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Muhamed M Farhan-Alanie,1 Jayne Ward,1 Michael B Kelly,2 Khalid Al-Hourani3 1Department of Trauma & Orthopaedics, University Hospital Coventry & Warwickshire, Coventry, UK; 2Department of Trauma & Orthopaedics, Southmead Hospital, Bristol, UK; 3Department of Trauma & Orthopaedics, Royal Infirmary of Edinburgh, UKCorrespondence: Muhamed M Farhan-Alanie, Email muhamed.farhan-alanie@nhs.netAbstract: Open tibial fractures may be associated with bone loss at the time of the injury or following surgical debridement of the fracture. This article discusses the various treatment options available and the latest developments surrounding the management of free bone fragments in open tibial fractures.Keywords: tibia, open, fracture, bone, fragments, trauma, devitalized, devitalised

Background: The optimal management strategy for instability afte total hip arthroplasty remains unclear. Acetabular lip augmentation devices may offer an operative solution for recurrent instability. This systematic review reports the clinical outcomes of acetabular lip augmentation devices in comparison to other treatment options. Methods: A literature search strategy was performed of Medline, EMBASE, and CENTRAL on September 19, 2020, for all studies reporting outcomes of acetabular lip augmentation devices for recurrent dislocation after total hip arthroplasty. Non-English language articles were excluded. Clinical and survivorship data were collated and analyzed. Results: Thirteen studies describing acetabular augmentation were included for analysis. A total of 644 hips in 636 patients were augmented with a mean age of 75 years (39 to 103). Five different augmentation devices were used. The posterior lip augmentation device (PLAD, DePuy) was the most used (406 hips). Overall, acetabular lip augmentation devices had a 10% postoperative dislocation rate at a mean follow-up of 49 months (0.2 to 132). The PLAD had a 3.9% subsequent dislocation rate with a mean follow-up of 51 months (0.2 to 132). Only one study compared the PLAD to a dual-mobility cup, which demonstrated shorter operative times with the PLAD but higher rates of dislocation and revision surgery. Conclusion: The quality of literature on lip acetabular augmentation devices is poor. In these studies, the postoperative dislocation rate after lip acetabular augmentation was relatively high. The PLAD (DePuy) has the most evidence and may offer a therapeutic option for recurrent instability, in very specific clinical situations.

Introduction: The addition of durvalumab after chemoradiation therapy (CRT) in unresectable stage III NSCLC significantly improves survival. The benefit of this approach in elderly patients is controversial given the toxicity associated with CRT and, thus, may be underutilized. We sought to investigate the outcomes of elderly patients treated with CRT without or without durvalumab at our center. Methods: We reviewed all stage III patients with NSCLC treated with CRT between 2018 and 2020. Patients were analyzed on the basis of age: less than 70 years and 70 years and older. The end points evaluated were treatment patterns, toxicity, progression-free survival, and overall survival. Results: The baseline characteristics including Eastern Cooperative Oncology Group performance status and comorbidities were similar among the 115 patients (44 elderly, 71 young). Completion rates of CRT (100%, 97%) and chemotherapy dose intensity (97%, 97%) were high in elderly and young patients, respectively. There was a trend toward increased hospitalizations in elderly patients because of infections (27% versus 13%, p = 0.08). Of those who did not have primary progression after CRT, 78% of eldery and 81% of young patients received durvalumab. The incidence of grade 3 or higher immune-related adverse events was 9% in elderly and 6% in young patients (p = 0.67). The median progression-free survival was similar (15.6 versus 10.5 mo, p = 0.10), even after adjusting for comorbidities (hazard ratio = 0.6, p = 0.09). The 12-month overall survival rates were 78% in the elderly and 76% in young patients (p = 0.98). Conclusions: Well-selected elderly patients can be treated safely with CRT followed by durvalumab with similar survival benefits compared with their younger counterparts. We would advocate for the referral of all elderly patients for oncologic assessment to avoid undertreatment.

Background: A large proportion of the plastic surgery literature is dedicated to the breast. It is one of the most common topics in our specialty, yet it is unclear which articles have been the most influential. The purpose of this study was to identify the top 100 most-cited articles on breast in the plastic surgery literature and examine the characteristics of each individual article. Methods: Using an electronic database through the Web of Science, we were able to determine the 6 journals that contributed to the 100 most-cited articles on breast in the plastic surgery literature. Results: Each article was examined individually looking at characteristics such as subject matter, article type, country of origin, institution, authorship, and year of publication. Plastic and Reconstructive Surgery contributed the most articles to the top 100 with 81 articles including the most-cited article which has been referenced 673 times to date. The United States produced 73% of the top 100 articles, and the most prolific institution was the University of Texas M. D. Anderson Cancer Center with 15 articles. Conclusions: This study has identified the most influential articles on breast in the plastic surgery literature over the past 68 years and highlighted many important scientific breakthroughs and landmarks that have occurred during this time.

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Objectives: To delineate whether a "safe" window exists for timing from definitive fixation to definitive soft tissue coverage in the treatment of open tibial diaphyseal fractures requiring flap coverage., Design: International multicenter, retrospective comparative cohort study., Patients/participants: Three hundred and seventy-three (n = 373) patients who sustained an open tibial shaft fracture requiring flap coverage., Methods: We evaluated the deep infection rates based on the timing between the definitive fixation and flap coverage. We determined several intervals of time from the day of definitive fixation (regardless of time from injury) and flap coverage. If performed on the same operative setting these were considered day 0. We evaluated coverage after 2 and 5 days from definitive fixation based on time versus infection rate curve inflection points. We adjusted for time to debridement and antibiotics within an hour., Main Outcome Measurement: Deep infection after definitive fixation and flap coverage., Results: The mean age of the cohort was 42.4 years (SD = 18.2) and 270 were male (72.4%). The deep infection rate after flap coverage was 20.6% (77/373). Definitive fixation to flap coverage time of up to 2 days was not associated with an increased risk of infection [relative risk (RR) = 1.12; 95% confidence interval, 0.92-1.37; P = 0.26]. There was an increased risk of deep infection for more than 2 days (RR = 1.59) and >5 days (RR = 1.64)., Conclusion: This study observed a "safe" window of up to 2 days between definitive fixation and flap coverage in open tibial shaft fractures requiring coverage before a statistical increase in risk of deep infection rate occurred., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Adequate debridement of an open fracture is a key component of successful management. Despite having set debridement principles, there is no structured technique available in the literature to guide the surgeon in achieving this. We therefore present a technical note detailing the structured approach to the debridement of any open tibial fracture. Our unit has developed a novel stepwise technique termed locally as the "three-vessel view". Identifying all three primary vessels of the leg facilitates confirmation of inspection of all lower limb compartments thus minimising the risk of missed devitalised tissue or neglected areas of contamination and the potential for consequent disastrous outcomes as a result of inadequate exposure., (© 2021. Crown.)

