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Choice reaction time tests are commonly used for the assessment of cognitive function, and may be useful to assess the effect of mild traumatic injuries or concussions. This study investigated the precision of the Integrated Cognitive Assessment (ICA; Cognetivity Neurosciences Ltd., Vancouver, Canada) test for the assessment of cognitive function in athletes. Thirty-one participants volunteered to take part in this study, from both contact (n= 22) and non-contact sports (n= 9). Participants performed the ICA test consecutively both before and after normal training session to simulate resting and post-sport conditions. Precision errors were calculated for three variables, ICA Index (overall information processing ability), ICA Speed (information processing speed) and ICA Accuracy (information processing accuracy). ICA precision errors [root mean squared-standard deviation, RMS-SD (coefficient of variation, %CV)] pre-sport were ICA Index: 5.18 (7.14%), ICA Speed: 3.98 (4.64%), and ICA Accuracy: 3.64 (5.00%); and post-sport were ICA Index: 3.96 (4.94%), ICA Speed: 2.14 (2.32%), and ICA Accuracy 3.40 (4.25%). The ICA test demonstrates high in-vivo precision with all variables, with all variables except ICA Index (7.14%) demonstrating an acceptable precision error of ≤5% %CV. The ICA test is suitable for the assessment of cognitive function pre- and post-sport.

Background Rugby union and rugby league are popular team contact sports, but they bring a high risk of injury. Although previous studies have reported injury occurrence across one or several seasons, none have explored the total number of injuries sustained across an entire career. As the first to do so, the aim of this study was to report on cumulative injuries and their perceived long-term impact in retired rugby code athletes compared to athletes from non-contact sports. Methods One hundred and eighty-nine former rugby code athletes (rugby union n = 145; rugby league n = 44) and 65 former non-contact athletes were recruited to the UK Rugby Health Project between September 2016 and December 2018. Details on sports participation, sports injuries and concussion history, sports injury-related surgeries, and previous and current health were obtained from a validated, online self-report questionnaire. Results Former elite rugby code athletes (n = 83) reported more total injuries per player (median 39, IQR 35) than former amateur rugby code athletes (n = 106; median 23, IQR 30; p = 0.014) and non-contact sports athletes (n = 65; median 7.5, IQR 15; p p = 0.003–0.045). The reported prevalence of osteoarthritis was more than twofold greater in the elite rugby code group than in non-contact athletes (51% v 22%, p p p = 0.028). Conclusion Across multiple injury types, past participation in rugby union and rugby league, particularly at elite level, is associated with a high cumulative injury load and a continued impact of previous injuries post-retirement. Given the high number of reported concussions (and their recurrence) and associations between previous injuries during a player’s career and current musculoskeletal conditions, efforts should be prioritized to reduce the occurrence and recurrence of injuries in rugby codes at all levels of the sport. Strategies should also be developed for supporting the specific physical health needs of rugby code athletes post-retirement.

Background Concerns have intensified over the health and wellbeing of rugby union and league players, and, in particular, about the longer-term effects of concussion. The purpose of this study was to investigate whether there were differences in mental health, sleep and alcohol use between retired elite and amateur rugby code players and non-contact athletes, and to explore associations with sports-related concussion. Methods 189 retired elite (ER, n = 83) and amateur (AR, n = 106) rugby code players (rugby union n = 145; rugby league n = 44) and 65 former non-contact athletes (NC) were recruited to the UK Rugby Health Project between 2016 and 2018. Details on sports participation and concussion history were obtained by questionnaire, which also included questions on mental health, anger, sleep, mood, alcohol use, social connections and retirement from injury. Data were compared between sports groups (ER, AR and NC), between exposure of three or more or five or more concussions and for years in sport. Results ER reported more concussions than AR (5.9 ± 6.3 vs. 3.7 ± 6.3, p = 0.022) and NC (0.4 ± 1.0, p d = 0.47, p = 0.003) and NC (7.1 ± 4.8, d = 0.57, p = 0.006) and a lower overall positive score (indicating good mental health) than NC (8.9 ± 4.1 vs. 10.7 ± 3.4, d = 0.46, p = 0.021). Negative scores were highest and positive scores lowest in those reporting three or more concussions (d = 0.36, p = 0.008; d = 0.28, p = 0.040, respectively) or five or more concussions (d = 0.56, p d = 0.325, p = 0.035, respectively). Reported symptoms for sleep disruption were more prevalent in ER than NC, and in former athletes with three or more concussions (d = 0.41–0.605, p p = 0.733). Global anger score and covert anger expression was higher in former athletes with five or more concussions (d = 0.32, p = 0.035; d = 0.37, p = 0.016). AR reported greater attachment to friends than NC (d = 0.46, p = 0.033) and 20% of ER reported that they would not turn to anyone if they had a problem or felt upset about anything. Conclusion There was a significantly higher prevalence of adverse mental health and sleep disruption in ER and in former athletes who reported a higher number of concussions. Anger and irritability were more prevalent in former athletes with a history of five or more concussions. Strategies are needed to address mental health and sleep disturbance in elite rugby code athletes, who are also less likely to seek help should they need it. Further research is needed to elucidate causation, and the neurobiological connection between concussion, sub-concussions and longer-term psychological health and wellbeing.

