, GPs, and sports medicine physicians, including a subset analysis for GP patients based on type of approval given by the radiologist. The authors also wanted to explore the association of age and sex on subsequent surgical intervention. They hypothesized that surgical incidence after MRI ordered by orthopaedic surgeons and sports medicine physicians would be higher than after MRI ordered by GPs. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Knee MRI referrals by the 3 physician cohorts during May to December 2017 were assessed. For GP patients, the types of approval or recommendation from a radiologist were categorized. Subsequent surgical intervention status was then compared among referral groups up to 2 years after MRI. Associations of age and sex with surgical occurrence were also assessed. Chi-square test, analysis of variance, and univariate/multivariable logistic regression were used for statistical analysis. RESULTS: Overall, 407 referrals were evaluated (GP, n = 173; orthopaedic, n = 176; sports medicine, n = 58). Surgical incidence was not significantly higher for orthopaedic and sports medicine than GP referrals at 3 months (10%, 3%, and 6%, respectively; P = .23), 6 months (20%, 17%, and 15%; P = .49), and 2 years (30%, 35%, and 24%; P = .25). Surgical incidence for GP patients was higher after discussion with a radiologist or when evaluating specific pathology on prior imaging versus less defined reasons (30.4% vs 15.7%, respectively; P = .03). Surgical incidence was lower for older patients (11% vs 31% for >60 years vs all other age groups combined; P = .002), and women were less likely to undergo surgery than men (22% vs 35%, respectively; P = .008). CONCLUSION: Surgical incidence after MRI was likely appropriately lower for older patients. Lower incidence for female patients is of uncertain cause and warrants further study.

Postoperative Rehabilitation After Rotator Cuff Repair: A Web-Based Survey of AANA and AOSSM Members.

BACKGROUND: Postoperative rehabilitation after arthroscopic rotator cuff repair (ARCR) remains controversial and suffers from limited high-quality evidence. Therefore, appropriate use criteria must partially depend on expert opinion. HYPOTHESIS/PURPOSE: The purpose of the study was to determine and report on the standard and modified rehabilitation protocols after ARCR used by member orthopaedic surgeons of the American Orthopaedic Society for Sports Medicine (AOSSM) and the Arthroscopy Association of North America (AANA). We hypothesized that there will exist a high degree of variability among rehabilitation protocols. We also predict that surgeons will be prescribing accelerated rehabilitation. STUDY DESIGN: Cross-sectional study; Level of evidence, 4. METHODS: A 29-question survey in English language was sent to all 3106 associate and active members of the AOSSM and the AANA. The questionnaire consisted of 4 categories: standard postoperative protocol, modification to postoperative rehabilitation, operative technique, and surgeon demographic data. Via email, the survey was sent on September 4, 2013. RESULTS: The average response rate per question was 22.7%, representing an average of 704 total responses per question. The most common immobilization device was an abduction pillow sling with the arm in neutral or slight internal rotation (70%). Surgeons tended toward later unrestricted passive shoulder range of motion at 6 to 7 weeks (35%). Strengthening exercises were most commonly prescribed between 6 weeks and 3 months (56%). Unrestricted return to activities was most commonly allowed at 5 to 6 months. The majority of the respondents agreed that they would change their protocol based on differences expressed in this survey. CONCLUSION: There is tremendous variability in postoperative rehabilitation protocols after ARCR. Five of 10 questions regarding standard rehabilitation reached a consensus statement. Contrary to our hypothesis, there was a trend toward later mobilization.

Prescribing competence of junior doctors: does it add up?

BACKGROUND: Prescribing errors complicate a significant number of paediatric admissions. Ongoing training and monitoring of prescribing competency in junior doctors has occurred in Cardiff since 2001, alongside national measures aimed at improving training and competency. AIM: Ongoing monitoring of junior doctors' prescribing competency to assess the effect of these national and local initiatives. METHODS: Junior doctors receive training and subsequent assessment on prescribing competency at induction. A 1 h bleep-free session concerning paediatric prescribing precedes completion of four prescribing tasks. British National Formulary for children and calculators are provided. Those scoring 0 or 1 are retrained before prescribing is permitted. Our previously published data of doctors between 2001 and 2004 was compared with assessment in 2007. RESULTS: 30 junior doctors were assessed in 2007 (32 in 2001-2004). All four questions were answered correctly by 22/30, compared to 10/32 (31%) in 2001-2004. The mean score in 2007 was 93.3% compared to 57.8% previously (see table 1). Comparison of means with previous results demonstrated statistically significant improvement with a mean difference of 36% (95% CI 24 to 47). In 2007, eight (27%) doctors got just one question wrong and no doctor answered all questions incorrectly. In 2001-2004, 22/32 (67%) made at least one error during previous assessment, and one doctor answered all questions incorrectly. Table 1Prescribing assessment scores in 2001-2004 and 2007 Answer scores2001-2004 (n=32)2007 (n=30)All questions correct10 (31%)22 (73%)One incorrect08 (27%)Two incorrect13 (41%)0Three incorrect8 (25%)0All questions incorrect1 (3%)0 CONCLUSION: Ongoing monitoring of junior doctors' prescribing ability has demonstrated improvements which may be due to local and national training initiatives.

