A brief look at the history of the Deaconess Hospital, Edinburgh, 1894-1990.

The Deaconess Hospital, Edinburgh, opened in 1894 and was the first establishment of its kind in the UK, maintained and wholly funded as it was by the Reformed Church. Through its 96-year lifetime it changed and evolved to time and circumstance. It was a school: for the training of nurses and deaconesses who took their practical skills all over the world. It was a sanctum: for the sick-poor before the NHS. It was a subsidiary: for the bigger hospitals of Edinburgh after amalgamation into the NHS. It was a specialised centre: as the Urology Department in Edinburgh and the Scottish Lithotripter centre. And now it is currently student accommodation. There is no single source to account for its history. Through the use of original material made available by the Lothian Health Services Archives - including Church of Scotland publications, patient records, a doctor's casebook and annual reports - we review its conception, purpose, development and running; its fate on joining the NHS, its identity in the latter years and finally its closure.

Validating the GTP-cyclohydrolase 1-feedback regulatory complex as a therapeutic target using biophysical and in vivo approaches.

BACKGROUND AND PURPOSE: 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4 ) is an essential cofactor for nitric oxide biosynthesis. Substantial clinical evidence indicates that intravenous BH4 restores vascular function in patients. Unfortunately, oral BH4 has limited efficacy. Therefore, orally bioavailable pharmacological activators of endogenous BH4 biosynthesis hold significant therapeutic potential. GTP-cyclohydrolase 1 (GCH1), the rate limiting enzyme in BH4 synthesis, forms a protein complex with GCH1 feedback regulatory protein (GFRP). This complex is subject to allosteric feed-forward activation by L-phenylalanine (L-phe). We investigated the effects of L-phe on the biophysical interactions of GCH1 and GFRP and its potential to alter BH4 levels in vivo. EXPERIMENTAL APPROACH: Detailed characterization of GCH1-GFRP protein-protein interactions were performed using surface plasmon resonance (SPR) with or without L-phe. Effects on systemic and vascular BH4 biosynthesis in vivo were investigated following L-phe treatment (100 mg·kg(-1) , p.o.). KEY RESULTS: GCH1 and GFRP proteins interacted in the absence of known ligands or substrate but the presence of L-phe doubled maximal binding and enhanced binding affinity eightfold. Furthermore, the complex displayed very slow association and dissociation rates. In vivo, L-phe challenge induced a sustained elevation of aortic BH4 , an effect absent in GCH1(fl/fl)-Tie2Cre mice. CONCLUSIONS AND IMPLICATIONS: Biophysical data indicate that GCH1 and GFRP are constitutively bound. In vivo, data demonstrated that L-phe elevated vascular BH4 in an endothelial GCH1 dependent manner. Pharmacological agents which mimic the allosteric effects of L-phe on the GCH1-GFRP complex have the potential to elevate endothelial BH4 biosynthesis for numerous cardiovascular disorders.

The growth hormone insulin-like growth factor 1 axis in children and adolescents with inflammatory bowel disease and growth retardation.

