First Constraints from DAMIC-M on Sub-GeV Dark-Matter Particles Interacting with Electrons.

We report constraints on sub-GeV dark matter particles interacting with electrons from the first underground operation of DAMIC-M detectors. The search is performed with an integrated exposure of 85.23 g days, and exploits the subelectron charge resolution and low level of dark current of DAMIC-M charge-coupled devices (CCDs). Dark-matter-induced ionization signals above the detector dark current are searched for in CCD pixels with charge up to 7e^{-}. With this dataset we place limits on dark matter particles of mass between 0.53 and 1000 MeV/c^{2}, excluding unexplored regions of parameter space in the mass ranges [1.6,1000] MeV/c^{2} and [1.5,15.1] MeV/c^{2} for ultralight and heavy mediator interactions, respectively.

Investigation of NO Role in Neural Tissue in Brain and Spinal Cord Injury.

Nitric oxide (NO) production in injured and intact brain regions was compared by EPR spectroscopy in a model of brain and spinal cord injury in Wistar rats. The precentral gyrus of the brain was injured, followed by the spinal cord at the level of the first lumbar vertebra. Seven days after brain injury, a reduction in NO content of 84% in injured brain regions and 66% in intact brain regions was found. The difference in NO production in injured and uninjured brain regions persisted 7 days after injury. The copper content in the brain remained unchanged one week after modeling of brain and spinal cord injury. The data obtained in the experiments help to explain the problems in the therapy of patients with combined brain injury.

Effects of Thryptophan Hydroxylase Blockade by P-Chlorophenylalanine on Contextual Memory Reconsolidation after Training of Different Intensity.

The processes of memory formation and its storage are extremely dynamic. Therefore, the determination of the nature and temporal evolution of the changes that underlie the molecular mechanisms of retrieval and cause reconsolidation of memory is the key to understanding memory formation. Retrieval induces the plasticity, which may result in reconsolidation of the original memory and needs critical molecular events to stabilize the memory or its extinction. 4-Chloro-DL-phenylalanine (P-chlorophenylalanine-PCPA) depresses the most limiting enzyme of serotonin synthesis the tryptophan hydroxylase. It is known that PCPA reduces the serotonin content in the brain up to 10 times in rats (see Methods). We hypothesized that the PCPA could behave the similar way in snails and could reduce the content of serotonin in snails. Therefore, we investigated the effect of PCPA injection on contextual memory reconsolidation using a protein synthesis blocker in snails after training according to two protocols of different intensities. The results obtained in training according to the first protocol using five electrical stimuli per day for 5 days showed that reminding the training environment against the background of injection of PCPA led to a significant decrease in contextual memory. At the same time, the results obtained in training according to the second protocol using three electrical stimuli per day for 5 days showed that reminding the training environment against the injection of PCPA did not result in a significant change in contextual memory. The obtain results allowed us to conclude that the mechanisms of processes developed during the reconsolidation of contextual memory after a reminding depend both on the intensity of learning and on the state of the serotonergic system.

Persistence, adherence, and medication-taking behavior in women with postmenopausal osteoporosis receiving denosumab in routine practice in Germany, Austria, Greece, and Belgium: 12-month results from a European non-interventional study.

UNLABELLED: Persistence with and adherence to osteoporosis therapy are critical for fracture reduction. This non-interventional study is evaluating medication-taking behavior of women with postmenopausal osteoporosis (PMO) receiving denosumab in Germany, Austria, Greece, and Belgium. Patients were representative of the PMO population and highly persistent with and adherent to denosumab at 12 months. INTRODUCTION: Persistence with and adherence to osteoporosis therapy are important for optimal treatment efficacy, namely fracture reduction. This ongoing, non-interventional study will evaluate medication-taking behavior of women with postmenopausal osteoporosis (PMO) receiving denosumab in routine practice in four European countries. METHODS: The study enrolled women who had been prescribed subcutaneous denosumab (60 mg every 6 months) in accordance with prescribing information and local guidelines. Persistence was defined as receiving the subsequent injection within 6 months + 8 weeks of the previous injection. Adherence was defined as receiving two consecutive injections within 6 months ± 4 weeks of each other. Medication coverage ratio (MCR) was calculated using the time a patient was covered with denosumab, as assessed from prescription records. Treatment was assigned prior to and independently of enrollment; outcomes are recorded during routine practice. RESULTS: These planned 12-month interim analyses included data from 1500 patients from 141 sites. Mean age was 66.4-72.4 years, mean baseline total hip T-scores ranged from -2.0 to -2.1 and femoral neck T-scores from -2.2 to -2.6, and 30.7-62.1% of patients had prior osteoporotic fracture. Persistence was 87.0-95.3%, adherence 82.7-89.3%, and MCR 91.3-95.4%. In a univariate analysis, increased age, decreased mobility, and increased distance to the clinic were associated with significantly decreased persistence; parental history of hip fracture was associated with significantly increased persistence. CONCLUSIONS: These data extend the real-world evidence regarding persistence with and adherence to denosumab, both of which are critical for favorable clinical outcomes, including fracture risk reduction.

