Adipose stem cells exhibit mechanical memory and reduce fibrotic contracture in a rat elbow injury model.

Fibrosis is driven by a misdirected cell response causing the overproduction of extracellular matrix and tissue dysfunction. Numerous pharmacological strategies have attempted to prevent fibrosis but have attained limited efficacy with some detrimental side effects. While stem cell treatments have provided more encouraging results, they have exhibited high variability and have not always improved tissue function. To enhance stem cell efficacy, we evaluated whether mechanical memory could direct cell response. We hypothesized that mechanically pre-conditioning on a soft matrix (soft priming) will delay adipose-derived stem cell (ASC) transition to a pro-fibrotic phenotype, expanding their regenerative potential, and improving healing in a complex tissue environment. Primary ASCs isolated from rat and human subcutaneous fat exhibited mechanical memory, demonstrated by a delayed cell response to stiffness following two weeks of soft priming including decreased cell area, actin coherency, and extracellular matrix production compared to cells on stiff substrates. Soft primed ASCs injected into our rat model of post-traumatic elbow contracture decreased histological evidence of anterior capsule fibrosis and increased elbow range-of-motion when evaluated by joint mechanics. These findings suggest that exploiting mechanical memory by strategically controlling the culture environment during cell expansion may improve the efficacy of stem cell-based therapies targeting fibrosis.

Temporal Patterns of Motion in Flexion-extension and Pronation-supination in a Rat Model of Posttraumatic Elbow Contracture.

BACKGROUND: The elbow is highly susceptible to contracture, which affects up to 50% of patients who experience elbow trauma. Previously, we developed a rat model to study elbow contracture that exhibited features similar to the human condition, including persistently decreased ROM and increased capsule thickness/adhesions. However, elbow ROM was not quantitatively evaluated over time throughout contracture development and subsequent mobilization of the joint. QUESTIONS/PURPOSES: The purposes of this study were (1) to quantify the time-dependent mechanics of contracture, including comparison of contracture after immobilization and free mobilization; and (2) to determine what changes occur in capsule and joint surface morphology that may support the altered joint mechanics. METHODS: A total of 96 male Long-Evans rats were randomized into control and injury (unilateral soft tissue injury/immobilization) groups. Flexion-extension and pronation-supination joint mechanics (n = 8/group) were evaluated after 3, 7, 21, or 42 days of immobilization (IM) or after 42 days of IM with either 21 or 42 days of free mobilization (63 or 84 FM, respectively). After measuring joint mechanics, a subset of these limbs (n = 3/group) was prepared for histologic analysis and blinded sections were scored to evaluate capsule and joint surface morphology. Joint mechanics and capsule histology at 42 IM and 84 FM were reported previously but are included to demonstrate the full timeline of elbow contracture. RESULTS: In flexion-extension, injured limb ROM was decreased compared with control (103° ± 11°) by 21 IM (70° ± 13°) (p = 0.001). Despite an increase in injured limb ROM from 42 IM (55° ± 14°) to 63 FM (83° ± 10°) (p < 0.001), injured limb ROM was still decreased compared with control (103° ± 11°) (p = 0.002). Interestingly, ROM recovery plateaued because there was no difference between injured limbs at 63 (83° ± 10°) and 84 FM (73° ± 19°) (p > 0.999). In pronation-supination, increased injured limb ROM occurred until 7 IM (202° ± 32°) compared with control (155° ± 22°) (p = 0.001), representative of joint instability. However, injured limb ROM decreased from 21 (182° ± 25°) to 42 IM (123° ± 47°) (p = 0.001), but was not different compared with control (155° ± 22°) (p = 0.108). Histologic evaluation showed morphologic changes in the anterior capsule (increased adhesions, myofibroblasts, thickness) and nonopposing joint surfaces (surface irregularities with tissue overgrowth, reduced matrix), but these changes did not increase with time. CONCLUSIONS: Overall, flexion-extension and pronation-supination exhibited distinct time-dependent patterns during contracture development and joint mobilization. Histologic evaluation showed tissue changes, but did not fully explain the patterns in contracture mechanics. Future work will use this rat model to evaluate the periarticular soft tissues of the elbow to isolate tissue-specific contributions to contracture to ultimately develop strategies for tissue-targeted treatments. CLINICAL RELEVANCE: A rat model of posttraumatic elbow contracture quantitatively described contracture development/progression and reiterates the need for rehabilitation strategies that consider both flexion-extension and pronation-supination elbow motion.

