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At least 25 inherited disorders in humans result from microsatellite repeat expansion. Dramatic variation in repeat instability occurs at different disease loci and between different tissues; however, cis-elements and trans-factors regulating the instability process remain undefined. Genomic fragments from the human spinocerebellar ataxia type 7 (SCA7) locus, containing a highly unstable CAG tract, were previously introduced into mice to localize cis-acting ''instability elements,'' and revealed that genomic context is required for repeat instability. The critical instability-inducing region contained binding sites for CTCF-a regulatory factor implicated in genomic imprinting, chromatin remodeling, and DNA conformation change. To evaluate the role of CTCF in repeat instability, we derived transgenic mice carrying SCA7 genomic fragments with CTCF binding-site mutations. We found that CTCF binding-site mutation promotes triplet repeat instability both in the germ line and in somatic tissues, and that CpG methylation of CTCF binding sites can further destabilize triplet repeat expansions. As CTCF binding sites are associated with a number of highly unstable repeat loci, our findings suggest a novel basis for demarcation and regulation of mutational hot spots and implicate CTCF in the modulation of genetic repeat instability. [ABSTRACT FROM AUTHOR]

Brain death was first defined in 1968, and since then laws on determining death have been implemented in all countries with active organ transplantation programs. As a prerequisite, the aetiology of brain death has to be known, and all reversible causes of coma have to be excluded. The regulations for the diagnosis of brain death are most commonly given by the national medical associations, and they vary between countries. Thus, the guidelines given in the medical textbooks are not universally applicable. The diagnosis is based on clinical examination, but confirmatory tests, such as angiography or EEG, are allowed on most occasions. Brain death is followed by cardiovascular and hormonal changes, which have implications in the management of a potential organ donor. Spinal reflexes are preserved, and motor and haemodynamic responses are frequently observed in brain dead patients. [ABSTRACT FROM AUTHOR]

Resistance to the passage of the tracheal tube has been reported to occur in up to 36% of patients subjected to orotracheal fibreoptic intubation. In this prospective study we assessed five radiological measurements of the upper airway in an attempt to find anatomical causes of obstruction to passage of the tube. Forty-nine patients undergoing fibreoptic orotracheal intubation under general anaesthesia were studied. Pre-operatively, the Mallampati grade and the thyromental distance were assessed. The plain films, CT scans or MR images of the cervical spine were used for measurement of the position of the vocal cords, the length of the epiglottis and the size of the tongue. The resistance to the passage of the tube was graded as none, mild, moderate or severe. The length of the epiglottis and the size of the tongue, but not the position of the vocal cords, had positive correlations with the severity of impingement. The pre-operative bedside tests did not correlate with difficulties in fibreoptic intubation. [ABSTRACT FROM AUTHOR]

The author reflects on the effect of videogames and practical tools on the developments in laryngoscopy and tracheal intubation. He said that no video laryngoscopes or fibreoptic instruments fill the virtual criteria of a universal piece of equipment to manage airways without failure. He added that some instruments have probably been designed to perform better than the Macintosh laryngoscope to facilitate learning of airway management.

Focuses on the influence of airway manipulation on heart rate and blood pressure. Changes observed in patients after anesthetized with thiopental on the mean rise of systolic arterial pressure; Attenuation of the hemodynamic response to laryngoscopy and intubation with topical anesthesia of the airway; Contribution of laryngoscopy and tracheal intubation to hemodynamic responses.

Background: Buprenorphine is used as maintenance therapy for opioid-dependent patients. In comparison with other opioids it is thought to be safer because it is less likely to cause serious respiratory depression. However, concomitant use of psychotropics, especially benzodiazepines, and intravenous injection of dissolved buprenorphine tablets increase the risk of a serious overdose.Methods: As part of a larger retrospective study of opioid overdoses in Helsinki, the emergency medical services (EMS) records from January 1995 to April 2002 were reviewed for overdoses involving buprenorphine. Hospital records were reviewed when available.Results: We report 11 overdoses in which buprenorphine was involved. The classic symptoms and signs of an opioid overdose (respiratory depression, miosis and central nervous system depression) were present in most of the cases. At least eight of the patients had an overdose that was potentially fatal. One of the patients had a heroin overdose and was reportedly 'treated' by his friends with intravenously administered buprenorphine.Conclusion: The high-dosage formulation of buprenorphine used for opioid-dependent patients might have caused several dangerous and potentially fatal overdoses in Helsinki. However, it does cause considerably less serious overdoses than heroin. Drug abusers might be intravenously administering buprenorphine themselves to treat heroin overdoses. [ABSTRACT FROM AUTHOR]