Objective: To determine health-related quality of life (HRQoL) in patients who sustained type IIIB open tibial diaphyseal (OTA/AO-42) fractures and underwent orthoplastic reconstruction using mechanically relevant devitalized bone (ORDB) versus those who did not require the use of devitalized bone as part of their orthoplastic reconstruction., Design: Consecutive cohort study., Patients/participants: The study included 74 patients who sustained a type IIIB open tibial diaphyseal fracture requiring orthoplastic reconstruction over a 4-year period in a major trauma center. All patients underwent a two-stage orthoplastic reconstruction protocol, with the second stage consisting of definitive fixation and flap coverage (free fascial anterolateral thigh flap) in a single sitting. Patients were contacted at a minimum of 30 months to measure HRQoL., Intervention: Patients requiring ORDB versus those who did not require the use of devitalized bone as part of their orthoplastic reconstruction., Main Outcome Measurements: The primary outcome measure was HRQoL ascertained using Euro-Qol (EQ)-5D and Short-Form (SF)-36 scores., Results: Thirty (n = 30) patients underwent ORDB with the remaining 44 not requiring devitalized bone as part of their reconstruction. The median age was 46.5 years [interquartile range (IQR) 29.0], with a median follow-up of 3.8 years (IQR 1.5). The median cohort EQ-5D was 0.743 (IQR 0.222), ORDB 0.743 (IQR 0.195) versus non-ORDB 0.748 (IQR 0.285), P = 0.71. The median physical component SF-36 score was 80 (IQR 50), ORDB 80 (IQR 34.5) versus non-ORDB 77.5 (IQR 58.75), P = 0.72. The median mental component SF-36 score was 80 (IQR 28), ORDB 80 (IQR 21) versus non-ORDB 80 (IQR 36), P = 0.29., Conclusions: In patients who sustained a type IIIB open tibial shaft fracture and who underwent a 2-stage orthoplastic reconstruction, ORDB does not seem to be associated with inferior health-related quality of life based on EQ-5D or SF-36 scores. The results of this approach should be considered within the strict combined orthoplastic approach in the study unit., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To determine the rate of acute compartment syndrome (ACS) in a series of patients with Gustilo-Anderson type IIIB open tibial shaft fractures that were treated using a specific 2-stage orthoplastic protocol., Design: Consecutive cohort study., Patients/participants: Ninety-three (n = 93) consecutive patients with a type IIIB open tibial shaft fracture (OTA/AO-42) treated using a 2-stage orthoplastic approach, between August 2015 and January 2018. After exclusions, 83 (n = 83) were eligible for analysis., Intervention: Colloid resuscitation and 2-stage orthoplastic reconstruction of type IIIB open tibial shaft fracture. Stage 1 consists of "3-vessel view" early debridement and temporary internal fixation, with stage 2 consisting of a single-stage fix and flap., Main Outcome Measurements: Rate of ACS. Secondary outcomes included early/late sequelae of missed ACS, deep infection, arterial injury, nonunion, and flap failure., Results: Eighty-three (n = 83) patients were included for analysis. The median age was 45.4 years [interquartile range (IQR) 35] with a median follow-up of 1.6 years (IQR 0.8). The median number of operations was 2.0 (IQR 4). For the primary outcome, there were a total of 0 (0/83) patients who required fasciotomy or developed early/late clinical sequelae of missed ACS. Six (6/83, 7.2%) patients developed deep infection, 18 patients (18/83, 21.7%) experienced nonischemic arterial injury, 5 patients (5/83, 6.0%) experienced nonunion, with 4 patients (4/83, 4.8%) experiencing flap failure. Diabetes was the only variable associated with deep infection (P = 0.025) and nonunion (P < 0.001)., Conclusions: Patients with type IIIB open tibial shaft fractures treated with colloid resuscitation and a 2-stage orthoplastic protocol, which includes early "3-vessel view" exposure and debridement, do not appear to develop ACS. Furthermore, no sequelae of missed compartment syndrome was observed at final follow-up., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To delineate if there were differences in outcomes between definitive fixation strategies in open tibial shaft fractures., Data Sources: MEDLINE, EMBASE, CENTRAL, and OpenGrey., Study Selection: Randomized and Quasi-randomized studies analyzing adult patients (>18 years) with open tibial shaft fractures (AO-42), undergoing definitive fixation treatment of any type., Data Extraction: Data regarding patient demographics, definitive bony/soft-tissue management, irrigation, type of antibiotics, and follow-up. Definitive intervention choices included unreamed intramedullary nailing (UN), reamed intramedullary nailing, plate fixation, multiplanar, and uniplanar external fixation (EF). The primary outcome was unplanned reoperation rate. Cochrane risk of bias tool and Grading of Recommendation Assessment, Development and Evaluation systems were used for quality analysis., Data Synthesis: A random-effects meta-analysis of head-to-head evidence, followed by a network analysis that modeled direct and indirect data was conducted to provide precise estimates [relative risk (RR) and associated 95% confidence interval (95% CI)]., Results: In open tibial shaft fractures, direct comparison UN showed a lower risk of unplanned reoperation versus EF (RR 0.67, 95% CI 0.43-1.05, P = 0.08, moderate confidence). In Gustilo type III open fractures, the risk reduction with nailing compared with EF was larger (RR 0.61, 95% CI 0.37-1.01, P = 0.05, moderate confidence). UN had a lower reoperation risk compared with reamed intramedullary nailing (RR 0.91, 95% CI 0.58-1.4, P = 0.68, low confidence); however, this was not significant and did not demonstrate a clear advantage., Conclusions: Intramedullary nailing reduces the risk of unplanned reoperation by a third compared with EF, with a slightly larger reduction in type III open fractures. Future trials should focus on major complication rates and health-related quality of life in high-grade tibial shaft fractures., Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Open complete articular injuries of this distal humerus are rare injuries which are challenging to manage. The study unit aims to present a small case series of Gustilo-Anderson type III open complete articular fractures which have undergone a single-stage definitive fixation and soft-tissue coverage, presenting their functional outcomes., Methods: Retrospective case series identifying all type IIIB AO 13-C3 distal humeral fractures from the unit trauma database. The primary outcome was the Oxford Elbow Score. Secondary outcomes included deep infection, nonunion, and reoperation., Results: A total of six patients were identified, (four open type IIIA, 2 type IIIB). All patients underwent single-sitting definitive fixation and soft-tissue coverage. Mean range of motion arc was 90 degrees. The median Oxford Elbow Score was 35 (range 21-43), representative of mild to moderate arthritis. One patient (n = 1) developed deep infection at 24 months and required reoperation. All patients (n = 6) proceeded to union at the latest follow-up. We present a case report of a 59-years-old patient who sustained a type IIIB, AO 13-C3 distal humeral fracture who underwent single-sitting definitive fixation and flap coverage., Conclusion: This case series reports that positive functional outcomes representative of mild/moderate arthritis at short to midterm follow-up can be achieved after definitive fixation and soft-tissue coverage in a single sitting, including when the soft tissue is deficient. This is a rare injury which is under-reported in the literature., (© 2021 The Authors.)

