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A diverse group of cell-surface receptors, including many G protein-coupled receptors and receptor tyrosine kinases, activate phospholipase C (PLC) isozymes to hydrolyze phosphatidylinositol 4,5-bisphosphate into the second messengers diacylglycerol and 1,4,5-inositol trisphosphate. Consequently, PLCs control various cellular processes, and their aberrant regulation contributes to many diseases, including cancer, atherosclerosis, and rheumatoid arthritis. Despite the widespread importance of PLCs in human biology and disease, it has been impossible to directly monitor the real-time activation of these enzymes at membranes. To overcome this limitation, here we describe XY-69, a fluorogenic reporter that preferentially partitions into membranes and provides a selective tool for measuring the real-time activity of PLCs as either purified enzymes or in cellular lysates. Indeed, XY-69 faithfully reported the membrane-dependent activation of PLC-β3 by Gαq. Therefore, XY-69 can replace radioactive phosphatidylinositol 4,5-bisphosphate used in conventional PLC assays and will enable high-throughput screens to identify both orthosteric and allosteric PLC inhibitors. In the future, cell-permeable variants of XY-69 represent promising candidates for reporting the activation of PLCs in live cells with high spatiotemporal resolution.

The P2Y14 receptor (P2Y14R), one of eight P2Y G protein-coupled receptors (GPCR), is involved in inflammatory, endocrine, and hypoxic processes and is an attractive pharmaceutical target. The goal of this research is to develop high-affinity P2Y14R fluorescent probes based on the potent and highly selective antagonist 4-(4-(piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl)-2-naphthoic acid (6, PPTN). A model of hP2Y14R based on recent hP2Y12R X-ray structures together with simulated antagonist docking suggested that the piperidine ring is suitable for fluorophore conjugation while preserving affinity. Chain-elongated alkynyl or amino derivatives of 6 for click or amide coupling were synthesized, and their antagonist activities were measured in hP2Y14R-expressing CHO cells. Moreover, a new Alexa Fluor 488 (AF488) containing derivative 30 (MRS4174, Ki = 80 pM) exhibited exceptionally high affinity, as compared to 13 nM for the alkyne precursor 22. A flow cytometry assay employing 30 as a fluorescent probe was used to quantify specific binding to P2Y14R. Known P2Y receptor ligands inhibited binding of 30 with properties consistent with their previously established receptor selectivities and affinities. These results illustrate that potency in this series of 2-naphthoic acid derivatives can be preserved by chain functionalization, leading to highly potent fluorescent molecular probes for P2Y14R. Such conjugates will be useful tools in expanding the SAR of this receptor, which still lacks chemical diversity in its collective ligands. This approach demonstrates the predictive power of GPCR homology modeling and the relevance of newly determined X-ray structures to GPCR medicinal chemistry.

Phospholipase C (PLC) isozymes are important signaling molecules, but few small molecule modulators are available to pharmacologically regulate their function. With the goal of developing a general approach for identification of novel PLC inhibitors, we developed a high-throughput assay based on the fluorogenic substrate reporter WH-15. The assay is highly sensitive and reproducible: screening a chemical library of 6280 compounds identified three novel PLC inhibitors that exhibited potent activities in two separate assay formats with purified PLC isozymes in vitro. Two of the three inhibitors also inhibited G protein-coupled receptor-stimulated PLC activity in intact cell systems. These results demonstrate the power of the high-throughput assay for screening large collections of small molecules to identify novel PLC modulators. Potent and selective modulators of PLCs will ultimately be useful for dissecting the roles of PLCs in cellular processes, as well as provide lead compounds for the development of drugs to treat diseases arising from aberrant phospholipase activity. Background: Phospholipase C (PLC) isozymes are increasingly attractive therapeutic targets; however, pharmacological modulators are lacking. Results: A facile fluorescent high-throughput screen was developed and used to identify small molecule inhibitors of PLC activity. Conclusion: The new assay is robust and suitable for the rapid discovery of novel PLC modulators. Significance: This new methodology eliminates the major roadblock hampering the discovery of small molecule PLC inhibitors.

