Engineering of chimeric natural killer cell receptors to develop precision adoptive immunotherapies for cancer.

Natural killer (NK) cells are innate immune effectors which play a crucial role in recognizing and eliminating virally infected and cancerous cells. They effectively distinguish between healthy and distressed self through the integration of signals delivered by germline-encoded activating and inhibitory cell surface receptors. The frequent up-regulation of stress markers on genetically unstable cancer cells has prompted the development of novel immunotherapies that exploit such innate receptors. One prominent example entails the development of chimeric antigen receptors (CAR) that detect cell surface ligands bound by NK receptors, coupling this engagement to the delivery of tailored immune activating signals. Here, we review strategies to engineer CARs in which specificity is conferred by natural killer group 2D (NKG2D) or other NK receptor types. Multiple preclinical studies have demonstrated the remarkable ability of chimeric NK receptor-targeted T cells and NK cells to effectively and specifically eliminate cancer cells and to reject established tumour burdens. Importantly, such systems act not only acutely but, in some cases, they also incite immunological memory. Moreover, CARs targeted with the NKG2D ligand binding domain have also been shown to disrupt the tumour microenvironment, through the targeting of suppressive T regulatory cells, myeloid-derived suppressor cells and tumour vasculature. Collectively, these findings have led to the initiation of early-phase clinical trials evaluating both autologous and allogeneic NKG2D-targeted CAR T cells in the haematological and solid tumour settings.

Full annual monitoring of Subantarctic Emiliania huxleyi populations reveals highly calcified morphotypes in high-CO2 winter conditions.

Ocean acidification is expected to have detrimental consequences for the most abundant calcifying phytoplankton species Emiliania huxleyi. However, this assumption is mainly based on laboratory manipulations that are unable to reproduce the complexity of natural ecosystems. Here, E. huxleyi coccolith assemblages collected over a year by an autonomous water sampler and sediment traps in the Subantarctic Zone were analysed. The combination of taxonomic and morphometric analyses together with in situ measurements of surface-water properties allowed us to monitor, with unprecedented detail, the seasonal cycle of E. huxleyi at two Subantarctic stations. E. huxleyi subantarctic assemblages were composed of a mixture of, at least, four different morphotypes. Heavier morphotypes exhibited their maximum relative abundances during winter, coinciding with peak annual TCO2 and nutrient concentrations, while lighter morphotypes dominated during summer, coinciding with lowest TCO2 and nutrients levels. The similar seasonality observed in both time-series suggests that it may be a circumpolar feature of the Subantarctic zone. Our results challenge the view that ocean acidification will necessarily lead to a replacement of heavily-calcified coccolithophores by lightly-calcified ones in subpolar ecosystems, and emphasize the need to consider the cumulative effect of multiple stressors on the probable succession of morphotypes.

Breast augmentation: Part III--preoperative considerations and planning.

The past four decades since the introduction of silicone mammary prostheses have seen significant improvements in their quality and durability. Advances in our understanding of the aetiopathology and prevention of adverse capsular contracture (ACC) have occurred such that surgical technique itself has now probably become the single most important determinant of both immediate and long-term outcome. Considered a simple, and in some quarters mindless, procedure it has evolved such that high-quality short- and stable long-term results are now expected. Whilst the fundamentals of breast augmentation (BA) remain, evolutionary philosophies confront today's surgeon with a wealth of options. Of fundamental importance has been the paradigm shift from a purely, or predominantly, volumetric, through biodimensional to a tissue-based approach. With BA, more than any other aesthetic procedure, possessing more variables, choice and influential external factors a thorough understanding of the myriad options available is essential. This review seeks to cover the key elements in obtaining an optimal primary result. It provides a rational basis for the selection of an option tailored to both the patient and the individual tissue characteristics in addition to the pertinent medico-legal issues.

Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility.