Persistent motion loss after free joint mobilization in a rat model of post-traumatic elbow contracture.

BACKGROUND: Post-traumatic joint contracture (PTJC) in the elbow is a challenging clinical problem due to the anatomical and biomechanical complexity of the elbow joint. METHODS: We previously established an animal model to study elbow PTJC, wherein surgically induced soft tissue damage, followed by 6 weeks of unilateral immobilization in Long-Evans rats, led to stiffened and contracted joints that exhibited features similar to the human condition. In this study, after 6 weeks of immobilization, we remobilized the animal (ie, external bandage removed and free cage activity) for an additional 6 weeks, after which the limbs were evaluated mechanically and histologically. The objective of this study was to evaluate whether this decreased joint motion would persist after 6 weeks of free mobilization (FM). RESULTS: After FM, flexion-extension demonstrated decreased total range of motion (ROM) and neutral zone length, and increased ROM midpoint for injured limbs compared with control and contralateral limbs. Specifically, after FM total ROM demonstrated a significant decrease of approximately 22% and 26% compared with control and contralateral limbs for injury I (anterior capsulotomy) and injury II (anterior capsulotomy with lateral collateral ligament transection), respectively. Histologic evaluation showed increased adhesion, fibrosis, and thickness of the capsule tissue in the injured limbs after FM compared with control and contralateral limbs, which is consistent with patterns previously reported in human tissue. CONCLUSION: Even with FM, injured limbs in this model demonstrate persistent joint motion loss and histologic results similar to the human condition. Future work will use this animal model to investigate the mechanisms responsible for PTJC and responses to therapeutic intervention.

Early Joint Use Following Elbow Dislocation Limits Range-of-Motion Loss and Tissue Pathology in Posttraumatic Joint Contracture.

BACKGROUND: Simple elbow dislocation occurs at an incidence of 2.9 to 5.21 dislocations per 100,000 person-years, with as many as 62% of these patients experiencing long-term elbow joint contracture, stiffness, and/or pain. Poor outcomes and the need for secondary surgical intervention can often be prevented nonoperatively with early or immediate active mobilization and physical therapy. However, immobilization or limited mobilization may be necessary following trauma, and it is unknown how different periods of immobilization affect pathological changes in elbow joint tissue and how these changes relate to range of motion (ROM). The purpose of this study was to investigate the effects of varying the initiation of free mobilization on elbow ROM and histological features in an animal model of elbow posttraumatic joint contracture. METHODS: Traumatic elbow dislocation was surgically induced unilaterally in rats. Injured forelimbs were immobilized in bandages for 3, 7, 14, or 21 days; free mobilization was then allowed until 42 days after injury. Post-mortem joint ROM testing and histological analysis were performed. One-way analysis of variance was used to compare ROM data between control and injured groups, and Pearson correlations were performed between ROM parameters and histological outcomes. RESULTS: Longer immobilization periods resulted in greater ROM reductions. The anterior and posterior capsule showed increases in cellularity, fibroblasts, adhesions, fibrosis, and thickness, whereas the measured outcomes in cartilage were mostly unaffected. All measured histological characteristics of the capsule were negatively correlated with ROM, indicating that higher degrees of pathology corresponded with less ROM. CONCLUSIONS: Longer immobilization periods resulted in greater ROM reductions, which correlated with worse histological outcomes in the capsule in an animal model of posttraumatic elbow contracture. The subtle differences in the timing of ROM and capsule tissue changes revealed in the present study provide new insight into the distinct timelines of biomechanical changes as well as regional tissue pathology. CLINICAL RELEVANCE: This study showed that beginning active mobilization 3 days after injury minimized posttraumatic joint contracture, thereby supporting an immediate-motion clinical treatment strategy (when possible). Furthermore, uninjured but pathologically altered periarticular tissues near the injury location may contribute to more severe contracture during longer immobilization periods as the disease state progresses.

The effects of NF-κB suppression on the early healing response following intrasynovial tendon repair in a canine model.