Treatment with denosumab reduces secondary fracture risk in women with postmenopausal osteoporosis.

OBJECTIVES: A history of prior fracture is one of the strongest predictors of a future fragility fracture. In FREEDOM, denosumab significantly reduced the risk of new vertebral, non-vertebral, and hip fractures. We carried out a post-hoc analysis of FREEDOM to characterize the efficacy of denosumab in preventing secondary fragility fractures in subjects with a prior fracture. METHODS: A total of 7808 women aged 60-90 years with a bone mineral density T-score of less than - 2.5 but not less than - 4.0 at either the lumbar spine or total hip were randomized to subcutaneous denosumab 60 mg or placebo every 6 months for 36 months. The anti-fracture efficacy of denosumab was analyzed by prior fracture status, to assess secondary fragility fracture, and by subject age, prior fracture site and history of prior osteoporosis medication use. RESULTS: A prior fragility fracture was reported for 45% of the overall study population. Compared with placebo, denosumab significantly reduced the risk of a secondary fragility fracture by 39% (incidence, 17.3% vs. 10.5%; p < 0.0001). Similar results were observed regardless of age or prior fracture site. In the overall population, denosumab significantly reduced the risk of a fragility fracture by 40% (13.3% vs. 8.0%; p < 0.0001), with similar results observed regardless of history of prior osteoporotic medication use. CONCLUSIONS: Denosumab reduced the risk of fragility fractures to a similar degree in all risk subgroups examined, including those with prior fragility fractures. Identifying and treating high-risk individuals could help to close the current care gap in secondary fracture prevention.

Nitric oxide is necessary for labilization of a consolidated context memory during reconsolidation in terrestrial snails.

Nitric oxide (NO) is known to be involved in associative memory formation. We investigated the influence of blocking NO function on the reconsolidation of context memory in terrestrial snails (Helix lucorum L.). After a 10 day session of electric shocks in one context only, context memory in snails was observed in test sessions as the significant difference of amplitudes of withdrawal responses to tactile stimuli in two different contexts. After a 1 day rest, a session of 'reminding' was performed, preceded by injection in different groups of the snails with either vehicle or combination of the protein synthesis blocker anisomycin (ANI) with one of the following drugs: the NO scavenger carboxy-PTIO, the NO-synthase inhibitors N-omega-nitro-L-arginin, nitroindazole and NG-nitro-L-arginine methyl ester hydrochloride, or the NO donor S-nitroso-N-acetyl-DL-penicillamine. Testing the context memory at different time intervals after the reminder under ANI injection showed that the context memory was impaired at 24 h and later, whereas the reminder under combined injection of ANI and each of the NO-synthase inhibitors used or the NO scavenger showed no impairment of long-term context memory. Injection of the NO donor S-nitroso-N-acetyl-DL-penicillamine with or without reminder had no effect on context memory. The results obtained demonstrated that NO is necessary for labilization of a consolidated context memory.

Spectrofluorimetric assessment of chlorzoxazone and ibuprofen in pharmaceutical formulations by using Eu-tetracycline HCl optical sensor doped in sol-gel matrix.

