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.     

Postoperative infection in cochlear implant patients.

OBJECTIVE: Recently, the association of meningitis with cochlear implants has raised concern over the safety of these devices. We examined the incidence of all postoperative infections in patients undergoing cochlear implant surgery.Study design and settings A retrospective chart review of all patients undergoing cochlear implants at a private tertiary referral center from 1993 to 2002 was performed. Cochlear implant surgeries in 462 adults and 271 children were reviewed. Patients with evidence of a postoperative infection or infectious complication related to cochlear implantation were identified, and data on patient characteristics, surgery, and treatment outcome were obtained. RESULTS: The overall incidence of postoperative infection in our cochlear implant series was 4.1%. Major infectious complications occurred in 3.0% of cases, and the majority of infections required surgical intervention. A history of chronic ear disease may increase the risk of infectious complications. There were no cases of meningitis. CONCLUSIONS: Cochlear implants remain a safe procedure with a low complication rate. The majority of infections can be managed without removing the implant device. Advances in surgical technique and flap design have decreased the occurrence of wound-related complications. However, identification of risk factors for infection and optimization of treatment regimens will further reduce the complications associated with postoperative infection.     

Effect of the TNF-alpha-promoter polymorphism on cardiac allograft rejection.

BACKGROUND: A polymorphism exists in the tumor necrosis factor alpha (TNF-alpha) promoter (position -308, G/A = TNFA1/TNFA2). The TNFA2 allele is associated with increased TNF-alpha production in vitro and has been reported to increase the risk of allograft rejection in pediatric recipients of cardiac transplantation. We examined the effect of the TNFA2 allele on the risk of allograft rejection in adult cardiac transplant recipients. METHODS: We prospectively analyzed 57 subjects (aged 54 +/- 11 years, 84% men, 49% ischemic) who underwent cardiac transplantation between October 1996 and July 2001. Patients were observed after transplantation (mean, 910 +/- 605 days) and the frequency of allograft rejection (biopsy Grade > or =2) in patients with the TNFA2 allele (Group A, n = 15) was compared with TNFA1 homozygotes (Group B, n = 42). Overall survival and time to rejection episodes also were compared between groups. RESULTS: The frequency of allograft rejection was similar between groups (Group A, 8/15 [56%]; Group B, 22/42 [52%]; p = 0.77). Time to rejection also was comparable (Group A, 17 +/- 11 days; Group B, 20 +/- 20 days, p = 0.74). Overall post-transplant survival was similar between groups (1- and 2-year percentage survival: Group A, 87% and 78%, Group B, 88% and 82%, p = 0.35). CONCLUSION: The TNFA2 allele was not associated with increased risk of rejection in adult cardiac transplant recipients. The impact of this polymorphism on overall post-transplant outcomes will require investigation in larger multicenter studies.     

Anesthetic management of a patient with congenital methemoglobinemia

A knowledge of congenital methemoglobinemia is essential to deliver a safe anesthetic to this group of patients. We report the case of a 33-year-old patient with congenital methemoglobinemia undergoing a gynecological procedure, and discuss the anesthetic implications. The etiology, pathophysiology, classification, diagnosis, clinical manifestations, anesthetic considerations, treatment options, and postoperative management are also discussed.     

Redefining prognosis in node-negative breast cancer: Can sentinel lymph node biopsy raise the threshold for systemic adjuvant therapy?

Sentinel lymph node (SLN) biopsy is a new standard of care for axillary node staging in breast cancer, which for the first time allows enhanced pathologic analysis on a routine basis. Although a number of retrospective studies, including our own series with 20-year follow-up, suggest that axillary nodal micrometastases found in this manner are prognostically significant, prospective trials now under way promise a definitive answer to this controversial subject. Enhanced pathology using serial sections and immunohistochemical staining identifies a high-risk minority of conventionally nodenegative patients who are converted to node-positive and thereby become candidates for systemic adjuvant chemotherapy. The developmental phase of SLN biopsy, now drawing to a close, has focused on the identification of this node-positive group. Enhanced pathology also identifies a majority of patients who are truly node-negative and whose expectation of long-term survival exceeds that of historic norms for node-negative breast cancer. The next era of SLN biopsy should focus on the characterization of this group. SLN biopsy in breast cancer has already extended the historic trend toward surgical conservatism. By defining more precisely a low-risk cohort of patients, SLN biopsy has the potential to initiate a trend toward medical conservatism as well.     

AC-Verletzungen: konservativ-funktionelle Therapie und Ergebnisse

Injuries involving the acromoclavicular joint account for more than 10% of all injuries to the shoulder girdle, making them the second most frequent type of shoulder injury. When categorized as Tossy I or II such injuries are generally treated conservatively, whereas Rockwood IV–VI injuries are treated operatively. There is still no agreement on the best way of treating Tossy class III injuries. More than 35 conservative treatments have been proposed, and over 50 operative methods. Regardless of the method of treatment applied, relatively good functional results are obtained. Persisting prominence of the clavicle cannot reliably be reduced by strapping, but the reduced shoulder strength that has been claimed to follow conservative treatment has not been verified by strength testing. Furthermore, after surgery rehabilitation takes longer, the period of inability to work and to engage in sporting activities is extended, and the complication rate is higher, in addition to which the costs of surgical treatment are higher. "Skillful neglect" of Tossy I–III injuries combined with brief immobilization of the shoulder joint, cryotherapy and functional treatment seems to be the method of choice even in patients whose work involves hard physical labour and in active athletes.     