Among the histamine receptors, growing evidence points to the histamine H3 receptor as a pharmacological candidate to counteract the autonomic neuropathy associated with diabetes. The study aimed to evaluate the effect of PF00868087 (also known as ZPL-868), a CNS-sparing histamine H3 receptor antagonist, on the autonomic neuropathy of the intestinal tract associated with diabetes. Diabetes was induced in male BALB/c mice by a single high dose of streptozotocin (150 mg/kg). Colorectal specimens from control and diabetic mice, randomized to vehicle or PF0086087 (10, 30, 100 mg/kg/day by oral gavage for 14 days), were processed for morphological and immunohistochemical analysis. A significant overproduction of mucus in the intestinal mucosa of diabetic mice compared to the controls was observed. PF0086087 at the highest dose prevented mucin overproduction. The immunohistochemistry analysis demonstrated that diabetes causes a decrease in the inhibitory component of enteric motility, measured as the percentage of neuronal nitric oxide synthase-positive neurons (p < 0.05) and a parallel increase in the excitatory component evaluated as substance P-positive fibres (p < 0.01). PF0086087 dose-dependently prevented these pathophysiological events. In conclusion, PF0086087 may be an essential tool in preventing nitrergic dysfunction in the myenteric plexus of the distal colon and diabetes-induced gastrointestinal complications.

Background: We present a pilot study of near-infrared (NIR) 1068 nm transcranial photobiomodulation therapy (PBM-T). Impact upon motor function, memory, and processing speed in healthy individuals, older than 45 years of age, was evaluated. Methods: PBM-T was performed at home using a transcranial phototherapy device, a helmet that comprised 14 air cooled light emitting diode panel arrays, with a peak wavelength of 1068 nm, full width at half maximum bandwidth of 60 nm and total average optical output power of 3.8 W. The device was used for 6 min twice daily on age-matched middle-aged subjects with normal intellectual function. The US Food and Drug Administration (FDA)-approved computerized assessment tool Automated Neuropsychological Assessment Metrics (ANAM) was adopted to quantify a series of cognitive and motor activities in the participating groups. Results: A significant improvement in motor function, memory performance, and processing speed was observed in healthy individuals with PBM-T compared to the placebo group. No adverse effects were reported. Conclusions: PBM-T may be a promising new approach to improve memory in healthy middle-aged individuals. ClinicalTrials.gov ID: NCT04568057.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Previous studies implicated the histamine H4 receptor in renal pathophysiology. The aim here is to elucidate the role of this receptor on renal function using H4 receptor knockout mice (H4R−/−). Healthy and diabetic H4R−/− mice compared to their C57BL/6J wild-type counterpart for renal function and the expression of crucial tubular proteins. H4R−/− and wild-type mice, matched for ages, showed comparable weight gain curves reaching similar median weight at the end of the study. However, H4R−/− mice displayed a higher basal glycemia. H4R−/− mice showed a lower urine 24 h outflow, and albumin-to-creatinine ratio (ACR) compared to wild-type mice. Consistently, H4R−/− mice presented a higher expression of megalin and a lower basal expression of the sodium-hydrogen exchanger (NHE)3 and aquaporin (AQP)2. According to these basal differences, diabetic H4R−/− mice developed more severe hyperglycemia and a higher 24 h urine volume, but a lower increase in ACR and decrease in urine pH were observed. These events were paralleled by a reduced NHE3 over-expression and megalin loss in diabetic H4R−/− mice. The AQP1 and AQP7 patterns were also different between H4R−/− and wild-type diabetic mice. The collected results highlight the role of the histamine H4 receptor in the control of renal reabsorption processes, particularly albumin uptake.

Plant natural products have a long history of being a rich source of neuroactive drugs.The total phenolic and flavonoid content, and antioxidant activity of ethanol, chloroform and aqueous extracts of AlgerianMedicagoSativaL, leaves were measured to discover new potential sources of Algerian natural antioxidants and neuroactives. All extracts were non-neurotoxic up to 1 mg/ ml for 24 h exposure. The total phenolcontent of M.Sativa extracts ranged between 38 and 69 mg GAE per g extracts. All of the extracts displayed antioxidant capacityassessed by two methods, but at different levels depending on the concentration and the extraction solvent used. The overall antioxidant potency was in the order water > chloroform> ethanol extracts, and the phenolic content exhibited a positive correlation with the antioxidant activity of M. Sativa extracts.Despite a weaker antioxidant activity, the ethanol extract elicited a calcium spike and suppressed the KCl-induced depolarisation response in neurons, indicating effect on ligand-and/or voltage gated calcium channels. In contrast, the chloroform and water extractsdisplayed no apparent direct functional effects. In conclusion, the antioxidant and functional properties related to phenolic content of Algerian Medicago Sativa L. in water and ethanol extracts, respectively.