The capacity to monitor spatiotemporal activity of phospholipase C (PLC) isozymes with a PLC-selective sensor would dramatically enhance understanding of the physiological function and disease relevance of these signaling proteins. Previous structural and biochemical studies defined critical roles for several of the functional groups of the endogenous substrate of PLC isozymes, phosphatidylinositol 4,5-bisphosphate (PIP(2)), indicating that these sites cannot be readily modified without compromising interactions with the lipase active site. However, the role of the 6-hydroxy group of PIP(2) for interaction and hydrolysis by PLC has not been explored, possibly due to challenges in synthesizing 6-hydroxy derivatives. Here, we describe an efficient route for the synthesis of novel, fluorescent PIP(2) derivatives modified at the 6-hydroxy group. Two of these derivatives were used in assays of PLC activity in which the fluorescent PIP(2) substrates were separated from their diacylglycerol products and reaction rates quantified by fluorescence. Both PIP(2) analogues effectively function as substrates of PLC-δ1, and the K(M) and V(max) values obtained with one of these are similar to those observed with native PIP(2) substrate. These results indicate that the 6-hydroxy group can be modified to develop functional substrates for PLC isozymes, thereby serving as the foundation for further development of PLC-selective sensors.

Uridine-5'-diphosphoglucose (UDPG) activates the P2Y(14) receptor, a neuroimmune system GPCR. P2Y(14) receptor tolerates glucose substitution with small alkyl or aryl groups or its truncation to uridine 5'-diphosphate (UDP), a full agonist at the human P2Y(14) receptor expressed in HEK-293 cells. 2-Thiouracil derivatives displayed selectivity for activation of the human P2Y(14) vs the P2Y(6) receptor, such as 2-thio-UDP 4 (EC(50) = 1.92 nM at P2Y(14), 224-fold selectivity vs P2Y(6)) and its beta-propyloxy ester 18. EC(50) values of the beta-methyl ester of UDP and its 2-thio analogue were 2730 and 56 nM, respectively. beta-tert-Butyl ester of 4 was 11-fold more potent than UDPG, but beta-aryloxy or larger, branched beta-alkyl esters, such as cyclohexyl, were less potent. Ribose replacement of UDP with a rigid North or South methanocarba (bicyclo[3.1.0]hexane) group abolished P2Y(14) receptor agonist activity. alpha,beta-Methylene and difluoromethylene groups were well tolerated at the P2Y(14) receptor and are expected to provide enhanced stability in biological systems. alpha,beta-Methylene-2-thio-UDP 11 (EC(50) = 0.92 nM) was 2160-fold selective versus P2Y(6). Thus, these nucleotides and their congeners may serve as important pharmacological probes for the detection and characterization of the P2Y(14) receptor.

The complications and difficulty associated with the minimally invasive surgery (MIS) two-incision technique in total hip replacement have been well publicized. In this report, the authors describe a modified technique for primary total hip replacement, using two small incisions and no fluoroscopy during surgery. Instead, a stepwise approach and adequate visualization of the surgical field during each step of the procedure are used to reliably and reproducibly perform the operation. In reviewing 102 consecutive hips, neither serious complications nor radiographic malpositioning were found. Provided that the surgeon has received appropriate training and is familiar with the anatomy of the anterior thigh, primary total hip replacement can done safely with the MIS two-incision technique. The advantages of this procedure are the cosmetically appealing incisions, the preservation of muscles and tendons, and superior recovery and return to function.

A review of the current orthopedic literature reveals some evidence that a limited incision approach may be associated with a higher complication rate, particularly in the learning phase of the minimally invasive joint replacement surgery (MIS) techniques. Some of these complications may be limited by computer assistance, but there may still be errors associated with computer assisted surgery (CAS). Surgeons must have sufficient experience in MIS techniques before realizing any potential benefits from CAS. Larger studies will be needed to establish definitively whether the combination of MIS and CAS will lead to improved long-term results.