Glenohumeral chondrolysis after shoulder arthroscopy associated with continuous bupivacaine infusion.

PURPOSE: To determine the incidence of glenohumeral chondrolysis associated with the use of a continuous-infusion device in shoulder arthroscopy. METHODS: A consecutive series of patients undergoing arthroscopic glenohumeral surgery with a postoperative continuous-infusion pump inserted into either the glenohumeral joint or subacromial space were evaluated for chondrolysis. Two pump types were used: group 1 received 100 mL of 0.5% bupivacaine without epinephrine infused at 2.08 mL/h, and group 2 received 270 mL of 0.5% bupivacaine without epinephrine infused at 4.16 mL/h. RESULTS: We followed up 65 patients at a mean of 40 months. Of these, 29 had glenohumeral catheters (13 in group 1 and 16 in group 2) and 36 had subacromial catheters (19 in group 1 and 17 in group 2). The overall postoperative Constant, American Shoulder and Elbow Surgeons, Rowe, Single Assessment Numeric Evaluation, and Simple Shoulder Test scores were 84, 87, 77, 86, and 10, respectively, in those with glenohumeral catheters and 93, 94, 95, 89, and 11, respectively, in those with subacromial catheters. Three glenohumeral catheter patients were diagnosed with chondrolysis, all in group 2. CONCLUSIONS: Chondrolysis developed in 3 of 16 patients (19%) with glenohumeral joint infusion of 0.5% bupivacaine without epinephrine at 4.16 mL/h for 65 hours. No patient using a 2.08-mL/h reservoir for 48 hours into the glenohumeral joint and no patient with a subacromial infusion device had chondrolysis. Clinical symptoms and radiographic evidence of chondrolysis developed before 12 months after surgery. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Cyclic load and failure behavior of arthroscopic knots and high strength sutures.

PURPOSE: To compare the biomechanical performance of several different sutures by evaluating knot security and load to failure strength using different arthroscopic knots. METHODS: Eight different No. 2 sutures (Ethibond [Ethicon, Somerville, NJ], FiberWire [Arthrex, Naples, FL], Orthocord [DePuy-Mitek, Norwood, MA], Hi-Fi [ConMed Linvatec, Largo, FL], Ultrabraid [Smith & Nephew, Andover, MA], ForceFiber [Stryker Endoscopy, San Jose, CA], MagnumWire [ArthroCare, Sunnyvale, CA], and MaxBraid PE [Arthrotek, Warsaw, IN]) were tied arthroscopically into standardized loops using 6 different knots (Weston, Tennessee slider, Duncan, SMC, Revo, and San Diego knot) 10 times each. The suture loops were pretensioned to 10N, cycled between 10N and 45N for 1,000 cycles, and loaded to failure. The failure load for each suture, each knot, and slippage trend during cyclic loading was recorded. RESULTS: The Revo and SMC knots (group A) were stronger than the Tennessee and San Diego knots (group B), which were stronger than the Weston knot, which was stronger than the Duncan loop (P < .05). This pattern also coincided with the loads at which these knots slipped. Evaluating the sutures showed that Ethibond had lower failure loads than all other sutures and FiberWire showed statistically higher loads (P < .05). Duncan loops (97.5%) and Weston knots (86.3%) slipped more than other knots (P < .001), while the SMC and Revo knots slipped least. Ethibond sutures were least likely to slip. CONCLUSIONS: The Duncan loop and Weston knot were more likely to slip than all other knots, and caution should be exercised when tying them with high-strength sutures. The Revo, Tennessee slider, San Diego, and SMC knots were least likely to slip (P < .001). CLINICAL RELEVANCE: While stronger than braided polyester sutures, newer sutures containing ultra-high molecular weight polyethylene have a greater tendency to slip. Backing up knots with 4 reversed half hitches with switched posts does not guarantee knot security.