CONTEXT: There is scarce knowledge about the growth hormone (GH) insulin-like growth factor-1 (IGF1) axis in children & adolescents with inflammatory bowel disease (IBD) and growth retardation. OBJECTIVE: To describe the pattern of GH and IGF1 secretion in children & adolescents with IBD. DESIGN: A retrospective review of 28 patients (23 M) of IBD (25 Crohn's Disease and three Ulcerative Colitis) and growth retardation who had investigation of the GH/IGF-1 axis. Height velocity (HV) and serum IGF1 were converted to standard deviation score (SDS); to account for delayed puberty in girls over 11 years and boys over 12 years, HV and serum IGF1 SDS were adjusted for bone age. RESULTS: Median (range) age and Ht SDS at the time of endocrine evaluation was 14.3 years (7.7,17.0) and -2.0(-3.6,-0.9), respectively. Median HVSDS over the prior 12 months was -2.2(-7.7,2.8). Median peak serum GH on insulin tolerance test (ITT) was 5.8 mcg/l (1.3, 24.0), and median serum IGF1 SDS was -0.9(-3.1, 0.1). Five of 28 (18%) had a peak serum GH of >12 mcg/l. Overall, four had biochemical evidence of functional GH deficiency (peak GH < 3 mcg/l and IGF1 SDS < 0) and 11 children had biochemical evidence suggesting GH resistance (peak GH > 6 mcg/l and IGF1 SDS < 0). However, only one child had a peak serum GH > 6 mcg/l and a very low IGF1 SDS of <-2.0. There was a negative association between peak serum GH and Ht SDS (r = -0.49, P = 0.008), but there was no association with HV and there was no association between IGF1 SDS and Ht or HV SDS. IGF1 SDS showed a negative association with erythrocyte sedimentation rate (r = -0.41, P = 0.04). CONCLUSION: Growth retardation in children and adolescents with IBD is commonly associated with a range of biochemical abnormalities ranging from functional GH deficiency to GH resistance. In these children, poor relationship between systemic markers of growth and height velocity point to an important role of growth factors at the target organ level in modulating growth in children with IBD. The value of assessing the GH/IGF-1 axis and whether it predicts subsequent response to growth-promoting therapy requires further exploration.

Lentiviral gene transfer to reduce atherosclerosis progression by long-term CC-chemokine inhibition.

CC-chemokines are important mediators in the pathogenesis of atherosclerosis. Atherosclerosis progression is reduced by high-level, short-term inhibition of CC-chemokine activity, for example by adenoviral gene transfer. However, atherosclerosis is a chronic condition where short-term effects, while demonstrating proof-of-principle, are unlikely to provide maximum therapeutic benefit. Accordingly, we generated a recombinant lentivirus, lenti35K, encoding the broad-spectrum CC chemokine inhibitor, 35K, derived from the vaccinia virus. To investigate the effects of prolonged broad-spectrum chemokine inhibition on atherosclerosis, lenti35K, or lentiGFP or PBS were delivered to 6-week-old ApoE knockout (ApoE-KO) mice by hydrodynamic injection. Sustained lentiviral transduction and transgene expression were demonstrated by 35K mRNA and viral DNA in liver tissue, and recombinant 35K protein circulating in the plasma, 3 months after gene transfer. Plasma from lenti35K animals had reduced chemokine activity compared with plasma from lentiGFP or PBS-treated animals. Histologic analysis of aortic sinus sections revealed that atherosclerotic plaque area in lenti35K mice was significantly reduced compared with both lentiGFP and PBS controls. Furthermore, plaque macrophage content was substantially reduced in lenti35K mice. Lentiviral 35K gene transfer is a promising experimental strategy to reduce atherosclerosis progression, and demonstrates the potential of long-term CC-chemokine inhibition as a potential therapeutic target in atherosclerosis.

The atRA-responsive gene neuron navigator 2 functions in neurite outgrowth and axonal elongation.

Neuron navigator 2 (Nav2) was first identified as an all-trans retinoic acid (atRA)-responsive gene in human neuroblastoma cells (retinoic acid-induced in neuroblastoma 1, RAINB1) that extend neurites after exposure to atRA. It is structurally related to the Caenorhabditis elegans unc-53 gene that is required for cell migration and axonal outgrowth. To gain insight into NAV2 function, the full-length human protein was expressed in C. elegans unc-53 mutants under the control of a mechanosensory neuron promoter. Transgene expression of NAV2 rescued the defects in unc-53 mutant mechanosensory neuron elongation, indicating that Nav2 is an ortholog of unc-53. Using a loss-of-function approach, we also show that Nav2 induction is essential for atRA to induce neurite outgrowth in SH-SY5Y cells. The NAV2 protein is located both in the cell body and along the length of the growing neurites of SH-SY5Y cells in a pattern that closely mimics that of neurofilament and microtubule proteins. Transfection of Nav2 deletion constructs in Cos-1 cells reveals a region of the protein (aa 837-1065) that directs localization with the microtubule cytoskeleton. Collectively, this work supports a role for NAV2 in neurite outgrowth and axonal elongation and suggests this protein may act by facilitating interactions between microtubules and other proteins such as neurofilaments that are key players in the formation and stability of growing neurites.