All peripheral membrane proteins must negotiate unique constraints intrinsic to the biological interface of lipid bilayers and the cytosol. Phospholipase C-β (PLC-β) isozymes hydrolyze the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) to propagate diverse intracellular responses that underlie the physiological action of many hormones, neurotransmitters, and growth factors. PLC-β isozymes are autoinhibited, and several proteins, including Gαq, Gβγ, and Rac1, directly engage distinct regions of these phospholipases to release autoinhibition. To understand this process, we used a novel, soluble analog of PIP2 that increases in fluorescence upon cleavage to monitor phospholipase activity in real time in the absence of membranes or detergents. High concentrations of Gαq or Gβ1γ2 did not activate purified PLC-β3 under these conditions despite their robust capacity to activate PLC-β3 at membranes. In addition, mutants of PLC-β3 with crippled autoinhibition dramatically accelerated the hydrolysis of PIP2 in membranes without an equivalent acceleration in the hydrolysis of the soluble analog. Our results illustrate that membranes are integral for the activation of PLC-β isozymes by diverse modulators, and we propose a model describing membrane-mediated allosterism within PLC-β isozymes.

Extended N(4)-(3-arylpropyl)oxy derivatives of uridine-5'-triphosphate were synthesized and potently stimulated phospholipase C stimulation in astrocytoma cells expressing G protein-coupled human (h) P2Y receptors (P2YRs) activated by UTP (P2Y2/4R) or UDP (P2Y6R). The potent P2Y4R-selective N(4)-(3-phenylpropyl)oxy agonist was phenyl ring-substituted or replaced with terminal heterocyclic or naphthyl rings with retention of P2YR potency. This broad tolerance for steric bulk in a distal region was not observed for dinucleoside tetraphosphate agonists with both nucleobases substituted. The potent N(4)-(3-(4-methoxyphenyl)-propyl)oxy analogue 19 (EC50: P2Y2R, 47 nM; P2Y4R, 23 nM) was functionalized for chain extension using click tethering of fluorophores as prosthetic groups. The BODIPY 630/650 conjugate 28 (MRS4162) exhibited EC50 values of 70, 66, and 23 nM at the hP2Y2/4/6Rs, respectively, and specifically labeled cells expressing the P2Y6R. Thus, an extended N(4)-(3-arylpropyl)oxy group accessed a structurally permissive region on three Gq-coupled P2YRs, and potency and selectivity were modulated by distal structural changes. This freedom of substitution was utilized to design of a pan-agonist fluorescent probe of a subset of uracil nucleotide-activated hP2YRs.

The nucleotide-sugar-activated P2Y14 receptor (P2Y14-R) is highly expressed in hematopoietic cells. Although the physiologic functions of this receptor remain undefined, it has been strongly implicated recently in immune and inflammatory responses. Lack of availability of receptor-selective high-affinity antagonists has impeded progress in studies of this and most of the eight nucleotide-activated P2Y receptors. A series of molecules recently were identified by Gauthier et al. (Gauthier et al., 2011) that exhibited antagonist activity at the P2Y14-R. We synthesized one of these molecules, a 4,7-disubstituted 2-naphthoic acid derivative (PPTN), and studied its pharmacological properties in detail. The concentration-effect curve of UDP-glucose for promoting inhibition of adenylyl cyclase in C6 glioma cells stably expressing the P2Y14-R was shifted to the right in a concentration-dependent manner by PPTN. Schild analyses revealed that PPTN-mediated inhibition followed competitive kinetics, with a KB of 434 pM observed. In contrast, 1 μM PPTN exhibited no agonist or antagonist effect at the P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, or P2Y13 receptors. UDP-glucose-promoted chemotaxis of differentiated HL-60 human promyelocytic leukemia cells was blocked by PPTN with a concentration dependence consistent with the KB determined with recombinant P2Y14-R. In contrast, the chemotactic response evoked by the chemoattractant peptide fMetLeuPhe was unaffected by PPTN. UDP-glucose-promoted chemotaxis of freshly isolated human neutrophils also was blocked by PPTN. In summary, this work establishes PPTN as a highly selective high-affinity antagonist of the P2Y14-R that is useful for interrogating the action of this receptor in physiologic systems.

