Successful treatment approaches for tumoral calcinosis in children and young people: A condition of diverse pathogenesis.

BACKGROUND: 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. AIM: We outline the successful treatment approaches in four children with TC (2 normophosphatemic TC, 2 HFTC) aged 2.5-10 years at initial presentation. CASES: 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. RESULTS: 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. CONCLUSION: 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.

Monitoring response to conventional treatment in children with XLH: Value of ALP and Rickets Severity Score (RSS) in a real world setting.

INTRODUCTION: X-linked hypophosphataemia (XLH) is conventionally managed with oral phosphate and active vitamin D analogues. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Health professionals' views about who would benefit from using a closed-loop system: a qualitative study.

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.

Elemental formula associated hypophosphataemic rickets.

OBJECTIVES: Hypophosphataemic rickets (HR) is usually secondary to renal phosphate wasting but may occur secondary to reduced intake or absorption of phosphate. We describe a series of cases of HR associated with the use of Neocate®, an amino-acid based formula (AAF). METHODS: A retrospective review of cases with HR associated with AAF use presenting to centres across the United Kingdom. RESULTS: 10 cases were identified, over a 9 month period, all associated with Neocate® use. The age at presentation was 5 months to 3 years. The majority (8/10) were born prematurely. Gastro oesophageal reflux disease (6/10) was the most frequent indication for AAF use. Radiologically apparent rickets was observed after a median of 8 months (range 3-15 months) of exclusive Neocate® feed. The majority (7/10) were diagnosed on the basis of incidental findings on radiographs: rickets (6/10) or fracture with osteopenia (5/10). All patients had typical biochemical features of HR with low serum phosphate, high alkaline phosphatase, normal serum calcium and 25 hydroxyvitamin D. However, in all cases the tubular reabsorption of phosphate (TRP) was ≥96%. Phosphate supplementation resulted in normalisation of serum phosphate within 1-16 weeks, and levels remained normal only after Neocate® cessation. In patients with sufficient follow up duration (4/10), normalisation of phosphate and radiological healing of rickets was noted after 6 months (range: 6-8 months) following discontinuation of Neocate®. CONCLUSION: The presence of a normal TRP and resolution of hypophosphataemia and rickets following discontinuation of Neocate® indicates this is a reversible cause likely mediated by poor phosphate absorption. Close biochemical surveillance is recommended for children on Neocate®, especially in those with gastrointestinal co-morbidities, with consideration of a change in feed or phosphate supplementation in affected children.

One-year outcome after prehospital intubation.

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.

Physical activity interventions in children and young people with Type 1 diabetes mellitus: a systematic review with meta-analysis.

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, PsycINFO, 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.

Expression levels of DNA replication and repair genes predict regional somatic repeat instability in the brain but are not altered by polyglutamine disease protein expression or age.

Expansion of CAG/CTG trinucleotide repeats causes numerous inherited neurological disorders, including Huntington's disease (HD), several spinocerebellar ataxias and myotonic dystrophy type 1. Expanded repeats are genetically unstable with a propensity to further expand when transmitted from parents to offspring. For many alleles with expanded repeats, extensive somatic mosaicism has been documented. For CAG repeat diseases, dramatic instability has been documented in the striatum, with larger expansions noted with advancing age. In contrast, only modest instability occurs in the cerebellum. Using microarray expression analysis, we sought to identify the genetic basis of these regional instability differences by comparing gene expression in the striatum and cerebellum of aged wild-type C57BL/6J mice. We identified eight candidate genes enriched in cerebellum, and validated four--Pcna, Rpa1, Msh6 and Fen1--along with a highly associated interactor, Lig1. We also explored whether expression levels of mismatch repair (MMR) proteins are altered in a line of HD transgenic mice, R6/2, that is known to show pronounced regional repeat instability. Compared with wild-type littermates, MMR expression levels were not significantly altered in R6/2 mice regardless of age. Interestingly, expression levels of these candidates were significantly increased in the cerebellum of control and HD human samples in comparison to striatum. Together, our data suggest that elevated expression levels of DNA replication and repair proteins in cerebellum may act as a safeguard against repeat instability, and may account for the dramatically reduced somatic instability present in this brain region, compared with the marked instability observed in the striatum.

Stroke volume-directed administration of hydroxyethyl starch or Ringer's acetate in sitting position during craniotomy.

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 kDa/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.

46XY girls: the importance of careful newborn examination.

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.

CTCF regulates ataxin-7 expression through promotion of a convergently transcribed, antisense noncoding RNA.