Diagnosis and management of olfactory disorders: survey of UK-based consultants and literature review.

BACKGROUND: The diagnosis and management of olfactory disorders is an often neglected topic in otolaryngology. This article evaluates current clinical practice within the United Kingdom, and provides a literature-based review of the diagnosis, management and prognosis of olfactory pathology. DESIGN: A questionnaire was sent to consultant and associate specialist members of the British Association of Otolaryngologists and Head and Neck Surgeons. The responses were documented to gain an impression of how olfactory disorders are managed in the United Kingdom. The literature relating to olfactory dysfunction was then evaluated and the findings summarised. CONCLUSIONS: Management of olfactory pathology varies across the United Kingdom. The literature suggests that chemosensory testing is optimal and that both forced-choice and threshold testing should be applied if objective evaluation is required. Imaging can be of value but the appropriate technique should be used. Olfactory function can recover following head injury, viral infection and chronic sinonasal disease, although varying degrees of dysfunction are likely to persist. There is a role for the use of corticosteroids, particularly when administered systemically. More research is needed to establish the appropriate dose and length of treatment.

Fatal and near-fatal encephalopathy with hyponatraemia in two siblings with fluticasone-induced adrenal suppression.

AIM: To document previously unreported acute effects of adrenal insufficiency. METHODS: We describe two siblings who presented acutely with hyponatraemia and cerebral oedema following prolonged treatment with high dose inhaled fluticasone. RESULTS: A girl aged 5.5 years presented with vomiting, headache, visual impairment and seizures. She was hyponatraemic but not hypoglycaemic. Her conscious level continued to deteriorate and she died, post mortem examination showing small adrenal glands and cerebral oedema. Four weeks later her 7-year-old brother presented with similar symptoms. Assessment showed hyponatraemia with cerebral oedema. His illness responded to intensive care. A diagnosis of adrenal insufficiency was made retrospectively in both cases. The siblings had been receiving Fluticasone propionate (FP) in doses of up to 2000 microg/day for several years. CONCLUSION: We believe that the hyponatraemia and cerebral oedema was related to cortisol deficiency, leading to impaired excretion of water. We emphasize the need for careful cerebral monitoring in acute adrenal insufficiency presenting with impaired consciousness.

Defective chemoattractant-induced calcium signalling in S100A9 null neutrophils.

The S100 family member S100A9 and its heterodimeric partner, S100A8, are cytosolic Ca2+ binding proteins abundantly expressed in neutrophils. To understand the role of this EF-hand-containing complex in Ca2+ signalling, neutrophils from S100A9 null mice were investigated. There was no role for the complex in buffering acute cytosolic Ca2+ elevations. However, Ca2+ responses to inflammatory agents such as chemokines MIP-2 and KC and other agonists are altered. For S100A9 null neutrophils, signalling at the level of G proteins is normal, as is release of Ca2+ from the IP(3) receptor-gated intracellular stores. However MIP-2 and FMLP signalling in S100A9 null neutrophils was less susceptible than wildtype to PLCbeta inhibition, revealing dis-regulation of the signalling pathway at this level. Downstream of PLCbeta, there was reduced intracellular Ca2+ release induced by sub-maximal levels of chemokines. Conversely the response to FMLP was uncompromised, demonstrating different regulation compared to MIP-2 stimulation. Study of the activity of PLC product DAG revealed that chemokine-induced signalling was susceptible to inhibition by elevated DAG with S100A9 null cells showing enhanced inhibition by DAG. This study defines a lesion in S100A9 null neutrophils associated with inflammatory agonist-induced IP3-mediated Ca2+ release that is manifested at the level of PLCbeta.