Histamine, acting via distinct histamine H1 , H2 , H3 , and H4 receptors, regulates various physiological and pathological processes, including pain. In the last two decades, there has been a particular increase in evidence to support the involvement of H3 receptor and H4 receptor in the modulation of neuropathic pain, which remains challenging in terms of management. However, recent data show contrasting effects on neuropathic pain due to multiple factors that determine the pharmacological responses of histamine receptors and their underlying signal transduction properties (e.g., localization on either the presynaptic or postsynaptic neuronal membranes). This review summarizes the most recent findings on the role of histamine and the effects mediated by the four histamine receptors in response to the various stimuli associated with and promoting neuropathic pain. We particularly focus on mechanisms underlying histamine-mediated analgesia, as we aim to clarify the analgesic potential of histamine receptor ligands in neuropathic pain. LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.

Histamine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Histamine Receptors [80, 173]) are activated by the endogenous ligand histamine. Marked species differences exist between histamine receptor orthologues [80]. The human and rat H3 receptor genes are subject to significant splice variance [12]. The potency order of histamine at histamine receptor subtypes is H3 = H4 > H2 > H1 [173]. Some agonists at the human H3 receptor display significant ligand bias [182]. Antagonists of all 4 histamine receptors have clinical uses: H1 antagonists for allergies (e.g. cetirizine), H2 antagonists for acid-reflux diseases (e.g. ranitidine), H3 antagonists for narcolepsy (e.g. pitolisant/WAKIX; Registered) and H4 antagonists for atopic dermatitis (e.g. adriforant; Phase IIa) [173] and vestibular neuritis (AUV) (SENS-111 (Seliforant, previously UR-63325), entered and completed vestibular neuritis (AUV) Phase IIa efficacy and safety trials, respectively) [216, 8].

Objectives: Cortisol is a glucocorticoid hormone produced through activation of the hypothalamic pituitary adrenal axis. It is known as the “stress hormone” for its primary role in the body's stress response and has been the focus of much modern clinical research. Within archaeology, only a few studies have analyzed cortisol in human remains and these have been restricted to hair (Webb et al., 2010; Webb, White, van Uum, & Longstaffe, 2015a; Webb, White, van Uum, & Longstaffe, 2015b). This study examines the utility of dentine and enamel, which survive well archaeologically, as possible reservoirs for detectable levels of cortisol. Materials and methods: Then, 69 teeth from 65 individuals from five Roman and Post-Roman sites in France were tested via competitive enzyme-linked immunosorbent assay (ELISA) to assess and quantify the cortisol concentrations present within tooth dentine and enamel. Results: In both tooth dentine and enamel, detectable concentrations of cortisol were identified in multiple teeth. However, concentrations were low and not all teeth yielded results that were measurable through cortisol ELISA. Differences in cortisol values between dentine and enamel could suggest different uptake mechanisms or timing. Discussion: These results suggest that cortisol is incorporated within tooth structures and merits further investigation in both modern and archaeological contexts. Analysis of the results through liquid chromatographic–mass spectrometry would verify current results and might yield values that could be better integrated with published cortisol studies. Future studies of cortisol in tooth structures would greatly expand the research potential of cortisol in the past and could have implications for studies of human stress across deep time.

Background Transcranial near-infrared (tNIR) stimulation was proven to be a safe, reliable, and effective treatment for cognitive and behavioral symptoms of dementia. Dementia patients of different genders differ in terms of gross anatomy, biochemistry, genetic profile, clinical presentations, and socio-psychological status. Studies of the tNIR effect on dementia have thus far been gender-neutral, with dementia subjects being grouped based on diagnoses or dementia severity. This trial hereby investigated how dementia subjects of different sex respond to tNIR treatment. Methods A total of 60 patient-caregiver dyads were enrolled and randomized to this double-blind, sham-controlled clinical trial. The tNIR light has a wavelength of 1,060 nm to 1,080 nm and was delivered via a photobiomodulation (PBM) unit. The active PBM unit emits near-infrared (NIR) light while the sham unit does not. The treatment consists of a six-minute tNIR light stimulation session twice daily for eight weeks. Neuropsychological assessments conducted at baseline (week 0) and endline (week 8) were compared within the female and male group and between different sex, respectively. Results Over the course of treatment, active-arm female subjects had a 20.2% improvement in Mini‐Mental State Exam (MMSE) (mean 4.8 points increase, p < 0.001) and active-arm male cohort had 19.3% improvement (p < 0.001). Control-arm female subjects had a 6.5% improvement in MMSE (mean 1.5 points increase, p < 0.03) and control-arm male subjects had 5.9% improvement (p = 0.35) with no significant differences in the mean MMSE between female and male subjects in both arms respectively. Other comparison of assessments including Clock Copying and Drawing Test, Logical Memory Test - immediate and delayed recall yielded nominal but not statistically significant differences. No significant differences were observed in the mean MMSE between female and male subjects in both arms respectively before treatment implementation (active arm, p = 0.12; control arm, p = 0.50) at week 0, or after treatment completion (active arm, p = 0.11; control arm, p = 0.74) at week 8. Conclusion Despite differences between female and male dementia subjects, the response to tNIR light stimulation does not demonstrate gender-based differences. Further studies are warranted to refine the tNIR treatment protocol for subjects suffering from dementia or dementia-related symptoms.