FasT-Fix meniscal repair: mid-term results.

PURPOSE: The purpose of this study was to evaluate the clinical success of the FasT-Fix meniscal repair device (Smith & Nephew Endoscopy, Andover, MA) associated with an accelerated rehabilitation program. METHODS: A prospectively collected consecutive series of meniscal repairs performed with the FasT-Fix device was studied. The Lysholm, Tegner, Cincinnati, and International Knee Documentation Committee activity scores, along with the clinical examination findings and adverse events, were recorded for all patients. Associated procedures were recorded. An accelerated postoperative rehabilitation program was followed, independent of concurrent anterior cruciate ligament surgery. RESULTS: Forty-one meniscal repairs were performed, with an average follow-up of 30.7 months (range, 12 to 58 months). Twenty-nine of 41 repairs were performed in conjunction with anterior cruciate ligment reconstruction. The other repairs were in stable knees. There were 26 medial and 15 lateral meniscus repairs. Both menisci were repaired in 5 knees. Repeat arthroscopies were performed for 12 repairs and 7 (17%) were found to have failed. The preoperative and postoperative Lysholm, Tegner, Cincinnati, and International Knee Documentation Committee activity scores were 47.3 and 87.4, 3.4 and 7.2, 38.7 and 82.8, and 2.3 and 3.4, respectively. CONCLUSIONS: The FasT-Fix meniscal repair associated with an accelerated rehabilitation program resulted in clinically effective meniscal repair in 83% at the time of follow-up. Clinical outcome measures all improved. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Suture anchor materials, eyelets, and designs: update 2008.

PURPOSE: Our purpose was to evaluate recently introduced sutures and suture anchors for single pull load to failure strength and failure mode. METHODS: Suture anchors were tested in fresh porcine metaphyseal cortex and cancellous troughs using an established protocol. An Instron machine applied tensile loads parallel to the axis of insertion at a rate of 12.5 mm per second until failure and mean anchor failure strengths were calculated. The mode of failure was recorded (anchor pullout, suture eyelet cut out, or suture failure). Anchors tested included the Kinsa, Kinsa RC, BioRaptor 2.3 PK, TwinFix PK FT 5.5 and 6.5, BioCleat, Healix Peek, VersaLok, BioKnotless, BioKnotless BR, Corkscrew FT III, SwiveLock C, and PEEK SutureTak. RESULTS: The mean cortical failure loads were as follows: Kinsa (219 N), Kinsa RC (222 N), BioRaptor 2.3 PK (172 N), TwinFix PK FT 5.5 (491 N) and 6.5 (503 N), BioCleat (218 N), Healix Peek (407 N), VersaLok (376 N), BioKnotless (249 N), BioKnotless BR (265 N), Corkscrew FT III (386 N), SwiveLock C (712 N), and PEEK SutureTak (168 N). Pullout was the predominant failure mode for the VersaLok, BioKnotless, BioKnotless BR, and BioRaptor 2.3PK anchors. Eyelet failure was the predominant failure mode for the Kinsa, Kinsa RC, BioCleat, Healix Peek, Corkscrew FT III, SwiveLock C, and PEEK SutureTak. CONCLUSIONS: The newer anchors showed markedly increased load to failure strengths. Two or more high-strength sutures are commonly used as well as new anchor materials (PEEK and Biocryl Rapide), new eyelet designs, and the increased use of a "knotless" concept. CLINICAL RELEVANCE: An anchor which fails principally by pull out at a low load to failure is at risk for creating an intra-articular loose body.

Analyzer-based imaging of spinal fusion in an animal model.

