'The last channel': vision at the temporal margin of the field.

The human visual field, on the temporal side, extends to at least 90° from the line of sight. Using a two-alternative forced-choice procedure in which observers are asked to report the direction of motion of a Gabor patch, and taking precautions to exclude unconscious eye movements in the direction of the stimulus, we show that the limiting eccentricity of image-forming vision can be established with precision. There are large, but reliable, individual differences in the limiting eccentricity. The limiting eccentricity exhibits a dependence on log contrast; but it is not reduced when the modulation visible to the rods is attenuated, a result compatible with the histological evidence that the outermost part of the retina exhibits a high density of cones. Our working hypothesis is that only one type of neural channel is present in the far periphery of the retina, a channel that responds to temporally modulated stimuli of low spatial frequency and that is directionally selective.

Metastasising Pleomorphic Salivary Adenoma: A Rare Case Report of a Massive Untreated Minor Salivary Gland Pleomorphic Adenoma with Concurrent Ipsilateral Cervical Node Metastases.

Salivary gland tumours constitute approximately 1-5% of all human neoplasms. Pleomorphic adenoma (PA) is the commonest benign neoplasm affecting the parotid gland most often (> 75%), followed by the submandibular gland (13%), then the palate (9%). Metastasising pleomorphic adenoma (MPA) is extremely rare. The effects can be severe and a reported 40% of MPA patients die with disease. This case represents the first known case in English literature of an untreated minor salivary gland PSA of the palate metastasising to an ipsilateral cervical node. We report a 61 year old female who presented with a large tumour occupying the palatal vault, and cervical neck mass. The oral tumour was believed to have been growing over four decades. The patient died eight months following surgical resection. Of known cases, male: female ratio is 35:51 and the mean age at diagnosis is 49.2. Most commonly, MPA is detected in bone 33.3% (n = 29), lung 31% (n = 27) and cervical lymph nodes 20.7% (n = 18). Thorough reporting is deemed essential to further understand the biological differences of non metastasising and metastasising PAs, treatment outcomes, prognosis and survival rates.

Measuring multi-dimensional, time-dependent mechanical properties of a human tibial fracture using an automated system.

This paper presents an element of a long-term research project determining a clinically quantifiable end point for fracture healing in humans. An automated loading and measurement device is presented. It has been developed as a research tool for the assessment of the mechanical properties of a healing human tibial fracture. The device has been specifically designed for use with patients treated with external fixation. The characteristics of the device have been presented together with an assessment of errors. A typical sample of results has been presented to demonstrate the significance of the device; subsequent papers will examine the whole data set in greater depth. The results presented here confirm the non-linear behaviour of callus and reinforce the requirement to measure the load rate when measuring the fracture stiffness. A new material property for the assessment of fracture healing, namely gamma, is examined and preliminary results are shown. Polar plots of stiffness demonstrate that, when measuring fracture stiffness, not only should the load rate be considered, but also the orientation of measurement. The results from this work support the view that the fracture stiffness should be measured in at least two planes. Currently a fracture can be considered healed when the fracture stiffness exceeds 15 N m/deg; this paper questions whether this value is now valid and suggests that it should be re-examined.

Are medical eponyms really dying out? A study of their usage in the historical biomedical literature.

Eponyms are a prominent feature of medical language. Many feel they have had their time and serve only to complicate medical education and conversation. Others argue that eponyms can make unmemorable concepts memorable, can concisely label complex concepts, and promote a valuable interest in medical history. It is frequently assumed that medical eponyms are marching towards extinction. However, this hypothesis has not been adequately tested. The fate of 8,636 eponyms from contemporary and historical registers is presented here. The annual usage of each eponym in PubMed indexed articles since 1900 is analysed with metrics of eponym prevalence, coinage and extinction. The fate of eponyms named for those implicated in Nazi war crimes is also measured. The analysis shows that more publications used an eponym in their title in 2014 than ever before. However, the proportion using an eponym title has fallen from a peak of 3% in 1991 to 2% today, while annual extinction of eponyms overtook coinage in the 1980s. This suggests that, while not in dramatic decline, they are perhaps losing market share to more scientific descriptions. There is no ambiguity in the fate of eponyms related to Nazi war crimes which have almost entirely fallen out of use in the last decade.

The Camitz transfer and its modifications: a review.