This paper reports two experiments that investigated the role of verbal behavior in the emergence and generalization of contextually controlled equivalence classes. During both experiments, participants were trained with two different combinations of the same easily nameable, yet formally unrelated, pictorial stimuli. Match-to-sample baselines for eight four-member classes were established under the contextual control of two colors. In the presence of one color, conditional relations were established between stimuli whose normative names rhymed. In the presence of the other color, conditional relations were established between stimuli whose normative names did not rhyme. Although, during Experiment 1, all participants demonstrated equivalence classes involving rhyming stimuli, none demonstrated the formation of nonrhyme equivalence classes. To investigate this finding, Experiment 2 evaluated whether participants would demonstrate both rhyme and nonrhyme equivalence classes given more extensive exposure to the experimental contingencies. All participants demonstrated contextually controlled rhyme and nonrhyme equivalence classes, although rhyme classes were demonstrated with greater facility than nonrhyme classes. Results indicate that visual stimuli are named, that verbal bases for stimulus classification can affect the emergence of contextually controlled equivalence classes, and that untrained contextually controlled conditional discriminations involving novel stimuli can emerge on the basis of participants' verbal behavior. [ABSTRACT FROM AUTHOR]

Ectopic calcification is inappropriate biomineralization of soft tissues occurring due to genetic or acquired causes of hyperphosphataemia and rarely in normophosphataemic individuals. Tumoral Calcinosis (TC) is a rare metabolic bone disorder commonly presenting in childhood and adolescence with periarticular extra-capsular calcinosis. Three subtypes of TC have been recognised: primary hyperphosphataemic familial TC (HFTC), primary normophosphataemic familial TC and secondary TC most commonly seen in chronic renal failure. In the absence of established treatment, management is challenging due to variable success rates with medical therapies and recurrence following surgery. We outline the successful treatment approaches in four children with TC (2 normophosphatemic TC, 2 HFTC) aged 2.5–10 years at initial presentation. Patient 1 (P1) presented at 10 years with a painless lump behind the right knee, P2 with swelling of the right knee anteriorly at 9 years, P3 and P4 with pain and swelling over the right elbow at 5 and 2.5 years respectively. All patients were of Black African-Caribbean origin and were previously reported to be fit and well with no family history of TC. P1, P2 had normophosphataemic TC and P3, P4 had HFTC with genetically confirmed GALNT3 mutation. All four patients had initial surgical resection with TC confirmed on histology. P1 had complete surgical resection with no recurrence at 27 months post-operatively. P2 had significant overgrowth of the tumour following surgery and was subsequently successfully managed with 25 % topical sodium metabisulphite (total duration of 8 months with a 4 month gap during which there was recurrence). P3 had post-surgical recurrence of TC on the right elbow and a new lesion on left elbow which resolved with oral acetazolamide monotherapy (15–20 mg/kg/day). P4 had recurrence of right elbow lesion following surgery and developed an extensive new hip lesion on sevelamer therapy which resolved completely with additional acetazolamide therapy (18–33 mg/kg/day). Acetazolamide was well tolerated with normal growth for 5 years in P3 and 6.5 years in P4 and no recurrence of lesions. The frequent post-surgical recurrence in TC and successful medical therapy on the other hand indicates that medical management as first line therapy should be adopted. Monotherapies with topical 25 % sodium metabisulphite in normophosphataemic and oral acetazolamide in HFTC are effective treatment strategies which are well tolerated. • Post-surgical recurrence of TC is frequent, hence medical treatment approaches must be explored before considering surgery. • Acetazolamide monotherapy can be a safe and effective treatment in HFTC • Topical sodium metabisulphite is an effective alternative to systemic sodium thiosulphate in normophosphataemic TC [ABSTRACT FROM AUTHOR]

