β1 Integrins Mediate Mechanosensitive Signaling Pathways in Osteocytes

Integrins are cell-substrate adhesion proteins that initiate intracellular signaling and may serve as mechanosensors in bone. MLO-Y4 cells were stably transfected with a dominant negative form of the β₁ integrin subunit (β₁DN) containing the transmembrane domain and cytoplasmic tail of β₁ integrin. Cells expressing β₁DN had reduced vinculin localization to focal contacts but no change in intracellular actin organization. When exposed to oscillatory fluid flow, β₁DN cells exhibited a significant reduction in the upregulation of cyclooxygenase-2 gene expression and prostaglandin E₂ release. Similarly, the ratio of receptor activator of NF-κB ligand mRNA to osteoprotegerin mRNA decreased significantly after exposure to fluid flow in control cells but not in β₁DN cells. Interfering with integrin signaling did not affect mechanically induced intracellular calcium mobilization. These data suggest that integrins may initiate the cellular response of osteocytes to dynamic fluid flow and may serve as mechanosensitive molecules in bone.     

Can Optical Coherence Tomography Be Used to Guide Treatment Decisions in Adult or Pediatric Multiple Sclerosis?

Purpose of review

With the recognition that neurodegeneration represents the principal substrate of disability in multiple sclerosis (MS), there has been increased strives towards identifying biomarkers for accurately quantifying and tracking neurodegeneration during the disease course. The retina provides an opportune “window” into the central nervous system (CNS) in MS, with retinal changes in MS reflecting not only local, but also global aspects of neurodegeneration and inflammation operative in the disease. Optical coherence tomography (OCT) is a rapid, inexpensive, reproducible, high-resolution imaging technique allowing accurate quantification of discrete retinal layers. OCT determined thinning of inner retinal layers such as the retinal nerve fiber layer (RNFL) and in particular the composite of the ganglion cell and inner plexiform (GCIP) layers, predominantly related to optic neuropathy, have been shown to not only correlate with high and low contrast visual function in MS, but also global MS disability scores, as well as whole brain and particularly gray matter volumes. Rates of GCIP thinning have been shown to be accelerated among MS patients exhibiting inflammatory activity outside of the visual pathways, as well as disability progression during follow-up. Moreover, baseline RNFL thickness in MS has been shown to have utility for predicting future disability accumulation. On the other hand, thickening of the inner nuclear layer (INL) in MS, the pathophysiologic basis of which remains to be elucidated, has been found to predict the development of clinical and radiological inflammatory activity, as well as subsequent disability progression in MS. Given the potential for OCT to provide insight into neurodegeneration and inflammation occurring in MS, this review focuses on the potential utility of OCT within the clinical setting to influence treatment decisions for MS patients.

Recent findings

The evolution of spectral domain-OCT technology, with improved resolution and reproducibility allowing intra-retinal layer segmentation, has facilitated the determination that the OCT derived measure GCIP thickness is a highly accurate measure for quantifying and tracking neurodegeneration, and conversely neuroprotection, in MS. The strong relationships between rates of GCIP and brain atrophy across MS subtypes over time underpin the insight derived regarding the global MS disease process from OCT and highlight OCT as an excellent complementary tool to magnetic resonance imaging (MRI) for tracking MS patients. More recently, longitudinal studies are emerging which support the utility of OCT for monitoring the differential effects of disease-modifying therapies (DMTs) in MS.

Summary

Although further work is required, there is mounting evidence supporting the utility of OCT in the clinical setting to monitor disease course in individual patients with MS and to aid in the prediction of disease course. As pharmacological treatment options in MS expand to also include potentially neuroprotective and/or remyelinating or neurorestorative drugs, OCT as a biomarker of neurodegeneration and neuroprotection (and neuroinflammation to a lesser degree) may become an invaluable tool in both the research and clinical settings.

     

Are Adult Ureteroscopes Safe in the Management of Urolithiasis in a Pediatric Population?

Introduction

Debate remains regarding the optimal caliber of ureteroscopes in the management of pediatric urolithiasis, ranging from pediatric scopes to standard scopes. The aim of this study was to assess the safety and efficacy of stone management in a pediatric population using standard adult ureteroscopes.

Methods

A retrospective review of all ureteroscopic procedures in patients under the age of 16 years was carried out. Standard adult 7.5 French semi-rigid and 6 French flexible ureteroscopes were used.

Results

During the study period, 8 patients underwent 21 ureteroscopic procedures. Two patients had rigid ureteroscopy, seven had flexible ureterorenoscopy and one had a subsequent open procedure. No patients required ureteric dilation. Double J ureteric stents were utilized in 7 patients. There were no complications. All patients required extra corporeal shock wave lithotripsy. Stone clearance was achieved in all patients.

Conclusion

Our series demonstrates that, in skilled hands, adult ureteroscopes can be use safely for the treatment of urolithiasis in pediatric patients.Key Words: Urolithiasis, Paediatric urolithiasis, Ureteroscopy     

Contemporary Management of Adult Intussusception: Who Needs a Resection?

Background

Surgical resection is often recommended in adults with intestinal intussusception (AI) because of its potential association with malignancy. We provide a contemporary algorithm for managing AI by focusing on the probability of discovering a lead point.

Methods

This is a retrospective study of adult patients with computed tomography (CT)-confirmed intussusception who underwent operative management of AI between 1996 and 2011 at a single academic institution.