Microscopic blood cell analysis is an important methodology for medical diagnosis, and complete blood cell counts (CBCs) are one of the routine tests operated in hospitals. Results of the CBCs include amounts of red blood cells, white blood cells and platelets in a unit blood sample. It is possible to diagnose diseases such as anemia when the numbers or shapes of red blood cells become abnormal. The percentage of white blood cells is one of the important indicators of many severe illnesses such as infection and cancer. The amounts of platelets are decreased when the patient suffers hemophilia. Doctors often use these as criteria to monitor the general health conditions and recovery stages of the patients in the hospital. However, many hospitals are relying on expensive hematology analyzers to perform these tests, and these procedures are often time consuming. There is a huge demand for an automated, fast and easily used CBCs method in order to avoid redundant procedures and minimize patients’ burden on costs of healthcare. In this research, we investigate a new CBC detection method by using deep neural networks, and discuss state of the art machine learning methods in order to meet the medical usage requirements. The approach we applied in this work is based on YOLOv3 algorithm, and our experimental results show the applied deep learning algorithms have a great potential for CBCs tests, promising for deployment of deep learning methods into microfluidic point-of-care medical devices. As a case of study, we applied our blood cell detector to the blood samples of COVID-19 patients, where blood cell clots are a typical symptom of COVID-19.

Anacyclus pyrethrum (L.) Lag has a long tradition of medical use in Algeria. We report for the first time the antioxidant, functional and neuroprotective properties of this plant from Algeria. Differences in biochemical and physiological properties for the aqueous and methanol extracts of A. pyrethrum are reported and related to the main chemical constituents. The A. pyrethrum extracts contained amino acids, caffeoylquinic acids, N-feruloyltyramine and alkaloids, including including N-alkylamides, common in this plant species. Aqueous extracts (0.1 mg/ml) are neuroprotective against H2O2-induced oxidative stress, while methanol extracts (high phenolic content), despite significant antioxidant and free-radical scavenging activity, caused dysregulation of calcium signalling in neurons and was not apparently neuroprotective. Such knowledge can provide incentive for the sustainable cultivation of Algerian A. pyrethrum, with the aim of supporting conservation strategies and preserving biodiversity.

A phytochemical and biological investigation of the endemic Mascarene Aloes (Aloe spp.), including A. tormentorii (Marais) L.E.Newton & G.D.Rowley, A. purpurea Lam, A. macra Haw., A. lomatophylloides Balf.f and A. vera (synonym A. barbadensis Mill.), which are used in the traditional folk medicine of the Mascarene Islands, was initiated. Methanolic extracts of the Aloes under study were analysed using high resolution LC-UV-MS/MS and compounds belonging to the class of anthraquinones, anthrones, chromones and flavone C-glycosides were detected. The Mascarene Aloes could be distinguished from A. vera by the absence of 2″-O-feruloylaloesin and 7-O-methylaloeresin. GC–MS analysis of monosaccharides revealed the presence of arabinose, fucose, xylose, mannose and galactose in all the Mascarene Aloes and in A. vera. The crude extracts of all Aloes analysed displayed antimicrobial activity against Bacillus cereus, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Only extracts of A. macra were active against P. aeruginosa and Klebsiella pneumoniae, while none of the Aloe extracts inhibited Propionibacterium acnes. A. macra displayed anti-tyrosinase activity, exhibiting 50% inhibition at 0.95 mg/mL, and extracts of A. purpurea (Mauritius) and A. vera displayed activity in a wound healing-scratch assay. In vitro cytotoxicity screening of crude methanolic extracts of the Aloes, using the MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) showed that only A. purpurea (Réunion) elicited a modest toxic effect against HL60 cells, with a percentage toxicity of 8.2% (A. purpurea-Réunion) and none of the Aloe extracts elicited a toxic effect against MRC 5 fibroblast cells at a concentration of 0.1 mg/mL. Mascarene Aloe species possess noteworthy pharmacological attributes associated with their rich phytochemical profiles.

Background and Objective: The dried tuber of Bongardia chrysogonum (L.) is a popular folk remedy for its use in the treatment of epilepsy in traditional medicine. The study aimed to evaluate the anti-oxidant and anti-convulsant activity of B. chrysogonum ethanolic-aqueous extract using the Pentylenetetrazole (PTZ) kindling animal model. Materials and Methods: Male mice were randomly selected and divided into 9 experimental groups including: Control group, pentylenetetrazole kindled mice, positive mice group receiving valproate (200 mg kg–1 p.o.) a classic anticonvulsant drug and 3 groups receiving B. chrysogonum tuber-ethanolic or aqueous extract at a doses of (600, 900 and 1200 mg kg–1 p.o.). All groups, except the control, were kindled by 11 injections of PTZ (40 mg kg–1, i.p.). All groups, except the control group, were tested at 12th PTZ challenge dose (75 mg kg–1 i.p.). The exhibited phases of seizure (0-6) were observed and noted; moreover, anti-oxidant effect of these extract was examined in in vitro study by using a spectrophotometric technique. The significance of differences between groups were determined using one-way analysis of variance (ANOVA) followed by post hoc test, Dunnett’s multiple comparison tests. Results: The data showed that both valproate and B. chrysogonum tuber extracts delay the onset of convulsions, decrease duration of the seizure and reduced mortality significantly (p

