Tau positron emission tomography imaging in C9orf72 repeat expansion carriers.

BACKGROUND AND PURPOSE: AV-1451 (18 F-AV-1451, flortaucipir) positron emission tomography was performed in C9orf72 expansion carriers to assess tau accumulation and disease manifestation. METHODS: Nine clinically characterized C9orf72 expansion carriers and 18 age- and gender- matched cognitively normal individuals were psychometrically evaluated and underwent tau positron emission tomography imaging. The regional AV-1451 standard uptake value ratios from multiple brain regions were analyzed. Spearman correlation was performed to relate the AV-1451 standard uptake value ratio to clinical, psychometric and cerebrospinal fluid measures. RESULTS: C9orf72 expansion carriers had increased AV-1451 binding in the entorhinal cortex compared to controls. Primary age-related tauopathy was observed postmortem in one patient. AV-1451 uptake did not correlate with clinical severity, disease duration, psychometric performance or cerebrospinal fluid markers. CONCLUSION: C9orf72 expansion carriers exhibited increased AV-1451 uptake in entorhinal cortex compared to cognitively normal controls, suggesting a propensity for primary age-related tauopathy. However, AV-1451 accumulation was not associated with psychometric performance in our cohort.

Impact of fluorescent protein fusions on the bacterial flagellar motor.

Fluorescent fusion proteins open a direct and unique window onto protein function. However, they also introduce the risk of perturbation of the function of the native protein. Successful applications of fluorescent fusions therefore rely on a careful assessment and minimization of the side effects, but such insight is still lacking for many applications. This is particularly relevant in the study of the internal dynamics of motor proteins, where both the chemical and mechanical reaction coordinates can be affected. Fluorescent proteins fused to the stator of the Bacterial Flagellar Motor (BFM) have previously been used to unveil the motor subunit dynamics. Here we report the effects on single motors of three fluorescent proteins fused to the stators, all of which altered BFM behavior. The torque generated by individual stators was reduced while their stoichiometry remained unaffected. MotB fusions decreased the switching frequency and induced a novel bias-dependent asymmetry in the speed in the two directions. These effects could be mitigated by inserting a linker at the fusion point. These findings provide a quantitative account of the effects of fluorescent fusions to the stator on BFM dynamics and their alleviation- new insights that advance the use of fluorescent fusions to probe the dynamics of protein complexes.

Risk of dementia and mild cognitive impairment in older people with subjective memory complaints: meta-analysis.

OBJECTIVE: To investigate whether people with subjective memory complaints (SMC) but no objective deficits are at increased risk of developing mild cognitive impairment (MCI) and dementia. METHOD: Major electronic databases were searched till 03/2014, and a meta-analysis was conducted using inception cohort studies. RESULTS: Across 28 studies, there were 29,723 unique individuals (14,714 with SMC and 15,009 without SMC) (mean 71.6 years) followed on average for 4.8 years through to dementia. The annual conversion rate (ACR) of SMC to dementia was 2.33% (95% CI = 1.93%-2.78%) a relative risk (RR) of 2.07 (95% CI = 1.76-2.44) compared with those without SMC (n = 15,009). From 11 studies the ACR of developing MCI was 6.67% (95% CI = 4.70-8.95%). In long-term studies over 4 years, 14.1% (9.67-19.1%) of people with SMC developed dementia and 26.6% (95% CI = 5.3-39.7) went on to develop MCI. The ACR from SMC to dementia and MCI were comparable in community and non-community settings. CONCLUSION: Older people with SMC but no objective complaints are twice as likely to develop dementia as individuals without SMC. Approximately 2.3% and 6.6% of older people with SMC will progress to dementia and MCI per year.

Localization of mGluR5, GABAB, GABAA, and cannabinoid receptors on the vago-vagal reflex pathway responsible for transient lower esophageal sphincter relaxation in humans: an immunohistochemical study.

