Medium-term outcomes in single anaesthetic bilateral total knee replacement surgery: a single surgeon series.

BACKGROUND: The lifetime risk of developing symptomatic knee osteoarthritis (OA) is estimated to be 45%, with up to two thirds of patients presenting with bilateral knee symptoms. Patients presenting with end stage bilateral knee OA may benefit from single anaesthetic bilateral total knee replacement (SABTKR). Our study aim was to compare the outcomes of SABTKR with unilateral total knee arthroplasty (TKA) in a single surgeon series over a 20 year period. METHODS: We performed a retrospective review of a single surgeon's data from the New Zealand Joint Registry (NZJR) over a 20-year period from January 1999 to December 2018. This review reports on patient demographics, functional outcomes, revision rates and mortality rates. RESULTS: 1225 total knee replacements were performed by the senior author (995 TKAs and 115 patients underwent SABTKRs) over the 20 year period reviewed. The mean ages of the TKA and SABTKR groups were 67.7 and 66.7 years, respectively. There was 16.9% mortality rate for the TKA group versus 7.8% in SABTKR group. There were no revisions in the SABTKR group versus 17 revisions in the TKA group representing a revision rate of 0.23/100 component years which can be viewed against a 20 year revision rate of 0.48/100 component years (p < 0.05) for all comers in the NZJR. CONCLUSION: This NZJR study demonstrates excellent medium term survival outcomes for selected patients having simultaneous bilateral total knee replacements.

Gq-mER signaling has opposite effects on hypothalamic orexigenic and anorexigenic neurons.

Two populations of cells within the hypothalamus exert opposite actions on food intake: proopiomelanocortin (POMC) neurons decrease it, while neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons increase it. 17ß-Estradiol (E2) is a potent anorexigenic hormone that exerts both genomic and non-genomic, rapid actions on these metabolic neurons. This review focuses on the rapid membrane effects of E2 in both POMC and NPY/AgRP neurons and how these combined effects mediate the anorexigenic effects of this steroid.

The membrane estrogen receptor ligand STX rapidly enhances GABAergic signaling in NPY/AgRP neurons: role in mediating the anorexigenic effects of 17ß-estradiol.

Besides its quintessential role in reproduction, 17ß-estradiol (E2) is a potent anorexigenic hormone. E2 and the selective Gq-coupled membrane estrogen receptor (Gq-mER) ligand STX rapidly increase membrane excitability in proopiomelanocortin (POMC) neurons by desensitizing the coupling of GABAB receptors to G protein-coupled inwardly rectifying K(+) channels (GIRKs), which upon activation elicit a hyperpolarizing outward current. However, it is unknown whether E2 and STX can modulate GABAB signaling in neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons. We used single-cell RT-PCR and whole cell patch clamping with selective pharmacological reagents to show that NPY/AgRP cells of mice express the GABAB-R1 and -R2 receptors and are hyperpolarized by the GABAB agonist baclofen in an E2-dependent manner. In males, E2 rapidly attenuated the coupling of GABAB receptors to GIRKs, which was blocked by the general PI3K inhibitors wortmannin and LY-294002 or the selective p110ß subunit inhibitor TGX-221. The ERα-selective agonist propyl pyrazole triol mimicked the effects of E2. STX, in contrast, enhanced the GABAB response in males, which was abrogated by the estrogen receptor (ER) antagonist ICI 182,780. In gonadectomized mice of both sexes, E2 enhanced or attenuated the GABAB response in different NPY/AgRP cells. Coperfusing wortmannin with E2 or simply applying STX always enhanced the GABAB response. Thus, in NPY/AgRP neurons, activation of the Gq-mER by E2 or STX enhances the GABAergic postsynaptic response, whereas activation of ERα by E2 attenuates it. These findings demonstrate a clear functional dichotomy of rapid E2 membrane-initiated signaling via ERα vs. Gq-mER in a CNS neuron vital for regulating energy homeostasis.

Does tuition for journal referees work? A quantitative evaluation of a half-day tuition course.