Background: Moderate to severe pain occurs after craniotomy in 60% of patients. We evaluated the feasibility and safety of patient-controlled analgesia (PCA) with oxycodone in neurosurgical patients, and compared the efficacy of paracetamol with ketoprofen.Methods: In the study there were 45 patients, who received either paracetamol 1000 mg or ketoprofen 100 mg three times a day. Oxycodone-boluses 0.03 mg/kg were given by PCA-device maximally three times an hour, lock-out time 10 min. The amount of oxycodone used, pain scores and side-effects were recorded.Results: The ketoprofen group required less oxycodone than the paracetamol group (medians 37.1 mg vs 19.6 mg, P < 0.05). The VAS scores were comparable between the groups at the beginning of the study, during the first postoperative evening and the next morning, but the paracetamol group had a higher score at the conclusion of the study (P < 0.05). The patients in both groups were equally satisfied with the pain relief. There were no differences in side-effects between the groups.Conclusions: PCA with oxycodone is a suitable method for pain control after craniotomy. No progressive hypoventilation, desaturation or excessive sedation were encountered. Ketoprofen appeared to be more effective than paracetamol. [ABSTRACT FROM AUTHOR]

Aim: To explore health professionals' views about who would benefit from using a closed‐loop system and who should be prioritized for access to the technology in routine clinical care. Methods: Health professionals (n = 22) delivering the Closed Loop from Onset in type 1 Diabetes (CLOuD) trial were interviewed after they had ≥ 6 months' experience supporting participants using a closed‐loop system. Data were analysed thematically. Results: Interviewees described holding strong assumptions about the types of people who would use the technology effectively prior to the trial. Interviewees described changing their views as a result of observing individuals engaging with the closed‐loop system in ways they had not anticipated. This included educated, technologically competent individuals who over‐interacted with the system in ways which could compromise glycaemic control. Other individuals, who health professionals assumed would struggle to understand and use the technology, were reported to have benefitted from it because they stood back and allowed the system to operate without interference. Interviewees concluded that individual, family and psychological attributes cannot be used as pre‐selection criteria and, ideally, all individuals should be given the chance to try the technology. However, it was recognized that clinical guidelines will be needed to inform difficult decisions about treatment allocation (and withdrawal), with young children and infants being considered priority groups. Conclusions: To ensure fair and equitable access to closed‐loop systems, prejudicial assumptions held by health professionals may need to be addressed. To support their decision‐making, clinical guidelines need to be made available in a timely manner. What's new?: Previous studies have overwhelmingly focused on users' perspectives and experiences of closed‐loop systems.This study offers an early and important insight into health professionals' views about who would benefit from using a closed‐loop system, and who should be prioritized for access to the technology in routine clinical care.Health professionals may hold prejudicial and erroneous views about the types of individual that would most benefit from using a closed‐loop system.Health professionals would benefit both from training to overcome these prejudicial assumptions and clinical guidelines to support decision‐making about allocating and withdrawing closed‐loop systems in routine clinical care. [ABSTRACT FROM AUTHOR]

Background The aim of physician staffed emergency medical services ( EMS) is to supplement other EMS units in the care of prehospital patients. The need for advanced airway management in critical prehospital patients can be considered as one indicator of the severity of the patient's condition. Our primary aim was to study the long-term outcome of critically ill patients (excluding cardiac arrest) who were intubated by EMS physicians in the prehospital setting. Methods Data of 845 patients, whose airways were secured by the EMS physicians during a 5-year (2007-2011) period, were retrospectively evaluated. After exclusions, the outcome of 483 patients (8.9% of all patients treated by EMS) was studied. Evaluation was based on hospital patient records 1 year after the incident. For assessment of neurological outcome, a modified Glasgow Outcome Score ( GOS) was used. Time and cause of death were recorded. Results 55.3% of the study patients had a good neurological recovery ( GOS 4-5) with independent life 1 year after the event. The overall 1-year mortality ( GOS 1) was 35.0%. Poor neurological outcome ( GOS 2-3) was found in 9.7% of the patients. Patients with intoxication or convulsions survived best, while those with suspected intracranial pathology had the worst prognosis. Of all survivors, 85% recovered well. Conclusion The majority of the study patients had a favourable neurological recovery with independent life at 1 year after the incident. More than 80% of all deaths occurred within 30 days of the incident. [ABSTRACT FROM AUTHOR]