The significance of MRI findings for non-rhinological disease.

OBJECTIVES: Mucosal changes in the paranasal sinuses are detected in 30-50% of scans for non-rhinological disease. This study assesses the relationship between symptoms of rhinosinusitis and radiological evidence of sinus pathology in patients undergoing magnetic resonance imaging (MRI) scans for unrelated pathology. DESIGN: Prospective observational study, evaluating symptoms of rhinosinusitis in patients undergoing MRI scanning of the internal acoustic meati. A visual analogue scale (VAS) of rhinological symptoms was completed immediately before scanning, specifying symptoms present at the time of completing the questionnaire. Symptom scores were recorded by one of the investigators, blinded to the MRI images. Two investigators independently rated sinus mucosal thickening for each scan, both of whom were blinded to the symptom scores. Lund and Mackay scoring systems were used for both symptom and radiological scores, which were then compared. SETTING: Otolaryngology and Radiology Departments in a large teaching hospital. PARTICIPANTS: Fifty consecutive patients were recruited over a 2-month period. MAIN OUTCOME MEASURES: Visual analogue scale symptom scores were compared with radiological scores for sinus mucosal thickening. RESULTS: No statistically significant relationship was demonstrated between rhinological symptoms and radiological features suggestive of rhinosinusitis in patients undergoing MRI scanning for non-rhinological disease. CONCLUSIONS: The relationship between rhinological symptoms and MRI findings of sinus pathology is not straightforward. Management decisions should be made on the basis of nasal history and endoscopy, rather than radiological findings. This is the first study assessing this relationship by documenting symptoms on the day of scanning, using a validated scoring system.

Lipoma of the parapharyngeal space.

A 75-year-old gentleman presented to our department with dysphagia, nocturnal cough and dysphonia. Clinical examination revealed a large parapharyngeal mass extending from the left nasopharynx to the glottis. A magnetic resonance imaging scan confirmed the lipomatous nature of the lesion and elegantly demonstrated its anatomy. We discuss the aetiology and management of such lesions and focus on the diagnostic radiology of the parapharyngeal space.

Management of the transgender voice.

Transsexualism is a condition involving a paradoxical feeling of belonging to the opposite sex. Acquiring a sex-appropriate voice is a crucial part of the patient gaining acceptance in their new gender. Speech and language therapists and otolaryngologists play an important role in influencing communication behaviour in transgender patients by altering the fundamental frequency of speech to one acceptable for the patient's sex. Review of the literature suggests that speech and language therapy is successful at creating an acceptable fundamental frequency in transgender patients, as well as influencing other communication behaviours. Laryngeal surgery, such as cricothyroid approximation, has an important role in raising the fundamental frequency in those who do not achieve acceptable voice via non-surgical means. There is little information on patient satisfaction and quality of life measures. Research is currently underway to explore this aspect further.

Adrenal responses to low dose synthetic ACTH (Synacthen) in children receiving high dose inhaled fluticasone.