The highly variable clinical outcomes noted after intrasynovial tendon repair have been associated with an early inflammatory response leading to the development of fibrovascular adhesions. Prior efforts to broadly suppress this inflammatory response have been largely unsuccessful. Recent studies have shown that selective inhibition of IkappaB kinase beta (IKK-ß), an upstream activator of nuclear factor kappa-light chain enhancer of activated B cells (NF-κB) signaling, mitigates the early inflammatory response and leads to improved tendon healing outcomes. In the current study, we test the hypothesis that oral treatment with the IKK-ß inhibitor ACHP (2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinenitrile an inhibitor) will modulate the postoperative inflammatory response and improve intrasynovial flexor tendon healing. To test this hypothesis, the flexor digitorum profundus tendon of 21 canines was transected and repaired within the intrasynovial region and assessed after 3 and 14 days. Histomorphometry, gene expression analyses, immunohistochemistry, and quantitative polarized light imaging were used to examine ACHP-mediated changes. ACHP led to reduction in phosphorylated p-65, indicating that NF-κB activity was suppressed. ACHP enhanced expression of inflammation-related genes at 3 days and suppressed expression of these genes at 14 days. Histomorphometry revealed enhanced cellular proliferation and neovascularization in ACHP-treated tendons compared with time-matched controls. These findings demonstrate that ACHP effectively suppressed NF-κB signaling and modulated early inflammation, leading to increased cellular proliferation and neovascularization without stimulating the formation of fibrovascular adhesions. Together, these data suggest that ACHP treatment accelerated the inflammatory and proliferative phases of tendon healing following intrasynovial flexor tendon repair. Clinical Significance: Using a clinically relevant large-animal model, this study revealed that targeted inhibition of nuclear factor kappa-light chain enhancer of activated B cells signaling with ACHP provides a new therapeutic strategy for enhancing the repair of sutured intrasynovial tendons.

The effect of tear size and nerve injury on rotator cuff muscle fatty degeneration in a rodent animal model.

BACKGROUND: Irreversible muscle changes after rotator cuff tears is a well-known negative prognostic factor after shoulder surgery. Currently, little is known about the pathomechanism of fatty degeneration of the rotator cuff muscles after chronic cuff tears. The purposes of this study were to (1) develop a rodent animal model of chronic rotator cuff tears that can reproduce fatty degeneration of the cuff muscles seen clinically, (2) describe the effects of tear size and concomitant nerve injury on muscle degeneration, and (3) evaluate the changes in gene expression of relevant myogenic and adipogenic factors after rotator cuff tears using the animal model. MATERIALS AND METHODS: Rotator cuff tears were created in rodents with and without transection of the suprascapular nerve. The supraspinatus and infraspinatus muscles were examined at 2, 8, and 16 weeks after injury for histologic evidence of fatty degeneration and expression of myogenic and adipogenic genes. RESULTS: Histologic analysis revealed adipocytes, intramuscular fat globules, and intramyocellular fat droplets in the tenotomized and neurotomized supraspinatus and infraspinatus muscles. Changes increased with time and were most severe in the muscles with combined tenotomy and neurotomy. Adipogenic and myogenic transcription factors and markers were upregulated in muscles treated with tenotomy or tenotomy combined with neurotomy compared with normal muscles. CONCLUSIONS: The rodent animal model described in this study produces fatty degeneration of the rotator cuff muscles similar to human muscles after chronic cuff tears. The severity of changes was associated with tear size and concomitant nerve injury.

Segmental Colitis Associated With Diverticulosis Masquerading as Polyploid-Appearing Mucosa in the Rectosigmoid Area on Endoscopy and as Focal Thickening on Imaging.

Segmental colitis associated with diverticulosis (SCAD) is an inflammatory disease affecting segments of the large bowel with diverticular disease. SCAD presents several challenges in diagnoses and treatment because it often mimics a range of disorders including inflammatory bowel disease and malignancy. Here, we present the case of a 72-year-old man with lower abdominal pain and bloody stools whose initial abdominal workup showed nonspecific large bowel thickening and concerns for malignancy. Ultimately, the patient was diagnosed with mild SCAD and treated conservatively with a resolution of symptoms. He had no symptoms at the three-month and 1-year follow-ups. This case highlights the importance of including SCAD in the initial differential diagnosis to allow accurate identification and treatment.

Pleiotropic Effects of Simvastatin and Losartan in Preclinical Models of Post-Traumatic Elbow Contracture.