The Mascarene Aloes are used in the traditional pharmacopoeia against various ailments including cutaneous diseases and as antispasmodics. Scientific evidence to support these claims is non-existent and mainly based on the scientific repute of A. vera. The antioxidant profile of methanolic leaf extracts of A. purpurea Lam., A. tormentorii (Marais) L. E. Newton & G. D. Rowley, A. lomatophylloides Balf. f., A. macra Haw. and A. vera (L.) Burm. f. was studied using the total antioxidant capacity, copper equivalent and superoxide dismutase assays. In vitro cytotoxicity was evaluated on CAD (Cath.-a-differentiated) neuronal cells by the methyl tetrazolium assay, and the neuroprotective profile was assessed using hydrogen peroxide-induced neurotoxicity with the CAD cells. The aloin and vitexin content were determined by high-performance liquid chromatography with diode-array detection. A. purpurea had the highest aloin content (546.6 nmol/g), while A. tormentorii had the highest vitexin content (67.3 nmol/g). A. macra (concentration

Background We present a pilot study of the Cerebrolite technology, where we explored the effect of multi-modality photo-biomodulation (PBM) therapy, with a peak wavelength of 1068 nm, upon motor function, memory and processing speed reversal in aged individuals who have been diagnosed with mild cognitive impairment (MCI) .Methods PBM therapy was performed at home, adopting the Cerebrolite Trans-cranial phototherapy device, an air-cooled light emitting diode LED pulse mounted inside the helmet, with a peak wavelength of 1068 nm, used for 6 min twice daily on age-matched middle-aged subjects. The FDA- approved computerised assessment tool ANAM was adopted to quantify a series of cognitive and motor activities in the treated groups.Results A significant improvement in motor function, memory and processing speed was observed in MCI aged individuals with PBM- compared to placebo-treated group. No adverse effects were reported.Conclusions PBM therapy may be a promising new non-invasive approach for middle-aged individuals with MCI.

Histamine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Histamine Receptors [75, 163]) are activated by the endogenous ligand histamine. Marked species differences exist between histamine receptor orthologues [75]. The human and rat H3 receptor genes are subject to significant splice variance [12]. The potency order of histamine at histamine receptor subtypes is H3 = H4 > H2 > H1 [163]. Some agonists at the human H3 receptor display significant ligand bias [171]. Antagonists of all 4 histamine receptors have clinical uses: H1 antagonists for allergies (e.g. cetirizine), H2 antagonists for acid-reflux diseases (e.g. ranitidine), H3 antagonists for narcolepsy (e.g. pitolisant/WAKIX; Registered) and H4 antagonists for atopic dermatitis (e.g. ZPL-3893787; Phase IIa) [163] and vestibular neuritis (AUV) (SENS-111 (Seliforant, previously UR-63325), entered and completed vestibular neuritis (AUV) Phase IIa efficacy and safety trials, respectively) [205, 8].

When exposed to an unfamiliar open space, animals experience fear and attempt to find an escape route. Anxiety emerges when animals are confronted with a challenging obstacle to this fear motivated escape. High anxiety animals do not take risks; they avoid the challenge. The present experiments investigated this risk avoidant behavior in mice. In experiment 1, BALB/c, C57BL/6J and CD-1 mice were exposed to a large platform with downward inclined steep slopes attached on two opposite sides. The platform was elevated 75 and 100 cm from the ground, in a standard (SPDS) and in a raised (RPDS) configuration, respectively. In experiment 2, the platform was elevated 75 cm from the ground. Mice had to climb onto a stand at the top of upward inclined slopes (SPUS). In experiment 3, BALB/c mice were exposed to SPDS with steep or shallow slopes either in early morning or in late afternoon. In all 3 test configurations, mice spent more time in the areas adjacent to the slopes than in the areas adjacent to void, however only C57BL/6J and CD-1 crossed onto the slopes in SPDS, and crossed onto the stands in SPUS whereas BALB/c remained on the platform in SPDS and explored the slopes in SPUS. Elevation of the platform from the ground reduced the crossings onto the slopes in C57BL/6J and CD-1, and no differences were observed between BALB/c and C57BL/6J. BALB/c mice demonstrated no difference in anxiety when tested early morning or late afternoon; they crossed onto shallow slopes and avoided the steep one.

Fibrosis of lung tissue is a disease where a chronic inflammatory process determines a pathological remodelling of lung parenchyma. The animal model obtained by intra-tracheal administration of bleomycin in C57BL/6 mice is one of the most validated murine model. Bleomycin stimulates oxidative stress and the production of pro-inflammatory mediators. Histamine H 4 R have recently been implicated in inflammation and immune diseases. This study was focused to investigate the effects of H 4 R ligands in the modulation of inflammation and in the reduction of lung fibrosis in C57BL/6 mice treated with bleomycin. C57BL/6 mice were treated with vehicle, JNJ7777120 (JNJ, selective H 4 R antagonist) or ST-1006 (partial H 4 R agonist), ST-994 (H 4 R neutral antagonist) and ST-1012 (inverse H 4 R agonist) at equimolar doses, released by micro-osmotic pumps for 21 days. Airway resistance to inflation was assayed and lung samples were processed to measure malondialdehyde (TBARS); 8-hydroxy-2⿲-deoxyguanosine (8OH d G); myeloperoxidase (MPO); COX-2 expression and activity as markers of oxidative stress and inflammation. Fibrosis and airway remodelling were evaluated throughout transforming growth factor-β (TGF-β), percentage of positive Goblet cells, smooth muscle layer thickness determination. Our results indicated that JNJ, ST-994 and ST-1012 decreased inflammation and oxidative stress markers, i.e. the number of infiltrating leukocytes evaluated as lung tissue MPO, COX-2 expression and activity, TBARS and 8OH d G production. They also reduced the level of TGF-β, a pro-fibrotic cytokine, collagen deposition, thickness of smooth muscle layer, Goblet cells hyperplasia; resulting in a decrease of airway functional impairment. The results here reported clearly demonstrated that H 4 R ligands have a beneficial effect in a model of lung fibrosis in the mouse, thus indicating that H 4 R antagonists or inverse agonists could be a novel therapeutic strategy for lung inflammatory diseases.