Caffeine is the most commonly ingested psychoactive substance in the world. Although caffeine-use disorder is not recognized as a formal diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, five disorders related to caffeine use are enumerated therein. An evolving literature suggests that caffeine is one of many licit substances that may cause psychotic symptoms in higher doses. Here, we present a case in which a defendant ingested large quantities of caffeine, which result in transient psychosis and a successful affirmative defense of involuntary intoxication. The purpose of this article is to summarize states' statutory approaches to involuntary intoxication, given that the term is defined variably, if defined at all. Evaluators must be careful to apply jurisdictionally appropriate standards in involuntary intoxication defenses because the bar for this total defense differs across localities., (© 2020 American Academy of Psychiatry and the Law.)

Three-column fixation of tibial plateau fractures is now an established philosophy. A direct posterior approach with the patient prone affords enhanced exposure of the posterior column and ease of access for fixation using a buttress plate and posterior-to-anterior screws. A "direct posterior" approach through a reverse L-shaped incision to back of the knee is popular, yet complications associated with raising a fascial flap can occur. We present a simple method of conceptualizing a direct posterior approach through a single longitudinal incision, by likening it to a commonly performed orthopedic approach, the flexor carpi radialis approach to the wrist.

Introduction: This study aimed to determine the practicality and estimate the effect of administering pre-operative blood product resuscitation to a consecutive, prospectively recruited cohort of 100 patients admitted to a single centre with a hip fracture with all other treatment unchanged., Method: 100 patients aged 65 years or over admitted acutely to our unit with unilateral fractured femoral neck during the study period were included in this study, regardless of cognitive function. Patients were excluded only if there were relevant medical comorbidities or consent was declined. Each patient was resuscitated with a single unit of packed red cells in the immediate perioperative period in addition to standard care. The primary outcome was to establish the feasibility of the study protocol employed in using blood products to resuscitate eligible patients and recording reasons for any failures to include eligible patients. Additional data regarding mortality at 30 days following injury, subsequent blood product use, any transfusion related adverse reactions and total blood product use was measured., Results: We were able to show that it is safe and practicable to deliver blood as an early resuscitative strategy in the frail elderly hip fracture population. The mortality rate of the study cohort was 3%. No adverse reaction was observed in any of the 99 patients given blood as a result of the resuscitation strategy and no morbidity was seen that could be attributed to the effect of giving blood. The total amount of blood received by comparable cohorts in the study period and the two preceding years were similar., Conclusions: The study suggests that in the hip fracture population it is both practical and beneficial to move away from reactive transfusion regimens, and instead centre efforts instead on optimal resuscitation at the initial presentation., Competing Interests: None., (© 2019 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.)

Aims: To assess current national practice in the management of severe open tibial fractures against national standards, using data collected by the Trauma and Audit Research Network., Materials and Methods: Demographic, injury-specific, and outcome data were obtained for all grade IIIB/C fractures admitted to Major Trauma Centres in England from October 2014 to January 2016., Results: Data was available for 646 patients with recorded grade IIIB/C fractures. The male to female ratio was 2.3:1, mean age 47 years. 77% received antibiotics within 3 h of admission, 82% were debrided within 24 h. Soft tissue coverage was achieved within 72 h of admission in 71%. The amputation rate was 8.7%. 4.3% of patients required further theatre visits for infection during the index admission. The timing of antibiotics and surgery could not be correlated with returns to theatre for early infection. There were significant differences in the management and outcomes of patients aged 65 and over, with an increase in mortality and amputation rates., Conclusions: Good outcomes are reported from the management of IIIB/C fractures in Major Trauma Centres in England. Overall compliance with national standards is particularly poor in the elderly. Compliance did not appear to affect rates of returning to theatre or early infection. Appropriately applied patient reported outcome measures are needed to enhance the evidence-base for management of these injuries., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

Aims: The aim of this study was to investigate the association between the type of operation used to treat a trochanteric fracture of the hip and 30-day mortality., Patients and Methods: Data on 82 990 patients from the National Hip Fracture Database were analyzed using generalized linear models with incremental case-mix adjustment for patient, non-surgical and surgical characteristics, and socioeconomic factors., Results: The use of short and long intramedullary nails was associated with an increase in 30-day mortality (adjusted odds ratio (OR) 1.125, 95% confidence interval (CI) 1.040 to 1.218; p = 0.004) compared with the use of sliding hip screws (12.5% increase). If this were causative, it would represent 98 excess deaths over the four-year period of the study and one excess death would be caused by treating 112 patients with an intramedullary nail rather than a sliding hip screw., Conclusion: There is a 12.5% increase in the risk of 30-day mortality associated with the use of an intramedullary nail compared with a sliding hip screw in the treatment of a trochanteric fractures of the hip.

Euthanasia is available in Belgium and Luxembourg for untreatable and unbearable suffering resulting from 'physical and/or psychological suffering that cannot be alleviated and results from a serious and incurable disease, caused by accident or illness'. Verhofstadt et al 's valuable analysis of testimonials from psychiatric patients requesting euthanasia demonstrates that elements of this suffering might well be alleviated. We should not kill our patients., Competing Interests: Declaration of interestNone., (© The Royal College of Psychiatrists 2017.)