Under conditions of reduced tissue oxygenation, hypoxia-inducible factor (HIF) controls many processes, including angiogenesis and cellular metabolism, and also influences cell proliferation and survival decisions. HIF is centrally involved in tumour growth in inherited diseases that give rise to renal cell carcinoma (RCC), such as Von Hippel-Lindau syndrome and tuberous sclerosis complex. In this study, we examined whether HIF is involved in tumour formation of RCC in Birt-Hogg-Dubé syndrome. For this, we analysed a Birt-Hogg-Dubé patient-derived renal tumour cell line (UOK257) that is devoid of the Birt-Hogg-Dubé protein (BHD) and observed high levels of HIF activity. Knockdown of BHD expression also caused a threefold activation of HIF, which was not as a consequence of more HIF1α or HIF2α protein. Transcription of HIF target genes VEGF, BNIP3 and CCND1 was also increased. We found nuclear localization of HIF1α and increased expression of VEGF, BNIP3 and GLUT1 in a chromophobe carcinoma from a Birt-Hogg-Dubé patient. Our data also reveal that UOK257 cells have high lactate dehydrogenase, pyruvate kinase and 3-hydroxyacyl-CoA dehydrogenase activity. We observed increased expression of pyruvate dehydrogenase kinase 1 (a HIF gene target), which in turn leads to increased phosphorylation and inhibition of pyruvate dehydrogenase. Together with increased protein levels of GLUT1, our data reveal that UOK257 cells favour glycolytic rather than lipid metabolism (a cancer phenomenon termed the 'Warburg effect'). UOK257 cells also possessed a higher expression level of the L-lactate influx monocarboxylate transporter 1 and consequently utilized L-lactate as a metabolic fuel. As a result of their higher dependency on glycolysis, we were able to selectively inhibit the growth of these UOK257 cells by treatment with 2-deoxyglucose. This work suggests that targeting glycolytic metabolism may be used therapeutically to treat Birt-Hogg-Dubé-associated renal lesions.

Breast augmentation: Part II--Adverse capsular contracture.

Although adverse capsular contracture (ACC) following breast augmentation remains an enigmatic phenomenon, significant progress has been made in diminishing its occurrence during the previous surgical generation. Given the rising global frequency of breast augmentation, however, ACC is likely to be with us for the foreseeable future and an understanding of its nature, and particularly prevention, will continue to be of foremost importance as breast augmentation undergoes a paradigm shift from anti-contracture to aesthetic result as the key outcome measure. Whilst clinical research has hitherto been the mainstay of investigation, providing both understanding and practical guidance, further improvements may derive from new developments in the fields of immunology and molecular biology: convergence of these complementary avenues may eventually yield a non-surgical treatment for ACC. This review presents a summary of our extant knowledge, providing evidence where it exists and a consensus view where it does not. It aims at providing a sound comprehension of the underlying aetiopathology that has provoked the measures seen to date and guides selection of the appropriate therapeutic strategy, which will be expanded in a future review.

Breast augmentation: Part I--A review of the silicone prosthesis.

The present importance of breast augmentation (BA) is shown by year-on-year increases: with 8439 augmentations performed by BAAPS members in 2007 the UK still lags America where 307,000 were performed. Having survived an almost hysterical media reaction to perceived silicone health risks in the 1990s, a growing body of evidence attests to the demonstrable benefits of BA. Improved implant design coupled with surgical advances mean that high quality results with few complications can now be expected in the majority and a précis of progress is perhaps timely. This article forms part of a series that has been written to provide a 'state-of-the-art' review of contemporaneous BA practice.

Exercise combined with continuous passive motion or slider board therapy compared with exercise only: a randomized controlled trial of patients following total knee arthroplasty.

