High-resolution MRI and micro-CT in an ex vivo rabbit anterior cruciate ligament transection model of osteoarthritis

OBJECTIVE: The aim of this study was to investigate the potential of using non-invasive, multi-modality imaging techniques to quantify disease progression in a rabbit model of experimentally induced osteoarthritis (OA). METHODS: High-resolution 4-T magnetic resonance imaging (MRI) and micro-computed tomography (micro-CT) techniques were implemented and validated in an ex vivo rabbit anterior cruciate ligament transection (ACLT) model of OA. A three-dimensional (3-D) rigid body registration technique was executed and evaluated to allow combined MR-CT analysis in co-registered image volumes of the knee. RESULTS: The 3-D MRI and micro-CT data formats made it possible to quantify cartilage damage, joint-space, and osseous changes in the rabbit ACLT model of OA. Spoiled gradient-recalled echo and fast-spin echo (FSE) sequences were jointly used to evaluate femorotibial cartilage and determine the sensitivity (78.3%) and specificity (95.3%) of 4-T MRI to detect clinically significant cartilage lesions. Overall precision error of the micro-CT technique for analysis of joint-space, volumetric bone mineral density (vBMD), and bone volume fraction (BV/TV) was 1.8%, 1.2%, and 2.0%, respectively. Co-registration of the 3-D data sets was achieved to within 0.36 mm for completed intermodality registrations, 0.22 mm for extrapolated intramodality registrations, and 0.50mm for extrapolated intermodality registrations. CONCLUSIONS: These results indicate that high-resolution 4-T MRI and micro-CT can be used to accurately quantify cartilage damage and calcified tissue changes in the rabbit ACLT model of OA. In addition, image volumes can be successfully co-registered to facilitate a comprehensive multi-modality examination of localized changes in both soft tissue and bone within the rabbit femorotibial joint.     

Reduced variability of acetabular cup positioning with use of an imageless navigation system

Positioning the acetabular component is one of the most important steps in total hip arthroplasty; malpositioned components can result in dislocations, impingement, limited range of motion, and increased polyethylene wear. Conventional surgery makes use of specialized alignment guides provided by the manufacturers of the implants. The use of mechanical guides has been shown to result in large variations of cup inclination and version. We investigated acetabular cup alignment with the nonimage-based hip navigation system compared with a conventional mechanically guided procedure in 12 human cadavers. Postoperative cup position relative to the pelvic reference plane was assessed in both groups with the use of a three-dimensional digitizing arm. In the navigated group, a median inclination of 45.5 degrees and a median anteversion of 21.9 degrees (goals, 45 degrees and 20 degrees) were reached. In the control group, the median inclination was 41.8 degrees and the median anteversion was 24.6 degrees. The ninetieth percentile showed a much wider range for the control group (36.1 degrees-51.8 degrees inclination, 15 degrees-33.5 degrees anteversion) than for the navigated group (43.9 degrees-48.2 degrees inclination, 18.3 degrees-25.4 degrees anteversion). This cadaver study shows that computer-assisted cup positioning using a nonimage-based hip navigation system allowed for more consistent placement of the acetabular component.     

Predictive Value of Four Kallikrein Markers for Pathologically Insignificant Compared With Aggressive Prostate Cancer in Radical Prostatectomy Specimens: Results From the European Randomized Study of Screening for Prostate Cancer Section Rotterdam

Background

Treatment decisions can be difficult in men with low-risk prostate cancer (PCa).

Objective

To evaluate the ability of a panel of four kallikrein markers in blood—total prostate-specific antigen (PSA), free PSA, intact PSA, and kallikrein-related peptidase 2—to distinguish between pathologically insignificant and aggressive disease on pathologic examination of radical prostatectomy (RP) specimens as well as to calculate the number of avoidable surgeries.

Design, setting, and participants

The cohort comprised 392 screened men participating in rounds 1 and 2 of the Rotterdam arm of the European Randomized Study of Screening for Prostate Cancer. Patients were diagnosed with PCa because of an elevated PSA ≥3.0 ng/ml and were treated with RP between 1994 and 2004.

Outcome measurements and statistical analysis

We calculated the accuracy (area under the curve [AUC]) of statistical models to predict pathologically aggressive PCa (pT3–T4, extracapsular extension, tumor volume >0.5 cm³, or any Gleason grade ≥4) based on clinical predictors (age, stage, PSA, biopsy findings) with and without levels of four kallikrein markers in blood.

Results and limitations

A total of 261 patients (67%) had significant disease on pathologic evaluation of the RP specimen. While the clinical model had good accuracy in predicting aggressive disease, reflected in a corrected AUC of 0.81, the four kallikrein markers enhanced the base model, with an AUC of 0.84 (p < 0.0005). The model retained its ability in patients with low-risk and very-low-risk disease and in comparison with the Steyerberg nomogram, a published prediction model. Clinical application of the model incorporating the kallikrein markers would reduce rates of surgery by 135 of 1000 patients overall and 110 of 334 patients with pathologically insignificant disease. A limitation of the present study is that clinicians may be hesitant to make recommendations against active treatment on the basis of a statistical model.