A novel, simple, sensitive and selective spectrofluorimetric method was developed for the determination of trace amounts of chlorzoxazone and Ibuprofen in pharmaceutical tablets using optical sensor Eu-Tetracycline HCl doped in sol-gel matrix. The chlorzoxazone or Ibuprofen can remarkably enhance the luminescence intensity of Eu-Tetracycline HCl complex doped in a sol-gel matrix in dimethylformamide (DMF) at pH 9.7 and 6.3, respectively, λ(ex) = 400 nm. The enhancing of luminescence intensity peak of Eu-Tetracycline HCl complex at 617 nm is proportional to the concentration of chlorzoxazone or Ibuprofen a result that suggested profitable application as a simple optical sensor for chlorzoxazone or Ibuprofen assessment. The dynamic ranges found for the determination of chlorzoxazone and Ibuprofen concentration are 5 × 10(-9)-1 × 10(-4) and 1 × 10(-8)-7 × 10(-5) mol L(-1), and the limit of detection (LOD) and quantitation limit of detection (LOQ) are 3.1 × 10(-10), 9.6 × 10(-10) and 5.6 × 10(-10), 1.7 × 10(-9) mol L(-1), respectively.

Evaluation of several novel alkynols, alkenols, and selected host odor blends as attractants to female Aedes albopictus and Culex quinquefasciatus.

The compound 1-octen-3-ol is a strong attractant for some mosquito species. Based on chemical structure, this may be due to a terminal site of unsaturation or high electron density, a structural capability for hydrogen bonding, e.g., -OH, -NH2, NHR, NR2, etc., a saturated hydrocarbon chain of a certain minimum length, and a certain relative distance between the region of high electron density and the alcohol (or other hydrogen-bonding) functional group. Based on this hypothesis, 4 novel alkynol (triple-bonded) analogs were synthesized and evaluated alone or in combination with acetone and dimethyl disulfide, and with and without carbon dioxide in Mosquito Magnet-X suction traps. Attraction of laboratory-reared adult Aedes albopictus and Culex quinquefasciatus to these analogs and combinations was compared to 1-octen-3-ol as a standard in semi-field trials. For both species none of the alkynols, with and without carbon dioxide or acetone and dimethyl disulfide, were significantly different from 1-octen-3-ol. The compounds 2-octyn-4-ol and 2-nonyn-4-ol alone and with carbon dioxide suppressed Cx. quinquefasciatus collections. An additional 6 alkenol (double-bonded) analogs were tested in mixtures with 3-n-propylphenol and 4-methylphenol in a ratio of 4:1:8, respectively. Using the same trapping methods, Cx. quinquefasciatus catches containing 3-decen-1-ol were increased nearly 3-fold when combined with carbon dioxide. Aedes albopictus collections in traps with the 3-decen-1-ol/phenol mixture and carbon dioxide were significantly greater than similar traps with 1-octen-3-ol. Traps baited with the phenol blends that incorporated (Z)-3-nonen-1-ol, (Z)-8-nonen-3-ol, or 1-octen-3-ol were considerably suppressed in the presence of carbon dioxide.

Mental health and tobacco use are correlated with PROMIS upper extremity and pain interference scores in patients with shoulder pathology.

PURPOSE: To determine whether patient demographics have predictive influence on patient-reported outcomes measurement information system (PROMIS) domains of pain interference (PROMIS-PI), depression (PROMIS-D), and upper extremity (PROMIS-UE) for patients with shoulder pathology treated nonoperatively. METHODS: Patients with partial rotator cuff tears, impingement, scapular dyskinesia, osteoarthritis, muscle strains, biceps tendonitis, instability, and acromioclavicular arthritis were retrospectively identified. Patients who underwent surgery were excluded. Demographic characteristics were documented, and PROMIS scores before and after nonoperative intervention were analyzed for correlations between each domain. RESULTS: A total of 638 questionnaires (PROMIS-UE, PROMIS-PI, and PROMIS-D) were analyzed. PROMIS-UE had a strong negative correlation with PROMIS-PI (R = - 0.73, P < .001). PROMIS-PI and PROMIS-D demonstrated a positive correlation of moderate strength (R = 0.54, P < .001). Patients who never used tobacco, compared to current or former users, had significantly higher PROMIS-UE scores (34.5 vs. 30.6 and 31.9; P < .001), lower PROMIS-PI (59.7 vs. 63.1 and 60.9; P < .001), and lower PROMIS-D scores (47.3 vs. 52.1 and 49.3; P < .001). Patients with body mass index < 24.8 had significantly higher PROMIS-UE scores than those with > 24.8 (P < .05). CONCLUSION: There is an inverse relationship between upper extremity physical function and pain and depression, as measured by PROMIS scores. Smoking and increased BMI are significant contributors to worse outcomes in patients with shoulder pathology, even in nonoperative populations. Counseling patients regarding prognosis and functional outcomes is important in managing their expectations in this patient population.