The first studies of histamine and diabetes date back to the 1950s. Since that time the involvement of histamine in diabetes was related to its well known vasoactive properties and permeability leakage effects. In particular, the first evidence for a correlation between histamine and diabetes arose in 1989 when an increase in plasma and leucocyte histamine content was observed. Limited independent evidence followed in the subsequent two decades, focusing on both histamine glyceamic control and macro- and microvascular complications of diabetes. However, recent observations have sparked the question whether it is time to reconsider the functional contribution of histamine in diabetes. We reveal an interesting upsurge in the field which provides scope for new insights into the role of histamine in diabetes.

Parkinson’s disease (PD) pathology is characterised by distinct types of cellular defects, notably associated with oxidative damage and mitochondria dysfunction, leading to the selective loss of dopaminergic neurons in the brain’s substantia nigra pars compacta (SNpc). Exposure to some environmental toxicants and heavy metals has been associated with PD pathogenesis. Raised iron levels have also been consistently observed in the nigrostriatal pathway of PD cases. This study explored, for the first time, the effects of an exogenous environmental heavy metal (vanadium) and its interaction with iron, focusing on the subtoxic effects of these metals on PD-like oxidative stress phenotypes in Catecholaminergic a-differentiated (CAD) cells and PTEN-induced kinase 1 (PINK−1)B9Drosophila melanogaster models of PD. We found that undifferentiated CAD cells were more susceptible to vanadium exposure than differentiated cells, and this susceptibility was modulated by iron. In PINK−1 flies, the exposure to chronic low doses of vanadium exacerbated the existing motor deficits, reduced survival, and increased the production of reactive oxygen species (ROS). Both Aloysia citrodora Paláu, a natural iron chelator, and Deferoxamine Mesylate (DFO), a synthetic iron chelator, significantly protected against the PD-like phenotypes in both models. These results favour the case for iron-chelation therapy as a viable option for the symptomatic treatment of PD.

Behavioural phenotyping of drosphila is an important means in biological and medical research to identify genetic, pathologic or psychologic impact on animal behviour. Automated behavioural phenotyping from videos has been a desired capability that can waive long-time boring manual work in behavioral analysis. In this paper, we introduced deep learning into this challenging topic, and proposed a new 2D+3D hybrid CNN framework for drosphila’s social behavioural phenotyping. In the proposed multitask learning framework, action detection and localization of drosphila jointly is carried out with action classification, and a given video is divided into clips with fixed length. Each clip is fed into the system and a 2-D CNN is applied to extract features at frame level. Features extracted from adjacent frames are then connected and fed into a 3-D CNN with a spatial region proposal layer for classification. In such a 2D+3D hybrid framework, drosophila detection at the frame level enables the action analysis at different durations instead of a fixed period. We tested our framework with different base layers and classification architectures and validated the proposed 3D CNN based social behavioral phenotyping framework under various models, detectors and classifiers.

LINKED ARTICLES This article is part of a themed section on New Uses for 21st Century Antihistamines. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.

Background: Extracts of several members of the monoterpene-rich Lamiaceae sub-family Nepetoideae, including those from the Salvia (sage), Melissa (Lemon balm) and Rosmarinus (rosemary) genera, evince cognitive and mood effects in humans that are potentially related to their effects on cholinergic and GABAergic neurotransmission. To date, despite promising in vitro properties, the cognitive and mood effects of the closely related Mentha spicata (spearmint) and Mentha piperita (peppermint) remain unexplored. This study therefore assessed the human cognitive/mood effects of the M. spicata/piperita essential oil with the most promising, brain-relevant in vitro properties according to pre-trial in vitro screening.\ud \ud Design: Organic spearmint and peppermint (Mentha spicata/piperita) essential oils were pre-screened for neurotransmitter receptor binding and acetylcholinesterase (AChE) inhibition. In a double-blind, placebo-controlled, balanced cross-over study, 24 participants (mean age 25.2 years) consumed single doses of encapsulated placebo and 50 µL and 100 µL of the most promising essential oil (peppermint with nicotinic/GABAA receptor binding and AChE inhibitory properties, that increased calcium influx in a CAD cell neuronal model). Psychological functioning was assessed with mood scales and a range of standardised, cognitively demanding tasks pre-dose and at 1, 3 and 6 h post-dose.\ud \ud Results: The highest (100 µL) dose of essential oil improved performance on the cognitively demanding Rapid Visual Information Processing task (RVIP) at 1 h and 3 h post-dose and both doses attenuated fatigue and improved performance of the Serial 3 s subtraction task at 3 h post-dose.\ud \ud Conclusion: Peppermint (Mentha piperita) essential oil with high levels of menthol/menthone and characteristic in vitro cholinergic inhibitory, calcium regulatory and GABAA/nicotinic receptor binding properties, beneficially modulated performance on demanding cognitive tasks and attenuated the increase in mental fatigue associated with extended cognitive task performance in healthy adults. Future investigations should consider investigating higher doses.

