What is a tibial pilon fracture and how should they be acutely managed? A survey of consultant British Orthopaedic Foot and Ankle Society members and non-members.

INTRODUCTION: Controversy exists around which distal tibial fractures are pilon fractures. We evaluated views to define a pilon fracture and support the development of standards of care. METHODS: Views regarding the characteristics of a pilon fracture and acute soft tissue management were determined through a questionnaire. This was trialled, approved by the British Orthopaedic Foot and Ankle Society and distributed to its members. This was also distributed nationally as part of the ENFORCE study. RESULTS: In total, 282 consultants from 27 units responded, of whom 24% (69/282) were foot and ankle specialists. Some 58% (163/282) agreed that a pilon fracture is primarily a soft tissue injury, 81% (228/282) that pilon fractures occur though high-energy transfer, 81% (228/282) that pilon fractures are sustained through an axial compression mechanism and 93% (265/282) that they are a potentially limb-threatening injury. Overall, 83% (234/282) agreed that in a length-unstable pilon fracture it is not possible to maintain the talus near anatomically under the tibial plafond without rigid fixation to control length - with 87% (246/282) agreeing that the acute first-line management should be a spanning external fixator. Opinions were that the time frame between diagnosis and intervention should be: less than 6h (63%; 154/246), 6-12h (31%; 77/246) and 12-24h (6%; 15/246). CONCLUSION: Consensus supports defining a pilon fracture as a potentially limb-threatening high-energy axial compression injury, and a spanning external fixator as the first-line management of a length-unstable injury less than 12h from diagnosis.

Reliable Initial Trauma CT Findings of Supraclavicular Brachial Plexus Injury in Patients Sustaining Blunt Injuries.

BACKGROUND AND PURPOSE: Traumatic brachial plexus injuries are uncommon but can be debilitating. Early diagnosis is critical. Most patients undergo CT after trauma. We sought to identify correlative CT findings of supraclavicular brachial plexus injuries to discern who may require further evaluation with MR imaging and to measure multireviewer performance for their interpretations. MATERIALS AND METHODS: We identified all MR imaging examinations of the brachial plexus from our institution from January 2010 to January 2021 and included those performed for trauma. We excluded patients with penetrating or infraclavicular injuries and without preceding CTA of the neck or CT of the cervical spine. The cohort of 36 cases and 50 controls remained for analysis and were assessed for 6 findings: scalene muscle edema/enlargement, interscalene fat pad effacement, first rib fracture, cervical spine lateral mass/transverse process fracture, extra-axial cervical spinal hemorrhage, and cervical spinal cord eccentricity, forming a reference key. A resident physician and 2 neuroradiologists (blinded to the MR imaging) independently reviewed each CT scan for these findings. We measured agreement (Cohen κ) between observers and against the reference key. RESULTS: Interscalene fat pad effacement (sensitivity, specificity, 94.44%, 90.00%; OR = 130.33; P < .001) and scalene muscle edema/enlargement (sensitivity, specificity, 94.44%, 88.00%; OR = 153.00; P < .001) correlated significantly with brachial plexus injury. Agreement between observers and the key was almost perfect for those findings and fractures (pooled κ ≥ 0.84; P < .001). Agreement between observers was variable (κ = 0.48-0.97; P < .001). CONCLUSIONS: CT can accurately predict brachial plexus injuries, potentially enabling earlier definitive evaluation. High interobserver agreement suggests that findings are consistently learned and applied.

Communication with young people in paediatric and adult endocrine consultations: an intervention development and feasibility study.

BACKGROUND: Communication is complex in endocrine care, particularly during transition from paediatric to adult services. The aims of this study were to examine the feasibility of interventions to support young people to interact with clinicians. METHODS: Development and evaluation of a complex intervention in 2 phases: Pre-intervention observational study; Intervention feasibility study. Purposive sample of recordings of 62 consultations with 58 young people aged 11-25 years with long-term endocrine conditions in two paediatric and two adult endocrine clinics. Proportion of time talked during consultations, number and direction of questions asked; Paediatric Consultation Assessment Tool (PCAT); OPTION shared decision making tool; Medical Information Satisfaction Scale (MISS- 21). Young people were invited to use one or more of: a prompt sheet to help them influence consultation agendas and raise questions; a summary sheet to record key information; and the www.explain.me.uk website. RESULTS: Nearly two thirds of young people (63%) chose to use at least one communication intervention. Higher ratings for two PCAT items (95% CI 0.0 to 1.1 and 0.1 to 1.7) suggest interventions can support consultation skills. A higher proportion of accompanying persons (83%) than young people (64%) directed questions to clinicians. The proportion of young people asking questions was higher (84%) in the intervention phase than in the observation phase (71%). CONCLUSIONS: Interventions were acceptable and feasible. The Intervention phase was associated with YP asking more questions, which implies that the availability of interventions could promote interactivity.