Spectrofluorimetric assessment of doxycycline hydrochloride in pharmaceutical tablets and serum sample based on the enhancement of the luminescence intensity of the optical sensor Sm3+ ion.

A simple and sensitive spectrofluorimetric method for determination of trace amount of doxycycline hydrochloride (DC) in pharmaceutical tablets and serum samples was developed. In ammonia buffer solution of pH 8.9 the doxycycline hydrochloride can remarkably enhance the luminescence intensity of the Sm(3+) ion in Sm(3+)- DC complex at λ(ex)=400 nm. The produced luminescence intensity of Sm(3+)- DC complex in DMSO is in proportion to the concentration of DC and used as optical sensor for its determination. The dynamic range for the determination of DC is 1 × 10(-8)-5 × 10(-6) mol L(-1) and in case of quantum yield calculations is 7 × 10(-9)-5 × 10(-6) mol L(-1) with detection limit of 6.5 × 10(-10) mol L(-1). The enhancement mechanism of the luminescence intensity in the Sm(3+)- DC system has been also discussed. A comparison with other spectrofluorimetric methods for tetracycline derivatives in which Eu(3+) ion is used instead of Sm(3+) ion is also studied.

National Basketball Association combine performance after a partial meniscectomy.

BACKGROUND: An arthroscopic meniscectomy is one of the most common orthopedic procedures in athletes. Return to play rates and deficits in muscle function have been reviewed after meniscectomy, but no study has reviewed functional performance after an isolated partial meniscectomy. HYPOTHESIS/PURPOSE: To compare the performance of elite-level basketball players after a partial meniscectomy to a control group of players with no previous reported knee injury. We believe that there is no difference between the two groups in functional performance. STUDY DESIGN: Case Series. METHODS: Functional performance results from the National Basketball Association (NBA) combine were reviewed between 2000 and 2015. Twelve out of 1092 players were found to have undergone a partial meniscectomy prior to competing in the NBA combine. The partial meniscectomy group was compared to an age-, size-, and position-matched control group with respect to functional performance testing such as the shuttle run test, lane agility test, ¾ court sprint, vertical jump (no step), and vertical jump (max). RESULTS: The meniscectomy and the control groups that there was no significant difference between the two groups in agility, quickness, sprinting, and jumping ability. However, there was a - 0.596 spearman correlation between months after surgery and agility (p = 0.041), while there was a + 0.690 and + 0.650 spearman correlation between both months after surgery and standing vertical and max vertical (p = 0.013 and p = 0.022). CONCLUSIONS: Athletes competing in the NBA combine who have undergone a partial meniscectomy perform as well as uninjured athletes in all NBA combine performance testing. Furthermore, as athletes are further out from surgery, they have an improvement in both standing and max vertical jump.

Early TB case detection by community-based mobile X-ray screening and Xpert testing in Balochistan.

SETTING: This survey was conducted at 35 sites of 20 cities in 15 districts with low programmatic TB case notifications in the past years in Balochistan. OBJECTIVE: To assess the effectiveness of the systemic community-based screening and diagnosis for early detection of TB; and 2) to describe the characteristics and understand the strengths and weaknesses of the intervention in Balochistan, and sociodemographic factors associated with it. DESIGN: This cross-sectional descriptive study was conducted using a mobile van equipped with a digital X-ray machine with computer-aided detection for TB (CAD4TB) software for screening, followed by confirmatory high sensitivity Xpert® MTB/RIF assay testing. RESULTS: A total of 236 (3.4%) TB cases was detected out of 6,899 screened. About 1,168 (17%) presumptive TB cases were identified and 1,065 (91%) sputum samples were tested on Xpert. Among those diagnosed, 166 (70%) were Mycobacterium tuberculosis-positive and 70 (30%) were with clinical suspicion. Of the sputum samples tested, 87% (923/1065) had a probability score of >70 on CAD4TB. CONCLUSION: Community-based screening with innovative activities, comprising sensitive screening and diagnostic tools, effectively improves TB case detection, which might suffice to reduce the prevalence of TB and break the chain of infection transmission in the at-risk population.