BACKGROUND AND PURPOSE: The primary purpose of this randomized controlled trial was to determine which method of mobilization - (1) standardized exercises (SE) and continuous passive motion (CPM), (2) SE and slider board (SB) therapy, using an inexpensive, nontechnical device that requires minimal knee active range of motion (ROM), or (3) SE alone-achieved the maximum degree of knee ROM in the fIrst 6 months following primary total knee arthroplasty (TKA). The secondary purpose was to compare health-related quality of life among these 3 groups. SUBJECTS: The subjects were 120 patients (n=40/group) who received a TEA at a teaching hospital between June 1997 and July 1998 and who agreed to participate in the study. METHODS: Subjects were examined preoperatively, at discharge, and at 3 and 6 months after surgery. The examination consisted of measurement of knee ROM and completion of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). RESULTS: The 3 treatment groups were similar with respect to age, sex, and diagnosis at the start of the study. There were no differences in knee ROM or in WOMAC Osteoarthritis Index or SF-36 scores at any of the measurement intervals. The rate of postoperative complications also was not different among the groups. DISCUSSION AND CONCLUSION: When postoperative rehabilitation regimens that focus on early mobilization of the patient are used, adjunct ROM therapies (CPM and SB) that are added to daily SE sessions are not required. Six months after TEA, patients attain a satisfactory level of knee ROM and function.

Standard anatomical medullary locking (AML) versus tricalcium phosphate-coated AML femoral prostheses.

OBJECTIVES: To compare the preliminary rate and amount of bony ingrowth and calcar resorption between patients receiving either a standard anatomical medullary locking (AML) or a tricalcium phosphate (TCP)-coated AML femoral prosthesis and to compare preliminary clinical results. DESIGN: A prospective, randomized, double-blind clinical trial. SETTING: An acute care tertiary institution. PATIENTS: Between January 1993 and March 1995, 92 patients underwent primary total hip arthroplasty (THA). They were randomized to 2 groups of 46--a control group or a treatment group. Of the 46 subjects enrolled in each group, no significant differences were seen preoperatively with respect to age, sex, diagnosis, clinical and radiographic assessment. Seventy-one patients were followed up for 24 months. INTERVENTIONS: Insertion of either a standard AML femoral implant (control group) or a TCP-coated AML femoral implant (treatment group). OUTCOME MEASURES: The degree of hypertrophy, calcar atrophy and the number of spot welds on standard postoperative radiographs at 6, 12 and 24 months. Clinically, assessment according to the Société internationale de chirurgie orthopédique et de traumatologie (SICOT) scale and a 100-point visual analogue scale (VAS) for pain. RESULTS: There were no prosthetic stem revisions in either group at the 24-month follow-up. Radiographically, bony ingrowth was not significantly different in the TCP-coated stem, by chi2 analysis of the degree of hypertrophy and number of spot welds present. Also by chi2 analysis, the degree of calcar atrophy was not significantly different between groups. The mean VAS score for pain at 24 months was 12.5 for the control and 12.1 for the treatment group. No significant differences were seen in any of the clinical categories of the SICOT Scale over the 24-month interval. CONCLUSION: The objective of TCP-coating--to increase the rate and amount of bony ingrowth while reducing the rate of calcar resorption in non-cemented THA--was not achieved by 24 months postoperatively in our study.

The impact of phosphorus on interactions of the hemiparasitic angiosperm Rhinanthus minor and its host Lolium perenne.

The effects of phosphorus supply on the outcome of interactions between the hemiparasitic angiosperm Rhinanthus minor L. with its host species Lolium perenne L. were investigated in a glasshouse experiment. Host plants were grown in 3-l pots in the presence and absence of R. minor at limiting (0.13 mM P) and optimal (0.65 mM P) concentrations of phosphorus for the growth of the host species. Phosphorus was supplied at 2-day intervals in the form of half-strength Long Ashton nitrate-based solution with phosphorus concentrations adjusted accordingly. Parasitism by R. minor significantly suppressed host growth, with final biomass losses ranging between 32% and 44%. Phosphorus supply had a marked impact on the outcome of the host-parasite interaction. By the end of the growing period, parasite biomass at 0.65 mM P was 90% lower than that achieved at 0.13 mM P. In contrast, host biomass at 0.65 mM P was 74% higher than achieved at 0.13 mM P, indicting that the negative impact of parasitism on the host species was reduced when phosphorus supply was increased. The effects of phosphorus on the host-parasite association appeared to be mediated by changes in both the morphological characteristics of the host roots and the relative sink strengths of the host and parasite.