UNLABELLED: The Camitz procedure involves transfer of the insertion of the palmaris longus tendon with a strip of the palmar aponeurosis to the insertion of abductor pollicis brevis in order to improve thumb opposition, and is usually done when severe carpal tunnel syndrome results in complete wasting of the thenar muscles. We carried out a systematic review of the published reports of this procedure. Analysis of available outcome data showed improvement in overall hand function in 86-100% of patients undergoing the original Camitz procedure. Several modifications of the original Camitz transfer have been described, with most focusing on the incorporation and placement of pulleys. All studies are limited by their small sample sizes. Overall, there is a lack of studies comparing the Camitz transfer with other opponensplasty techniques and comparing the various modifications of the original procedure. LEVEL OF EVIDENCE: IV.

Medium- and long-term results of high tibial osteotomy using Garches external fixator and gait analysis for dynamic correction in varus osteoarthritis of the knee.

In arthritis of the varus knee, a high tibial osteotomy (HTO) redistributes load from the diseased medial compartment to the unaffected lateral compartment. We report the outcome of 36 patients (33 men and three women) with 42 varus, arthritic knees who underwent HTO and dynamic correction using a Garches external fixator until they felt that normal alignment had been restored. The mean age of the patients was 54.11 years (34 to 68). Normal alignment was achieved at a mean 5.5 weeks (3 to 10) post-operatively. Radiographs, gait analysis and visual analogue scores for pain were measured pre- and post-operatively, at one year and at medium-term follow-up (mean six years; 2 to 10). Failure was defined as conversion to knee arthroplasty. Pre-operative gait analysis divided the 42 knees into two equal groups with high (17 patients) or low (19 patients) adductor moments. After correction, a statistically significant (p < 0.001, t-test,) change in adductor moment was achieved and maintained in both groups, with a rate of failure of three knees (7.1%), and 89% (95% confidence interval (CI) 84.9 to 94.7) survivorship at medium-term follow-up. At final follow-up, after a mean of 15.9 years (12 to 20), there was a survivorship of 59% (95% CI 59.6 to 68.9) irrespective of adductor moment group, with a mean time to conversion to knee arthroplasty of 9.5 years (3 to 18; 95% confidence interval ± 2.5). HTO remains a useful option in the medium-term for the treatment of medial compartment osteoarthritis of the knee but does not last in the long-term. Cite this article: Bone Joint J 2016;98-B:601-7.

Engineering an NADPH/NADP+ Redox Biosensor in Yeast.

Genetically encoded biosensors have emerged as powerful tools for timely and precise in vivo evaluation of cellular metabolism. In particular, biosensors that can couple intercellular cues with downstream signaling responses are currently attracting major attention within health science and biotechnology. Still, there is a need for bioprospecting and engineering of more biosensors to enable real-time monitoring of specific cellular states and controlling downstream actuation. In this study, we report the engineering and application of a transcription factor-based NADPH/NADP+ redox biosensor in the budding yeast Saccharomyces cerevisiae. Using the biosensor, we are able to monitor the cause of oxidative stress by chemical induction, and changes in NADPH/NADP+ ratios caused by genetic manipulations. Because of the regulatory potential of the biosensor, we also show that the biosensor can actuate upon NADPH deficiency by activation of NADPH regeneration. Finally, we couple the biosensor with an expression of dosage-sensitive genes (DSGs) and thereby create a novel tunable sensor-selector useful for synthetic selection of cells with higher NADPH/NADP+ ratios from mixed cell populations. We show that the combination of exploitation and rational engineering of native signaling components is applicable for diagnosis, regulation, and selection of cellular redox states.

The effects of endothelin-A receptor blockade during the progression of pacing-induced congestive heart failure.

OBJECTIVES: We sought to identify the effects of endothelin (ET) subtype-A (ET(A))) receptor blockade during the development of congestive heart failure (CHF) on left ventricle (LV) function and contractility. BACKGROUND: Congested heart failure causes increased plasma levels of ET and ET(A) receptor activation. METHODS: Yorkshire pigs were assigned to four groups: 1) CHF: 240 beats/min for 3 weeks; n=7; 2) CHF/ET(A)-High Dose: paced for 2 weeks then ET(A) receptor blockade (BMS 193884, 50 mg/kg, b.i.d.) for the last week of pacing; n=6; 3) CHF/ET(A)-Low Dose: pacing for 2 weeks then ET(A) receptor blockade (BMS 193884, 12.5 mg/kg, b.i.d.) for the last week, n=6; and 4) CONTROL: n=8. RESULTS: Left ventricle fractional shortening decreased with CHF compared with control (12+/-1 vs. 39+/-1%, p < 0.05) and increased in the CHF/ET(A) High and Low Dose groups (23+/-3 and 25+/-1%, p < 0.05). The LV peak wall stress and wall force increased approximately twofold with CHF and remained increased with ET(A) receptor blockade. With CHF, systemic vascular resistance increased by 120%, was normalized in the CHF/ET(A) High Dose group, and fell by 43% from CHF values in the Low Dose group (p < 0.05). Plasma catecholamines increased fourfold in the CHF group and were reduced by 48% in both CHF/ET(A) blockade groups. The LV myocyte velocity of shortening was reduced with CHF (32+/-3 vs. 54+/-3 microm/s, p < 0.05), was higher in the CHF/ET(A) High Dose group (39+/-1 microm/s, p < 0.05), and was similar to CHF values in the Low Dose group. CONCLUSIONS: ET(A) receptor activation may contribute to the progression of LV dysfunction with CHF.