CADRE: Cette enquête a été menée dans 35 sites de 20 villes dans 15 districts au Baloutchistan où le nombre de notifications de cas de TB était faible au cours des dernières années. OBJECTIVE: 1) Évaluer l'efficacité du dépistage et du diagnostic systémiques communautaires pour la détection précoce de la TB ; et 2) décrire les caractéristiques et comprendre les forces et les faiblesses de l'intervention au Baloutchistan, ainsi que les facteurs sociodémographiques qui y sont associés. MÉTHODE: Cette étude descriptive transversale a été menée à l'aide d'une camionnette mobile équipée d'un appareil à rayons X numérique avec logiciel de détection assistée par ordinateur pour la dépistage de la TB (CAD4TB), suivi d'un test de confirmation à haute sensibilité, l'Xpert® MTB/RIF. RÉSULTATS: Sur les 6 899 dépistés, 236 (3,4%) cas de TB a été détecté. Environ 1 168 (17%) cas présumés de TB ont été identifiés et 1 065 (91%) échantillons de crachats ont été testés avec Xpert. Parmi les cas diagnostiqués, 166 (70%) étaient positifs à Mycobacterium tuberculosis et 70 (30%) avaient une suspicion clinique. Parmi les échantillons de crachats testés, 87% (923/1 065) avaient un score de probabilité de >70 en CAD4TB. CONCLUSION: Le dépistage communautaire avec des activités innovantes, comprenant des outils de dépistage et de diagnostic sensibles, améliore efficacement la détection des cas de TB, ce qui pourrait suffire à réduire la prévalence de la TB et à rompre la chaîne de transmission de l'infection dans la population à risque.

Biomicrofluidic Systems for Hematologic Cancer Research and Clinical Applications.

A persistent challenge in developing personalized treatments for hematologic cancers is the lack of patient specific, physiologically relevant disease models to test investigational drugs in clinical trials and to select therapies in a clinical setting. Biomicrofluidic systems and organ-on-a-chip technologies have the potential to change how researchers approach the fundamental study of hematologic cancers and select clinical treatment for individual patient. Here, we review microfluidics cell-based technology with application toward studying hematologic tumor microenvironments (TMEs) for the purpose of drug discovery and clinical treatment selection. We provide an overview of state-of-the-art microfluidic systems designed to address questions related to hematologic TMEs and drug development. Given the need to develop personalized treatment platforms involving this technology, we review pharmaceutical drugs and different modes of immunotherapy for hematologic cancers, followed by key considerations for developing a physiologically relevant microfluidic companion diagnostic tool for mimicking different hematologic TMEs for testing with different drugs in clinical trials. Opportunities lie ahead for engineers to revolutionize conventional drug discovery strategies of hematologic cancers, including integrating cell-based microfluidics technology with machine learning and automation techniques, which may stimulate pharma and regulatory bodies to promote research and applications of microfluidics technology for drug development.

The utility of botulinum toxin A in the repair of distal biceps tendon ruptures.