Aims To synthesize evidence from randomized and non-randomized studies of physical activity interventions in children and young people with Type 1 diabetes so as to explore clinically relevant health outcomes and inform the promotion of physical activity. Method We conducted a search of CINAHL Plus, the Cochrane Library, EMBASE, MEDLINE, Psyc INFO, SCOPUS, SportDiscus and Web of Science between October and December 2012. Eligible articles included subjects aged ≤18 years with Type 1 diabetes and a physical activity intervention that was more than a one-off activity session. Physiological, psychological, behavioural or social outcomes were those of interest. Results A total of 26 articles (10 randomized and 16 non-randomized studies), published in the period 1964-2012, were reviewed. Although there was heterogeneity in study design, methods and reporting, 23 articles reported at least one significant beneficial health outcome at follow-up. Meta-analyses of these studies showed potential benefits of physical activity on HbA1c (11 studies, 345 participants, standardized mean difference -0.52, 95% CI -0.97 to -0.07; P = 0.02), BMI (four studies, 195 participants, standardized mean difference -0.41, 95% CI -0.70 to -0.12; P = 0.006) and triglycerides (five studies, 206 participants, standardized mean difference -0.70, 95% CI -1.25 to -0.14; P = 0.01).The largest effect size was for total cholesterol (five studies, 206 participants, standardized mean difference -0.91, 95% CI -1.66 to -0.17; P = 0.02). Conclusions Physical activity is important for diabetes management and has the potential to delay cardiovascular disease, but there is a lack of studies that are underpinned by psychological behaviour change theory, promoting sustained physical activity and exploring psychological outcomes. There remains a lack of knowledge of how to promote physical activity in people with Type 1 diabetes. [ABSTRACT FROM AUTHOR]

Background To determine the volumes required for stable haemodynamics and possible effects on the coagulation, we studied stroke volume ( SV)-directed administration of hydroxyethyl starch ( HES 130 k Da/0.4) and Ringer's acetate ( RAC) in neurosurgical patients operated on in a sitting position. Methods Thirty craniotomy patients were randomised to receive either HES or RAC. Before positioning, SV, measured by arterial pressure waveform analysis, was maximised by boluses of fluid until SV did not increase more than 10%. SV was maintained by repeated administration of fluid. RAC 3 ml/kg/h was infused in both groups during surgery. Results Comparable haemodynamics were achieved with the mean [standard deviation ( SD)] cumulative doses of HES or RAC 271 (47) or 264 (50) ml ( P = 0.699) before the sitting position. Mean ( SD) doses of HES or RAC at 30 min after the positioning were 343 (94) or 450 (156) ml ( P = 0.036), and at the end of surgery 464 (284) or 707 (425) ml, respectively ( P = 0.087). The intraoperative fluid balance was more positive in the RAC than in the HES group [ P = 0.044, 95% confidence interval ( CI) −978 to −14]. Cardiac and stroke volume indexes [ CI and stroke volume index ( SVI)] increased in the HES group ( P < 0.05) but not in the RAC group [non significant (N.S.)]. Neither coagulation profile nor blood loss differed between the groups. Conclusion Fluid filling with HES boluses resulted in a positive response in CI and SVI during the sitting position. The 34% smaller volume of HES than crystalloid and less positive fluid balance in the HES group might be important in craniotomy patients with decreased brain compliance. [ABSTRACT FROM AUTHOR]

Summary: Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder caused by CAG/polyglutamine repeat expansions in the ataxin-7 gene. Ataxin-7 is a component of two different transcription coactivator complexes, and recent work indicates that disease protein normal function is altered in polyglutamine neurodegeneration. Given this, we studied how ataxin-7 gene expression is regulated. The ataxin-7 repeat and translation start site are flanked by binding sites for CTCF, a highly conserved multifunctional transcription regulator. When we analyzed this region, we discovered an adjacent alternative promoter and a convergently transcribed antisense noncoding RNA, SCAANT1. To understand how CTCF regulates ataxin-7 gene expression, we introduced ataxin-7 mini-genes into mice, and found that CTCF is required for SCAANT1 expression. Loss of SCAANT1 derepressed ataxin-7 sense transcription in a cis-dependent fashion and was accompanied by chromatin remodeling. Discovery of this pathway underscores the importance of altered epigenetic regulation for disease pathology at repeat loci exhibiting bidirectional transcription. Video Abstract: Display Omitted [ABSTRACT FROM AUTHOR]