BACKGROUND: Transient lower esophageal sphincter relaxations (TLESRs) are the predominant mechanisms underlying gastro-esophageal reflux. TLESRs are mediated by a vago-vagal reflex, which can be blocked by interaction with metabotropic Glutamate Receptor 5 (mGluR5), γ-aminobutyric acid type B (GABA(B)), γ-aminobutyric acid type A (GABA(A)), and cannabinoid (CB) receptors. However, the distribution of these receptors in the neural pathway underlying the triggering of TLESRs has not been evaluated in humans. METHODS: Using immunohistochemistry, we investigated the distribution of mGluR5, GABA(A), GABA(B), CB1, and CB2 receptors in the human nodose ganglion, the brain stem, and the myenteric plexus of the esophagus. KEY RESULTS: MGluR5, GABA(B), CB1, and CB2 receptors are abundantly expressed in neurons of the myenteric plexus of the LES, nodose ganglion cell bodies and nerve fibers, the dorsal motor nucleus, and nucleus of the solitary tract in the brain stem. GABA(A) receptors are expressed in the same regions except in the nodose ganglion and myenteric plexus of the LES. CONCLUSIONS & INFERENCES: Human mGluR5, GABA(A,B), and CB(1,2) receptors are abundantly expressed along the vago-vagal neural pathway and involved in the triggering of TLESRs. These findings are not only in line with the central side effects observed during treatment with reflux inhibitors such as GABA(B) receptor agonists and mGluR5 antagonists, but also suggest that peripherally acting compounds may be effective.

The GABA(B) receptor agonist AZD9343 inhibits transient lower oesophageal sphincter relaxations and acid reflux in healthy volunteers: a phase I study.

BACKGROUND: Transient lower oesophageal sphincter relaxations (TLESRs) represent an interesting target for the treatment of gastro-oesophageal reflux. Baclofen reduces TLESRs and reflux episodes, but is not optimal for clinical application because of its central side effects. Therefore, new agents are required. AIM: To study the effect of AZD9343, a new selective GABA(B) receptor agonist, in healthy volunteers. METHODS: A total of 27 subjects participated in a placebo-controlled, randomized, two-centre phase I study. Subjects underwent oesophageal manometry and pH-metry for 3 h postprandially. Before meal ingestion, a single oral dose of placebo, 60 and 320 mg AZD9343 or 40 mg baclofen was given on four separate days. RESULTS: Somnolence was reported after 320 mg AZD9343 and baclofen. Reversible short-lasting paraesthesia was reported after AZD9343. AZD9343 320 mg and baclofen significantly reduced the number of TLESRs with 32% and 40% respectively. Acid reflux was significantly decreased by AZD9343 and baclofen. Like baclofen, AZD9343 increased LES pressure before meal intake. AZD9343 320 mg and baclofen significantly reduced the swallowing rate. CONCLUSIONS: Like baclofen, AZD9343 dose-dependently decreases the number of TLESRs and acid reflux episodes, increases LES pressure and reduces swallowing, extending the concept that GABA(B) agonists are potent reflux inhibitors. However, discovery of analogues with an improved side effect profile is warranted.

Stepwise radiofrequency ablation of Barrett's esophagus preserves esophageal inner diameter, compliance, and motility.

BACKGROUND AND AIM: Stepwise endoscopic circumferential and focal radiofrequency ablation is safe and effective for the eradication of Barrett's esophagus. In contrast to other techniques, radiofrequency ablation appears to avoid significant esophageal scarring or stenosis. Our aim was to evaluate whether radiofrequency ablation has an adverse effect on esophageal function in patients treated for Barrett's esophagus containing intramucosal cancer and/or high-grade dysplasia. METHODS: Twelve patients with Barrett's esophagus containing intramucosal cancer or high-grade dysplasia were included in the study. After endoscopic resection of visible abnormalities, stepwise circumferential and focal ablation were performed every 2 months up to a maximum of five sessions. Measurement of the inner diameter was performed at 1-cm intervals in the distal esophagus. Manometry was performed using a water-perfused sleeve catheter. Compliance was evaluated using the functional lumen imaging probe (FLIP), measuring eight cross-sectional areas within a saline-filled bag with two pressure side holes, one proximal to and one inside the bag. Esophageal sizing, manometry, and compliance were recorded in patients at baseline and at least 2 months after the final ablation session. In addition, FLIP and manometry measurements were performed in 10 healthy volunteers. RESULTS: All patients achieved complete eradication of dysplasia and Barrett's esophagus, without severe complications or ablation-related stenoses. The esophageal diameter was unchanged by the ablation. Lower esophageal sphincter pressure and length and esophageal contraction amplitude before and after ablation were not significantly different. Baseline compliance was significantly different between healthy volunteers and Barrett's esophagus patients. Compliance was not, however, significantly changed by ablation. CONCLUSIONS: Stepwise circumferential and focal ablation of Barrett's esophagus is an effective and safe treatment modality for early Barrett's neoplasia that appears to preserve the functional characteristics of the esophagus.