AIM: Most consultants participating as referees in the peer review process of papers submitted to scholarly journals have had no training or tuition. This study attempted to evaluate the effect on reviewing of a half-day course held at the Royal Society of Medicine. METHOD: Registered consultant delegates were sent two 'doctored' papers, a case report and an original paper, well before the meeting to review at home using the standard computerized score sheet issued with referee requests by Colorectal Disease. At the start of the meeting the scores were entered into a computer as 'Before'. After each paper had been presented and then discussed, it was re-marked to give the 'After' score. The Before and After scores were compared with the post-meeting feedback forms. RESULTS: The Before and After scores provided by the participants for the two papers each reviewed were not significantly different for the questions relating to the publication/rejection decision. The Before score was higher than the After score for questions relating to the Abstract, Introduction and Method sections. Feedback forms regarding the tuition were universally positive and appreciative. CONCLUSION: Consultants already have the expertise to decide whether a paper should be rejected. The study day appears to give an additional insight that may change an initial opinion. In general a paper scored before the meeting was scored lower after it was presented and discussed at the meeting (the tuition).

Navigated knee kinematics after cutting of the ACL and its secondary restraint.

PURPOSE: The purpose of this study is to evaluate the kinematics changes of the knee after cutting of the ACL with or without injury of the anterolateral structures. METHODS: In this study, the role of the ACL and one of the secondary restraints in controlling knee stability using a navigation system was evaluated. The kinematics of the knee was evaluated in different conditions of instability: ACL intact, after dissection of the posterolateral (PL) bundle, after dissection of the anteromedial (AM) bundle, and after lesion of the lateral capsular ligament (LCL). Anterior tibial translation and rotation were measured with a computer navigation system in 10 fresh-frozen cadaveric knees by use of a manual maximum load. Anterior translation was evaluated at 30°, 60°, and 90° of flexion; rotation at 0°, 15°, 30°, 45°, 60°, and 90°. RESULTS: Cutting the PL bundle does not increase anterior translation and rotation of the knee. Cutting the AM bundle significantly increased the anteroposterior (AP) translation at 30° and 60° (P = 0.01), but does not increase rotation of the knee. Cutting the LCL increased anterior translation at 60° (P = 0.04) and rotation at 30°, 45°, and 60° (P = 0.03). CONCLUSIONS: Within the testing conditions of this study, the PL bundle does not affect anterior translation and rotation of the knee; the AM bundle is the primary restraint of the anterior translation but does not affect rotation of the knee while the lesion of the LCL increases tibial rotation and could be related to the pivot shift phenomenon, so it is more correct and biomechanical valid to assess and repair the associated lesion of the antero-lateral structure of the knee at the time of ACL surgery.

18 F-FDG PET/CT influences management in patients with known or suspected pancreatic cancer.

BACKGROUND: The aims of this study were (i) to assess and validate the incremental information of positron emission tomography/computed tomography (PET/CT) over conventional staging investigations (CSI) and (ii) to assess the management impact of PET/CT in patients with known or suspected pancreatic cancer. METHODS: Between October 2007 and September 2008, 22 PET/CT scans were performed using a dedicated PET/CT scanner in 21 patients with known or suspected pancreatic cancer. Follow up was used to reconcile discordance between PET/CT and CSI. The pre-PET/CT management plan and/or intent were prospectively recorded in all scans. The post-PET/CT management plan was determined from the medical record and/or discussions with treating clinicians. The management impact of PET/CT was classified as high, medium, low or none defined using Australian and New Zealand Association of Physicians in Nuclear Medicine PET data collection project criteria. RESULTS: PET/CT and CSI were discordant in 14/22 (64%: 95% CI; 43-84%) scans. Of the 14 discordant scans, PET/CT assessment was correct in eight, conventional imaging in four and there was insufficient information in two. Overall, PET/CT management impact was classified as high (n= 6), medium (n= 3), low (n= 9) or none (n= 4). Significant changes in management (high or medium impact) were induced by PET/CT in 9/22 scans (41%: 95% CI; 20-62%) predominantly by correctly modifying the disease extent. CONCLUSION: PET/CT has an incremental benefit over CSI and has a significant impact on management in patients with known or suspected pancreatic cancer. PET/CT merits consideration as part of the non-invasive evaluation of patients with known or suspected pancreatic cancer.

Are smokers with acute cough in primary care prescribed antibiotics more often, and to what benefit? An observational study in 13 European countries.

Little is known about actual clinical practice regarding management of smokers compared with ex-smokers and nonsmokers presenting with acute cough in primary care, and whether a lower threshold for prescribing antibiotics benefits smokers. This was a multicentre 13-country European prospective observational study of primary care clinician management of acute cough in consecutive immunocompetent adults presenting with an acute cough of

Lymph node retrieval in colorectal cancer resection specimens: national standards are achievable, and low numbers are associated with reduced survival.