The effects of atorvastatin in experimental autoimmune uveitis.

AIM: To investigate the effect of atorvastatin (Lipitor), a commonly used drug for dyslipidaemia in experimental autoimmune uveitis (EAU). METHODS: 48 B10-RIII mice were immunised with human interphotoreceptor retinoid binding protein (IRBP) peptide p161-180. They were divided into three groups of 16 each and treated orally once daily for 14 days; group one received phosphate buffered saline (control group), group two received 1 mg/kg of atorvastatin (low dose group), and group three received 10 mg/kg (high dose). On day 14 lymph nodes, spleens, and right eyes were harvested. RNA was extracted from lymph nodes for RNase protection assay (RPA) to determine proinflammatory (IL-1 alpha and IL-1 beta), Th1 (TNF-alpha, IL-2, IL-12), and Th2 (IL-4, IL-5, and IL-10) cytokine levels. Protein was extracted from spleens for western blot to detect the expression of phosphorylated signal transducer and activator of transcription (STAT) 4 and STAT6. The severity of inflammation in enucleated eyes was graded by a masked observer. Paired t test was performed for the mean difference in histological scoring between treated groups and the immunised control group. RESULTS: Surprisingly, atorvastatin did not modulate the immune response. The proinflammatory cytokines, IL-1 alpha and IL-1 beta, and Th1 cytokines, TNF-alpha and IL-2, were upregulated equally in control and atorvastatin treated groups. IL-12 and Th2 cytokines were not upregulated in all three groups. Western blot analysis showed high levels of phosphorylated STAT4, but not STAT6 protein in the control and atorvastatin treated groups. Mean differences in histological scoring between treated groups and the immunised control group were not statistically significant. CONCLUSIONS: Atorvastatin treatment had no effect on Th1 and Th2 cytokine transcription. Although histological grading suggested mildly decreased inflammation in the high dose treated group, the equivalence of cytokine expression in all groups suggests that the statins may not modulate IRBP induced uveoretinitis.

Nicotinic regulation of c-fos and osteopontin expression in human-derived osteoblast-like cells and human trabecular bone organ culture.

Long-term in vivo studies have highlighted smoking as a risk factor in postmenopausal osteoporosis, bone fracture incidence, and increased nonunion rates. In contrast, there are few data postulating the effects of smoking at the cellular level in human skeletal tissue. In this study, we present novel evidence demonstrating that the nicotinic receptor alpha4 subunit is present in human primary bone cells by using reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, we demonstrate direct cellular effects of nicotine on primary human bone cells and blockage of these effects with a nicotinic receptor antagonist, D-tubocurarine. Nicotine effects on cell proliferation were biphasic with toxic, antiproliferative effects at high levels of nicotine (>1 mmol/L) and stimulatory effects at very low levels (0.01-10 micromol/L) after 72 h. This nicotine-induced increase in cell proliferation was inhibited in a dose-dependent manner by the addition of D-tubocurarine. In addition, proliferation effects from low-level treatment correlated with an upregulation of expression of the AP-1 transcription factor, c-fos, within 1 h, which was blocked by incubation with D-tubocurarine. To determine in situ bone cell responses within their trabecular matrix, cores of human bone isolated from biopsies were perfused with 0.1 micromol/L nicotine for 24 h. Western analysis of proteins isolated from the cores highlighted an increase in osteopontin, a bone matrix protein implicated in regulating resorption, which was partially inhibited by the addition of D-tubocurarine. To conclude, our results suggest that nicotine has a direct effect on human bone cells in modulating proliferation, upregulation of the c-fos transcription factor, and the synthesis of the bone matrix protein, osteopontin.

Selected contribution: regulatory pathways involved in mechanical induction of c-fos gene expression in bone cells.