Phaeochromocytoma and Acromegaly: a unifying diagnosis.

UNLABELLED: A 52-year-old lady was referred after a 5 cm left adrenal mass was detected on computed tomography (CT) scanning. She was asymptomatic although was noted to have acromegalic facies. Blood pressure (BP) was normal but plasma normetanephrines were raised to 2.81 mmol/l (<1.09) and urinary normetadrenaline excretion 5.3 µmol/24 h (0-4.3). Adrenal biochemistry screen was otherwise normal. Metaiodobenzylguanidine (MIBG) scan demonstrated uptake in the adrenal lesion. Growth hormone (GH) nadir on oral glucose tolerance test (OGTT) was 2.2 ng/ml with an elevated IGF1 level of 435 ng/ml (72-215), confirming acromegaly biochemically. The remainder of the pituitary screen was normal. A magnetic resonance imaging (MRI) scan of the pituitary revealed an enlarged pituitary gland with a microadenoma/cyst of 2-3 mm in diameter. Alpha blockade was achieved with a titrated dose of phenoxybenzamine before a successful laparoscopic hand-assisted left adrenalectomy. Postoperative biochemical testing revealed a normal plasma normetanephrine level of 0.6 nmol/l (<1.09) and a metanephrine level of 0.35 nmol/l (<0.46 nmol/l). Nadir on OGTT was normal at 0.07 ng/ml with an IGF1 level within the reference range at 111 ng/ml (75-215). Histology demonstrated a well-circumscribed and encapsulated oval mass with microscopic features typical for a phaeochromocytoma. The sections stained strongly positive for GHRH in 20% of cells on immunocytochemistry. Genetic analysis showed no pathogenic mutation. This is a report of the rare condition of a phaeochromocytoma co-secreting GHRH resulting in clinical and biochemical acromegaly. Neuroendocrine tumours can stain positive for GHRH without coexisting acromegaly, but the resolution of patient symptoms and normalisation of serum GH and IGF1 levels following surgery imply that this was functional secretion. Pituitary surgery should be avoided in such cases. LEARNING POINTS: Incidental findings on imaging require thorough investigation to determine the presence of serious pathology.Acromegaly and phaeochromocytoma are rarely coincident in the same patient. If this occurs, co-secretion of GHRH from the phaeochromocytoma or the presence of underlying genetic abnormalities must be considered.Acromegaly is due to ectopic GHRH-secreting neuroendocrine tumours in <1% of cases, most commonly pancreatic or bronchial lesions.Co-secretion of GHRH from a phaeochromocytoma is extremely rare.In such cases, the pituitary gland may appear enlarged but pituitary surgery should be avoided and surgical treatment of the neuroendocrine tumour attempted.

Wnt signalling in pituitary development and tumorigenesis.

Wnt signalling is activated in both pituitary organogenesis and its mature function. Wnt ligands and Wnt signalling pathways are critical for the regulation of the formation of the pituitary. In the mature pituitary, Wnt signalling pathways control cell activity and may stimulate cell proliferation in both physiological and pathological processes. This review compares Wnt signalling pathways active in the developing and mature pituitary and explores how this gives us further insight into the development of pituitary adenomas.

Npas4 is activated by melatonin, and drives the clock gene Cry1 in the ovine pars tuberalis.

Seasonal mammals integrate changes in the duration of nocturnal melatonin secretion to drive annual physiologic cycles. Melatonin receptors within the proximal pituitary region, the pars tuberalis (PT), are essential in regulating seasonal neuroendocrine responses. In the ovine PT, melatonin is known to influence acute changes in transcriptional dynamics coupled to the onset (dusk) and offset (dawn) of melatonin secretion, leading to a potential interval-timing mechanism capable of decoding changes in day length (photoperiod). Melatonin offset at dawn is linked to cAMP accumulation, which directly induces transcription of the clock gene Per1. The rise of melatonin at dusk induces a separate and distinct cohort, including the clock-regulated genes Cry1 and Nampt, but little is known of the up-stream mechanisms involved. Here, we used next-generation sequencing of the ovine PT transcriptome at melatonin onset and identified Npas4 as a rapidly induced basic helix-loop-helix Per-Arnt-Sim domain transcription factor. In vivo we show nuclear localization of NPAS4 protein in presumptive melatonin target cells of the PT (α-glycoprotein hormone-expressing cells), whereas in situ hybridization studies identified acute and transient expression in the PT of Npas4 in response to melatonin. In vitro, NPAS4 forms functional dimers with basic helix loop helix-PAS domain cofactors aryl hydrocarbon receptor nuclear translocator (ARNT), ARNT2, and ARNTL, transactivating both Cry1 and Nampt ovine promoter reporters. Using a combination of 5'-deletions and site-directed mutagenesis, we show NPAS4-ARNT transactivation to be codependent upon two conserved central midline elements within the Cry1 promoter. Our data thus reveal NPAS4 as a candidate immediate early-response gene in the ovine PT, driving molecular responses to melatonin.