Objective: To examine whether the timing of delivery of intravenous antibiotics following open limb fractures has an effect on deep infection rates and other outcomes., Design: We published an a priori study protocol in PROSPERO. Our search strategy combined terms for antibiotics, timing of administration and fractures. Two independent reviewers screened, selected, assessed quality and extracted data from identified studies., Data Sources: We searched five electronic databases with no limits and performed grey literature searches., Eligibility Criteria for Selecting Studies: Randomised and non-randomised controlled studies, prospective and retrospective observational studies in which the effect of the timing of delivery of antibiotics on the outcome of deep infection in open fractures was considered were included., Results: Eight studies were included according to the above criteria. There were no randomised or non-randomised controlled trials. None of the included studies provided data on patient reported or health-related quality of life. The overall deep infection rate ranged from 5% to 17.5%. All of the studies were at substantial risk of bias. One study reported a reduced infection rate with the delivery of antibiotics within 66 min of injury and seven studies reporting no effect., Conclusions: Sufficiently robust evidence is not available currently to determine whether the timing of delivery of intravenous antibiotics has an effect on the risk of deep infection or other outcomes following open limb fractures. There is therefore a need for a randomised controlled trial in this area before policy changes should be instigated., Trial Registration Number: PROSPERO (CRD42015016729)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

To evaluate the evidence for the resuscitation of patients with hip fracture in the preoperative or perioperative phase of their treatment and its impact on mortality., Design: We searched MEDLINE, EMBASE, CENTRAL and PROSPERO databases using a systematic search strategy for randomised trials and observational studies investigating the fluid resuscitation of any patient with hip fracture. No language limits were applied to the search, which was complemented by manually screening the reference lists of appropriate studies., Outcome Measures: Mortality at 1 week, 30 days and 1 year following surgery., Results: Two hundred and ninety-eight citations were identified, and 12 full manuscripts were reviewed; no studies satisfied the inclusion criteria. The background literature showed that the mortality for these patients at 30 days is approximately 8.5% and that bone cement implantation syndrome is insufficient to explain this. The literature was explored to define the need for an interventional investigation into the preoperative resuscitation of patients with hip fracture., Conclusions: Patients with hip fracture show similar physiological disturbance to major trauma patients. Nineteen per cent of patients presenting with hip fracture are hypoperfused and 50% show preoperative anaemia suggesting that under resuscitation is a common problem that has not been investigated. A properly conducted interventional trial could improve the outcome of these vulnerable patients., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The gut microbiome is emerging as an important factor in regulating mental health yet it remains unclear what the target should be for psychiatric treatment. We aimed to elucidate the complement of the gut-microbiome community for individuals with bipolar disorder relative to controls; and test for relationships with burden of disease measures. We compared the stool microbiome from individuals with bipolar disorder (n = 115) and control subjects (n = 64) using 16S ribosomal RNA (rRNA) gene sequence analysis. Analysis of molecular variance (AMOVA) revealed global community case-control differences (AMOVA p = 0.047). Operational Taxonomical Unit (OTU) level analysis revealed significantly decreased fractional representation (p < 0.001) of Faecalibacterium after adjustment for age, sex, BMI and false discovery rate (FDR) correction at the p < 0.05 level. Within individuals with bipolar disorder, the fractional representation of Faecalibacterium associated with better self-reported health outcomes based on the Short Form Health Survey (SF12); the Patient Health Questionnaire (PHQ9); the Pittsburg Sleep Quality Index (PSQI); the Generalized Anxiety Disorder scale (GAD7); and the Altman Mania Rating Scale (ASRM), independent of covariates. This study provides the first detailed analysis of the gut microbiome relationships with multiple psychiatric domains from a bipolar population. The data support the hypothesis that targeting the microbiome may be an effective treatment paradigm for bipolar disorder., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Recent publications indicate increased mortality in patients admitted to hospital at the weekend, but these findings may be subject to inadequate adjustment for case-mix and the complexities of resource provision. Hip fractures generally occur in a frail comorbid population with a consistent diagnosis precipitating admission as an emergency. We therefore aimed to examine the association between the day of the week of milestones in the care pathway and 30-day mortality in this population., Methods: Using data from a prospective national database of hip fractures, we investigated the association between day of the week of admission, surgery, inpatient stay, and discharge (care pathway milestones) and 30-day mortality using generalised linear models. Data was collected between January 1, 2011, and December 31, 2014, on 241,446 patients. An incremental case-mix adjustment strategy was performed using patient characteristics, non-surgical interventions, surgical interventions and discharge characteristics., Results: The day of admission was not associated with 30-day mortality. Sunday surgery (OR, 1.094; 95% CI, 1.043-1.148; P < 0.0001) and a delay to surgery of more than 24-hours (OR, 1.094; 95% CI, 1.059, 1.130; P < 0.0001) were both associated with a 9.4% increase in 30-day mortality. Discharge from the hospital on a Sunday (OR, 1.515; 95% CI, 1.224, 1.844; P < 0.0001) or out-of-hours discharge (OR, 1.174; 95% CI, 1.081, 1.276; P < 0.0001) were associated with a 51.5% and 17.4% increase in 30-day mortality, respectively. Mortality during the inpatient stay was 5.6% lower (IRR, 0.944; 95% CI, 0.909, 0.980; P = 0.003) at the weekend compared to weekdays., Conclusions: There is limited evidence of a generalised weekend effect in patients admitted to hospital for hip fracture. Optimising resource utilisation is an essential element of planning and delivering healthcare services. Interventions that lead to surgery within 24-hours of admission are justified. Factors such as Sunday operations, discharge and out-of-hours discharge require further investigation.