Analyzer-based imaging (ABI) utilizes synchrotron radiation sources to create collimated monochromatic x-rays. In addition to x-ray absorption, this technique uses refraction and scatter rejection to create images. ABI provides dramatically improved contrast over standard imaging techniques. Twenty-one adult male Wistar rats were divided into four experimental groups to undergo the following interventions: (1) non-injured control, (2) decortication alone, (3) decortication with iliac crest bone grafting and (4) decortication with iliac crest bone grafting and interspinous wiring. Surgical procedures were performed at the L5-6 level. Animals were killed at 2, 4 and 6 weeks after the intervention and the spine muscle blocks were excised. Specimens were assessed for the presence of fusion by (1) manual testing, (2) conventional absorption radiography and (3) ABI. ABI showed no evidence of bone fusion in groups 1 and 2 and showed solid or possibly solid fusion in subjects from groups 3 and 4 at 6 weeks. Metal artifacts were not present in any of the ABI images. Conventional absorption radiographs did not provide diagnostic quality imaging of either the graft material or fusion masses in any of the specimens in any of the groups. Synchrotron-based ABI represents a novel imaging technique which can be used to assess spinal fusion in a small animal model. ABI produces superior image quality when compared to conventional radiographs.

Diffraction-enhanced imaging of a porcine eye.

BACKGROUND: Diffraction-enhanced imaging (DEI) is a synchrotron-based x-ray imaging technique that has dramatically improved contrast over standard x-ray imaging techniques. It is possible to acquire images that analyze the x-ray refraction and the apparent absorption (elimination of small-angle scattering) of the object. METHODS: Three formalin-fixed porcine eyes were studied at the National Synchrotron Light Source using DEI. Conventional absorption-type radiography was conducted for comparison. RESULTS: Conventional absorption radiography did not yield significant detail of the eye anatomy. DEI showed excellent characterization of many ocular structures. The cornea, iris, lens, retina, optic nerve, as well as choroidal vasculature and the ampullae of the vortex veins could all be visualized. INTERPRETATION: DEI represents a novel, high-resolution imaging technique that has excellent characterization of ocular anatomy. Further application of this imaging modality will be undertaken to study cataract and choroidal tumors and to examine ocular surface structures, such as the extraocular muscle insertions, more closely.

Diffraction-enhanced imaging of the rat spine.

INTRODUCTION: Diffraction-enhanced imaging (DEI) uses monochromatic synchrotron X-rays to image tissue. This technique has been shown to produce superior bony and soft tissue characterization when compared with conventional absorption radiography. Application of this imaging modality is under investigation, and this study represents the first DEI analysis of the vertebral column. METHODS: Four male Wistar rats were studied. Spine muscle blocks were imaged in 3 of the rats after thoracic laminectomy (n = 1), after lumbar laminectomy (n = 1), and in a control condition (n = 1). The fourth rat was imaged as a whole animal control. Conventional radiography and synchrotron-supported DEI at 40 keV were performed on all specimens. We compared images side by side, using a nonvalidated subjective assessment technique. RESULTS: DEI produced superior visualization of the vertebral anatomy, compared with conventional absorption radiography for all specimens. Greater bony and soft tissue detail was noted, with improved image contrast. In addition to imaging the anatomical structures, DEI showed the polyglactin suture material used for fascial closure in the 2 animals that underwent surgery. Artifact from air bubbles was present on DEI images but not on plain radiographs. CONCLUSIONS: This represents the first use of DEI, a novel imaging modality, to image the vertebral column. It provides excellent anatomic detail with superior contrast and visualization of both bone and soft tissue when compared with conventional radiography. Future applications of this investigational technique may include analysis of spinal fusion as well as degenerative and neoplastic conditions of the spine.

Using annotated peptide mass spectrum libraries for protein identification.

A system for creating a library of tandem mass spectra annotated with corresponding peptide sequences was described. This system was based on the annotated spectra currently available in the Global Proteome Machine Database (GPMDB). The library spectra were created by averaging together spectra that were annotated with the same peptide sequence, sequence modifications, and parent ion charge. The library was constructed so that experimental peptide tandem mass spectra could be compared with those in the library, resulting in a peptide sequence identification based on scoring the similarity of the experimental spectrum with the contents of the library. A software implementation that performs this type of library search was constructed and successfully used to obtain sequence identifications. The annotated tandem mass spectrum libraries for the Homo sapiens, Mus musculus, and Saccharomyces cerevisiae proteomes and search software were made available for download and use by other groups.

Hand trauma in shop class.

The environment and equipment used in shop class are potential sources of serious injury. There has been little published to date on injuries sustained in shop class, with no reports examining injuries to the hand. The authors report a case series collected from a health records database at a pediatric and hand surgery referral center. Fifteen patients who sustained injuries to their wrist or hand in shop class were identified. Sixty percent of the injuries were caused by table saws. Eighty percent required treatment from a hand surgeon. Sixty-seven percent of patients sustained a serious injury in the form of amputation or tendon or neurovascular injury. Most of the patients had functional deficits at final follow-up. Shop class is a setting where serious hand trauma can occur. School administrators and educators should direct efforts at preventing these injuries. Parents and students must recognize the risks associated with shop class. Physicians should be prepared for severe injuries and the frequent need for hand surgical consultation.