Conclusions

Our study provided proof of principle that predictions based on levels of four kallikrein markers in blood distinguish between pathologically insignificant and aggressive disease after RP with good accuracy. In the future, clinical use of the model could potentially reduce rates of immediate unnecessary active treatment.     

Transcranial Doppler versus transthoracic echocardiography for the detection of patent foramen ovale in patients with cryptogenic cerebral ischemia: A systematic review and diagnostic test accuracy meta‐analysis

Schwannomatosis is a genetic disorder characterized by the occurrence of multiple peripheral schwannomas. Segmental schwannomatosis is diagnosed when schwannomas are restricted to 1 extremity and is thought to be caused by genetic mosaicism. We studied 5 patients with segmental schwannomatosis through microstructural magnetic resonance neurography and mutation analysis of NF2, SMARCB1, and LZTR1. In 4 of 5 patients, subtle fascicular nerve lesions were detected in clinically unaffected extremities. Two patients exhibited LZTR1 germline mutations. This appears contrary to a simple concept of genetic mosaicism and suggests more complex and heterogeneous mechanisms underlying the phenotype of segmental schwannomatosis than previously thought. Ann Neurol 2016;80:625–628     

Four of the six Drosophila rhodopsin‐expressing photoreceptors can mediate circadian entrainment in low light

Light is the major stimulus for the synchronization of circadian clocks with day–night cycles. The light‐driven entrainment of the clock that controls rest–activity rhythms in Drosophila relies on different photoreceptive molecules. Cryptochrome (CRY) is expressed in most brain clock neurons, whereas six different rhodopsins (RH) are present in the light‐sensing organs. The compound eye includes outer photoreceptors that express RH1 and inner photoreceptors that each express one of the four rhodopsins RH3–RH6. RH6 is also expressed in the extraretinal Hofbauer–Buchner eyelet, whereas RH2 is only found in the ocelli. In low light, the synchronization of behavioral rhythms relies on either CRY or the canonical rhodopsin phototransduction pathway, which requires the phospholipase C‐β encoded by norpA (no receptor potential A). We used norpA^P24 cry⁰² double mutants that are circadianly blind in low light and restored NORPA function in each of the six types of photoreceptors, defined as expressing a particular rhodopsin. We first show that the NORPA pathway is less efficient than CRY for synchronizing rest–activity rhythms with delayed light–dark cycles but is important for proper phasing, whereas the two light‐sensing pathways can mediate efficient adjustments to phase advances. Four of the six rhodopsin‐expressing photoreceptors can mediate circadian entrainment, and all are more efficient for advancing than for delaying the behavioral clock. In contrast, neither RH5‐expressing retinal photoreceptors nor RH2‐expressing ocellar photoreceptors are sufficient to mediate synchronization through the NORPA pathway. Our results thus reveal different contributions of rhodopsin‐expressing photoreceptors and suggest the existence of several circuits for rhodopsin‐dependent circadian entrainment. J. Comp. Neurol. 524:2828–2844, 2016. © 2016 Wiley Periodicals, Inc.     

Rapidly acquired valgus deformity of the knee after osteochondroma resection in multiple hereditary exostoses pediatric patients: A report of two cases

Patients with multiple hereditary exostoses (MHE) often develop leg length discrepancies and limb alignment deformity around the knee as part of the natural course of the disease. Limb alignment deformity occurring post-resection of an osteochondroma has been described in one case report and only pertaining to the proximal medial tibia location. Here we describe the case of 2 patients with MHE, a 7-year-old female who underwent resection of distal femur and proximal tibia osteochondromas and a 9-year-old female who had a distal femur osteochondroma resected. Both patients developed rapidly progressive valgus knee deformity requiring surgical intervention. Excision of osteochondromas near the physis of a skeletally immature patient can cause overgrowth from the involved side of the growth plate resulting in a rapidly progressing unilateral coronal plane deformity. Surgeons should be aware of this potential complication and closely follow growing patients with serial alignment radiographs and counsel the family regarding the potential of acquired limb deformity and subsequent surgeries.     

Disappointing short-term results with the DePuy ASR XL metal-on-metal total hip arthroplasty

Outcomes of ultralarge-diameter femoral heads used in metal-on-metal (MOM) total hip arthroplasty (THA) are relatively unknown. This study reports on early failures of the ASR XL (Depuy, Warsaw, Ind) and assesses whether a correlation with cup positioning exists. A retrospective review of 70 consecutive MOM THAs with ultralarge-diameter femoral head and monoblock acetabular component was conducted. Minimum follow-up was 24 months. Of 70 THAs, 12 (17.1%) required revision within 3 years for pain (7), loosening (3), and squeaking (2). Three additional THAs noted squeaking, 2 noted grinding, and 3 additional hips had persistent pain. In total, 20 (28.6%) of 70 demonstrated implant dysfunction. Acetabular components for all symptomatic hips were in acceptable range of cup abduction and anteversion. The failures noted with this design do not correlate to cup placement. The high rate of implant dysfunction at early follow-up suggests serious concerns with the concept of MOM THA with an ultralarge-diameter femoral head paired with a monoblock acetabular cup.     