Effect of delta9-tetrahydrocannabinol, a cannabinoid receptor agonist, on the triggering of transient lower oesophageal sphincter relaxations in dogs and humans.

BACKGROUND AND PURPOSE: Transient lower oesophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastro-oesophageal reflux and are a potential pharmacological treatment target. We evaluated the effect of the CB(1)/CB(2) receptor agonist delta(9)-tetrahydrocannabinol (delta(9)-THC) on TLESRs in dogs. Based on these findings, the effect of delta(9)-THC was studied in healthy volunteers. EXPERIMENTAL APPROACH: In dogs, manometry was used to evaluate the effect of delta(9)-THC in the presence and absence of the CB(1) receptor antagonist SR141716A on TLESRs induced by gastric distension. Secondly, the effect of 10 and 20 mg delta(9)-THC was studied in 18 healthy volunteers in a placebo-controlled study. Manometry was performed before and for 3 h after meal ingestion on three occasions. KEY RESULTS: In dogs, delta(9)-THC dose-dependently inhibited TLESRs and reduced acid reflux rate. SR141716A significantly reversed the effects of delta(9)-THC on TLESRs. Similarly, in healthy volunteers, delta(9)-THC significantly reduced the number of TLESRs and caused a non-significant reduction of acid reflux episodes in the first postprandial hour. In addition, lower oesophageal sphincter pressure and swallowing were significantly reduced by delta(9)-THC. After intake of 20 mg, half of the subjects experienced nausea and vomiting leading to premature termination of the study. Other side-effects were hypotension, tachycardia and central effects. CONCLUSIONS AND IMPLICATIONS: Delta(9)-THC significantly inhibited the increase in meal-induced TLESRs and reduced spontaneous swallowing in both dogs and humans. In humans, delta(9)-THC significantly reduced basal lower oesophageal sphincter pressure. These findings confirm previous observations in dogs and indicate that cannabinoid receptors are also involved in the triggering of TLESRs in humans.

The role of GABA(A) receptors in the control of transient lower oesophageal sphincter relaxations in the dog.

BACKGROUND AND PURPOSE: Transient lower oesophageal sphincter relaxations (TLESRs) are triggered by activation of mechanosensitive gastric vagal afferents and are the major cause of gastroesophageal reflux and therefore an important target for therapeutic intervention in gastroesophageal reflux disease (GERD). Activation of the metabotropic GABA(B) receptor has shown to inhibit TLESRs. The aim of the present study was to assess the role of the ionotropic GABA(A) receptor in the regulation of TLESRs. EXPERIMENTAL APPROACH: TLESRs were quantified using Dentsleeve manometry in dogs, and GABA(A) agonists were given i.v. prior to gastric distension. Immunohistochemistry and RT-PCR were used to localize GABA(A) receptors in the dog nodose ganglion, the source of vagal afferents which initiate TLESRs. KEY RESULTS: The prototypical GABA(A) agonist muscimol produced a dose-dependent inhibition of TLESRs ranging from 19 to 56%. The two other GABA(A) agonists evaluated, isoguvacine and 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP), as well as the GABA(A) positive allosteric modulator diazepam, had no major effects on TLESRs. Evaluation of higher doses was limited by emesis (THIP and isoguvacine) or restlessness/sedation (diazepam). Of the predominant GABA(A) receptor subunits (alpha, beta and gamma components), alpha and beta but not gamma were detected in the dog nodose ganglion by RT-PCR, while immunohistochemistry in addition demonstrated nerve fibres expressing the gamma subunit. CONCLUSIONS AND IMPLICATIONS: The present observations demonstrate that GABA(A) receptors exert an inhibitory control of TLESRs. These results warrant further studies using GABA(A) isoform-selective agonists to define the identity of receptors involved.