Spontaneous spinal epidural hematoma during pregnancy.

BACKGROUND: Spontaneous spinal epidural hematoma is a rare phenomenon that has no distinct etiology. Spontaneous spinal epidural hematoma (SSEH) during pregnancy is extremely rare. We present what we believe to be the fifth reported case of spontaneous spinal epidural hematoma associated with pregnancy in the English literature. METHODS: A 31-year-old female presented with acute onset of paraplegia at 32 weeks of pregnancy. The patient had a T2 sensory level and complete paralysis of all lower extremity motor groups. Magnetic resonance imaging of the thoracic spine showed an acute epidural hematoma posterior to the thoracic spinal cord between the second and fourth thoracic vertebrae. RESULTS: The patient was taken to the operating room were her child was delivered by caesarean section. She then underwent a posterior laminectomy and evacuation of a spinal epidural hematoma. Follow-up selective spinal angiography was negative for any vascular malformation. The patient gradually recovered lower extremity function and was independently ambulating at six month follow-up. Voluntary bowel and bladder function returned within four months but twice daily intermittent catheterization remained necessary for excessive post-void residual urine. CONCLUSIONS: Spontaneous spinal epidural hematoma in pregnancy is a rare phenomenon. It is postulated that elevated venous pressure associated with pregnancy may be a contributing factor. In the reported cases of SSEH in pregnancy most patients presented with acute symptoms, thoracic location and profound neurological deficits but, with prompt surgical treatment, generally had good long term recovery.

An improved model for prediction of retention times of tryptic peptides in ion pair reversed-phase HPLC: its application to protein peptide mapping by off-line HPLC-MALDI MS.

The proposed model is based on the measurement of the retention times of 346 tryptic peptides in the 560- to 4,000-Da mass range, derived from a mixture of 17 protein digests. These peptides were measured in HPLC-MALDI MS runs, with peptide identities confirmed by MS/MS. The model relies on summation of the retention coefficients of the individual amino acids, as in previous approaches, but additional terms are introduced that depend on the retention coefficients for amino acids at the N-terminal of the peptide. In the 17-protein mixture, optimization of two sets of coefficients, along with additional compensation for peptide length and hydrophobicity, yielded a linear dependence of retention time on hydrophobicity, with an R2 value about 0.94. The predictive capability of the model was used to distinguish peptides with close m/z values and for detailed peptide mapping of selected proteins. Its applicability was tested on columns of different sizes, from nano- to narrow-bore, and for direct sample injection, or injection via a pre-column. It can be used for accurate prediction of retention times for tryptic peptides on reversed-phase (300-A pore size) columns of different sizes with a linear water-ACN gradient and with TFA as the ion-pairing modifier.

Implementation of an algorithm for modeling disulfide bond patterns using mass spectrometry.

The paper describes the implementation of a software system based on the Fenyö disulfide bond assignment algorithm. The system allows an investigator to enter data derived from mass spectrum peak assignments, a target protein sequence and other experimental conditions. The output of the system is the set of disulfide bonding pattern models that are consistent with the experimental evidence. The software and code are available through a public web site, which also has a functioning, publicly accessible version of the disulfide bond modeler. This implementation was tested as part of a project to check homology-based assignments disulfide bonding patterns of human integrins.

Tissue distribution and functional expression of a cDNA encoding a novel mixed lineage kinase.

Hypertrophy is an adaptive response of the heart to myocardial injury or hemodynamic overload that may progress and contribute to cardiac decompensation and eventually to heart failure. The signaling pathways controlling this response in the cardiac myocyte are poorly understood. A data mining effort of a human failed heart cDNA library was undertaken in an effort to identify novel signaling molecules involved in cardiac hypertrophy. This effort identified a novel kinase (MLK7) homologous to the mixed lineage kinase family of proteins. The mixed lineage kinases are mitogen-activated protein kinase kinase kinases (MAPKKKs) which activate stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 kinase pathways. They contain a catalytic domain with homology to both serine/threonine and tyrosine-specific kinases and a dual leucine zipper. MLK7 is identical to leucine zipper and sterile-alpha motif protein kinase (ZAK) through the leucine zipper domain but has a completely divergent COOH-terminus and shares approximately 40% homology with the other MLKs overall. Expression of MLK7 mRNA is most abundant in skeletal muscle and heart, with expression restricted to the cardiac myocyte. The recombinant histidine tagged MLK7 expressed and purified from insect cells exhibited serine/threonine kinase activity in vitro with myelin basic protein as substrate. When expressed in cardiac myocytes, MLK7 activated SAPK/JNK1, and ERK and p38 to a lesser extent. Additionally, MLK7 altered fetal gene expression and increased protein synthesis in cardiac myocytes. These data suggest that MLK7 is a new member of the mixed lineage kinase family that modulates cardiac SAPK/JNK pathway and may play a role in cardiac hypertrophy and progression to heart failure.