Cultured cortical neurons exposed to the Human Immunodeficiency Virus gp120 coat protein undergo apoptosis involving activation of both caspase-8 and caspase-9. Additionally, gp120-mediated neuronal apoptosis requires the pro-apoptotic transcription factor p53. As caspase-8-induced apoptosis does not typically require p53, we examined the possibility of a novel role for p53 in caspase-8 activation initiated by gp120. We observed that gp120 treatment of cultured cortical neurons induced caspase-8 activity and Bid cleavage independently of p53, but induction of caspase-3 enzymatic activity required p53 expression. These findings suggested the possibility that p53 down-regulates a caspase-3 inhibitor. We observed high-level expression of the caspase-3/9 inhibitor X-linked inhibitor of apoptosis protein (XIAP) in cultured cortical neurons. Adenoviral expression of p53 or induction of endogenous p53 by camptothecin treatment reduced XIAP protein in neurons. Infection with a p53 expressing adenovirus increased expression of the mRNA for Omi/HtrA2, a protease that cleaves and inactivates XIAP. These findings suggest that p53 regulates neuronal apoptosis, in part, by suppressing the anti-apoptotic protein XIAP via transcriptional activation of Omi/HtrA2. [ABSTRACT FROM AUTHOR]

Background: Naloxone is an opioid receptor antagonist. Even when used in modest doses, it has been associated with serious cardiopulmonary side-effects. In this experimental porcine study, we examined the cardiac effects of naloxone during an opioid overdose. Methods: Cardiac parameters, changes in the left ventricular compliance and the magnitude of catecholamine release were evaluated in eight spontaneously breathing piglets under propofol sedation. Cardiac parameters were recorded every 30 s and transthoracic echocardiography was used for the continuous assessment of cardiac performance. Respiratory arrest was induced by morphine (8 mg/kg). Ten minutes after morphine administration, naloxone (80 μg/kg) was injected intravenously. Every 5 min, arterial blood gases were measured and, every 10 min, a sample for the analysis of plasma catecholamines was drawn. Results: There were no statistically significant changes in left ventricular ejection fraction and no signs of pulmonary hypertension. There was a statistically significant increase in the mean arterial pressure immediately after naloxone administration and in norepinephrine concentration before naloxone administration. After naloxone administration, the plasma catecholamine levels decreased in all but one animal. Two animals developed cardiac arrest (pulseless electrical activity and ventricular fibrillation) shortly after receiving naloxone. Although they were both administered naloxone prematurely due to hypoxic bradycardia, naloxone could have contributed to the development of ventricular fibrillation. Conclusion: Naloxone did not cause changes in ejection fraction or mean pulmonary artery pressure in hypoxic and hypercarbic conditions. After naloxone administration, the plasma catecholamine levels returned to baseline in all but one animal, and two animals developed cardiac arrest. [ABSTRACT FROM AUTHOR]

Background: In patients with presumed heroin overdose, the recommended time of observation after reversing heroin toxicity with naloxone varies widely. The aims of this study were to examine the incidence of recurrent opioid toxicity and the time interval in which it occurs after pre-hospital treatment in presumed heroin overdose patients. Methods: We undertook a retrospective study in Helsinki (population, 560,000). Records were reviewed from 1 January 1995 to 31 December 2000. Patients included were treated by the emergency medical service (EMS) for a presumed heroin overdose. Patients with known polydrug/alcohol use or the use of opioids other than heroin were excluded. The EMS records were compared with the cardiac arrest database and the medical examiners’ records. Results: One hundred and forty-five patients were included. The median dose of pre-hospital administered naloxone was 0.4 mg. After pre-hospital care, 84 patients refused further care and were not transported to an emergency department (ED). Seventy-one received pre-hospital naloxone, and no life-threatening events were recorded during a 12-h follow-up period in these patients. After pre-hospital care, 61 patients were transported to an ED. Twelve patients received naloxone in the ED for respiratory depression. All had signs of heroin use-related adverse events within 1 h after receiving pre-hospital naloxone. Conclusions: Allowing presumed heroin overdose patients to sign out after pre-hospital care with naloxone is safe. If transported to an ED, a 1-h observation period after naloxone administration seems to be adequate for recurrent heroin toxicity. [ABSTRACT FROM AUTHOR]