Muscarinic receptor subtypes in porcine detrusor: comparison with humans and regulation by bladder augmentation

The properties of muscarinic acetylcholine␣receptors of porcine and human bladder detrusor were␣compared in radioligand binding studies using [³H]quinuclidinylbenzylate as the radioligand. The receptor affinity for the radioligand and the density of␣muscarinic receptors was similar in male and female pigs and in humans (K _d = 35 ± 8 pM, B _max = 153 ± 30 fmol/mg protein). Atropine and subtype-selective antagonists had steep and monophasic competition curves in porcine and human detrusor with a rank order of potency of atropine ≫ hexahydro-sila-difenidol ≥ AF-DX 116 ≥ pirenzepine, indicating the presence of a␣homogeneous population of M₂ muscarinic receptors. In female pigs bladder outflow obstruction generated by partial urethral ligation or its surgical treatment by ileum augmentation or autoaugmentation did not significantly alter expression of muscarinic receptors or of α_2A-adrenoceptors, but the power was insufficient to exclude alterations of less than 60%. We conclude that porcine and human detrusor express muscarinic receptors of the M₂ subtype; despite these qualitative similarities the use of the porcine model may be limited by large biological variance with regard to quantitative receptor expression. Received: 9 June 1997 / Accepted: 27 October 1997     

p16INK4A immunoexpression and HPV in situ hybridization signal patterns: potential markers of high-grade cervical intraepithelial neoplasia

Integration of human papillomavirus (HPV) into the cell genome is considered to be an important event in the progression of cervical neoplasia. p16, also a useful biomarker of cervical intraepithelial neoplasia (CIN), shows increased immunoexpression with worsening grades of CIN. This study examines the correlation between p16 immunoexpression, grade of CIN, HPV type, and HPV in situ hybridization diffuse and punctate signal patterns (linked to episomal and integrated viral particles, respectively) in 44 cervical biopsies/LEEP excisions classified as CIN 1 and CIN 2/3. In 22 of 25 (88%) CIN 1 lesions, p16 immunoexpression was confined to the lower half of the epithelium, with sporadic to focal staining in 11 of 25 cases (44%). In CIN 2/3 lesions, 15 of 17 (88.2%) showed diffuse, two-thirds to full-thickness staining of the epithelium. High-risk HPV types were found in 20 (80%) CIN 1 lesions and 17 (100%) CIN 2/3 lesions. Punctate signals were detected in only 3 (13.6%) of high-risk HPV-positive CIN 1 lesions and in 17 of 17 (100%) CIN 2/3 lesions (P<0.001). p16 immunoexpression and the presence of punctate signal on HPV in situ hybridization correlated with the degree of cervical neoplasia (P<0.001). However, 3 cases of CIN 1 demonstrating punctate signals did not demonstrate a comparable CIN 2/3 p16 staining pattern. Similarly, two CIN 1 lesions with comparable CIN 2/3 p16 staining showed no evidence of viral integration. Both increased p16 immunoexpression and punctate signal correlate with CIN 2/3 grade, supporting the use of either, or both, tests to confirm CIN 2/3. Strong p16 immunostaining in CIN 1 appears independent of HPV punctate signal type.     

Intramedullary nailing of distal metaphyseal tibial fractures

BACKGROUND: The treatment of distal metaphyseal tibial fractures remains controversial. This study was performed to evaluate the results of intramedullary nailing of distal tibial fractures located within 5 cm of the ankle joint. METHODS: Over a sixteen-month period at two institutions, thirty-six tibial fractures that involved the distal 5 cm of the tibia were treated with reamed intramedullary nailing with use of either two or three distal interlocking screws. Ten fractures with articular extension were treated with supplementary screw fixation prior to the intramedullary nailing. Radiographs were reviewed to determine the immediate and final alignments and fracture-healing. The Short Form-36 (SF-36) and Musculoskeletal Function Assessment (MFA) questionnaires were used to evaluate functional outcome. RESULTS: Acceptable radiographic alignment, defined as <5 degrees of angulation in any plane, was obtained in thirty-three patients (92%). No patient had any change in alignment between the immediate postoperative and the final radiographic evaluation. Complications included one deep infection and one iatrogenic fracture at the time of the intramedullary nailing. Six patients could not be followed. The remaining thirty fractures united at an average of 23.5 weeks. Three patients with associated traumatic bone loss underwent a staged autograft procedure, and they had fracture-healing at an average of 44.3 weeks. The functional outcome was determined at a minimum of one year for nineteen patients and at a minimum of two years (average, 4.5 years) for fifteen patients. At one year, there were significant limitations in several domains despite fracture union and maintenance of alignment, but there was improvement in the MFA scores with time. CONCLUSIONS: Intramedullary nailing is an effective alternative for the treatment of distal metaphyseal tibial fractures. Simple articular extension of the fracture is not a contraindication to intramedullary fixation. Functional outcomes improve with time.