Objectives: To compare magnetic resonance spectroscopic imaging (MRSI) findings from the hippocampal regions of military veterans with blast-related mild traumatic brain injury (blast mTBI) and post-traumatic stress disorder (PTSD) to those with PTSD only; and to examine the relationship of MRSI findings to cognitive and neuromotor impairment., Methods: 35 military veterans-23 with blast mTBI and PTSD (blast mTBI/PTSD) and 12 with PTSD only participated in the study. Whole plane MRSI data including N-acetyl aspartate (NAA) and choline (Ch) were acquired at 7T for the hippocampus. Concurrent cognitive and neuromotor data were collected using established assessments. General linear models (GLMs) with Bonferroni correction were used to compare the two groups on NAA/Ch ratios across regions of the hippocampus. Spearman's correlations were used to examine correlations between NAA/Ch and cognitive and neuromotor impairment., Results: The NAA/Ch results for the left hippocampus were lower in the blast mTBI/PTSD group than the PTSD-only group. The blast mTBI/PTSD group also scored worse on the WAIS-IV-vocabulary. Significant correlations between NAA/Ch and neuromotor outcomes-including vestibular impairment-were supported., Conclusions: Combined MRSI and cognitive and neuromotor data may help inform more objective and accurate diagnoses and effective treatments for patients with blast mTBI and PTSD., (Reprint & Copyright © 2017 Association of Military Surgeons of the U.S.)

As general medicine moves away from 'paternalism' and places an increasing emphasis on patient choice and autonomy, George Szmukler and Brendan D. Kelly debate whether conventional mental health legislation should be replaced with a model that focuses on the person's decision-making capabilities., (© The Royal College of Psychiatrists 2016.)

Background: Grade III open fractures of the tibia represent a serious injury. It is recognised that combined management of these cases by experienced orthopaedic and plastic surgeons improves outcomes. Previous studies have not considered the timing of definitive soft tissue cover in relation to the definitive orthopaedic management. This paper reviews the outcomes in patients treated in an orthoplastic unit where the emphasis was on undertaking the definitive orthopaedic and plastic surgical procedures in a single stage, following initial debridement and temporary stabilisation as necessary., Methods: We reviewed medical notes of 73 consecutive patients with 74 Grade III open tibia fractures (minimum 1 year follow up), to compare deep infection rates in patients who had (a) a single-stage definitive fixation and soft tissue coverage vs. those who had separate operations, and (b) those who had definitive treatment completed in <72h vs. >72h., Results: (a) Combined Single-stage Orthoplastic Fixation and Coverage: 48 fractures were managed with definitive orthopaedic fixation and plastic surgical coverage performed at the same time, whilst 26 had these performed at separate stages. Of those subjects that had definitive fixation and coverage in one procedure 2 (4.2%) developed deep infections, compared with 9 (34.6%) deep infections (p<0.001) in those who underwent definitive fixation and coverage at separate operations. (b) Timing of surgery: Of the fractures that had definitive fixation and coverage completed within 72h of injury, 5 (20%) developed deep infections, compared with 6 (12.2%) deep infections (p=0.492) in those whose definitive fixation/coverage was completed at later than 72h., Conclusion: Joint orthoplastic operating lists facilitate simultaneous definitive fixation and cover that greatly reduces infection rates. Based on our experience presented in this paper, we believe that emphasis should be placed on timely transfer to a specialist centre, aiming for a single-stage combined orthoplastic procedure to achieve definitive fixation and soft tissue coverage and optimal outcomes., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: Forty percent of breast cancers occur among older patients. Unfortunately, there is a lack of evidence for treatment guidelines for older breast cancer patients. The aim of this study is to compare treatment strategy and relative survival for operable breast cancer in the elderly between The Netherlands and Ireland., Material and Methods: From the Dutch and Irish national cancer registries, women aged ≥65 years with non-metastatic breast cancer were included (2001-2009). Proportions of patients receiving guideline-adherent locoregional treatment, endocrine therapy, and chemotherapy were calculated and compared between the countries by stage. Secondly, 5-year relative survival was calculated by stage and compared between countries., Results: Overall, 41,055 patients from The Netherlands and 5,826 patients from Ireland were included. Overall, more patients received guideline-adherent locoregional treatment in The Netherlands, overall (80% vs. 68%, adjusted p<0.001), stage I (83% vs. 65%, p<0.001), stage II (80% vs. 74%, p<0.001) and stage III (74% vs. 57%, P<0.001) disease. On the other hand, more systemic treatment was provided in Ireland, where endocrine therapy was prescribed to 92% of hormone receptor-positive patients, compared to 59% in The Netherlands. In The Netherlands, only 6% received chemotherapy, as compared 24% in Ireland. But relative survival was poorer in Ireland (5 years relative survival 89% vs. 83%), especially in stage II (87% vs. 85%) and stage III (61% vs. 58%) patients., Conclusion: Treatment for older breast cancer patients differed significantly on all treatment modalities between The Netherlands and Ireland. More locoregional treatment was provided in The Netherlands, and more systemic therapy was provided in Ireland. Relative survival for Irish patients was worse than for their Dutch counterparts. This finding should be a strong recommendation to study breast cancer treatment and survival internationally, with the ultimate goal to equalize the survival rates for breast cancer patients across Europe.

Background: Hip fracture care has evolved, largely due to standardisation of practice, measurement of outcomes and the introduction of the Best Practice Tariff, leading to the sustained improvements documented by the National Hip Fracture Database (NHFD). The treatment of distal femoral fractures in this population has not had the same emphasis. This study defines the epidemiology, current practice and outcomes of distal femoral fractures in four English centres., Patients and Methods: 105 patients aged 50 years or greater with a distal femoral fracture, presenting to four UK major trauma centres between October 2010 and September 2011 were identified. Data was collected using an adapted NHFD data collection tool via retrospective case note and radiograph review. Local ethics approval was obtained., Results: Mean age was 77 years (range 50-99), with 86% female. 95% of injuries were sustained from a low energy mechanism, and 72% were classified as either 33-A1 or 33-C1. The mean Parker mobility score and Barthel Independence Index were 5.37 (0-9) and 75.5 (0-100) respectively. Operative management was performed in 84%, and 86% had their surgery within 36 h. Three quarters were fixed with a peri-articuar locking plate. There was no consensus on post operative rehabilitation, but no excess of complications in the centres where weight bearing as tolerated was the standard. 45% were seen by an orthogeriatrician during their admission. Mean length of stay was 29 days. Mortality at 30 days, 6 months, and 1 year was 7%, 16% and 18% respectively., Discussion: This study demonstrates that the distal femoral and hip fracture populations are similar, and highlights the current disparity in their management. The metrics and standards of care currently applied to hip fractures should be applied to the treatment of distal femoral fractures. Optimal operative treatment and rehabilitation remains unclear, and is in need of further research., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Myeloma is a challenging blood cancer characterized by bone destruction, hypercalcaemia, renal insufficiency and anaemia. Although myeloma remains incurable, recent advancements in treatments have resulted in significant improvements in morbidity. The use of immunomodulatory drugs-thalidomide, lenalidomide, pomalidomide (in clinical trials)-and the proteasome inhibitor, bortezomib, in conjunction with conventional chemotherapy and supportive therapies, have resulted in a significant shift in approaches to treatment and an improvement in patients' quality of life. Nurses must remain up-to-date with current treatments for myeloma and their related side-effects. In addition, nurses play a key role in the coordination of a multidisciplinary approach to care for myeloma patients.