Background: The survival of heroin overdose patients resuscitated from cardiac arrest is reported to be poor. The aim of our study was to investigate the outcome and characteristics of survivors after cardiac arrest caused by heroin overdose. Methods: This was a retrospective study in a medium-sized city (population, 560,000). Between 1 January 1997 and 31 December 2000, there were 94 combined cardiac arrests caused by acute drug poisonings. The main outcome measure was survival to discharge. Results: Cardiopulmonary resuscitation was attempted in 19 heroin overdose patients (group A) and in 53 patients with cardiac arrest caused by other poisonings (group B). Three (16%) vs. six (11%) patients were discharged alive (group A vs. B, respectively). The survivors in group A had an Emergency Medical Service (EMS)-witnessed cardiac arrest or the Emergency Dispatching Centre was called before the arrest occurred. There was no statistically significant difference between the two groups in terms of survival. Survivors in both groups suffered from acute renal failure (two), hypoglycaemia (four) and hypothermia (three). Conclusion: Survival after cardiac arrest caused by heroin overdose is possible if the arrest is EMS witnessed or the Emergency Dispatching Centre is called before the cardiac arrest occurs. In comparison with cardiac arrests caused by other poisonings, there was no difference in survival. The incidence and mechanism of hypoglycaemia should be examined in further studies. [ABSTRACT FROM AUTHOR]

Non-neuronal cells may be pivotal in neurodegenerative disease, but the mechanistic basis of this effect remains ill-defined. In the polyglutamine disease spinocerebellar ataxia type 7 (SCA7), Purkinje cells undergo non-cell-autonomous degeneration in transgenic mice. We considered the possibility that glial dysfunction leads to Purkinje cell degeneration, and generated mice that express ataxin-7 in Bergmann glia of the cerebellum with the Gfa2 promoter. Bergmann glia-specific expression of mutant ataxin-7 was sufficient to produce ataxia and neurodegeneration. Expression of the Bergmann glia-specific glutamate transporter GLAST was reduced in Gfa2-SCA7 mice and was associated with impaired glutamate transport in cultured Bergmann glia, cerebellar slices and cerebellar synaptosomes. Ultrastructural analysis of Purkinje cells revealed findings of dark cell degeneration consistent with excitotoxic injury. Our studies indicate that impairment of glutamate transport secondary to glial dysfunction contributes to SCA7 neurodegeneration, and suggest a similar role for glial dysfunction in other polyglutamine diseases and SCAs. [ABSTRACT FROM AUTHOR]

Abstract: CAG and CTG repeat expansions are the cause of at least a dozen inherited neurological disorders. In these so-called “dynamic mutation” diseases, the expanded repeats display dramatic genetic instability, changing in size when transmitted through the germline and within somatic tissues. As the molecular basis of the repeat instability process remains poorly understood, modeling of repeat instability in model organisms has provided some insights into potentially involved factors, implicating especially replication and repair pathways. Studies in mice have also shown that the genomic context of the repeat sequence is required for CAG/CTG repeat instability in the case of spinocerebellar ataxia type 7 (SCA7), one of the most unstable of all CAG/CTG repeat disease loci. While most studies of repeat instability have taken a candidate gene approach, unbiased screens for factors involved in trinucleotide repeat instability have been lacking. We therefore attempted to use Drosophila melanogaster to model expanded CAG repeat instability by creating transgenic flies carrying trinucleotide repeat expansions, deriving flies with SCA7 CAG90 repeats in cDNA and genomic context. We found that SCA7 CAG90 repeats are stable in Drosophila, regardless of context. To screen for genes whose reduced function might destabilize expanded CAG repeat tracts in Drosophila, we crossed the SCA7 CAG90 repeat flies with various deficiency stocks, including lines lacking genes encoding the orthologues of flap endonuclease-1, PCNA, and MutS. In all cases, perfect repeat stability was preserved, suggesting that Drosophila may not be a suitable system for determining the molecular basis of SCA7 CAG repeat instability. [Copyright &y& Elsevier]