4-Alkyloxyimino derivatives of pyrimidine nucleotides display high potency as agonists of certain G protein-coupled P2Y receptors (P2YRs). In an effort to functionalize a P2Y6R agonist for fluorescent labeling, we probed two positions (N4 and γ-phosphate of cytidine derivatives) with various functional groups, including alkynes for click chemistry. Functionalization of extended imino substituents at the 4 position of the pyrimidine nucleobase of CDP preserved P2Y6R potency generally better than γ-phosphoester formation in CTP derivatives. Fluorescent Alexa Fluor 488 conjugate 16 activated the human P2Y6R expressed in 1321N1 human astrocytoma cells with an EC50 of 9 nM, and exhibited high selectivity for this receptor over other uridine nucleotide-activated P2Y receptors. Flow cytometry detected specific labeling with 16 to P2Y6R-expressing but not to wild-type 1321N1 cells. Additionally, confocal microscopy indicated both internalized 16 (t1/2 of 18 min) and surface-bound fluorescence. Known P2Y6R ligands inhibited labeling. Theoretical docking of 16 to a homology model of the P2Y6R predicted electrostatic interactions between the fluorophore and extracellular portion of TM3. Thus, we have identified the N4-benzyloxy group as a structurally permissive site for synthesis of functionalized congeners leading to high affinity molecular probes for studying the P2Y6R.

We explored the influence of modifications of uridine 5'-methylenephosphonate on biological activity at the human P2Y(2) receptor. Key steps in the synthesis of a series of 5-substituted uridine 5'-methylenephosphonates were the reaction of a suitably protected uridine 5'-aldehyde with [(diethoxyphosphinyl)methylidene]triphenylphosphorane, C-5 bromination and a Suzuki-Miyaura coupling. These analogues behaved as selective agonists at the P2Y(2) receptor, with three analogues exhibiting potencies in the submicromolar range. Although maximal activities observed with the phosphonate analogues were much less than observed with UTP, high concentrations of the phosphonates had no effect on the stimulatory effect of UTP. These results suggest that these phosphonates bind to an allosteric site of the P2Y(2) receptor.

We explored the influence of modifications of uridine 5'-methylenephosphonate on biological activity at the human P2Y(2) receptor. Key steps in the synthesis of a series of 5-substituted uridine 5'-methylenephosphonates were the reaction of a suitably protected uridine 5'-aldehyde with [(diethoxyphosphinyl)methylidene]triphenylphosphorane, C-5 bromination and a Suzuki-Miyaura coupling. These analogues behaved as selective agonists at the P2Y(2) receptor, with three analogues exhibiting potencies in the submicromolar range. Although maximal activities observed with the phosphonate analogues were much less than observed with UTP, high concentrations of the phosphonates had no effect on the stimulatory effect of UTP. These results suggest that these phosphonates bind to an allosteric site of the P2Y(2) receptor.

P2Y(2) and P2Y(4) receptors are G protein-coupled receptors, activated by UTP and dinucleoside tetraphosphates, which are difficult to distinguish pharmacologically for lack of potent and selective ligands. We structurally varied phosphate and uracil moieties in analogues of pyrimidine nucleoside 5'-triphosphates and 5'-tetraphosphate esters. P2Y(4) receptor potency in phospholipase C stimulation in transfected 1321N1 human astrocytoma cells was enhanced in N(4)-alkyloxycytidine derivatives. OH groups on a terminal δ-glucose phosphoester of uridine 5'-tetraphosphate were inverted or substituted with H or F to probe H-bonding effects. N(4)-(Phenylpropoxy)-CTP 16 (MRS4062), Up(4)-[1]3'-deoxy-3'-fluoroglucose 34 (MRS2927), and N(4)-(phenylethoxy)-CTP 15 exhibit ≥10-fold selectivity for human P2Y(4) over P2Y(2) and P2Y(6) receptors (EC(50) values 23, 62, and 73 nM, respectively). δ-3-Chlorophenyl phosphoester 21 of Up(4) activated P2Y(2) but not P2Y(4) receptor. Selected nucleotides tested for chemical and enzymatic stability were much more stable than UTP. Agonist docking at CXCR4-based P2Y(2) and P2Y(4) receptor models indicated greater steric tolerance of N(4)-phenylpropoxy group at P2Y(4). Thus, distal structural changes modulate potency, selectivity, and stability of extended uridine tetraphosphate derivatives, and we report the first P2Y(4) receptor-selective agonists.