Rediscovering contact inhibition in the embryo.

The cellular reaction called contact inhibition of locomotion was initially characterised by Michael Abercrombie more than 60 years ago. In his most general definition, it is defined as the stopping of the continued locomotion of a cell in the direction which has produced a collision with another cell. This deceptively simple response has been widely studied in vitro in a number of cell types over the years, yet it is still often misunderstood by the scientific community. Abercrombie spent much of his life studying the failure of the response shown by cancer cell types and how this might lead to malignant invasion of normal tissue. However, since Abercrombie's time, a role for this response in living organisms has been left to the realm of speculation. Here, we discuss the history of contact inhibition research, clarify some of the misconceptions about the response and reclaim misused terminology. We will also highlight our recent work, which for the first time elucidates a functional role for contact inhibition in vivo during embryogenesis.

The prolactin gene: a paradigm of tissue-specific gene regulation with complex temporal transcription dynamics.

Transcription of numerous mammalian genes is highly pulsatile, with bursts of expression occurring with variable duration and frequency. The presence of this stochastic or 'noisy' expression pattern has been relatively unexplored in tissue systems. The prolactin gene provides a model of tissue-specific gene regulation resulting in pulsatile transcription dynamics in both cell lines and endocrine tissues. In most cell culture models, prolactin transcription appears to be highly variable between cells, with differences in transcription pulse duration and frequency. This apparently stochastic transcription is constrained by a transcriptional refractory period, which may be related to cycles of chromatin remodelling. We propose that prolactin transcription dynamics result from the summation of oscillatory cellular inputs and by regulation through chromatin remodelling cycles. Observations of transcription dynamics in cells within pituitary tissue show reduced transcriptional heterogeneity and can be grouped into a small number of distinct patterns. Thus, it appears that the tissue environment is able to reduce transcriptional noise to enable coordinated tissue responses to environmental change. We review the current knowledge on the complex tissue-specific regulation of the prolactin gene in pituitary and extra-pituitary sites, highlighting differences between humans and rodent experimental animal models. Within this context, we describe the transcription dynamics of prolactin gene expression and how this may relate to specific processes occurring within the cell.

Novel approaches to in vitro transgenesis.

The study of gene expression is a major focus in biological research and is recognised to be critical for our understanding of physiological and pathophysiological processes. Methods to study gene expression range from in vitro biochemical assays through cultured cells and tissue biopsies to whole organisms. In the early stages of project development, considerations about which model system to use should be addressed and may influence future experimental procedures. The aim of this review is to briefly describe advantages and disadvantages of the existing techniques available to study eukaryote gene expression in vitro, including the mechanism of transgene integration (transient or stable), the different transgenesis systems available, including plasmids, viruses and targeted integration and knockin approaches, and paying particular attention to expression systems such as bacterial artificial chromosomes and episomal vectors that offer a number of advantages and are increasing in popularity. We also discuss novel approaches that combine some of the above techniques, generating increasingly complex but physiologically accurate expression systems.

Treatment of cooling tower blowdown water containing silica, calcium and magnesium by electrocoagulation.

This research investigated the effectiveness of electrocoagulation using iron and aluminium electrodes for treating cooling tower blowdown (CTB) waters containing dissolved silica (Si(OH)(4)), Ca(2 + ) and Mg(2 + ). The removal of each target species was measured as a function of the coagulant dose in simulated CTB waters with initial pH values of 5, 7, and 9. Experiments were also performed to investigate the effect of antiscaling compounds and coagulation aids on hardness ion removal. Both iron and aluminum electrodes were effective at removing dissolved silica. For coagulant doses < or =3 mM, silica removal was a linear function of the coagulant dose, with 0.4 to 0.5 moles of silica removed per mole of iron or aluminium. Iron electrodes were only 30% as effective at removing Ca(2 + ) and Mg(2 + ) as compared to silica. There was no measurable removal of hardness ions by aluminium electrodes in the absence of organic additives. Phosphonate based antiscaling compounds were uniformly effective at increasing the removal of Ca(2 + ) and Mg(2 + ) by both iron and aluminium electrodes. Cationic and amphoteric polymers used as coagulation aids were also effective at increasing hardness ion removal.

Failure of antibody response to polysaccharide antigen in treated panhypopituitary adults.