X-linked spinal and bulbar muscular atrophy (SBMA) is an inherited neuromuscular disorder characterized by lower motor neuron degeneration. SBMA is caused by polyglutamine repeat expansions in the androgen receptor (AR). To determine the basis of AR polyglutamine neurotoxicity, we introduced human AR yeast artificial chromosomes carrying either 20 or 100 CAGs into mouse embryonic stem cells. The AR100 transgenic mice developed a late-onset, gradually progressive neuromuscular phenotype accompanied by motor neuron degeneration, indicating striking recapitulation of the human disease. We then tested the hypothesis that polyglutamine-expanded AR interferes with CREB binding protein (CBP)-mediated transcription of vascular endothelial growth factor (VEGF) and observed altered CBP-AR binding and VEGF reduction in AR100 mice. We found that mutant AR-induced death of motor neuron-like cells could be rescued by VEGF. Our results suggest that SBMA motor neuronopathy involves altered expression of VEGF, consistent with a role for VEGF as a neurotrophic/survival factor in motor neuron disease. [Copyright &y& Elsevier]

X-linked hypophosphataemia (XLH) is conventionally managed with oral phosphate and active vitamin D analogues. To evaluate long term treatment response by assessing biochemical disease activity [serum alkaline phosphatase (ALP)], radiological rickets severity score (RSS), growth and morbidity in patients with XLH on conventional therapy and assess the correlation between serum ALP and RSS. XLH patients from 3 UK tertiary centres with ≥3 radiographs one year apart were included. Data was collected retrospectively. The RSS was assessed from routine hand and knee radiographs and ALP z scores were calculated using age-specific reference data. Thirty-eight (male = 12) patients met the inclusion criteria. The mean ± SD knee, wrist and total RSS at baseline (median age 1.2 years) were 2.0 ± 1.2, 1.9 ± 1.2 and 3.6 ± 1.3 respectively; and at the most recent clinic visit (median age 9.0 years, range 3.3–18.9) were 1.6 ± 1.0, 1.0 ± 1.0 and 2.5 ± 1.5 respectively. The mean ± SD serum ALP z scores at baseline and the most recent visit were 4.2 ± 2.3 and 4.0 ± 3.3. Median height SDS at baseline and most recent visit were −1.2 and −2.1 (p = 0.05). Dental abscess, craniosynostosis, limb deformity requiring orthopaedic intervention and nephrocalcinosis were present in 31.5%, 7.9%, 31.6% and 42.1% of the cohort respectively. There was no statistically significant (p > 0.05) correlation between ALP z scores and knee (r = 0.07) or total (r = 0.12) RSS. Conventional therapy was not effective in significantly improving biochemical and radiological features of disease. The lack of association between serum ALP and rickets severity on radiographs limits the value of ALP as the sole indicator of rickets activity in patients receiving conventional therapy. • Children with XLH on long term conventional therapy have evidence of ongoing rickets on radiographs. • Rickets severity is significantly more at the knee than wrist in weight bearing children. • Serum alkaline phosphatase (ALP) activity correlates poorly with radiological disease severity. • Serum ALP should not be used as the sole indicator of disease activity. [ABSTRACT FROM AUTHOR]

Abstract: Study Objective: To understand the timing and factors affecting diagnosis of phenotypically female 46XY children. Design, Setting, and Participants: We studied all phenotypically female 46XY children who attended our multidisciplinary disorders of sexual differentiation (DSD) clinic in Nottingham England in a 3-year period since its inception. Case notes from a prospectively maintained database were reviewed and data were analyzed on the age at presentation, family history, findings on genital examination, and underlying endocrine abnormality. Results: Eleven children were studied, all of whom were being raised as girls. The median age of presentation was 18 months (range birth-15 years). Although the newborn examination detected the possibility of DSD in only 3 cases; 10 of 11 children had at least one significant abnormality in their external genitalia at presentation. Conclusion: Careful neonatal genital examination can identify children with DSD. However, not all children with these conditions are identified early. Early diagnosis, when possible, is important, as it has the potential to make the management of this difficult condition more straightforward. [Copyright &y& Elsevier]