PURPOSE: The purpose of our study is to report the outcomes and complications in patients who underwent distal biceps tendon repair with the use of Botulinum toxin A (BoNT-A) as an adjunct to surgery. METHODS: A retrospective review of 14 patients who underwent 15 distal biceps tendon repairs was performed. All repaired tendons had their correlating muscle bellies injected intraoperatively with a mixture of 100U of BoNT-A and 10 ml of normal saline. Each patient was evaluated for surgical and post-operative complications and followed with Disabilities of the Arm, Shoulder and Hand (DASH) Disability Scores. RESULTS: The cohort was exclusively male, 14/14 (100%). The mean age at procedure was 52.1 years (range: 29-65 years). Types of injuries repaired included: 12 acute biceps tendon ruptures, one chronic partial (> 50% of tendon) biceps tear, and two chronic biceps ruptures. Average final follow-up was 32.9 months (SD: 19.6; range: 7.07-61.72). Average time to repair of chronic injury was 5.75 months (range: 2-12 months). There were no intraoperative complications, and all patients were discharged home on the day of surgery. Average DASH score at latest follow-up was 4.9 (range: 0.0-12.5). All patients had return of function of paralyzed muscle prior to final follow-up. One patient required an incision and drainage for a deep infection 1 week post-operatively, without any further complications. Another patient required operative removal of heterotopic ossification located around the tendon fixation site, which was the result of a superficial infection treated with antibiotics 2 weeks post-operatively. This patient later healed with improvement in supination/pronation range-of-motion and no further complications. CONCLUSIONS: Injection of BoNT-A is safe and effective to protect distal biceps tendon repair during the early phases of bone-tendon healing. CLINICAL RELEVANCE: BoNT-A may is safe and effective to protect distal biceps tendon repair. The utility of BoNT-A as an adjunct to surgical repair may be applicable to acute or chronic tears as well as repairs in the non-compliant patient without decreases in functional scores after return of function of the biceps muscle. LEVEL OF EVIDENCE: Level 4.

Impairing of Serotonin Synthesis by P-Chlorphenylanine Prevents the Forgetting of Contextual Memory After Reminder and the Protein Synthesis Inhibition.

HIGHLIGHTS The injection of p-chlorophenylalanine, specific blocker of 5-HT synthesis 3 days before reminder with anisomycin administration prevented forgetting. It is known that the reminder cause reactivation of the long-term memory and it leads to reconsolidation of memory. We showed earlier that the disruption of the reconsolidation of contextual memory in terrestrial snail was caused by anisomycin, the inhibitor of protein syntheses (Gainutdinova et al., 2005; Balaban et al., 2014). In this paper we investigated the possible changes of the memory reconsolidation under the conditions of serotonin deficit, caused by administration of p-chlorophenylalanine, the inhibitor of tryptophan hydroxylase synthesis (intermediate stage of the synthesis of serotonin). It was shown that the forgetting process for contextual memory after reminder and inhibition of protein synthesis did not occur if the serotonin transmission in nervous system was impaired. This effect was significantly different from the direct action of anisomycin, which blocked the reconsolidation of contextual memory. We concluded that the serotonin system was included to the process of memory reconsolidation.

Molecular Bases of Brain Preconditioning.

Preconditioning of the brain induces tolerance to the damaging effects of ischemia and prevents cell death in ischemic penumbra. The development of this phenomenon is mediated by mitochondrial adenosine triphosphate-sensitive potassium ([Formula: see text]) channels and nitric oxide signaling (NO). The aim of this study was to investigate the dynamics of molecular changes in mitochondria after ischemic preconditioning (IP) and the effect of pharmacological preconditioning (PhP) with the [Formula: see text]-channels opener diazoxide on NO levels after ischemic stroke in rats. Immunofluorescence-histochemistry and laser-confocal microscopy were applied to evaluate the cortical expression of electron transport chain enzymes, mitochondrial [Formula: see text]-channels, neuronal and inducible NO-synthases, as well as the dynamics of nitrosylation and nitration of proteins in rats during the early and delayed phases of IP. NO cerebral content was studied with electron paramagnetic resonance (EPR) spectroscopy using spin trapping. We found that 24 h after IP in rats, there is a two-fold decrease in expression of mitochondrial [Formula: see text]-channels (p = 0.012) in nervous tissue, a comparable increase in expression of cytochrome c oxidase (p = 0.008), and a decrease in intensity of protein S-nitrosylation and nitration (p = 0.0004 and p = 0.001, respectively). PhP led to a 56% reduction of free NO concentration 72 h after ischemic stroke simulation (p = 0.002). We attribute this result to the restructuring of tissue energy metabolism, namely the provision of increased catalytic sites to mitochondria and the increased elimination of NO, which prevents a decrease in cell sensitivity to oxygen during subsequent periods of severe ischemia.

Responses of Withdrawal Interneurons to Serotonin Applications in Naïve and Learned Snails Are Different.