The regulatory pathways involved in the rapid response of the AP-1 transcription factor, c-fos, to mechanical load in human primary osteoblast-like (HOB) cells and the human MG-63 bone cell line were investigated using a four-point bending model. HOB and MG-63 cells showed upregulation of c-fos expression on fibronectin and collagen type I substrates; however, MG-63 cells did not respond on laminin YIGSR substrates. Addition of cytochalasin D and Arg-Gly-Asp peptides during loading did not inhibit the response, whereas addition of beta(1)-integrin antibodies inhibited the load response. The role of Ca(2+) signaling has been demonstrated by blocking upregulation with addition of 2 mM EGTA, which chelates extracellular Ca(2+), and gadolinium (10 microM), which inhibits stretch-activated channels. Addition of the Ca(2+) ionophore A-23187 induced upregulation without loading; however, addition of nifedipine (10 microM), the L-type channel blocker, failed to prevent the load response. Inhibitors of downstream pathways indicated the involvement of protein kinase C. Our results demonstrate a key involvement of Ca(2+) signaling pathways and integrin binding in the c-fos response to mechanical strain.

Fracture stiffness as a guide to the management of tibial fractures.

We have studied the progression of healing in 103 unstable fractures of the tibia. In 76 patients we removed the external fixator once the stiffness had reached 15 Nm/degrees in the sagittal plane. Deformity at the site of the fracture subsequently occurred in four patients. In a further 27, we measured stiffness in several planes and removed the fixator only when the stiffness reached 15 Nm/degrees in each. We found that stiffness in two orthogonal planes may differ widely (maximum difference 9.0 Nm/degrees, mean 4.1 Nm/degrees). There were no failures in the second group. We advocate that fracture stiffness be measured in two orthogonal planes when assessing tibial healing and suggest that values above 15 Nm/degrees in two planes give an indication that it is safe to remove the fixator.

Cortex distraction forces caused by the insertion of external fixator pins.

OBJECTIVE: Insertion of a bicortical threaded external fixator pin can cause bone damage. An unexpected crack can propagate along the bone when the pin touches the far cortex. The objective of this study was to investigate whether drilling and inserting bicortical pins into the shafts of long bones can cause large distraction forces to be generated between the cortices. DESIGN: Two flat samples of bone or bone substitute (Tufnol) were mounted parallel at each end of a specially designed force measurement column. Three common pin designs were inserted into the samples: tapered, self-threading and self-drilling, and self-threading pins. The axial thrust and the cortex distraction force between the two samples were measured as the pins were inserted. RESULTS: High distraction forces were measured between the cortices for all pin designs, typically 700 to 1,000 Newtons. CONCLUSIONS: The clinical significance of these findings is that the insertion of bicortical pins of the designs tested may generate a large distraction force between the cortices. This may drive a fracture apart or propagate an undisplaced fracture. Therefore, care must be taken to ensure that bicortical pins are inserted in locations free of local defects.

A data-logging system to monitor bone fracture movement continuously.

A compact system is presented, which can continuously monitor the occurrence of fracture site movement in patients with tibial shaft fractures treated with an Orthofix external fixator allowing limited axial movement. The system comprises a microswitch and data logger board, which are both attached to the fixator. Each time the switch is closed by the movement of the fixator, the data logger records it as an event. The number of events per half hour is stored to the board's memory. The data logger can record the frequency of movement for at least a four-week period, at which time, the data can be transferred to a computer via a serial link. The system has been proven in a limited patient trial. The results highlight the variation in patient mobility. The significance of continuously monitoring the fracture site movement during the healing period is discussed.

Mechanical properties of callus in human tibial fractures: a preliminary investigation.

OBJECTIVE: Investigate the mechanical properties of callus in tibial fractures treated with external fixation. In particular any time-dependent or non-linear characteristics. DESIGN: A clinical-based investigative study. BACKGROUND: A fracture bending stiffness in the sagittal plane of 15 N m/deg. has been stated as a satisfactory endpoint of clinical healing. However using this criterion in 76 previous tibial fractures, four continued to a malunion. METHODS: Fracture properties were measured in clinic. The fixator was removed for the tests and a specially designed system was used to measure displacement and load. Fracture stiffness was measured in different planes and at various loading rates. Passive stressing of the leg was performed whilst fracture displacement was recorded. A constant load was applied for a longer period to assess creep properties. RESULTS: Fracture stiffness was found to vary between different planes of measurement and on load rate. The visco-elastic characteristics of the callus changed with time. In early measurements, the callus absorbed a large proportion of energy when a load was applied. Later tests showed a progressive change with the callus absorbing less energy. This demonstrates that the properties of the callus changed with time, with the viscous element diminishing and the elastic element increasing. This sometimes occurred with no change in the measured fracture stiffness. CONCLUSIONS: Further investigation is needed, focusing on the visco-elastic properties of callus, to develop a more reliable method of determining clinical union. RELEVANCE: Improved understanding of the mechanical properties of callus could result in improved methods of measuring fracture healing.

