Wide Variation of Surgical Cost in the Treatment of Periarticular Lower Extremity Injuries Between 6 Fellowship-Trained Trauma Surgeons.

OBJECTIVES: We hypothesized that negligible surgical material cost variation exists between traumatolgists for treatment of bimalleolar ankle and bicondylar tibial plateau fractures. DESIGN: Retrospective medical record review. SETTING: Academic level 1 Trauma Center; 2-year period. PATIENTS/PARTICIPANTS: Current Procedure Terminology codes for open treatment of bimalleolar ankle and bicondylar tibial plateau fractures identified patients. Patients who had operative treatment of other injuries under the same anesthetic session were excluded. Only definitive treatment procedures were analyzed. INTERVENTION: We analyzed the intraoperative material costs of these procedures and compared them between surgeons. This analysis was done with a newly developed proprietary program designed for inventory and cost analysis. MAIN OUTCOME MEASUREMENTS: Mean and median total case material costs were compared using one-way analysis of variance. Individual items that significantly increased costs were identified. RESULTS: We identified 88 bimalleolar ankle and 46 bicondylar tibial plateau fractures treated by 6 surgeons. The mean intraoperative material cost per bimalleolar ankle fracture was $1099. The least expensive surgeon's mean case cost was $613, which was significantly less than the most expensive surgeon's $2243 (P = 0.009). The median cost range was $598-$784. The top quartile of cases resulted in 57% of overall material cost for ankle fractures. The mean intraoperative material cost per bicondylar tibial plateau fracture was $3219 (range $1839-$4088, P = 0.064). The range of median costs ($1826-$3989) was significantly wider than for ankle fractures. Bone void fillers, locking plates, adjunctive external fixators, mini-fragment locking plates, cannulated screws, single-use taps, guidewires, and drill bits all substantially increased costs. CONCLUSION: This study demonstrated variation in intraoperative material cost between 6 traumatologists resulting from practice variations despite similar specialty training. The cost differences resulting from practice variation reveal potential savings through increased standardization of surgical care for similar injuries. We identified high-cost items, which could lead to cost savings if used only when they will have clinical benefit.

CLRN1 is nonessential in the mouse retina but is required for cochlear hair cell development.

Mutations in the CLRN1 gene cause Usher syndrome type 3 (USH3), a human disease characterized by progressive blindness and deafness. Clarin 1, the protein product of CLRN1, is a four-transmembrane protein predicted to be associated with ribbon synapses of photoreceptors and cochlear hair cells, and recently demonstrated to be associated with the cytoskeleton. To study Clrn1, we created a Clrn1 knockout (KO) mouse and characterized the histological and functional consequences of Clrn1 deletion in the retina and cochlea. Clrn1 KO mice do not develop a retinal degeneration phenotype, but exhibit progressive loss of sensory hair cells in the cochlea and deterioration of the organ of Corti by 4 months. Hair cell stereocilia in KO animals were longer and disorganized by 4 months, and some Clrn1 KO mice exhibited circling behavior by 5-6 months of age. Clrn1 mRNA expression was localized in the retina using in situ hybridization (ISH), laser capture microdissection (LCM), and RT-PCR. Retinal Clrn1 transcripts were found throughout development and adulthood by RT-PCR, although expression peaked at P7 and declined to undetectable levels in adult retina by ISH. LCM localized Clrn1 transcripts to the retinas inner nuclear layer, and WT levels of retinal Clrn1 expression were observed in photoreceptor-less retinas. Examination of Clrn1 KO mice suggests that CLRN1 is unnecessary in the murine retina but essential for normal cochlear development and function. This may reflect a redundancy in the mouse retina not present in human retina. In contrast to mouse KO models of USH1 and USH2, our data indicate that Clrn1 expression in the retina is restricted to the Müller glia. This is a novel finding, as most retinal degeneration associated proteins are expressed in photoreceptors, not in glia. If CLRN1 expression in humans is comparable to the expression pattern observed in mice, this is the first report of an inner retinal protein that, when mutated, causes retinal degeneration.

Transport of truncated rhodopsin and its effects on rod function and degeneration.