Recent reports have suggested that a delay in the management of type-III supracondylar fractures of the humerus does not affect the outcome. In this retrospective study we examined whether the timing of surgery affected peri-operative complications, or the need for open reduction. There were 171 children with a closed type-III supracondylar fracture of the humerus and no vascular compromise in our study. They were divided into two groups: those treated less than eight hours from presentation to the Accident and Emergency Department (126 children), and those treated more than eight hours from presentation (45 children). There were no differences in the rate of complications between the groups, but children waiting more than eight hours for reduction were more likely to undergo an open reduction (33.3% vs 11.2%, p < 0.05) and there was a weak correlation (p = 0.062) between delay in surgery and length of operating time. Consequently, we would still recommend treating these injuries at the earliest opportunity.

Background: The human preoccupation of experimenting with potentially toxic substances at sublethal doses to enhance beauty spans the ages. The Botox injection is the fastest growing cosmetic procedure, and its physiologic safety profile is considered to be excellent. The psychosocial consequences of Botox have been largely ignored in the literature., Methods: This cross-sectional study investigated the psychosocial issues that can arise as either an antecedent to the treatment or a consequence of it., Results: Significant differences between clients and control subjects were observed in the four major areas of psychosocial functioning implicated in this study: (a) distress arising from the procedure (anxiety/phobia), (b) worry about the facial changes after the procedure, (c) expectations, involving the discrepancy between expected and actual outcomes of treatment; and (d) dependence, involving the desire for repetitive administration., Conclusions: The impact of Botox on the psychosocial functioning of individuals was investigated in this study from a psychosocial and clinical perspective in an effort to pave the way for the formulation of national standardized guidelines for the use of Botox. This study empowers the clinician to understand the basis for the relative contraindications of Botox, which are largely psychological in nature, and thus to ensure its administration in a safe and responsible manner.

The routine use of surgical drains in total hip arthroplasty remains controversial. They have not been shown to decrease the rate of wound infection significantly and can provide a retrograde route for it. Their use does not reduce the size or incidence of post-operative wound haematomas. This prospective, randomised study was designed to evaluate the role of drains in routine total hip arthroplasty. We investigated 552 patients (577 hips) undergoing unilateral or bilateral total hip arthroplasty who had been randomised to either having a drain for 24 hours or not having a drain. All patients followed standardised pre-, intra-, and post-operative regimes and were independently assessed using the Harris hip score before operation and at six, 18 and 36 months follow-up. The rate of superficial and deep infection was 2.9% and 0.4%, respectively, in the drained group and 4.8% and 0.7%, respectively in the undrained group. One patient in the undrained group had a haematoma which did not require drainage or transfusion. The rate of transfusion after operation in the drained group was significantly higher than for undrained procedures (p < 0.042). The use of a drain did not influence the post-operative levels of haemoglobin, the revision rates, Harris hip scores, the length of hospital stay or the incidence of thromboembolism. We conclude that drains provide no clear advantage at total hip arthroplasty, represent an additional cost, and expose patients to a higher risk of transfusion.

A case is presented in which the decision to admit and treat an adult with musculoskeletal pain and pyrexia was based on her markedly raised c-reactive protein (CRP). At the time of admission she was apyrexial and the CRP was the only haematological investigation that was out of the normal range. She subsequently became precipitously septic with pneumococcal bacteraemia and meningitis. The CRP is an important investigation for emergency departments.

Excessive laxity of the tarso-ligamentous sling of the lower eyelid may be caused by inadequate muscular support (resulting from injury to the muscle, facial palsy or senile degeneration) or prolonged mechanical distension (exophthalmia). Numerous techniques have been devised for functional reconstruction of the distended lower eyelid, based upon the principle that restoring the lower eyelid to its anatomical position will improve lacrimal transit andre-establish its natural protective function. We now use an autologous conchal cartilage graft to treat the distended or atonic lower eyelid. We review our results in a retrospective study of 20 patients, and aim to identify the indications for this procedure and to evaluate its advantages and disadvantages relative to other existing methods. All of our patients reported functional improvement after the operation in terms of decreased dry-eye symptoms, less epiphora and a decline in keratitis and conjunctivitis. All patients also reported a visible cosmetic improvement postoperatively. The major drawback of this operation is the partial loss of the visual field when looking down, due to the limited lowering of the lower eyelid. The stability of our results compares favourably with that achieved using other currently available techniques. We conclude that autologous conchal cartilage grafting is an effective procedure for improving both the function and the appearance of the atonic lower eyelid., (Copyright 2002 The British Association of Plastic Surgeons.)

Congenital microphthalmos and anophthalmos are rare conditions in which orbital growth is deficient. Hypoplasia of the globe affects the bony orbit (micro-orbitism), the conjunctival sac, and eyelids (microblepharism), and it may be associated with abnormalities of the entire hemifacial skeleton (hemifacial microsomia). In the present article, the authors review a series of 19 patients with microphthalmos (nine had right-sided, one had bilateral, and nine had left-sided microphthalmos) who were treated in the Orbitopalpebral Unit at Hospital Foch over a period of 15 years (follow-up, 5 months to 18 years).Orbital expansion was achieved using spherical implants (n = 13), orbital osteotomies (n = 4), and orbital expanders (n = 2). Both expanders were removed within 6 months because of failure (one infection and one rupture). The current preferred method for orbital expansion is to use serial implants in the growing orbit and osteotomies in cases of late referral or insufficient orbital volume in the older child. The target proportions of the reconstructed orbit are not planned to mirror the healthy side exactly. The inferior orbital rim is kept higher to support the orbital implant, and the orbit is kept shallow to avoid a sunken appearance. Cranial bone grafts were used to augment deficient orbital contours; they were assisted by anterior transposition of the temporalis muscle (n = 5) when additional orbital volume was required. Conjunctival sac reconstruction was achieved by the use of serial conformers placed in the conjunctival sac during the neonatal period, followed by grafts of buccal mucosa and full-thickness skin maintained in place with a tarsorrhaphy for 3 to 6 months. Eyelid reconstruction using local flaps and skin grafts proved to be necessary in cases treated by osteotomy expansion, although reconstruction was not required after expansion using serial solid shapes. The results illustrate an evolution in approach and concepts of reconstruction of the microphthalmic orbit and emphasize the need for an integrated craniofacial approach for this complex deformity.