Reducing arthroplasty costs via vendor contracts.

OBJECTIVE: To describe a method of reducing the costs of implants in hip and knee arthroplasty. DESIGN: Implant costs were compared before and after the implementation of a 2-year contract with implant vendors, providing increased volume for decreased implant cost. An additional 20% of arthroplasties could be done outside the contract for research or special purposes. SETTING: A regional health authority involving 2 acute care hospitals. METHOD: Costs were obtained for 942 hip and knee arthroplasties performed in 1993/94 and compared with costs of 1656 hip and knee arthroplasties performed in 1996/97. OUTCOME MEASURES: Implant cost and number of joint arthroplasty procedures performed. RESULTS: A 40% decrease in the cost per implant for primary knee arthroplasty and an 18% decrease in the cost per implant for primary hip arthroplasty were achieved. A rebate, calculated as a percentage of volume used, was received from the vendor to support general orthopedic research and education. A new contract for 3 years has recently been signed with 3 vendors designated as primary vendors for 80% of the volume. CONCLUSION: The vendor-contract economic strategy effectively reduced the cost of hip and knee arthroplasty and may be useful at other centres looking for cost reduction methods that maintain adequate patient care and support clinical research and education.

British Airways flightdeck mortality study, 1950-1992.

OBJECTIVE: To study the mortality and life expectancy of male British Airways flightdeck crew and to establish whether proportionate mortality excesses shown earlier for brain/CNS cancer, colon cancer and melanoma remained evident. METHODS: A Standardized Mortality Ratio study (SMR) using England and Wales as the comparison population was carried out for 6209 male pilots and 1153 male flight engineers employed for at least 1 yr between January 1, 1950 and December 31, 1992. Internal relative risk comparisons were made between shorthaul and longhaul operations defined broadly as flights within Europe and beyond Europe, respectively. RESULTS: The all-causes SMR for pilots of 61 (592 deaths) and 56 for flight engineers (127 deaths) confirmed the expected Healthy Worker Effect. In pilots apart from the known excess of deaths from aircraft accidents (SMR 14694), most of the comparisons showed significant deficits in mortality. The SMR's for brain/CNS cancer (143) and colon cancer (111) were no longer statistically significant. The SMR of 333 for melanoma was significantly raised in pilots but was not evident in flight engineers. Life expectancy for longhaul pilots and flight engineers was 4-5 yr better than England and Wales for ages 55-65 while the advantage for shorthaul pilots was reduced to between 2-3 yr. Cases of leukemia and aleukaemia in pilots were less than expected and less than the positive excess predicted from modeling based on radiation dose. CONCLUSION: The study confirms that flightdeck crew live longer than the England and Wales population and do not exhibit patterns of death that could be directly attributable to occupation.

Vertical scar breast reduction with medial flap or glandular transposition of the nipple-areola.

Vertical scar breast reduction is a well accepted technique which we believe improves the shape and projection of the breast and leaves no horizontal scars. Lassus and Lejour described superiorly based nipple flaps; we describe a medially based flap or glandular transposition of the nipple in small reductions. Fifty-seven consecutive patients are presented. Thirty-three patients had medial transposition of the nipple-areola with a mean resection of 608 g (range 220-1250 g). Twenty-four patients had a glandular transposition of the nipple-areola, with a mean resection of 380 g (range 220-600 g); transposition of the areola should be less than 5 cm in this group. After a short learning curve, the complications have been few and minor.

Exposure to cosmic radiation of British Airways flying crew on ultralonghaul routes.