Histamine is a neurotransmitter and chemical mediator in multiple physiological processes. Histamine H3 receptor is expressed in the nervous system, heart, and gastrointestinal tract; however, little is known about H3 receptor in skeletal muscle. The aim of this study was to investigate the role of H3 receptor in skeletal myotubes. The expression of H3 receptor and myosin heavy chain (MHC), a late myogenesis marker, was assessed by real-time PCR and immunostaining in C2C12 skeletal myogenesis and adult mid-urethral skeletal muscle tissues. H3 receptor mRNA showed a significant increase upon differentiation of C2C12 into myotubes: 1-, 26-, 91-, and 182-fold at days 0, 2, 4, and 6, respectively. H3 receptor immunostaining in differentiated C2C12 cells and adult skeletal muscles was positive and correlated with that of MHC. The functional role of H3receptor in differentiated myotubes was assessed using an H3 receptor agonist, (R)-a-methylhistamine ((R)-α-MeHA). Ca(2+) imaging, stimulated by electric pacing, was decreased by 55% after the treatment of mature C2C12 myotubes with 1μM (R)-α-MeHA for 10min and 20min, while treatment with 100nm (R)-α-MeHA for 5min caused 45% inhibition. These results suggested that H3 receptor may participate in the maintenance of the relaxed state and prevention of over-contraction in mature differentiated myotubes. The elucidation of the role of H3R in skeletal myogenesis and adult skeletal muscle may open a new direction in the treatment of skeletal muscle disorders, such as muscle weakness, atrophy, and myotonia in motion systems or peri-urethral skeletal muscle tissues.

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. The anaphylactoid reaction described follows cessation of ranitidine in a 19 year old female with the disease cluster: mast cell activation syndrome, hypermobile Ehlers-Danlos syndrome and postural tachycardia syndrome. Anaphylaxis can give wide-ranging symptoms, from rhinorrhea and urticaria to tachycardia and system-wide, life-threatening, anaphylactic shock. Individuals with a disorder of mast cell activation can experience many such symptoms. H2 receptor antagonists, such as ranitidine, are commonly prescribed in this population. A mechanism for the reaction is proposed in the context of ranitidine, as an inverse agonist, causing upregulation of H2 histamine receptors and raised histamine levels due to enzyme induction. This effect, following extended and/or high antihistamine dosing, may have implications for other individuals with a disorder of mast cell activation, such as mastocytosis or mast cell activation syndrome. There are potential policy and patient guidance implications for primary and secondary care with respect to cessation of H2 antagonists.

Due to the incidence of diabetes and the related morbidity of diabetic nephropathy, identification of new therapeutic strategies represents a priority. In the last few decades new and growing evidence on the possible role of histamine in diabetes has been provided. In particular, the histamine receptor H 4 R is emerging as a new promising pharmacological target for diabetic nephropathy. The aim of this study was to evaluate the efficacy of selective H 4 R antagonism by JNJ39758979 on the prevention of diabetic nephropathy progression in a murine model of diabetes induced by streptozotocin injection. JNJ39758979 (25, 50, 100 mg/kg/day p.o.) was administered for 15 weeks starting from the onset of diabetes. Functional parameters were monitored throughout the experimental period. JNJ39758979 did not significantly affect glycaemic status or body weight. The urine analysis indicated a dose-dependent inhibitory effect of JNJ39758979 on Albumin-Creatinine- Ratio , the Creatinine Clearance, the 24 h urine volume, and pH urine acidification ( P 0.05). The beneficial effects of JNJ39758979 on renal function paralleled comparable effects on renal morphological integrity. These effects were sustained by a significant immune infiltration and fibrosis reduction. Notably, megalin and sodium-hydrogen-exchanger 3 expression levels were preserved. Our data suggest that the H 4 R participates in diabetic nephropathy progression through both a direct effect on tubular reabsorption and an indirect action on renal tissue architecture via inflammatory cell recruitment. Therefore, H 4 R antagonism emerges as a possible new multi-mechanism therapeutic approach to counteract development of diabetic nephropathy development.