Ablative surgery for tumors of the globe and its adnexal structures is frequently the cause of major orbitofacial deformity. Radiotherapy compounds the problem because it suppresses skeletal growth in the growing patient and induces a contraction of the remaining soft tissues in the orbit. Goals for reconstruction in these patients include the restoration of orbital structures to allow the fitting of an ocular prosthesis and the correction of distorted orbitofacial relationships. The authors present a series of 53 patients (mean age, 29 years; 28 male) who were treated over the past 18 years by composite reconstruction of the post-tumoral anophthalmic orbit. The follow-up ranged from 5 months to 18 years (mean, 7.75 years). Four patients were treated primarily (immediate reconstruction after tumor ablation), and 49 were treated secondarily (mean oncological follow-up since ablative surgery, 14.8 years). Twenty-eight patients underwent orbital enucleation (including three bilateral cases), 23 underwent orbital exenteration, and two underwent evisceration. Forty-two patients received radiotherapy, including 20 enucleation patients, 15 exenteration patients, and seven others in whom details of primary therapy were incomplete. A staged reconstruction was undertaken in each case; it considered, in turn, the bony orbital volume (orbital remodeling and cranial bone grafts), orbital contents (implant, temporalis muscle transposition, cranial bone grafts, and dermafat grafts), conjunctival sac (mucosal and skin grafts), ocular prosthesis, eyelids (local flaps and skin grafts), and additional procedures to restore orbitofacial symmetry. The authors conclude that the long-term results of post-tumoral orbital reconstruction are favorable, and they particularly recommend the use of autogenous tissues in irradiated orbits.

Techniques used in craniofacial surgery have found extensive application in the management of skull base tumours. The improved exposure gained via osteotomies for facial disassembly has facilitated the en-bloc resection of tumours with clear surgical margins, and the advent of vascularised seals has significantly reduced the risk of meningeal contamination. We present our experience with the extirpation and reconstruction of 71 benign and malignant tumours of the anterior skull base over a 5-year period. Survival and functional outcome data are presented, with an emphasis on the wide range of pathologies and primary treatment strategies seen at presentation. Criteria used in flap selection and the role of prosthetics are discussed. Observations are offered on salvage surgery, demonstrating that excellent palliation can be achieved, even in cases with massive recurrent disease., (Copyright 2000 The British Association of Plastic Surgeons.)

In a patient with severe, recurrent bilateral carpal tunnel syndrome secondary to mucolipidosis, the 'turnover' palmaris brevis flap was used in conjunction with internal neurolysis. The procedure was effective in alleviating symptoms of recurrent carpal tunnel compression in both hands.

Protein kinase Calpha (PKCalpha) has been shown to contain two discrete activator sites with differing binding affinities for phorbol esters and diacylglycerols. The interaction of diacylglycerol with a low-affinity phorbol ester binding site leads to enhanced high-affinity phorbol ester binding and to a potentiated level of activity [Slater, S. J., Ho, C., Kelly, M. B., Larkin, J. D. , Taddeo, F. J., Yeager, M. D., and Stubbs, C. D. (1996) J. Biol. Chem. 271, 4627-4631]. In this study, the mechanism of this enhancement of activity was examined with respect to the Ca2+ dependences of membrane association and accompanying conformational changes that lead to activation. The association of PKCalpha with membranes containing 12-O-tetradecanoylphorbol 13-acetate (TPA) or 1, 2-dioleoylglycerol (DAG), determined from tryptophan to dansyl-PE resonance energy transfer (RET) measurements, was found to occur at relatively low Ca2+ levels (

A modification in the design of the pedicled latissimus dorsi musculocutaneous flap is described that aims to minimize the cosmetic morbidity of its donor site. The implications of this variation are discussed with particular reference to use of the flap in postmastectomy reconstruction.

The activity of membrane-associated protein kinase C (PKC) has previously been shown to be regulated by two discrete high and low affinity binding regions for diacylglycerols and phorbol esters (Slater, S. J., Ho, C., Kelly, M. B., Larkin, J. D., Taddeo, F. J., Yeager, M. D., and Stubbs, C. D. (1996) J. Biol. Chem. 271, 4627-4631). PKC is also known to interact with both cytoskeletal and nuclear proteins; however, less is known concerning the mode of activation of this non-membrane form of PKC. By using the fluorescent phorbol ester, sapintoxin D (SAPD), PKCalpha, alone, was found to possess both low and high affinity phorbol ester-binding sites, showing that interaction with these sites does not require association with the membrane. Importantly, a fusion protein containing the isolated C1A/C1B (C1) domain of PKCalpha also bound SAPD with low and high affinity, indicating that the sites may be confined to this domain rather than residing elsewhere on the enzyme molecule. Both high and low affinity interactions with native PKCalpha were enhanced by protamine sulfate, which activates the enzyme without requiring Ca2+ or membrane lipids. However, this "non-membrane" PKC activity was inhibited by the phorbol ester 4beta-12-O-tetradecanoylphorbol-13-acetate (TPA) and also by the fluorescent analog, SAPD, opposite to its effect on membrane-associated PKCalpha. Bryostatin-1 and the soluble diacylglycerol, 1-oleoyl-2-acetylglycerol, both potent activators of membrane-associated PKC, also competed for both low and high affinity SAPD binding and inhibited protamine sulfate-induced activity. Furthermore, the inactive phorbol ester analog 4alpha-TPA (4alpha-12-O-tetradecanoylphorbol-13-acetate) also inhibited non-membrane-associated PKC. In keeping with these observations, although TPA could displace high affinity SAPD binding from both forms of the enzyme, 4alpha-TPA was only effective at displacing high affinity SAPD binding from non-membrane-associated PKC. 4alpha-TPA also displaced SAPD from the isolated C1 domain. These results show that although high and low affinity phorbol ester-binding sites are found on non-membrane-associated PKC, the phorbol ester binding properties change significantly upon association with membranes.