OBJECTIVES: The current guidelines identify the retrieval of at least 12 lymph nodes as crucial for accurate staging of colorectal cancer. We set out to review our figures from a single centre to see whether this standard has been met, and to examine for factors which may influence the number of lymph nodes retrieved. The influence of a low lymph node harvest on survival in patients with Dukes' A and B cancers was specifically investigated. METHOD: Data were collected from all patients with colorectal cancer undergoing resectional surgery from our prospectively compiled database between June 1998 and May 2007. A multivariate analysis was performed to identify factors resulting in low lymph node yields in those patients undergoing formal resection. Survival analyses were performed in patients with Dukes' A and B cancers to assess whether a low lymph node yield negatively impacted on survival. RESULTS: A total of 2449 patients underwent formal resection and were included in the analysis. The median lymph node retrieval was 13 nodes (range 0-136). On multivariate analysis, preoperative chemo-radiotherapy, operation type, specimen length and patient age all independently influenced lymph node retrieval. Patient gender, ethnicity, operative mode, operative team and consultant presence had no influence. Survival in patients with Dukes' A and B cancers was significantly reduced if <12 nodes were sampled. CONCLUSIONS: As a unit, we are achieving the national standard for lymph node harvest. This standard was maintained whether the surgeon performing the surgery was a consultant or a trainee, and also when the surgery was performed in the emergency setting. These data support the concept of 12 nodes being required for accurate staging.

Evaluation of pulmonary nodules and lung cancer with one-inch crystal gamma coincidence positron emission tomography/CT versus dedicated positron emission tomography/CT.

Dedicated positron emission tomography (PET)/CT scanners using BGO and related detectors (d-PET) have become standard imaging instruments in many malignancies. Hybrid gamma camera systems using NaI detectors in coincidence mode (g-PET) have been compared to d-PET but reported usefulness has been variable when gamma cameras with half-inch to three-fourth-inch thick crystals have been used without CT. Our aim was to compare g-PET with a 1-in.-thick crystal and inbuilt CT for lesion localization and attenuation correction (g-PET/CT) and d-PET/CT in patients presenting with potential and confirmed lung malignancies. One hour after (18)F-fluorodeoxyglucose (FDG), patients underwent BGO d-PET/CT from jaw to proximal thigh. This was followed by one to two bed position g-PET/CT 194 +/- 27 min after FDG. Each study pair was independently analysed with concurrent CT. d-PET/CT was interpreted by a radiologist experienced in both PET and CT, and g-PET/CT by consensus reading of an experienced PET physician and an experienced CT radiologist. A TNM score was assigned and studies were then unblinded and compared. Fifty-seven patients underwent 58 scan pairs over 2 years. Eighty-nine per cent concordance was shown between g-PET/CT and d-PET/CT for the assessment of intrapulmonary lesions, with 100% concordance for intrapulmonary lesions >10 mm (36 of 36). Eighty-eight per cent (51 of 58) concordance was shown between g-PET/CT and d-PET/CT for TNM staging. Coincidence imaging using an optimized dual-head 1-in.-thick crystal gamma camera with inbuilt CT compares reasonably well with dedicated PET/CT for evaluation of indeterminate pulmonary lesions and staging of pulmonary malignancies and may be of some value when d-PET/CT is not readily available.

Cross-talk between membrane-initiated and nuclear-initiated oestrogen signalling in the hypothalamus.

It is increasingly evident that 17beta-oestradiol (E(2)), via a distinct membrane oestrogen receptor (Gq-mER), can rapidly activate kinase pathways to have multiple downstream actions in central nervous system (CNS) neurones. We have found that E(2) can rapidly reduce the potency of the GABA(B) receptor agonist baclofen and mu-opioid receptor agonist DAMGO to activate G-protein-coupled, inwardly rectifying K(+) (GIRK) channels in hypothalamic neurones, thereby increasing the excitability (firing activity) of pro-opiomelanocortin (POMC) and dopamine neurones. These effects are mimicked by the membrane impermeant E(2)-BSA and a new ligand (STX) that is selective for the Gq-mER that does not bind to ERalpha or ERbeta. Both E(2) and STX are fully efficacious in attenuating the GABA(B) response in ERalpha, ERbeta and GPR 30 knockout mice in an ICI 182 780 reversible manner. These findings are further proof that E(2) signals through a unique plasma membrane ER. We have characterised the coupling of this Gq-mER to a Gq-mediated activation of phospholipase C leading to the up-regulation of protein kinase Cdelta and protein kinase A activity in these neurones, which ultimately alters gene transcription. Finally, as proof of principle, we have found that STX, similar to E(2), reduces food intake and body weight gain in ovariectomised females. STX, presumably via the Gq-mER, also regulates gene expression of a number of relevant targets including cation channels and signalling molecules that are critical for regulating (as a prime example) POMC neuronal excitability. Therefore, E(2) can activate multiple receptor-mediated pathways to modulate excitability and gene transcription in CNS neurones that are critical for controlling homeostasis and motivated behaviors.