BACKGROUND AND AIMS: Clinical adrenal insufficiency has been reported with doses of inhaled fluticasone proprionate (FP) > 400 microg/day, the maximum dose licensed for use in children with asthma. Following two cases of serious adrenal insufficiency (one fatal) attributed to FP, adrenal function was evaluated in children receiving FP outwith the licensed dose. METHODS: Children recorded as prescribed FP > or = 500 microg/day were invited to attend for assessment. Adrenal function was measured using the low dose Synacthen test (500 ng/1.73 m2 intravenously) and was categorised as: biochemically normal (peak cortisol response > 500 nmol/l); impaired (peak cortisol < or = 500 nmol/l); or flat (peak cortisol < or = 500 nmol/l with increment of < 200 nmol/l and basal morning cortisol < 200 nmol/l). RESULTS: A total of 422 children had been receiving FP alone or in combination with salmeterol; 202 were not investigated (137 FP within license; 24 FP discontinued); 220 attended and 217 (age 2.6-19.3 years) were successfully tested. Of 194 receiving FP > or = 500 microg/day, six had flat responses, 82 impaired responses, 104 were normal, and in 2 the LDST was unsuccessful. Apart from the index child, the other five with flat responses were asymptomatic; a further child with impairment (peak cortisol 296 nmol/l) had encephalopathic symptoms with borderline hypoglycaemia during an intercurrent illness. The six with flat responses and the symptomatic child were all receiving FP doses of > or = 1000 microg/day. CONCLUSION: Overall, flat adrenal responses in association with FP occurred in 2.8% of children tested, all receiving > or = 1000 microg/day, while impaired responses were seen in 39.6%. Children on above licence FP doses should have adrenal function monitoring as well as a written plan for emergency steroid replacement.

Nasal polyposis in the laryngectomee.

We report the cases of two laryngectomy patients who were diagnosed with de novo nasal polyposis, more than 15 years after their laryngectomies. This phenomenon has not previously been reported in the literature. We discuss the changes in nasal physiology of the laryngectomy patient, with regards to the aetiology of polyp formation, and highlight the importance of examining the nose in such patients.

Auxological outcome and time to menarche following long-acting goserelin therapy in girls with central precocious or early puberty.

OBJECTIVE: Following a successful clinical trial in 1996, the long-acting GnRH analogue goserelin (Zoladex LA 10.8 mg; Astra Zeneca) has been our preferred treatment for central early (CEP) or precocious puberty (CPP). However, some female patients have expressed concern about perceived weight gain during therapy and delay in the onset or resumption of menses on completion of therapy. The primary aim of this study was to investigate these concerns by determining the auxological parameters and timing of menarche or re-menarche in all girls with CEP/CPP who have completed a course of Zoladex LA treatment. The secondary aim was to assess auxological outcome in girls who have attained final height. DESIGN AND PATIENTS: Case records of all girls with idiopathic CEP/CPP or CEP/CPP secondary to CNS pathology treated with Zoladex LA since 1996 were reviewed. A total of 46 girls who have completed therapy were identified, of whom 11 had reached final height. measurements Height, weight and bone age (RUS (TW2) method) were measured before treatment, when Zoladex LA was stopped and at final height. Body mass index (BMI) was calculated as a clinical measure of body fatness. Pubertal status was assessed pre- and post-treatment by Tanner staging and pelvic ultrasonography. Timing of menarche or re-menarche following cessation of treatment was recorded. RESULTS: The mean (range) age of starting GnRH analogue therapy was 8.3 (1.8-10.5) years and the duration of treatment was 2.9 (0.7-8.9) years. Pre-treatment height was above average at 0.72 SD but had declined to 0.28 SD by the end of therapy. The 46 girls were heavier than average before treatment (Wt SDS 1.04) with no change in weight status on completion of therapy. Mean BMI SDS increased significantly from 0.93 to 1.2 during treatment, indicating that the girls became relatively fatter. Using recommended BMI cut-off values for defining overweight and obesity in children of the 85th and 95th centiles, 41% of the cohort were overweight and 28% were obese before treatment, rising to 59% and 39%, respectively, at the end of therapy. The average time interval to onset or resumption of menses after stopping treatment was 1.46 years (median 1.5, range 0.8-2.0 years). None of the following variables was found to be predictive of the time interval to menarche after completion of therapy: duration of treatment; chronological age; bone age; Tanner breast stage or uterine maturation at the end of treatment; the frequency of injections required to suppress puberty; or treatment with alternative GnRH analogue prior to Zoladex LA. Mean final height in 11 girls was 159.7 cm (-0.63 SD), close to the mean parental target height of 160.9 cm (-0.48 SD). Nine of the 11 girls (82%) attained final heights within or above their target range. In keeping with the whole cohort this subset of girls became fatter during treatment, although this difference was not statistically significant. However, they returned to their pretreatment size at final height (mean BMI SDS 1.18, 1.41 and 1.16 before, at the end of treatment and at final height, respectively). CONCLUSIONS: Our cohort of 46 girls treated with long-acting goserelin was already considerably overweight at the start of therapy and became fatter during treatment. However, adiposity appeared to return to pretreatment levels in the 11 girls followed up to final height. Most of the girls who have attained final height are within or above their expected target range. The relatively long time interval to menarche of 1.5 years after stopping treatment is unexplained but may reflect a residual suppressive effect on the hypothalamo-pituitary axis of this long-acting GnRH analogue. Anticipation of the timing of menarche has proved to be of value in planning when to stop therapy in girls in whom treatment is mainly for practical and/or psychological reasons.