Results

Sixty-four patients were diagnosed with AI by CT scan and then managed operatively. The incidence of colonic (CI), small bowel (SBI), and retrograde intussusception (RI) was 14, 55, and 31 %, respectively. All patients with CI had a lead point, whereas none were found among patients with RI. Some 46 % of patients with SBI had a lead point. The probability of discovering a lead point in SBI was increased by past history of malignancy (RR, 3.7, p < 0.001), a mass seen on preoperative CT scan (RR, 2.9, p = 0.005), and age over 60 years (RR, 2.2, p = 0.07).

Conclusions

A pathologic lead point is likely with CI but not with RI. Patients with SBI who are over the age of 60 years and have a history of malignancy or a mass noted on CT scan have a higher likelihood of harboring a pathologic lead point.     

Multiple papillomas of the breast: Is current management adequate?

Multiple papillomas (MP) are subject to debate in terms of their clinical and pathological significance and management. To date the ideal management is still not well established. The Royal Perth Hospital Multidisciplinary Breast Service has prospectively accrued clinical and pathological data on over 9000 patients since 1994. The database was interrogated and all pathology reports retrospectively reviewed. A total of 23 cases with the diagnosis of MP were retrieved from the database between 1994 and 2004. Of these 23 cases, 13 (56.5%) were diagnosed by core biopsy, nine (39.1%) on excision biopsy, and one (4.4%) on a mastectomy specimen. The average age of patients was 56.4 years (range 44-74 years). The average duration of follow up is 4.1 years (range 1-10 years). In our series a close association with malignancy was noted for MP, which was also associated with a spectrum of proliferative breast disease. Contemporary guidelines should be developed for this controversial condition. We recommend that all patients with MP, especially when associated with atypia, undergo wide excision of the lesion with clear margins of at least 10mm and that these patients be monitored closely with annual imaging.     

Multiple Trauma in Young and Elderly: Are There Any Differences?

Abstract Background:  Old age is considered a risk factor; however, its effect on the prognosis of injured elderly patients remains uncertain. Aim:  To find the effect of old age on final outcome of elderly patients withmultiple trauma and to determine whether a different therapeutic approach is needed. Methods:  All patients with at least two injured body regions, as defined by the ISS, of grade 4 in AIS, were included. Results:  We studied 165 patients up to 64 years (Y) of age and 56 patients older than 65 years (E) in a 10-year period. On presentation 21.2% of Y and 25% of E, were hypovolemic (p = NS). No significant difference in number of injuries/patient was noted between Y and E patients, hemodynamically stable (HS) and unstable (HU) – (3.0 vs. 2.9 and 3.9 vs. 3.6). An increased relative frequency of chest and abdomen injuries was noted in Y and E, who died or were HU on presentation. A higher relative frequency of long bone and pelvis fractures was noted in the E. The ISS was not different among HS and HU, Y and E. Hospitalization in ICU was more common in E than in Y (69.6 vs. 47.3%), but there was no difference in the final outcome: overall mortality was 10.3% in Y versus 16.1% in E (p = NS), mortality in HU was 42.9% in Y versus 50% in E (p = NS). ISS was not associated with mortality in either group. Conclusions:  Old age has no influence on final outcome of E multi trauma patients; hence, the therapeutic approach of these patients should be the same in Y.     

Characterization of the Effects of Cyclooxygenase-2 Inhibition in the Regulation of Apoptosis in Human Small and Non–Small Cell Lung Cancer Cell Lines

Background Cyclooxygenase-2 enzyme (COX-2) is overexpressed in human non–small cell lung cancer (NSCLC) but is not expressed in small cell lung cancer. Selective COX-2 inhibitors have been shown to induce apoptosis in NSCLC cells, an effect which is associated with the regulation of intracellular MAP kinase (MAPK) signal pathways. Our aims were to characterize the effects of COX-2 inhibition by rofecoxib on apoptosis in human NSCLC and small cell lung cancer cell lines. Methods The human NSCLC cell line NCI-H2126 and small cell lung cancer cell line DMS-79 were used. Constitutive COX-2 protein levels were first determined by Western blot test. Levels of apoptosis were evaluated by using propidium iodide staining on FACScan analysis after incubation of NCI-H2126 and DMS-79 with p38 MAPK inhibitor SB202190 (25 μM), NF-κB inhibitor SN50 (75 μg/mL), and rofecoxib at 100 and 250 μM. All statistical analysis was performed by analysis of variance. Results Western blot test confirmed the presence of COX-2 enzyme in NCI-H2126 and absence in DMS-79. Interestingly, rofecoxib treatment demonstrated a dose-dependent increase in apoptosis in both cell lines. Given this finding, the effect of rofecoxib on NF-κB and p38 MAPK pathways was also examined. Apoptosis in both cell lines was unaltered by SN50, either alone or in combination with rofecoxib. A similar phenomenon was observed in NCI-H2126 cells treated with SB202190, either alone or in combination with rofecoxib. In contrast, p38 MAPK inhibition greatly upregulated DMS-79 apoptosis in a manner that was unaltered by the addition of rofecoxib. Conclusions Rofecoxib led to a dose-dependent increase in apoptosis in both tumor cell lines. This effect occurred independently of COX-2, NF-κB, and p38 MAPK pathways in DMS-79 cells. As such, rofecoxib must act on alternative pathways to regulate apoptosis in human small cell lung cancer cells. Presented at the Society of Surgical Oncology (SSO) Annual Meeting, New York, 18th-21st March 2004.