Tibolone rapidly attenuates the GABAB response in hypothalamic neurones.

Tibolone is primarily used for the treatment of climacteric symptoms. Tibolone is rapidly converted into three major metabolites: 3 alpha- and 3beta-hydroxy (OH)-tibolone, which have oestrogenic effects, and the Delta 4-isomer (Delta 4-tibolone), which has progestogenic and androgenic effects. Because tibolone is effective in treating climacteric symptoms, the effects on the brain may be explained by the oestrogenic activity of tibolone. Using whole-cell patch clamp recording, we found previously that 17beta-oestradiol (E(2)) rapidly altered gamma-aminobutyric acid (GABA) neurotransmission in hypothalamic neurones through a membrane oestrogen receptor (mER). E(2) reduced the potency of the GABA(B) receptor agonist baclofen to activate G-protein-coupled, inwardly rectifying K(+) (GIRK) channels in hypothalamic neurones. Therefore, we hypothesised that tibolone may have some rapid effects through the mER and sought to elucidate the signalling pathway of tibolone's action using selective inhibitors and whole cell recording in ovariectomised female guinea pigs and mice. A sub-population of neurones was identified post hoc as pro-opiomelanocortin (POMC) neurones by immunocytochemical staining. Similar to E(2), we have found that tibolone and its active metabolite 3 beta OH-tibolone rapidly reduced the potency of the GABA(B) receptor agonist baclofen to activate GIRK channels in POMC neurones. The effects were blocked by the ER antagonist ICI 182 780. Other metabolites of tibolone (3 alpha OH-tibolone and Delta 4-tibolone) had no effect. Furthermore, tibolone (and 3 beta OH-tibolone) was fully efficacious in ER alpha knockout (KO) and ER beta KO mice to attenuate GABA(B) responses. The effects of tibolone were blocked by phospholipase C inhibitor U73122. However, in contrast to E(2), the effects of tibolone were not blocked by protein kinase C inhibitors or protein kinase A inhibitors. It appears that tibolone (and 3 beta OH-tibolone) activates phospholipase C leading to phosphatidylinositol bisphosphate metabolism and direct alteration of GIRK channel function. Therefore, tibolone may enhance synaptic efficacy through the G(q) signalling pathways of mER in brain circuits that are critical for maintaining homeostatic functions.

Structural model and functional significance of pH-dependent talin-actin binding for focal adhesion remodeling.

Actin filament binding by the focal adhesion (FA)-associated protein talin stabilizes cell-substrate adhesions and is thought to be rate-limiting in cell migration. Although F-actin binding by talin is known to be pH-sensitive in vitro, with lower affinity at higher pH, the functional significance of this pH dependence is unknown. Because increased intracellular pH (pH(i)) promotes cell migration and is a hallmark of metastatic carcinomas, we asked whether it increases FA remodeling through lower-affinity talin-actin binding. Talin contains several actin binding sites, but we found that only the COOH-terminal USH-I/LWEQ module showed pH-dependent actin binding, with lower affinity and decreased maximal binding at higher pH. Molecular dynamics simulations and NMR of this module revealed a structural mechanism for pH-dependent actin binding. A cluster of titratable amino acids with upshifted pK(a) values, including His-2418, was identified at one end of the five-helix bundle distal from the actin binding site. Protonation of His-2418 induces changes in the conformation and dynamics of the remote actin binding site. Structural analyses of a mutant talin-H2418F at pH 6.0 and 8.0 suggested changes different from the WT protein, and we confirmed that actin binding by talin-H2418F was relatively pH-insensitive. In motile fibroblasts, increasing pH(i) decreased FA lifetime and increased the migratory rate. However, expression of talin-H2418F increased lifetime 2-fold and decreased the migratory rate. These data identify a molecular mechanism for pH-sensitive actin binding by talin and suggest that FA turnover is pH-dependent and in part mediated by pH-dependent affinity of talin for binding actin.