Long-term changes in membrane potential after associative training were described previously in identified premotor interneurons for withdrawal of the terrestrial snail Helix. Serotonin was shown to be a major transmitter involved in triggering the long-term changes in mollusks. In the present study we compared the changes in electrophysiological characteristics of identifiable premotor interneurons for withdrawal in response to bath applications of serotonin (5-HT) or serotonin precursor 5-hydroxytryptophan (5-HTP) in preparations from naïve, neurotoxin-injected or associatively trained snails. It was found that 5-HT or 5-HTP applications caused a significant decrease of membrane potential in premotor interneurons of naïve snails, associatively trained snails and snails with impaired serotonergic system by injection of a selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) 1 week before the experiments. Applications of 5-HT or 5-HTP did not cause significant changes in the action potential (AP) threshold potential of these neurons in naïve snails. Conversely, applications of 5-HT or 5-HTP to the premotor interneurons of previously trained or 5,7-DHT-injected snails caused a significant increase in the firing threshold potential in spite of a depolarizing shift of the resting membrane potential. Results demonstrate that responsiveness of premotor interneurons to extracellularly applied 5-HT or 5-HTP changes for days after the associative training or serotonin depletion. Similarity of the effects in trained and 5,7-DHT-injected animals may be due to massive release of serotonin elicited by 5,7-DHT injection. Our results suggest that serotonin release due to aversive conditionining or elicited by the neurotoxin administration triggers similar changes in resting membrane potential and AP threshold in response to bath applications of 5-HT or its precursor 5-HTP.

Factors associated with high 24-month persistence with denosumab: results of a real-world, non-interventional study of women with postmenopausal osteoporosis in Germany, Austria, Greece, and Belgium.

Persistence with osteoporosis therapy is vital for fracture prevention. This non-interventional study of postmenopausal women receiving denosumab in Germany, Austria, Greece, and Belgium found that persistence with denosumab remains consistently high after 24 months in patients at high risk of fracture. PURPOSE: Continued persistence with osteoporosis therapy is vital for fracture prevention. This non-interventional study of clinical practice evaluated medication-taking behavior of postmenopausal women receiving denosumab in Germany, Austria, Greece, and Belgium and factors influencing persistence. METHODS: Subcutaneous denosumab (60 mg every 6 months) was assigned according to prescribing information and local guidelines before and independently of enrollment; outcomes were recorded during routine practice for up to 24 months. Persistence was defined as receiving the subsequent injection within 6 months + 8 weeks of the previous injection and adherence as administration of subsequent injections within 6 months ± 4 weeks of the previous injection. Medication coverage ratio (MCR) was calculated as the proportion of time a patient was covered by denosumab. Associations between pre-specified baseline covariates and 24-month persistence were assessed using multivariable logistic regression. RESULTS: The 24-month analyses included 1479 women (mean age 66.3-72.5 years) from 140 sites; persistence with denosumab was 75.1-86.0%, adherence 62.9-70.1%, and mean MCR 87.4-92.4%. No covariate had a significant effect on persistence across all four countries. For three countries, a recent fall decreased persistence; patients were generally older with chronic medical conditions. In some countries, other covariates (e.g., older age, comorbidity, immobility, and prescribing reasons) decreased persistence. Adverse drug reactions were reported in 2.3-6.9% patients. CONCLUSIONS: Twenty-four-month persistence with denosumab is consistently high among postmenopausal women in Europe and may be influenced by patient characteristics. Further studies are needed to identify determinants of low persistence.

Cholecystitis in otters (Lutra lutra) and mink (Mustela vison) caused by the fluke Pseudamphistomum truncatum.

Between 1988 and 2004, postmortem examinations were carried out on 445 otters found dead, mostly as a result of road traffic accidents, in southern and south-west England. Thickened, shrunken gall bladders were observed in 10 cases, the first in 2000 and the others between February 2002 and August 2004. A digenean fluke, Pseudamphistomum truncatum, was found in the gall bladders of three cases and also in three of seven American mink examined. Nine of the 10 otters and all the mink came from a localised area of Somerset, indicating that the fluke has become established in the local fish population. P. truncatum has not been recorded previously in Britain, and the results suggest that it has been introduced recently, possibly in imported fish.