A series of 5-modified 5’-phosphonate derivatives of UMP has been prepared in 6 steps from uridine. The analogs were evaluated for their affinity at the P2Y2 receptor. Several derivatives showed partial agonistic activity at the P2Y2 receptor.

We previously synthesized a series of potent and selective A(3) adenosine receptor (AR) agonists (North-methanocarba nucleoside 5'-uronamides) containing dialkyne groups on extended adenine C2 substituents. We coupled the distal alkyne of a 2-octadiynyl nucleoside by Cu(I)-catalyzed "click" chemistry to azide-derivatized G4 (fourth-generation) PAMAM dendrimers to form triazoles. A(3)AR activation was preserved in these multivalent conjugates, which bound with apparent K(i) of 0.1-0.3 nM. They were substituted with nucleoside moieties, solely or in combination with water-solubilizing carboxylic acid groups derived from hexynoic acid. A comparison with various amide-linked dendrimers showed that triazole-linked conjugates displayed selectivity and enhanced A(3)AR affinity. We prepared a PAMAM dendrimer containing equiproportioned peripheral azido and amino groups for conjugation of multiple ligands. A bifunctional conjugate activated both A(3) and P2Y(14) receptors (via amide-linked uridine-5'-diphosphoglucuronic acid), with selectivity in comparison to other ARs and P2Y receptors. This is the first example of targeting two different GPCRs with the same dendrimer conjugate, which is intended for activation of heteromeric GPCR aggregates. Synergistic effects of activating multiple GPCRs with a single dendrimer conjugate might be useful in disease treatment.

The P2Y14 receptor was initially identified as a G protein-coupled receptor activated by UDP-glucose and other nucleotide sugars. We have developed several cell lines that stably express the human P2Y14 receptor, allowing facile examination of its coupling to native Gi family G proteins and their associated downstream signaling pathways (J Pharmacol Exp Ther 330:162–168, 2009). In the current study, we examined P2Y14 receptor-dependent inhibition of cyclic AMP accumulation in human embryonic kidney (HEK) 293, C6 glioma, and Chinese hamster ovary (CHO) cells stably expressing this receptor. Not only was the human P2Y14 receptor activated by UDP-glucose, but it also was activated by UDP. The apparent efficacies of UDP and UDP-glucose were similar, and the EC50 values (74, 33, and 29 nM) for UDP-dependent activation of the P2Y14 receptor in HEK293, CHO, and C6 glioma cells, respectively, were similar to the EC50 values (323, 132, and 72 nM) observed for UDP-glucose. UDP and UDP-glucose also stimulated extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in P2Y14 receptor-expressing HEK293 cells but not in wild-type HEK293 cells. A series of analogs of UDP were potent P2Y14 receptor agonists, but the naturally occurring nucleoside diphosphates, CDP, GDP, and ADP exhibited agonist potencies over 100-fold less than that observed with UDP. Two UDP analogs were identified that selectively activate the P2Y14 receptor over the UDP-activated P2Y6 receptor, and these molecules stimulated phosphorylation of ERK1/2 in differentiated human HL-60 promyeloleukemia cells, which natively express the P2Y14 receptor but had no effect in wild-type HL-60 cells, which do not express the receptor. We conclude that UDP is an important cognate agonist of the human P2Y14 receptor.