Spontaneous maxillary sinus rupture in the absence of pre-existing sinus disease: case report.

INTRODUCTION: Spontaneous fracture of the maxillary sinus is usually associated with enophthalmos and pre-existing sinus disease. CASE REPORT: We present a case of spontaneous maxillary sinus fracture without enophthalmos and with no preceding history of trauma or evidence of sinusitis. DISCUSSION: The closest condition to that presented is silent sinus syndrome. The differences between our case and this syndrome are reviewed. There are no previously reported cases of lateral wall maxillary fracture and associated facial surgical emphysema following nose-blowing.

Danazol for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in pre menopausal women. Medical therapy, with the avoidance of possibly unnecessary surgery is an attractive treatment option, but there is considerable variation in practice and uncertainty about the most effective therapy. Danazol is a synthetic steroid with anti-oestrogenic and anti progestogenic activity, and weak androgenic properties. Danazol suppresses oestrogen and progesterone receptors in the endometrium, leading to endometrial atrophy (thinning of the lining of the uterus) and reduced menstrual loss and to amenorrhoea in some women. OBJECTIVES: To determine the effectiveness and tolerability of Danazol when used for heavy menstrual bleeding in women of reproductive years. SEARCH STRATEGY: We searched the Menstrual Disorders and Subfertility Group's Specialised Register (April 2007). We also searched the Cochrane Controlled Trials Register (Cochrane Library, Issue 2, 2007), MEDLINE (1966 to April 2007), EMBASE (1980 to April 2007, CINAHL (1982 to April 2007). Attempts were also made to identify trials from citation lists of included trials and relevant review articles. SELECTION CRITERIA: Randomised controlled trials of Danazol versus placebo, any other medical (non-surgical) therapy or Danazol in different dosages for heavy menstrual bleeding in women of reproductive age with regular HMB measured either subjectively or objectively. Trials that included women with post menopausal bleeding, intermenstrual bleeding and pathological causes of heavy menstrual bleeding were excluded. DATA COLLECTION AND ANALYSIS: Nine RCTs, with 353 women, were identified that fulfilled the inclusion criteria. Quality assessment and data extraction were performed independently by two reviewers. The main outcomes were menstrual blood loss, the number of women experiencing adverse effects, weight gain, withdrawals due to adverse effects and dysmenorrhoea. If data could not be extracted in a form suitable for meta-analysis, they were presented in a descriptive format. MAIN RESULTS: Most data were not in a form suitable for meta analysis, and the results are based on a small number of trials, all of which are under-powered. Danazol appears to be more effective than placebo, progestogens, NSAIDs and the OCP at reducing MBL, but confidence intervals were wide. Treatment with Danazol caused more adverse events than NSAIDs (OR 7.0; 95% CI 1.7 to 28.2) and progestogens (OR 4.05, 95% CI 1.6 to10.2). Danazol was shown to significantly lower the duration of menses when compared with NSAIDs (WMD -1.0; 95% CI -1.8 to -0.3) and a progesterone releasing IUD (WMD -6.0; 95% CI -7.3 to -4.8). There were no randomised trials comparing Danazol with tranexamic acid or the levonorgestrel-releasing intrauterine system. AUTHORS' CONCLUSIONS: Danazol appears to be an effective treatment for heavy menstrual bleeding compared to other medical treatments. The use of Danazol may be limited by its side effect profile, its acceptability to women and the need for continuing treatment. The small number of trials, and the small sample sizes of the included trials limit the recommendations for clinical care. Further studies are unlikely in the future and this review will not be updated unless further studies are identified.

Rate of progression of cognitive decline in Alzheimer's disease: effect of butyrylcholinesterase K gene variation.

OBJECTIVE: To determine whether individuals with Alzheimer's disease (AD) and the K variant allele of butyrylcholinesterase have a slower rate of cognitive decline than those without the K variant allele of butyrylcholinesterase. METHOD: The cognitive status of 339 community based subjects with AD was assessed with the Mini Mental State Examination at baseline and yearly over a three year follow up period. The rates of cognitive decline of subjects with and without the K variant allele were compared. RESULT: Presence of the K allele was associated with a slower average rate of cognitive decline in subjects with severe AD. CONCLUSIONS: This finding is consistent with the suggestion that the K variant of butyrylcholinesterase has an important role in disease progression in AD, and this may have implications for treatment.