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.

Sporadic ALS has compartment-specific aberrant exon splicing and altered cell-matrix adhesion biology.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive weakness from loss of motor neurons. The fundamental pathogenic mechanisms are unknown and recent evidence is implicating a significant role for abnormal exon splicing and RNA processing. Using new comprehensive genomic technologies, we studied exon splicing directly in 12 sporadic ALS and 10 control lumbar spinal cords acquired by a rapid autopsy system that processed nervous systems specifically for genomic studies. ALS patients had rostral onset and caudally advancing disease and abundant residual motor neurons in this region. We created two RNA pools, one from motor neurons collected by laser capture microdissection and one from the surrounding anterior horns. From each, we isolated RNA, amplified mRNA, profiled whole-genome exon splicing, and applied advanced bioinformatics. We employed rigorous quality control measures at all steps and validated findings by qPCR. In the motor neuron enriched mRNA pool, we found two distinct cohorts of mRNA signals, most of which were up-regulated: 148 differentially expressed genes (P

CTCF cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination.

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.

Activation of the extrinsic caspase pathway in cultured cortical neurons requires p53-mediated down-regulation of the X-linked inhibitor of apoptosis protein to induce apoptosis.

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.

Recurrent opioid toxicity after pre-hospital care of presumed heroin overdose patients.

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.

Cardiovascular changes after naloxone administration in propofol-sedated piglets during opioid overdose.

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 microg/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.

Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1alpha in Huntington's disease neurodegeneration.

Huntington's disease (HD) is a fatal, dominantly inherited disorder caused by polyglutamine repeat expansion in the huntingtin (htt) gene. Here, we observe that HD mice develop hypothermia associated with impaired activation of brown adipose tissue (BAT). Although sympathetic stimulation of PPARgamma coactivator 1alpha (PGC-1alpha) was intact in BAT of HD mice, uncoupling protein 1 (UCP-1) induction was blunted. In cultured cells, expression of mutant htt suppressed UCP-1 promoter activity; this was reversed by PGC-1alpha expression. HD mice showed reduced food intake and increased energy expenditure, with dysfunctional BAT mitochondria. PGC-1alpha is a known regulator of mitochondrial function; here, we document reduced expression of PGC-1alpha target genes in HD patient and mouse striatum. Mitochondria of HD mouse brain show reduced oxygen consumption rates. Finally, HD striatal neurons expressing exogenous PGC-1alpha were resistant to 3-nitropropionic acid treatment. Altered PGC-1alpha function may thus link transcription dysregulation and mitochondrial dysfunction in HD.

Outcome after heroin overdose and cardiopulmonary resuscitation.

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.

Dexmedetomidine as an anaesthetic adjuvant in patients undergoing intracranial tumour surgery: a double-blind, randomized and placebo-controlled study.

BACKGROUND: Dexmedetomidine (DEX) has been shown to provide good perioperative haemodynamic stability with decreased intraoperative opioid requirements. It may have neural protective effects, and thus may be a suitable anaesthetic adjuvant to neurosurgical anaesthesia. METHODS: Fifty-four patients scheduled for elective surgery of supratentorial brain tumour were randomized to receive in a double-blind manner a continuous DEX infusion (plasma target concentration 0.2 or 0.4 ng ml(-1)) or placebo, beginning 20 min before anaesthesia and continuing until the start of skin closure. The DEX groups received fentanyl 2 microg kg(-1) at the induction of anaesthesia and before the start of operation, the placebo group 4 microg kg(-1), respectively. Anaesthesia was maintained with nitrous oxide in oxygen and isoflurane. RESULTS: The median times from the termination of N2O to extubation were 6 (3-27), 3 (0-20) and 4 (0-13) min in placebo, DEX-0.2 and DEX-0.4 groups, respectively (P<0.05 anova all-over effect). The median percentage of time points when systolic blood pressure was within more or less than 20% of the intraoperative mean was 72, 77 and 85, respectively (P<0.01), DEX-0.4 group differed significantly from the other groups. DEX blunted the tachycardic response to intubation (P<0.01) and the hypertensive response to extubation (P<0.01). DEX-0.4 group differed in the heart rate variability from placebo (93 vs 82%, P<0.01). CONCLUSIONS: DEX increased perioperative haemodynamic stability in patients undergoing brain tumour surgery. Compared with fentanyl, the trachea was extubated [corrected] faster without respiratory depression.

Bergmann glia expression of polyglutamine-expanded ataxin-7 produces neurodegeneration by impairing glutamate transport.

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.