Background: External fixation is widely used for trauma and reconstruction of the lower extremity. External fixator devices spanning the ankle or portions of the foot often utilize pins placed across the metatarsal bases. While this forefoot fixation is occasionally necessary to achieve reduction and alignment, it is also useful to prevent an equinus contracture. We undertook an anatomical study to evaluate the safety of pins placed across the bases of the first and second metatarsals, spanning the first intermetarsal space. Methods: Under fluoroscopy, a single 4.0-mm Schanz pin was advanced percutaneously from medial to lateral across the bases of the first and second metatarsals in ten cadaver feet. This was accomplished in a fashion identical to the application of typical forefoot external fixation as described in the literature. Specimens were then dissected. Injury to the deep plantar branch of the dorsalis pedis artery, when present, was recorded. When injury was not present, the distance from the pin to the deep plantar branch was recorded. Results: In five of the ten feet, the deep plantar branch of the dorsalis pedis artery was lacerated by the transmetatarsal pin. In four feet, the pin contacted the artery but did not visibly damage it. In the remaining foot, the pin was noted to be only 4 mm from the artery. Any pin with a starting point within 18 mm of the first metatarsocuneiform joint placed the artery at risk. Conclusions: Placement of external fixation pins through the proximal bases of the first and second metatarsals, within 2 cm of the first tarsometatarsal joint, consistently places the deep plantar branch of the dorsalis pedis artery at risk. Given the clinical importance of this artery, transmetatarsal pinning in this fashion is not advised. Other methods of obtaining forefoot or midfoot external fixation are recommended in order to avoid vascular injury.

The authors report a case of a complete posterior dislocation of the acromioclavicular (AC) joint with an ipsilateral medial epiphyseal clavicular fracture in a 20-year-old male. Open reduction was indicated because a maintained closed reduction of the AC joint was unsuccessful, and the described treatment maintained a successful reduction.

We present an unusual case in which hip sepsis occurred in a healthy adult. This case emphasizes the necessity of a meticulous history and physical examination and the mandatory formulation of a differential diagnosis. A 37-year-old Caucasian female in otherwise unremarkable health presented with

Chronic inflammation contributes to vascular insulin resistance and endothelial dysfunction. Systemic infusion of TNF-alpha abrogates insulin's action to enhance skeletal muscle microvascular perfusion. In skeletal muscle TNF-alpha induces insulin resistance via the p38 MAPK pathway. To examine whether p38 MAPK also regulates TNF-alpha-induced vascular insulin resistance, bovine aortic endothelial cells (bAECs) were incubated+/-TNF-alpha (5 ng/ml) for 6 h in the presence or absence of SB203580 (p38 MAPK specific inhibitor, 10 microM) after serum starvation for 10 h. For the last 30 min, cells were treated+/-1 nM insulin, and insulin receptor substrate (IRS)-1, Akt, endothelial nitric oxide synthase (eNOS), p38 MAPK, ERK1/2, c-Jun N-terminal kinase, and AMP-activated protein kinase (AMPK) phosphorylation, and eNOS activity were measured. TNF-alpha increased p38 MAPK phosphorylation, potently stimulated IRS-1 serine phosphorylation, and blunted insulin-stimulated IRS-1 tyrosine and Akt phosphorylation and eNOS activity. TNF-alpha also potently stimulated the phosphorylation of ERK1/2 and AMPK. Treatment with SB203580 decreased p38 MAPK phosphorylation back to the baseline and restored insulin sensitivity of IRS-1 tyrosine and Akt phosphorylation and eNOS activity in TNF-alpha-treated bAECs without affecting TNF-alpha-induced ERK1/2 and AMPK phosphorylation. We conclude that in cultured bAECs, TNF-alpha induces insulin resistance in the phosphatidylinositol 3-kinase/Akt/eNOS pathway via a p38 MAPK-dependent mechanism and enhances ERK1/2 and AMPK phosphorylation independent of the p38 MAPK pathway. This differential modulation of TNF-alpha's actions by p38 MAPK suggests that p38 MAPK plays a key role in TNF-alpha-mediated vascular insulin resistance and may contribute to the generalized endothelial dysfunction seen in type 2 diabetes mellitus and the cardiometabolic syndrome.

The intact meniscus provides protection for healing of tibial plateau fractures, prevention of early posttraumatic arthritis, and maintenance of knee stability. However, tibial plateau fractures may have associated meniscal injury that may impair this function. In addition, the meniscotibial ligaments are often divided during submeniscal arthrotomy for exposure. Repair or reattachment of the meniscus can be difficult. We describe the technique of using Kirschner wire holes in proximal tibial plates for anchoring the meniscus.