Danazol for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in pre menopausal women. Medical therapy, with the avoidance of possibly unnecessary surgery is an attractive treatment option, but there is considerable variation in practice and uncertainty about the most effective therapy. Danazol is a synthetic steroid with anti-oestrogenic and anti progestogenic activity, and weak androgenic properties. Danazol suppresses oestrogen and progesterone receptors in the endometrium, leading to endometrial atrophy (thinning of the lining of the uterus) and reduced menstrual loss and to amenorrhoea in some women. OBJECTIVES: To determine the effectiveness and tolerability of danazol when used for heavy menstrual bleeding in women of reproductive years. SEARCH STRATEGY: All studies which might describe randomised controlled trials of danazol for the treatment of heavy menstrual bleeding were obtained by electronic searches of MEDLINE, EMBASE, Current Contents, CINAHL, National Research Register and the Menstrual Disorders and Subfertility Group's Specialist Register of controlled trials (on 6 November 2001). Attempts were also made to identify trials from citation lists of included trials and relevant review articles. In most cases the first author of each included trial was contacted for unpublished additional information. SELECTION CRITERIA: Randomised controlled trials of danazol versus placebo, any other medical (non-surgical) therapy or danazol in different dosages for heavy menstrual bleeding in women of reproductive age with regular HMB measured either subjectively or objectively. Trials that included women with post menopausal bleeding, intermenstrual bleeding and pathological causes of heavy menstrual bleeding were excluded. DATA COLLECTION AND ANALYSIS: Nine RCTs, with 353 women, were identified that fulfilled the inclusion criteria for this review. Quality assessment and data extraction were performed independently by two reviewers. The main outcomes were menstrual blood loss, the number of women experiencing adverse effects, weight gain, withdrawals due to adverse effects and dysmenorrhoea. If data could not be extracted in a form suitable for meta-analysis, they were presented in a descriptive format. MAIN RESULTS: Most data were not in a form suitable for meta analysis, and the results are based on a small number of trials, all of which are under-powered. Danazol appears to be more effective than placebo, progestogens, NSAIDs and the OCP at reducing MBL, but confidence intervals were wide. Treatment with danazol caused more adverse events than NSAIDs (OR 7.0; 95% CI 1.7, 28.2) and progestogens (OR 4.05, 95% CI 1.6, 10.2), but this did not appear to affect adherence to treatment. Danazol was shown to significantly lower the duration of menses when compared with NSAIDs (WMD -1.0; 95% CI -1.8, -0.3) and a progesterone releasing IUD (WMD -6.0; 95% CI -7.3, -4.8). There were no randomised trials comparing danazol with tranexamic acid or the levonorgestrel-releasing intrauterine system. REVIEWER'S CONCLUSIONS: Danazol appears to be an effective treatment for heavy menstrual bleeding compared to other medical treatments, though it is uncertain whether it is acceptable to women. The use of danazol may be limited by its side effect profile, its acceptability to women and the need for continuing treatment. Overall no strong recommendations can be made due to the small number of trials, and the small sample sizes of the included trials.

Embryonic mortality during the pre- and post-implantation periods of pregnancy in mature mice after superovulation.

Sexually mature mice were stimulated to superovulate by giving exogenous gonadotrophins at known stages of the oestrous cycle. Untreated animals which ovulated spontaneously served as controls. The number of oocytes ovulated by each female was estimated from counts of the number of CL of pregnancy, and the incidence of embryonic mortality during the pre- and post-implantation stages of pregnancy was assessed from the number of zygotes recovered from the reproductive tract at 2-0 and 4-0 days post coitum and of conceptuses examined at 7-5 and 11-5 days post coitum. The mean number of oocytes ovulated by treated animals was 39-54, compared with 12-80 in controls: in mice which had superovulated, 44% of the ova were lost before implantation compared with about 10% in the controls. Further losses occurred about the time of implantation and at mid-pregnancy and thus the number of embryos classified as normal rarely exceeded the maximum found in controls. Death at mid-pregnancy seemed to be preceded by developmental retardation. The possibility that genetic and environmental factors play a role in embryonic loss after superovulation is discussed.