Elbow trauma can lead to post-traumatic joint contracture (PTJC), which is characterized by loss of motion associated with capsule/ligament fibrosis and cartilage damage. Unfortunately, current therapies are often unsuccessful or cause complications. This study aimed to determine the effects of prophylactically administered simvastatin (SV) and losartan (LS) in two preclinical models of elbow PTJC: an in vivo elbow-specific rat injury model and an in vitro collagen gel contraction assay. The in vivo elbow rat (n = 3-10/group) injury model evaluated the effects of orally administered SV and LS at two dosing strategies [i.e., low dose/high frequency/short duration (D1) vs. high dose/low frequency/long duration (D2)] on post-mortem elbow range of motion (via biomechanical testing) as well as capsule fibrosis and cartilage damage (via histopathology). The in vitro gel contraction assay coupled with live/dead staining (n = 3-19/group) evaluated the effects of SV and LS at various concentrations (i.e., 1, 10, 100 µM) and durations (i.e., continuous, short, or delayed) on the contractibility and viability of fibroblasts/myofibroblasts [i.e., NIH3T3 fibroblasts with endogenous transforming growth factor-beta 1 (TGFß1)]. In vivo, no drug strategy prevented elbow contracture biomechanically. Histologically, only SV-D2 modestly reduced capsule fibrosis but maintained elevated cellularity and tissue hypertrophy, and both SV strategies lessened cartilage damage. SV modest benefits were localized to the anterior region, not the posterior, of the joint. Neither LS strategy had meaningful benefits in capsule nor cartilage. In vitro, irrespective of the presence of TGFß1, SV (≥10 µM) prevented gel contraction partly by decreasing cell viability (100 µM). In contrast, LS did not prevent gel contraction or affect cell viability. This study demonstrates that SV, but not LS, might be suitable prophylactic drug therapy in two preclinical models of elbow PTJC. Results provide initial insight to guide future preclinical studies aimed at preventing or mitigating elbow PTJC.

Type IIB procollagen NH(2)-propeptide induces death of tumor cells via interaction with integrins alpha(V)beta(3) and alpha(V)beta(5).

Cartilage is resistant to tumor invasion. In the present study, we found that the NH(2)-propeptide of the cartilage-characteristic collagen, type IIB, PIIBNP, is capable of killing tumor cells. The NH(2)-propeptide is liberated into the extracellular matrix prior to deposition of the collagen fibrils. This peptide adheres to and kills cells from chondrosarcoma and cervical and breast cancer cell lines via the integrins alpha(v)beta(5) and alpha(v)beta(3). Adhesion is abrogated by blocking with anti alpha(v)beta(5) and alpha(v)beta(3) antibodies. When alpha(v) is suppressed by small intefering RNA, adhesion and cell killing are blocked. Normal chondrocytes from developing cartilage do not express alpha(v)beta(3) and alpha(v)beta(5) integrins and are thus protected from cell death. Morphological, DNA, and biochemical evidence indicates that the cell death is not by apoptosis but probably by necrosis. In an assay for invasion, PIIBNP reduced the number of cells crossing the membrane. In vivo, in a tumor model for breast cancer, PIIBNP was consistently able to reduce the size of the tumor.

The role of transforming growth factor beta isoforms in tendon-to-bone healing.

The purpose of this study was to examine the role of two of the three transforming growth factor beta (TGF-ß) isoforms at the healing tendon-to-bone insertion. The supraspinatus tendons of 64 rats were transected at their bony insertions and repaired to the humeral head. One shoulder of each rat received an osmotic pump for sustained delivery of the following factors at the repair site: (1) TGF-ß1 and neutralizing antibodies to TGF-ß2 and 3 (TGF-ß1 group), (2) TGF-ß3 and neutralizing antibodies to TGF-ß1 and 2 (TGF-ß3 group), (3) neutralizing antibodies to TGF-ß1, 2, and 3 (anti-TGF-ß group), and (4) saline (saline group). The contralateral shoulders received saline to serve as paired controls. The repairs were evaluated at multiple time points postmortem using histology-based assays and biomechanical testing. Treated shoulders in the TGF-ß1 group showed increased type III collagen production compared to the paired control shoulders, indicative of a scar-mediated response. There was a trend toward reduced mechanical properties in the TGF-ß1 group, but these changes did not reach statistical significance. The anti-TGF-ß group showed no difference in tissue volume, but significantly inferior mechanical properties, compared to the paired control shoulders. The TGF-ß3 group did not show any differences compared to the paired control shoulders. Although TGF-ß isoforms play important roles in tendon-to-bone development and healing, application of exogenous TGF-ß isoforms and neutralizing antibodies to the subacromial space using osmotic pumps did not improve supraspinatus tendon-to-bone healing.