BACKGROUND: Total hip replacement performed through a small incision theoretically results in less trauma to the underlying structures, reduced blood loss, less pain, and a shorter hospital stay, but it may result in increased complications, particularly early in a surgeon's experience with a new technique. In the present study, we reviewed the early results of two techniques involving the use of smaller incisions; specifically, we evaluated one series of primary total hip replacements that had been performed through two small incisions and another series of total hip replacements that had been performed through a single small incision. METHODS: Eighty-nine consecutive primary total hip replacements were performed with use of the two-incision technique as described by Mears and Berger; all procedures were performed without cement and with use of fluoroscopic guidance. Outcomes data were reviewed at a minimum of six months following the procedure. The results of these procedures were retrospectively compared with those of a historical control series of ninety-six total hip replacements that had been performed by the same surgeon with use of a single miniincision technique. No special attempt was made to discharge any patient early from the hospital. In preparation for the use of the two-incision technique, the surgeon attended a two-day seminar that included cadaveric training and mentoring by surgeons who had experience with this technique. RESULTS: In the two-incision group, nine patients (nine hips; 10%) required repeat surgery because of a femoral fracture that had been identified postoperatively (two hips), dislocation (one hip), a wound complication (two hips), or subsidence and loosening of the femoral implant (four hips). Twenty-two patients (twenty-two hips; 25%) sustained an injury of the lateral femoral cutaneous nerve, and one patient (one hip) had a neuropraxia of the femoral nerve. In the comparative series of ninety-six total hip arthroplasties that had been performed with use of a single mini-incision and a direct lateral exposure of the hip joint, the overall complication rate was 6% (six of ninety-six) and the reoperation rate was 3% (three of ninety-six). The rate of complications associated with the two-incision technique decreased significantly as the surgeon gained experience with the procedure (p = 0.0202). CONCLUSIONS: Although total hip arthroplasty with use of the two-incision technique was performed by a surgeon who was experienced in the performance of total hip replacement surgery with use of a single small incision, the rates of complications and repeat surgery associated with the two-incision technique initially were very high. While the rate diminished with increasing experience, total hip replacement with use of two incisions and fluoroscopic guidance is a technically demanding procedure that may be associated, especially initially, with higher rates of complications and repeat surgery.

Total hip replacement performed through a small incision theoretically results in less trauma to the underlying structures, reduced blood loss, less pain, and a shorter hospital stay, but it may result in increased complications, particularly early in a surgeon's experience with a new technique. In the present study, we reviewed the early results of two techniques involving the use of smaller incisions; specifically, we evaluated one series of primary total hip replacements that had been performed through two small incisions and another series of total hip replacements that had been performed through a single small incision.Eighty-nine consecutive primary total hip replacements were performed with use of the two-incision technique as described by Mears and Berger; all procedures were performed without cement and with use of fluoroscopic guidance. Outcomes data were reviewed at a minimum of six months following the procedure. The results of these procedures were retrospectively compared with those of a historical control series of ninety-six total hip replacements that had been performed by the same surgeon with use of a single miniincision technique. No special attempt was made to discharge any patient early from the hospital. In preparation for the use of the two-incision technique, the surgeon attended a two-day seminar that included cadaveric training and mentoring by surgeons who had experience with this technique.In the two-incision group, nine patients (nine hips; 10%) required repeat surgery because of a femoral fracture that had been identified postoperatively (two hips), dislocation (one hip), a wound complication (two hips), or subsidence and loosening of the femoral implant (four hips). Twenty-two patients (twenty-two hips; 25%) sustained an injury of the lateral femoral cutaneous nerve, and one patient (one hip) had a neuropraxia of the femoral nerve. In the comparative series of ninety-six total hip arthroplasties that had been performed with use of a single mini-incision and a direct lateral exposure of the hip joint, the overall complication rate was 6% (six of ninety-six) and the reoperation rate was 3% (three of ninety-six). The rate of complications associated with the two-incision technique decreased significantly as the surgeon gained experience with the procedure (p = 0.0202).Although total hip arthroplasty with use of the two-incision technique was performed by a surgeon who was experienced in the performance of total hip replacement surgery with use of a single small incision, the rates of complications and repeat surgery associated with the two-incision technique initially were very high. While the rate diminished with increasing experience, total hip replacement with use of two incisions and fluoroscopic guidance is a technically demanding procedure that may be associated, especially initially, with higher rates of complications and repeat surgery.