British Airways has carried out radiation monitoring in Concorde for more than 20 years and has used a heuristic model based on data quoted by the National Aeronautics and Space Administration (NASA) to model radiation exposure in all longhaul fleets. From these data it has been calculated that no flight deck crew would exceed the control level of 6 mSv/y currently under consideration by regulatory authorities, which is three tenths of the occupational dose limit of 20 mSv/y recommended by the International Commission on Radiological Protection (ICRP). The model suggested that less than 4% of cabin crew based in Tokyo flying only between London and Japan could reach or exceed the 6 mSv/y level, based on a predicted effective dose rate of 7 microSv/h. To validate this calculation a sampling measurement programme was carried out on nine round trips flown by a Boeing 747-400 between London and Tokyo. The radiation field was measured with dosimeters used for routine personal monitoring (thermoluminescence dosimeters (TLDs) and polyallydiglycol carbonate neutron dosimeters). The limitations of the methodology are acknowledged, but the results indicate that the effective dose rate was 6 microSv/h which is consistent with the predicted effective dose rate of 7 microSv/h. This result, which is in accordance with other reported studies indicates that it is unlikely that any of the cabin crew based in Tokyo exceeded the 6 mSv/y level. In accordance with "as low as reasonably achievable" principles British Airways will continue to monitor flying crew routes and hours flown to ensure compliance.

Nail gun injury: a barbed problem.

A case of nail gun injury is reported. Preoperative radiographs are essential to determine whether copper barbs project from the nail shaft before any attempt is made to remove the nail. Thorough exploration is required.

Use of split-skin grafting in the treatment of chronic leg ulcers.

Chronic leg ulcers are a common problem for which many different forms of treatment have been used. In this study we reviewed the results of split-skin grafting of ulcers of different aetiologies; 26 patients were reviewed. The mean duration of ulceration was 27.5 months. Of the 28 ulcers, ten were due to venous disease, three arterial disease, six rheumatoid arthritis, seven traumatic, and two diabetic. Healing rates of 85% for traumatic and 67% for rheumatoid ulcers were achieved, whereas rates of only 20% and 33% were achieved for venous and arterial ulcers (P < 0.02 Fisher's exact test). We conclude that in the presence of vascular disease, split-skin grafting is not an effective treatment for chronic leg ulceration. Vascular assessment and treatment should be carried out before attempting skin grafting.

Sensory innervation of the little finger by an anomalous branch of the median nerve associated with recurrent, atypical carpal tunnel syndrome.

Superficial sensory communication between the ulnar and median nerves is well recognized. In the vast majority of cases this communication is from the ulnar nerve to the median nerve. We report a case in which a communicating branch passed from the median nerve to the ulnar nerve immediately proximal to the wrist to supply sensation to the little finger. The presence of this branch correlated with the presence of symptoms which had persisted in spite of conventional open carpal release 7 years earlier. Surgical decompression of this branch led to complete resolution of those symptoms.

Multidisciplinary approach to the management of head and neck arteriovenous malformations.

Arteriovenous malformations (AVM) of the head and neck are quite rare in contrast to low-flow vascular anomalies, but often present with significant haemorrhage or cosmetic defects. Treatment of these high-flow vascular anomalies is hazardous and has a predictably high incidence of recurrence if not managed correctly. Intervention is indicated for complications such as pain, haemorrhage, pressure symptoms, ischaemic ulceration and even congestive cardiac failure. A multidisciplinary team approach is required in the assessment and treatment of these lesions, and involves preoperative angiography with superselective embolisation, followed by resection of the lesion, ideally within 72 h. Recent advances in microsurgery and in therapeutic radiology have greatly improved the prognosis for patients with these malformations. We present a series of four patients who have undergone preoperative embolisation and subsequent surgical excision, with a mean follow-up of 28 months. The complication rate has remained low and there has been no re-expansion of the lesions to date.