Heparin-induced thrombocytopenia and cerebral venous sinus thrombosis: case report and literature review.

BACKGROUND: Heparin-induced thrombocytopenia (HIT)-related cerebral venous sinus thrombosis (CVST) has been described in 10 prior case reports in the English language medical literature. We report the first case of low molecular weight HIT-related CVST with detailed clinical course and novel therapeutic approach. METHODS: A 69-year-old woman presented with a focal seizure after total hip replacement. Enoxaparin for venous thromboembolism prophylaxis had been initiated 8 days prior to the seizure. RESULTS: The patient experienced progressive neurologic deterioration, and MRI and CT angiography were consistent with cerebral sinus thrombosis (CVST). The new onset of thrombocytopenia, thrombosis, and positive heparin ELISA (enzyme-linked immunosorbent assay) and SRA (serotonin release assay) assays confirmed HIT. In spite of aggressive management of HIT-related CVST, including argatroban therapy and endovascular mechanical thrombolysis, the patient expired. CONCLUSIONS: A review of the previous 10 case reports in the literature confirms that HIT-related CVST is often a fatal condition, particularly when diagnosed in comatose patients. Because the diagnosis is rare and often delayed relative to initial presentation, prevention is the key to improve patient outcomes. Newer anticoagulants with different mechanism of action than heparin are currently under review by the FDA; they will facilitate prevention of HIT-related CVST and other HIT-related neurological complications.

Females and males exhibit similar functional, mechanical, and morphological outcomes in a rat model of posttraumatic elbow contracture.

Posttraumatic joint contracture (PTJC) is a debilitating condition characterized by loss of joint motion following injury. Previous work in a rat model of elbow PTJC investigated disease etiology, progression, and recovery in only male animals; this study explored sex-based differences. Rat elbows were subjected to a unilateral anterior capsulotomy and lateral collateral ligament transection followed by 42 days of immobilization and 42 days of free mobilization. Grip strength and gait were collected throughout the free mobilization period while joint mechanical testing, microcomputed tomography and histological analysis were performed postmortem. Overall, few differences were seen between sexes in functional, mechanical, and morphological outcomes with PTJC being similarly debilitating in male and female animals. Functional measures of grip strength and gait showed that, while some baseline differences existed between sexes, traumatic injury produced similar deficits that remained significantly different long-term when compared to control animals. Similarly, male and female animals both had significant reductions in joint range of motion due to injury. Ectopic calcification (EC), which had not been previously evaluated in this injury model, was present in all limbs on the lateral side. Injury caused increased EC volume but did not alter mineral density regardless of sex. Furthermore, histological analysis of the anterior capsule showed minor differences between sexes for inflammation and thickness but not for other histological parameters. A quantitative understanding of sex-based differences associated with this injury model will help inform future therapeutics aimed at reducing or preventing elbow PTJC.

SRp54 (SFRS11), a regulator for tau exon 10 alternative splicing identified by an expression cloning strategy.

The tau gene encodes a microtubule-associated protein that is critical for neuronal survival and function. Splicing defects in the human tau gene lead to frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), an autosomal dominant neurodegenerative disorder. Genetic mutations associated with FTDP-17 often affect tau exon 10 alternative splicing. To investigate mechanisms regulating tau exon 10 alternative splicing, we have developed a green fluorescent protein reporter for tau exon 10 skipping and an expression cloning strategy to identify splicing regulators. A role for SRp54 (also named SFRS11) as a tau exon 10 splicing repressor has been uncovered using this strategy. The overexpression of SRp54 suppresses tau exon 10 inclusion. RNA interference-mediated knock-down of SRp54 increases exon 10 inclusion. SRp54 interacts with a purine-rich element in exon 10 and antagonizes Tra2beta, an SR-domain-containing protein that enhances exon 10 inclusion. Deletion of this exonic element eliminates the activity of SRp54 in suppressing exon 10 inclusion. Our data support a role of SRp54 in regulating tau exon 10 splicing. These experiments also establish a generally useful approach for identifying trans-acting regulators of alternative splicing by expression cloning.

Use of a magnesium-based bone adhesive for flexor tendon-to-bone healing.