Vertical transtalar Steinmann pin fixation for unstable ankle fractures.

Ankle fractures are common injuries and can usually be managed by either cast immobilisation or open reduction and internal fixation. Occasionally, both of these methods are contra-indicated. In such cases, one solution is the use of a vertical transtalar Steinmann pin to stabilise the fracture. Over the last 7 years, we have managed 8 patients with severe ankle fractures using vertical transtalar Steinmann pin fixation. The median age of these patients was 76 years (range, 35-94 years). This method was used in two patients with open contaminated wounds, in 5 with atrophic and blistered skin, and in one following failure of internal fixation in a patient with atrophic skin. In all patients, a satisfactory reduction was achieved and maintained after removal of the pin. Although all patients began to develop osteo-arthritic changes secondary to their original fractures, no complications were directly attributable to the use of the pin. In unstable ankle fractures where damage and contamination of soft tissues would preclude internal fixation, we recommend the use of vertical transtalar Steinmann pin fixation.

The current management of tibial fractures: are clinical guidelines effective?

BACKGROUND: The production of clinical guidelines is increasing and will continue to do so with the introduction of clinical governance. In 1997, the British Orthopaedic Association (BOA) and the British Association of Plastic Surgeons (BAPS) published joint guidelines on the management of open tibial fractures. It is not known whether these guidelines reached their target audience, or indeed influenced clinical practice. METHODS: We determined the effectiveness of these guidelines by sending a postal questionnaire survey to 172 orthopaedic surgeons. RESULTS: Only 57% of consultants were aware of the guidelines, 70% of registrars and 25% of staff grades. Less than 29% of orthopaedic consultants would choose to consult the plastic surgical team pre-operatively in the management of an open tibial fracture and only 43% would seek plastic surgical involvement at all. The primary aim of increasing multidisciplinary communication has not been achieved. CONCLUSIONS: The awareness of, and adherence to, these guidelines is sub-optimal. This clearly has implications for both the future management of open tibial fractures and the further production of guidelines.

A fracture movement monitoring system to aid in the assessment of fracture healing in humans.

This paper presents a new design for a device to monitor the motion of fracture fragments in diaphyseal tibial fractures. The device measures the motion that occurs at the fracture site when loaded by gait or by manipulation. It has undergone rigorous calibration and acceptance trials. The device has been used in ethically approved research clinics held at the North Staffordshire Hospital (40 patients). The paper presents a selection of results obtained using the new device. The results demonstrate several new ways of assessing fracture healing by examining fracture site motion. The following conclusions were drawn: 1. If fracture monitoring devices are to be attached to bone screws, it is essential to minimize bone screw errors. To do this, each patient must have similar bone screw lengths, orientations, alignment and siting. This is only achievable using a peroperative reduction device. 2. If fracture stiffness is to be used as a measure of fracture healing, load rate should be controlled; at the very least strain rate should be controlled. 3. It is imperative that fracture stiffness be measured in more than one plane by a biplanar device so that asymmetry may be accommodated. 4. Fracture stiffness, on its own, is probably not a sufficiently rigorous measure of healing end-point. The quantifiably viscoelastic properties of healing callus should be taken into account.

A device for improved reduction of tibial fractures treated with external fixation.

A widely used method of treatment for unstable tibial shaft fractures is unilateral external fixation. The majority of fixators act as three distinct devices: an intra-operative reduction device, a device to maintain fracture alignment during healing and an aid to healing by allowing movement at the fracture site. Conventional operative techniques require the surgeon to manipulate a number of degrees of freedom at once, making reduction of the fracture difficult, and results in the fixator being out of alignment with the long axis of the bone. An operative method has been developed that separates reduction and fixation. A dedicated device has been designed to improve the per-operative control of fracture fragments during fracture reduction. The device has been used in clinical trials for the reduction of 22 diaphyseal tibial fractures. Compared with previous operative techniques there has been a saving of 53 per cent in fracture reduction time and an overall saving of 10 per cent in operating time. Fracture alignment has been improved compared with reductions achieved with a fixator which potentially improves healing and lowers the rate of malunion. In each case the fixator has been applied in alignment with the bone, improving dynamization and reducing the likelihood of malunion due to fixator cam slippage.