PURPOSE: Most transgenic animal models of retinal degeneration caused by rhodopsin mutations express the rhodopsin transgene on a wild-type (WT) genetic background. Previous studies have demonstrated that one mechanism of retinal degeneration is rhodopsin overexpression. To study the effect of C-terminal truncation of rhodopsin without the confounding factors of overexpression, several lines of transgenic mice were generated that expressed a C-terminal rhodopsin mutation on rhodopsin-knockout backgrounds. METHODS: Two lines of transgenic mice, expressing different levels of C-terminal truncated rhodopsin (S334ter) were mated with heterozygous rhodopsin-knockout (rho+/-) mice to express S334ter rhodopsin on a background with reduced endogenous rhodopsin expression. S334ter mice were mated to homozygous knockout (rho-/-) mice to examine the effect of S334ter rhodopsin on a null rhodopsin background. S334ter rhodopsin expression was estimated by Western blot. Retinal function was assessed by ERG and retinal degeneration by histopathology and morphometry. C-terminal rhodopsin sorting and trafficking was examined by fluorescence immunocytochemistry with detection by electron microscope. RESULTS: Expression of S334ter truncated rhodopsin at low levels in the presence of decreased total rhodopsin in rods (S334ter, rho+/-) increased the rate of rod cell death in comparison to rho+/- littermates. In addition, S334ter rhodopsin prolonged the recovery time of the rod ERG to a light flash and diminished the a-wave amplitudes in comparison to their (rho+/-) littermates. Photoreceptors of S334ter mice on a homozygous rhodopsin-knockout background (S334ter+, rho-/-) had a fraction of mutant rhodopsin localized to the ciliary membranes. CONCLUSIONS: Expression of S334ter rhodopsin without overexpression of total opsin in the rod photoreceptor decreased rod cell contribution to the ERG and compromised rod cell survival in adult mice. The increased cell death may be a consequence of C-terminal truncated rhodopsin mislocalization in membranes of the inner segment. Another possible pathologic mechanism is prolonged activation of phototransduction from the presence of mutant rhodopsin in the outer segment lacking the normal C-terminal binding sites for shutoff by arrestin and phosphorylation. These results suggest that rhodopsin lacking a C-terminal trafficking signal can be transported to the rod outer segment without cotransporting with full-length rhodopsin.

Characterization of peripherin/rds and rom-1 transport in rod photoreceptors of transgenic and knockout animals.

PURPOSE: Peripherin/rds and rom-1 have structural roles in morphogenesis and stabilization of the outer segment, but little is known about their transport and sorting to the rod outer segment. Peripherin/rds and rom-1 trafficking were studied in several knockout and transgenic animal models. METHODS: Rod outer segment formation and distribution of peripherin/rds and rom-1 were examined by immunohistochemistry, electron microscopy, and molecular biological methods in wild-type, rhodopsin-knockout, and peripherin/rds-knockout mice. C-terminally truncated peripherin/rds (Xper38)-GFP chimeric protein sorting was followed by immunofluorescence microscopy in transgenic Xenopus. RESULTS: In developing wild-type photoreceptors, peripherin/rds was detected exclusively in the distal tip of the connecting cilium in advance of outer segment formation. Rhodopsin-knockout mice failed to create normal rod outer segments and instead, elaborated membranous protrusions at the distal cilium tip. Peripherin/rds and rom-1 localized to this ciliary membrane in rhodopsinless photoreceptors. In transgenic Xenopus, a C-terminally truncated peripherin/rds-GFP fusion predominantly localized to its normal location within disc rims. In developing rds mice, rom-1 accumulated primarily in distal ciliary membranes. CONCLUSIONS: Peripherin/rds transport and localization are polarized to the site of outer segment morphogenesis before disc formation in developing photoreceptors. Peripherin/rds and rom-1 trafficking is maintained in rhodopsin-knockouts, suggesting that rim proteins and rhodopsin have separate transport pathways. The presence of truncated peripherin/rds-GFP in the outer segment supports previous evidence that peripherin/rds mice form homotetramers for outer segment targeting. The finding that rom-1 transports to the outer segment domain in rds mice suggests that rom-1 may possess its own sorting and transport signals.

The role of matrix metalloproteinase 9 in the pathogenesis of chronic lymphocytic leukaemia.

Matrix metalloproteinases (MMPs) are important for the pathogenesis and progression of different tumours. MMPs-2 and -9 are the principal MMPs produced by lymphocytes; these enzymes can degrade a number of matrix proteins but are the two main MMPs that digest type IV collagen, the major component of basement membranes. Therefore, these enzymes are potentially important for tissue invasion and remodelling by malignant lymphocytes. This study showed that chronic lymphocytic leukaemia (CLL) cells produce and secrete variable amounts of pro-MMP-9, but no MMP-2 or tissue inhibitor of metalloproteinase 1 (TIMP-1). The pro-enzyme was found in monomeric and dimeric forms and also complexed with lipocalin. Moreover, a small fraction of secreted monomer became associated with the cell surface and activated upon cell adhesion to insolubilized type IV collagen. High levels of intracellular MMP-9 were associated with advanced (stage C) disease and with poor patient survival. Immunohistochemical studies demonstrated that MMP-9 was associated with areas of tissue invasion and remodelling. The relatively specific MMP-9 inhibitors, Ro31-9790 (3 micromol/l) and TIMP-1, reduced CLL-cell migration through type IV collagen and through endothelial monolayers suggesting that the enzyme may also be important in malignant cell entry and egress to and from involved tissue. Our data raise the possibility that MMP-9 modulation may have therapeutic potential in advanced CLL.