PURPOSE: Our previous studies in a canine animal model demonstrated that the flexor tendon-to-bone insertion site has a poor capacity to heal. Magnesium-based adhesives have the potential to improve tendon-to-bone healing. Therefore, we hypothesized that magnesium-based bone adhesive (MBA) will improve the tendon-to-bone biomechanical properties initially and in the early period after repair. METHODS: Flexor digitorum profundus tendons were injured and repaired into bone tunnels in the distal phalanges of dogs. The bone tunnels were either filled with MBA before completing the repair or left empty (control [CTL]). Histologic appearance, tensile properties, range of motion, and bone density were examined at time zero and 21 days after the repair. RESULTS: There was no histologic evidence of acute inflammation. There appeared to be more mast cells in the MBA group than in the CTL group. Chronic inflammatory infiltrate and fibrosis was slightly higher in the MBA group compared with the CTL group. Tensile properties at time zero were significantly higher in the MBA group compared with the CTL group. However, tensile properties were significantly lower in the MBA group compared with the CTL group at 21 days. Range of motion and bone density were significantly lower in the MBA and CTL groups compared with normal (ie, uninjured) at 21 days; no differences were seen when comparing MBA with CTL. CONCLUSIONS: We found that the initial biomechanical properties of flexor tendon-to-bone repairs can be improved with MBA. However, MBA use in vivo led to a decrease in the biomechanical properties of the repair. There was no effect of MBA on bone density or range of motion in the early period after repair. Our histologic analysis suggests that the poor healing in the MBA group may have been due to an allergic response or to increased chronic inflammation resulting from the foreign material.

Complete removal of load is detrimental to rotator cuff healing.

HYPOTHESIS: This study evaluated the effect of the mechanical environment on the healing rotator cuff by paralyzing the supraspinatus muscle in the operative shoulder of a rat model of rotator cuff injury and repair. METHODS: Unilateral shoulders of rats underwent a supraspinatus injury and repair. Botulinum toxin A was used to paralyze the muscle after repair. Postoperatively, 1 group was immobilized and 1 group was allowed free range of motion. Saline-injected, casted rats were used as the control group. Repairs were evaluated histologically, geometrically, and biomechanically. RESULTS: Specimens from the saline-injected rats had greater scar volume and cross-sectional area of the repair compared with the paralyzed groups. Structural properties were increased in the saline group compared with the paralyzed groups. Free range of motion (ie, uncasted group) resulted in modest improvements in biomechanical properties but did not obviate the effect of paralysis. CONCLUSIONS: Complete removal of load was detrimental to rotator cuff healing, especially when combined with immobilization.

Decellularized bovine placentome for portacavally-interposed heterotopic liver transplantation in rats.

Scaffolds from healthy placentae offer advantages for tissue engineering with undamaged matrix, associated cytoprotective molecules, and embedded vessels for revascularization. As size disparities in human placenta and small recipients hamper preclinical studies, we studied alternative of bovine placentomes in smaller size ranges. Multiple cow placentomes were decellularized and anatomical integrity was analyzed. Tissue engineering used inbred donor rat livers. Placentomes were hepatized and immediately transplanted in rats with perfusion from portal vein and drainage into inferior vena cava. Cows yielded 99 ±â€¯16 placentomes each. Of these, approximately 25% had 3 to 9 cm diameter and 7 to 63 ml volume, which was suitable for transplantation. After decellularization, angiography and casts documented 100% of vessels and vascular networks were well-perfused without disruptions or leaks. The residual matrix also remained intact for transplantation of placentomes. Perfusion in transplanted placentomes was maintained over up to 30 days. Liver tissue reassembled with restoration of hepatic acinar and sinusoidal structure. Transplanted tissue was intact without apoptosis, or necrosis. Hepatic functions were maintained. Preservation of hepatic homeostasis was verified by cytofluorimetric analysis of hepatocyte ploidy. The prevalence in healthy and transplanted liver of diploid, tetraploid and higher ploidy classes was similar with 57%, 41% and 2% versus 51%, 46.5% and 2.6%, respectively, p = 0.77, ANOVA. CONCLUSIONS: Cow placentomes will allow therapeutic development with disease models in small animals. This will also advance drug or toxicology studies. Portasystemic interposition of engineered liver will be particularly suitable for treating hepatic insufficiencies (metabolic, secretory or detoxification needs), including for children or smaller adults.