Genes associated with membrane-initiated signaling of estrogen and energy homeostasis.

During the reproductive cycle, fluctuations in circulating estrogens affect multiple homeostatic systems controlled by hypothalamic neurons. Two of these neuronal populations are arcuate proopiomelanocortin and neuropeptide Y neurons, which control energy homeostasis and feeding. Estradiol modulates these neurons either through the classical estrogen receptors (ERs) to control gene transcription or through a G protein-coupled receptor (mER) activating multiple signaling pathways. To differentiate between these two divergent ER-mediated mechanisms and their effects on homeostasis, female guinea pigs were ovariectomized and treated systemically with vehicle, estradiol benzoate (EB) or STX, a selective mER agonist, for 4 wk, starting 7 d after ovariectomy. Individual body weights were measured after each injection day for 28 d, at which time the animals were euthanized, and the arcuate nucleus was microdissected. As predicted, the body weight gain was significantly lower for EB-treated females after d 5 and for STX-treated females after d 12 compared with vehicle-treated females. Total arcuate RNA was extracted from all groups, but only the vehicle and STX-treated samples were prepared for gene microarray analysis using a custom guinea pig gene microarray. In the arcuate nucleus, 241 identified genes were significantly regulated by STX, several of which were confirmed by quantitative real-time PCR and compared with EB-treated groups. The lower weight gain of EB-treated and STX-treated females suggests that estradiol controls energy homeostasis through both ERalpha and mER-mediated mechanisms. Genes regulated by STX indicate that not only does it control neuronal excitability but also alters gene transcription via signal transduction cascades initiated from mER activation.

Prioritization of colorectal referrals: a review of the 2-week wait referral system.

OBJECTIVE: The 2-week wait (TWW) fast-track referral system for patients suspected of having colorectal cancer (CRC) has fallen well short of its expectations of streamlining prioritization of colorectal referrals. Our study reviews most of the audits/studies that have been published on the system as its inception. Our aim was to identify where the shortcomings are and also to review the various alternatives that have recently been put forward. METHOD: All articles on the TWW system published in mainstream peer reviewed journals were reviewed, as were all the abstracts on the system presented at the Association of Coloproctology and the British Society of Gastroenterology meetings. Implementation, compliance with guidelines, cancer detection rate, impact on waiting times and the overall effectiveness of the system are evaluated. RESULTS: While the implementation of the system has been generally robust in most centres, the compliance with guidelines has been poor. This coupled with the inherently poor specificity of the system has resulted in a poor (and decreasing) cancer detection rate and a steadily growing volume of the hospital referrals. The system has been shown to have an adverse impact on the waiting times for routine colorectal referrals - a group that contributes significantly to the total number of CRC detected. The various alternatives to the TWW system that have been proposed recently, including our own, are discussed. CONCLUSION: The shortcomings of the TWW system in its original form have now been demonstrated beyond doubt. What is needed is a fresh approach to find a cost effective and viable alternative in a climate of increased expectations and finite resources.

Results of a survey of the role of multidisciplinary team coordinators for colorectal cancer in England and Wales.

OBJECTIVE: Over the last 6 years, multidisciplinary teams (MDTs) have been established and play a key role in organizing the delivery of cancer care in the UK. There are no published data on the roles of their co-coordinators. To seek the views of colorectal multidisciplinary team co-ordinators (MDTCs) on what they do and how they do it. METHOD: Questionnaires were sent to the colorectal MDTC, or equivalent, in all 180 NHS hospital trusts in England and Wales where colorectal cancer surgery is performed. RESULTS: There was a 70% response rate. Seventy-one per cent of trusts now have a dedicated MDTC, whereas in 2002, only 40% had one. MDTCs generally keep their information on databases, but these differ, and are not coordinated with data entry into the national colorectal cancer database of the Association of Coloproctology of Great Britain and Ireland. In only 26 trusts does the MDTC communicate decisions to primary care, and the patients seem almost completely excluded from this process. CONCLUSION: The recently formed national MDTC Forum should grasp the opportunity of coordinating all of this well-intentioned but pluralistic activity to the benefit of patients, primary care and hospital teams. An effective MDTC with a robust database will be the key in achieving cancer waiting time targets with useful audit, thereby improving patient care.