Although pituitary hormones are known to affect immune function, treated hypopituitarism is not a recognized cause of immune deficiency in humans. We set out to assess integrity of baseline and stimulated immune function in severely hypopituitary adults. Twenty-one panhypopituitary adults (group 1), on stable pituitary replacement including growth hormone, and 12 healthy volunteers (group 2) were studied. Lymphocyte subsets, pneumococcal antibody levels pre- and 1 month after polysaccharide vaccination, T cell numbers and in-vitro interferon (IFN)-gamma response were studied. There were no significant differences in T cell numbers or IFN-gamma secretion. B cell numbers were lower in group 1, especially those with low prolactin levels. Independent of this finding, nine of 21 patients in this group had low antibody response to polysaccharide antigen. This was most striking in those with low insulin-like growth factor 1 levels and appeared to be independent of the use of anti-convulsants or corticosteroid replacement. Significant humoral immune deficiency is seen in panhypopituitarism and may contribute to morbidity.

Ovarian neoplasm development by 7,12-dimethylbenz[a]anthracene (DMBA) in a chemically-induced rat model of ovarian failure.

OBJECTIVES: The objectives were to determine the time course for ovarian failure in rats caused by 4-vinylcyclohexene diepoxide (VCD) and develop a model for ovarian cancer in which ovarian neoplasms were chemically induced in an animal that was follicle depleted, but retained residual ovarian tissue. METHODS: Initially, female Fisher 344 rats were treated with VCD (to induce ovarian failure) or vehicle control (sesame oil). Three or 6 months after treatment, ovaries were collected and processed for histological evaluation for confirmation of ovarian failure. A further set of female rats was assigned to four groups exposed to combinations of vehicle control, VCD and/or DMBA (directly applied to the ovary) in a novel model for examining early stages of ovarian neoplasia. RESULTS: Three and 6 months following VCD dosing there was a significant reduction of ovarian weight and follicle number. Treatment with DMBA subsequent to VCD resulted in tumors in 42% of animals at 3 months and 57% at 5 months. All neoplasms were classified Sertoli-Leydig cell tumors (SLCT). No tumor occurred in animals treated with vehicle or DMBA alone. CONCLUSIONS: These studies demonstrate that the VCD-treated rat can be used as a model for peri- and post-menopause. DMBA induction of ovarian neoplasms was greater in those rats treated with VCD. Whether this increase was due to tumor initiation by VCD or was the result of ovarian failure cannot be distinguished from these results. This represents the only animal model to date for sex cord stromal tumors.

Human prolactin gene promoter regulation by estrogen: convergence with tumor necrosis factor-alpha signaling.

Estrogens have been implicated in the regulation of prolactin gene expression in man, although previous studies have not defined the molecular mechanism whereby estradiol activates the human prolactin gene promoter (hPrl). We found that estradiol induced a reproducible 1.8-fold activation of the hPrl gene promoter, using pituitary GH3 cells stably transfected with a 5000-bp hPrl promoter fragment linked to luciferase reporter gene. This activation was blocked by treatment with estrogen receptor (ER) antagonists 4-hydroxytamoxifen and ICI-182,780. Promoter deletion and mutagenesis experiments identified a functional estrogen response element (ERE) sequence 1189 bp upstream of the transcription start site that was responsible for estrogen-mediated promoter activation. This site differed from the consensus ERE sequence by two base pairs, one in each half-site. This ERE was identified to be functional through binding ERalpha in EMSAs. Chromatin immunoprecipitation assays confirmed ERalpha binding to this sequence in vivo in the absence of ligand, with increased recruitment when cells were cultured in the presence of estradiol. When cells were treated with both estradiol and TNFalpha, we observed synergistic activation of the hPrl promoter, which was mediated by the -1189-bp ERE. Mutagenesis of this ERE abolished the promoter-activating effect not only of estradiol but also of TNFalpha. These data suggest a novel, promoter-specific signaling interaction between estrogen and TNFalpha signaling, which is likely to be important for prolactin regulation in vivo.

Hyperprolactinaemia.

Hyperprolactinaemia is a frequent cause of reproductive problems encountered in clinical practice. A variety of pathophysiological conditions can lead to hyperprolactinaemia; therefore, pregnancy, drug effects, hypothyroidism and polycystic ovary syndrome should be excluded before investigating for prolactin-secreting pituitary tumours. Prolactinomas are mainly diagnosed in women aged 20-40 years. They present with clinical features of hyperprolactinaemia (galactorrhoea, gonadal dysfunction), and more rarely with large tumours, headache and visual field loss due to optic chiasm compression. Medical therapy with dopamine agonists is the treatment of choice for both micro- and macroprolactinomas. Tumour shrinkage and restoration of gonadal function are achieved in the majority of cases with dopamine agonists. A trial of withdrawal of medical therapy may be considered in many patients with close follow-up. Pituitary surgery and radiotherapy currently have very limited indications. Pregnancies in patients with prolactinomas need careful planning and close monitoring.