Imaging of liver disease: comparison between quadruple-phase multidetector computed tomography and magnetic resonance imaging.

BACKGROUND AND AIM: To compare quadruple-phase multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) for the assessment of focal and diffuse liver disease. METHODS: Quadruple-phase contrast-enhanced MDCT and MRI of 37 consecutive patients were retrospectively reviewed by two readers (R1 and R2). In patients with focal liver lesions, the gold standard was histopathology (n = 17) and/or long-term (>6 months) follow-up imaging (n = 27) or transarterial chemoembolization (n = 1). Diffuse liver disease was confirmed by histopathology in all patients, when present. RESULTS: Both readers identified 60 focal liver lesions on MDCT and 56 focal liver lesions on MRI. Gold standard diagnoses revealed 48 focal liver lesions in 25 patients. Diagnosis of malignant liver lesions revealed a sensitivity of 88% (R1) and 91% (R2) for MRI; 63% (R1) and 66% (R2) for MDCT; and a specificity of 75% (R1) and 79% (R2) for MRI; 50% (R1) and 64% (R2) for MDCT. MRI was superior to MDCT for the diagnosis of malignant focal liver lesions, when the mean areas under the alternative free-response receiver operating characteristic curves (A(Z)) were compared (MRI = 0.93 vs CT = 0.69), (P < 0.00001). Thirty-three patients had histopathologically confirmed diffuse liver disease. Overall diagnosis of diffuse liver disease revealed a sensitivity of 88% (R1) and 92% (R2) for MRI; 75% (R1) and 74% (R2) for MDCT; and a specificity of 100% for both modalities by both readers. CONCLUSIONS: MRI is superior for the assessment of malignant focal liver lesions and diffuse liver disease compared to quadruple-phase MDCT, and can be considered as primary diagnostic imaging modality for liver imaging.

Liver schwannoma: findings on MRI.

Magnetic resonance imaging features of benign liver schwannoma in a 52-year-old woman are described. An oval shaped, 4.4x3.6x2.9-cm lesion was located in Segment 7 of the right hepatic lobe. The lesion was hypointense on T(1)-weighted images and mixed hypo- and hyperintense on T(2)-weighted images. On serial contrast-enhanced images, the lesion revealed gradually increasing centrilobular enhancement. The tumor was surgically removed thereafter.

Comparison between malignant and benign abdominal lymph nodes on diffusion-weighted imaging.

RATIONALE AND OBJECTIVES: The purpose of this study is to review the apparent diffusion coefficient (ADC) values of benign and metastatic abdominal lymph nodes on diffusion-weighted imaging (DWI). MATERIALS AND METHODS: Twenty-eight patients with a total of 40 benign (20 patients) and 16 malignant (8 patients) lymph nodes who underwent DWI MRI of the abdomen (b = 0.600) were enrolled in the study. ADC values of the lymph nodes were measured and comparison was made between benign and malignant groups. RESULTS: Mean ADC value of lymph nodes was 2.38 +/- 0.29 and 1.84 +/- 0.37 x 10(-3) mm(2)/sec in the benign and malignant groups, respectively. There was a significant statistical difference between the ADC values of benign and malignant lymph nodes (P < .0005). CONCLUSION: A wide range of ADC values exist in patients with metastatic abdominal lymph nodes, with a tendency of higher ADC values in benign lymph nodes.

Extrapulmonary small cell carcinoma: involvement of the brain without evidence of extracranial malignancy by serial PET/CT scans.

BACKGROUND: Extrapulmonary small cell carcinoma (EPSCC) involving the brain is a rare manifestation of an uncommon tumor type. CASE PRESENTATION: We report a 59 year-old Caucasian female diagnosed with an EPSCC involving the left parietal lobe without detectable extracranial primary tumor followed by serial positron emission tomography/computed tomography (PET/CT) imaging. Histopathological examination at both initial presentation and recurrence revealed small cell carcinoma. Serial PET/CT scans of the entire body failed to reveal any extracranial [18F]2-fluoro-2-deoxy-D-glucose (FDG) avid lesions at either diagnosis or follow-up. CONCLUSION: Chemotherapy may show a transient response in the treatment of EPSCC. Further studies are needed to help identify optimal treatment strategies. Combination PET/CT technology may be a useful tool to monitor EPSCC and assess for an occult primary malignancy.