A modified skin forceps is presented that combines the advantages of skin hook and dressing forceps. Its use facilitates the atraumatic placement of continuous intradermal sutures by the surgeon who is working unassisted.

The key signal transduction enzyme protein kinase C (PKC) contains a hydrophobic binding site for alcohols and anesthetics (Slater, S. J., Cox, K. J. A., Lombardi, J. V., Ho, C., Kelly, M. B., Rubin, E., and Stubbs, C. D. (1993) Nature 364, 82-84). In this study, we show that interaction of n-alkanols and general anesthetics with PKCalpha results in dramatically different effects on membrane-associated compared with lipid-independent enzyme activity. Furthermore, the effects on membrane-associated PKCalpha differ markedly depending on whether activity is induced by diacylglycerol or phorbol ester and also on n-alkanol chain length. PKCalpha contains two distinct phorbol ester binding regions of low and high affinity for the activator, respectively (Slater, S. J., Ho, C., Kelly, M. B., Larkin, J. D., Taddeo, F. J., Yeager, M. D., and Stubbs, C. D. (1996) J. Biol. Chem. 271, 4627-4631). Short chain n-alkanols competed for low affinity phorbol ester binding to the enzyme, resulting in reduced enzyme activity, whereas high affinity phorbol ester binding was unaffected. Long chain n-alkanols not only competed for low affinity phorbol ester binding but also enhanced high affinity phorbol ester binding. Furthermore, long chain n-alkanols enhanced phorbol ester induced PKCalpha activity. This effect of long chain n-alkanols was similar to that of diacylglycerol, although the n-alkanols alone were weak activators of the enzyme. The cellular effects of n-alkanols and general anesthetics on PKC-mediated processes will therefore depend in a complex manner on the locality of the enzyme (e.g. cytoskeletal or membrane-associated) and activator type, apart from any isoform-specific differences. Furthermore, effects mediated by interaction with the region on the enzyme possessing low affinity for phorbol esters represent a novel mechanism for the regulation of PKC activity.

The effect of variation of the degree of cis-unsaturation on cell membrane protein functioning was investigated using a model lipid bilayer system and protein kinase C (PKC). This protein is a key element of signal transduction. Furthermore it is representative of a class of extrinsic membrane proteins that show lipid dependent interactions with cell membranes. To test for dependence of activity on the phospholipid unsaturation, experiments were devised using a vesicle assay system consisting of phosphatidylcholine (PC) and phosphatidylserine (PS) in which the unsaturation was systematically varied. Highly purified PKC alpha and epsilon were obtained using the baculovirus-insect cell expression system. It was shown that increased PC unsaturation elevated the activity of PKC alpha. By contrast, increasing the unsaturation of PS decreased the activity of PKC alpha, and to a lesser extent PKC epsilon. This result immediately rules out any single lipid bilayer physical parameter, such as lipid order, underlying the effect. It is proposed that while PC unsaturation effects are explainable on the basis of a contribution to membrane surface curvature stress, the effects of PS unsaturation may be due to specific protein-lipid interactions. Overall, the results indicate that altered phospholipid unsaturation in cell membranes that occurs in certain disease states such as chronic alcoholism, or by dietary manipulations, are likely to have profound effects on signal transduction pathways involving PKC and similar proteins.

Based on marked differences in the enzymatic properties of diacylglycerols compared with phorbol ester-activated protein kinase C (PKC), we recently proposed that activation induced by these compounds may not be equivalent (Slater, S. J., Kelly, M. B., Taddeo, F. J., Rubin, E., and Stubbs, C. D. (1994) J. Biol. Chem. 269, 17160-17165). In the present study, direct evidence is provided showing that phorbol esters and diacylglycerols bind simultaneously to PKC alpha. Using a novel binding assay employing the fluorescent phorbol ester, sapintoxin-D (SAPD), evidence for two sites of high and low affinity was obtained. Thus, both binding and activation dose-response curves for SAPD were double sigmoidal, which was also observed for dose-dependent activation by the commonly used phorbol ester, 4beta-12-O-tetradecanoylphorbol-13-acetate (TPA). TPA removed high affinity SAPD binding and also competed for the low affinity site. By contrast with TPA, low affinity binding of SAPD was inhibited by sn-1,2-dioleoylglycerol (DAG), while binding to the high affinity site was markedly enhanced. Again contrasting with both TPA and DAG, the potent PKC activator, bryostatin-I (B-I), inhibited SAPD binding to its high affinity site, while low affinity binding was unaffected. Based on these findings, a model for PKC activation is proposed in which binding of one activator to the low affinity site allosterically promotes binding of a second activator to the high affinity site, resulting in an enhanced level of activity. Overall, the results provide direct evidence that PKCalpha contains two distinct binding sites, with affinities that differ for each activator in the order: DAG > phorbol ester > B-I and B-I > phorbol ester > DAG, respectively.

The key metabolite of vitamin D3, 1 alpha,25-dihydroxyvitamin D3 (1,25-D3), induces rapid cellular responses that constitute a so-called "non-genomic" response. This effect is distinguished from its "classic" genomic role in calcium homeostasis involving the nuclear 1,25-D3 receptor. Evidence is presented that protein kinase C (PKC) is directly activated by 1,25-D3 at physiological concentrations (EC50 = 16 +/- 1 nM). The effect was demonstrable with single PKC-alpha, -gamma, and -epsilon isoform preparations, assayed in a system containing only purified enzyme, substrate, co-factors, and lipid vesicles, from which it is inferred that a direct interaction with the enzyme is involved. The finding that calcium-independent isoform PKC-epsilon was also activated by 1,25-D3 shows that the calcium binding C2 domain is not required. The level of 1,25-D3-induced activation, paired with either diacylglycerol or 4 beta-12-O-tetradecanoylphorbol-13-acetate, was greater than that achievable by any individual activator alone, each at a saturating concentration, a result that implies two distinct activator sites on the PKC molecule. Phosphatidylethanolamine present in the lipid vesicles potentiated 4 beta-12-O-tetradecanoylphorbol-13-acetate- and diacylglycerol-induced PKC activities, whereas 1,25-D3-induced activity decreased, consistent with 1,25-D3-activated PKC possessing a distinct conformation. The results suggest that PKC is a "membrane-bound receptor" for 1,25-D3 and that it could be important in the control of non-genomic cellular responses to the hormone.