Safety of the insulin tolerance test.

Concerns have been raised about the hazards of the insulin tolerance test (ITT), used to measure growth hormone secretion. In Glasgow, we continue to use this test, adhering to a strict protocol. A review of outcome over a 10 year period (1989-99), during which 550 ITTs were performed, was undertaken. No serious adverse events occurred; in particular, no child fitted or required intravenous glucose. Fewer tests were done during the latter five years, with a higher yield of growth hormone (GH) deficiency, reflecting our increasingly conservative approach to paediatric GH therapy during this period. We conclude that the ITT is safe and reliable in a paediatric setting provided that a strict procedure is followed.

Gigantism due to growth hormone excess in a boy with optic glioma.

True gigantism is rare in early childhood and is usually due to excess GH secretion from a pituitary adenoma. We report a case in which the endocrine abnormality is secondary to an optic glioma. Careful endocrine evaluation has shown that GH peak amplitude was not increased but rather there was failure of GH levels to suppress to baseline and a lack of pulsatility. There is no evidence of a direct secretory role for the tumour and we postulate that the tumour is affecting GH secretion through an effect on somatostatin tone. Specific tumour therapy is not indicated for this patient in the absence of mass effect or visual disturbance. The GH excess is being treated with somatostatin analogue (Octreotide) and as he has developed precocious puberty he is also receiving long acting GnRH analogue (Zoladex). This boy appears likely to have neurofibromatosis type 1 (NF1) which raises the question of subtle GH excess in NF1 patients with tall stature.

Efficacy of Zoladex LA (goserelin) in the treatment of girls with central precocious or early puberty.

OBJECTIVE: To assess the efficacy of a longer acting preparation of the gonadotrophin releasing hormone (GnRH) analogue goserelin (Zoladex LA, 10.8 mg) in 12 girls with central precocious or early puberty. METHODS: Two girls started treatment de novo; the remainder had been on suppressive treatment for a median duration of 1.5 (range, 0.2-5.6) years. Assessment comprising auxology, pubertal staging, and pelvic ultrasound examination was carried out at weeks 0, 4, 8, 10, and 12 (first cycle) and weeks 8, 10, and 12 (second cycle) to evaluate the required injection frequency. Thereafter, assessment was performed on the day of injection. Zoladex LA was given every 12 weeks unless pubertal progression occurred. RESULTS: Satisfactory control was achieved in eight patients using this regimen, and three patients required more frequent injections. One girl was removed from the study because of clinical progression and extreme mood swings. No serious adverse effects occurred. Mean height velocity during the study period was 4.5 cm/year (range, 3.1-6.6) compared with 6.5 cm/year (range, 3.8-9.6) before treatment in nine patients for whom data were available. CONCLUSIONS: Zoladex LA was effective in controlling precocious puberty in girls when given at intervals of 9-12 weeks and it is recommended that an initial assessment is made eight weeks after beginning treatment.