Akromioklavikulargelenkverletzungen

There is some controversy over the treatment of acromioclavicular injuries. The use of the Rockwood classification as the basis for decisions on whether operative or nonoperative treatment is indicated is discussed critically, and the authors' preferred operative technique is described and illustrated by examples. We treat injuries classified according to the Rockwood classification as types I and II with conservative methods. In type III injuries the patient's age, job and free time activities determine whether or not surgery is indicated. In the case of type IV or type VI injuries we always perform temporary internal fixation of the acromioclavicular joint, using transarticular K-wire fixation or hookplate osteosynthesis. Satisfactory results of both operative and nonoperative treatment are reported in the literature. The authors' own results are presented.     

Selection of Women Aged 50–64 Yr for Bone Density Measurement

The fracture risk assessment tool from the World Health Organization (FRAX^®) estimates 10-yr major osteoporotic and hip fracture probabilities from multiple clinical risk factors and optionally femoral neck bone mineral density (BMD). FRAX without BMD has been proposed as a method to select postmenopausal women younger than 65 yr for BMD measurement, but the efficiency of this strategy and its concordance with National Osteoporosis Foundation (NOF) treatment guidelines is unknown. The osteoporosis self-assessment test (OST) is another simple screening tool based on age and weight alone. A historical cohort of 18,315 women aged 50–64 yr, drawn from the Manitoba Bone Density Program database, which contains clinical BMD results for the Province of Manitoba, Canada, was used to determine the performance of these screening tools in selecting postmenopausal women younger than 65 yr for BMD testing. FRAX was closely aligned with indicators of high fracture risk (area under the receiver operating characteristic curve [AUROC]: 0.89), whereas OST was better for detecting women with osteoporotic BMD (AUROC: 0.72). The combination of major fracture probability 10% or higher from FRAX without BMD or OST less than 1 identified 42% of women for BMD testing, capturing 72% of women meeting any NOF treatment criteria (90% of women with NOF criteria for high risk from FRAX or prior fracture). The negative predictive value to exclude qualification for treatment under the NOF criteria was 90%. These data may help to inform an evidence-based approach for targeting BMD testing in postmenopausal women younger than 65 yr under the NOF treatment guidelines.     

Collapsin Response Mediator Protein 4 Expression is Associated with Liver Metastasis and Poor Survival in Pancreatic Cancer

Background

Pancreatic cancer is an aggressive malignancy with one of the worst mortality rates of all cancers. Recently, collapsin response mediator proteins (CRMPs) were reported to be associated with proliferation, apoptosis, differentiation, and invasion in several cancers. However, CRMP expression and their role in pancreatic cancer have not been investigated. This study aimed to clarify the clinical significance of CRMPs in pancreatic cancer.

Methods

Expression of crmp genes in 11 pairs of pancreatic cancer and corresponding noncancerous pancreas tissues were examined by real-time RT-PCR. Knockdown of CRMP4 expression using siRNA was examined in pancreatic cancer cell lines to determine whether CRMP4 regulates cell proliferation and invasion in vitro. Furthermore, CRMP4 protein levels in primary tumors of pancreatic cancer (n = 53) were examined by immunohistochemistry and compared with the clinicopathological features of the tumors.

Results

Of all the CRMPs, only CRMP4 was differentially expressed in pancreatic cancer tissues (p = 0.008). CRMP4 knockdown using siRNA reduced cellular invasion, but did not affect proliferation. The expression of CRMP4 was detected immunohistochemically in 34 (64.2 %) of the 53 pancreatic cancer samples, and CRMP4 expression was correlated with severe venous invasion (p = 0.044), stage (p = 0.019), and liver metastasis (p = 0.021). Multivariate analyses suggested that venous invasion and CRMP4 overexpression were prognostic factors for survival.

Conclusions

Our results suggested that CRMP4 is significantly associated with poor prognosis by promoting liver metastasis and can serve as a novel therapeutic target for pancreatic cancer.

     

<Emphasis Type="Italic">KRAS</Emphasis> and <Emphasis Type="Italic">BRAF</Emphasis> Mutations in 203 Esophageal Squamous Cell Carcinomas: Pyrosequencing Technology and Literature Review

Background

Epidermal growth factor receptor (EGFR) signaling is one of the most promising targets for molecular-targeted therapies in esophageal squamous cell carcinoma (ESCC). Thus, the molecular diagnosis of KRAS and BRAF mutations is clinically important in therapeutic decision making. However, the frequency of KRAS and BRAF mutations in ESCCs remains inconclusive because of the limited sample sizes of previous studies (all N ≤ 80). Pyrosequencing is a nonelectrophoretic nucleotide extension sequencing technology that can be used for mutation testing.

Methods

The frequency of KRAS and BRAF mutations was examined using a nonbiased database of 203 resected ESCCs and a high-throughput pyrosequencing assay.

Results

The validity of the KRAS pyrosequencing method was initially demonstrated by detection of all 4 types of KRAS mutations [c.35G>T (codon 12 GGT>GTT), c.35G>A (codon 12 GGT>GAT), c.34G>T (codon 12 GGT>TGT), c.38G>A mutation (codon 13 GGC>GAC)], which had been previously diagnosed using Scorpion-ARMS technology, in 9 colon cancer tissues (9 of 9; 100 %). Similar results were demonstrated for BRAF mutational status in 3 colon cancer cell lines (HCT116, Colo201, and HT29), which were validated by Sanger dideoxy sequencing. Subsequently, the KRAS mutation was found to be extremely rare (1 of 203; 0.5 %), and the BRAF mutation was absent (0 of 203; 0 %), in the dataset of 203 ESCCs.

Conclusions

These results suggest that KRAS and BRAF mutations play a limited role in the development of ESCC and that mutation analysis is not useful as a screening test for sensitivity to anti-EGFR therapy in ESCC.