A 7-kDa prion protein (PrP) fragment, an integral component of the PrP region required for infectivity, is the major amyloid protein in Gerstmann-Sträussler-Scheinker disease A117V.

Gerstmann-Sträussler-Scheinker disease (GSS) is a cerebral amyloidosis associated with mutations in the prion protein (PrP) gene (PRNP). The aim of this study was to characterize amyloid peptides purified from brain tissue of a patient with the A117V mutation who was Met/Val heterozygous at codon 129, Val(129) being in coupling phase with mutant Val117. The major peptide extracted from amyloid fibrils was a approximately 7-kDa PrP fragment. Sequence analysis and mass spectrometry showed that this fragment had ragged N and C termini, starting mainly at Gly88 and Gly90 and ending with Arg148, Glu152, or Asn153. Only Val was present at positions 117 and 129, indicating that the amyloid protein originated from mutant PrP molecules. In addition to the approximately 7-kDa peptides, the amyloid fraction contained N- and C-terminal PrP fragments corresponding to residues 23-41, 191-205, and 217-228. Fibrillogenesis in vitro with synthetic peptides corresponding to PrP fragments extracted from brain tissue showed that peptide PrP-(85-148) readily assembled into amyloid fibrils. Peptide PrP-(191-205) also formed fibrillary structures although with different morphology, whereas peptides PrP-(23-41) and PrP-(217-228) did not. These findings suggest that the processing of mutant PrP isoforms associated with Gerstmann-Sträussler-Scheinker disease may occur extracellularly. It is conceivable that full-length PrP and/or large PrP peptides are deposited in the extracellular compartment, partially degraded by proteases and further digested by tissue endopeptidases, originating a approximately 7-kDa protease-resistant core that is similar in patients with different mutations. Furthermore, the present data suggest that C-terminal fragments of PrP may participate in amyloid formation.

Senile dementia associated with amyloid beta protein angiopathy and tau perivascular pathology but not neuritic plaques in patients homozygous for the APOE-epsilon4 allele.

Amyloid beta protein deposition in cortical and leptomeningeal vessels, causing the most common type of cerebral amyloid angiopathy, is found in sporadic and familial Alzheimer's disease (AD) and is the principal feature in the hereditary cerebral hemorrhage with amyloidosis, Dutch type. The presence of the Apolipopriotein E (APOE)-epsilon4 allele has been implicated as a risk factor for AD and the development of cerebral amyloid angiopathy in AD. We report clinical, pathological and biochemical studies on two APOE-epsilon4 homozygous subjects, who had senile dementia and whose main neuropathological feature was a severe and diffuse amyloid angiopathy associated with perivascular tau neurofibrillary pathology. Amyloid beta protein and ApoE immunoreactivity were observed in leptomeningeal vessels as well as in medium-sized and small vessels and capillaries in the parenchyma of the neocortex, hippocampus, thalamus, cerebellum, midbrain, pons, and medulla. The predominant peptide form of amyloid beta protein was that terminating at residue Val40, as determined by immunohistochemistry, amino acid sequence and mass spectrometry analysis. A crown of tau-immunopositive cell processes was consistently present around blood vessels. DNA sequence analysis of the Amyloid Precursor Protein gene and Presenilin-1 (PS-1) gene revealed no mutations. In these APOE-epsilon4 homozygous patients, the pathological process differed from that typically seen in AD in that they showed a heavy burden of perivascular tau-immunopositive cell processes associated with severe amyloid beta protein angiopathy, neurofibrillary tangles, some cortical Lewy bodies and an absence of neuritic plaques. These cases emphasize the concept that tau deposits may be pathogenetically related to amyloid beta protein deposition.