The aim of this study is to evaluate the expression of the histamine receptors, particularly focusing on the H4R in human renal tubules. The ex vivo evaluation was carried on specimens from human renal cortex. Primary and immortalized tubular epithelial cells (TECs) and the HK-2 cell line were used as in vitro models. Cells were pretreated for 10 min with chlorpheniramine maleate 10 μM (H1R antagonist), ranitidine 10 µM (H2R antagonist), GSK189254 1 µM (H3R antagonist) or JNJ7777120 10 µM (H4R antagonist), and then exposed to histamine (3 pM–10 nM) for 30 min. The ex vivo evaluation on specimens from human renal cortex was performed by immunohistochemistry. The expression of histamine receptors on primary and immortalized TECs and the HK-2 cell line was evaluated at both gene (RT-PCR) and protein (immunocytofluorescence) levels. The pharmacological analysis was performed by TR-FRET measurements of second messenger (IP3 and cAMP) production induced by histamine with or without the selective antagonists. Our data revealed the presence of all histamine receptors in human tubules; however, only TECs expressed all the receptors. Indeed, histamine elicited a sigmoid dose–response curve for IP3 production, shifted to the right by chlorpheniramine maleate, and elicited a double bell-shaped curve for cAMP production, partially suppressed by the selective H2R, H3R and H4R antagonists when each added alone, and completely ablated when combined together. Herein, we report the identification of all four histamine receptors in human renal tubules.

Background and Objective: Although Bongardia chrysogonum L. (family Berberidaceae) has been used in many countries in traditional medicine to treat gastrointestinal tract disorders, scientific evidence for this treatment is lacking. The present study was carried out to assess the antimicrobial activity and to evaluate the antispasmodic potential of B. chrysogonum tuber extract. Materials and Methods: Extracts were also evaluated for antimicrobial potential against Bacillus subtilis, Staphylococcus aureus, S. epidermidis, Escherichia coli and Pseudomonas aeruginosa using the agar well diffusion method. Minimum inhibitory concentration and minimum bactericidal concentration were determined by using the micro dilution method. To evaluate the antispasmodic activity of B. chrysogonum extract on contractions induced by the spasmogens acetylcholine, BaCl2 and KCl, contractions of rat duodenum were recorded using an isolated tissue bath chamber with an isotonic transducer and oscillographic device. Results were compared by one-way analysis of variance (ANOVA) followed by Dunnett’s post test. Results: Preliminary phytochemical screening of the tuber extract revealed the presence of alkaloids, saponins, tannins and carbohydrates, including monosaccharides. No antimicrobial activity was observed against gram-positive or gram-negative bacteria; however, ethanolic B. chrysogonum tuber extract attenuated the basal contractile activity of rat duodenum smooth muscle and decreased contractions induced by acetylcholine, KCl and BaCl2, suggesting an antimuscarinic effect and/or interference of calcium influx. Alkaloids and saponins present in the extract may account for this antispasmodic effect, suggesting multiple mechanisms that can be explored in future studies. Conclusion: Taken together, results demonstrate that B. chrysogonum tuber extract possesses antispasmodic activity but not antimicrobial activity and supports its traditional use to alleviate gastrointestinal spasms.

The anaphylactoid reaction described follows cessation of ranitidine in a 19‐year‐old female with the disease cluster: mast cell activation syndrome, hypermobile Ehlers‐Danlos syndrome and postural tachycardia syndrome. Anaphylaxis can give wide‐ranging symptoms from rhinorrhoea and urticaria to tachycardia and system‐wide, life‐threatening, anaphylactic shock. Individuals with a disorder of mast cell activation can experience many such symptoms. H(2) receptor antagonists, such as ranitidine, are commonly prescribed in this population. A mechanism for the reaction is proposed in the context of ranitidine, as an inverse agonist, causing upregulation of H(2) histamine receptors and raised histamine levels due to enzyme induction. This effect, following extended and/or high antihistamine dosing, may have implications for other individuals with a disorder of mast cell activation, such as mastocytosis or mast cell activation syndrome. There are potential policy and patient guidance implications for primary and secondary care with respect to cessation of H(2) antagonists.

Due to the incidence of diabetes and the related morbidity of diabetic nephropathy, identification of new therapeutic strategies represents a priority. In the last few decades new and growing evidence on the possible role of histamine in diabetes has been provided. In particular, the histamine receptor H

Background and Purpose The histamine H4 receptor has a primary role in inflammatory functions, making it an attractive target for the treatment of asthma and refractory inflammation. These observations suggested a facilitating action on autoimmune diseases. Here we have assessed the role of H4 receptors in experimental autoimmune encephalomyelitis (EAE) a model of multiple sclerosis (MS). Experimental Approach We induced EAE with myelin oligodendrocyte glycoprotein (MOG35–55) in C57BL/6 female mice as a model of MS. The histamine H4 receptor antagonist 5-chloro-2-[(4-methylpiperazin-1-yl)carbonyl]-1H-indole (JNJ7777120) was injected i.p. daily starting at day 10 post-immunization (D10 p.i.). Disease severity was monitored by clinical and histopathological evaluation of inflammatory cells infiltrating into the spinal cord, anti-MOG35–55 antibody production, assay of T-cell proliferation by [3H]-thymidine incorporation, mononucleate cell phenotype by flow cytometry, cytokine production by elisa assay and transcription factor quantification of mRNA expression. Key Results Treatment with JNJ7777120 exacerbated EAE, increased inflammation and demyelination in the spinal cord of EAE mice and increased IFN-γ expression in lymph nodes, whereas it suppressed IL-4 and IL-10, and augmented expression of the transcription factors Tbet, FOXP3 and IL-17 mRNA in lymphocytes. JNJ7777120 did not affect proliferation of anti-MOG35–55 T-cells, anti-MOG35–55 antibody production or mononucleate cell phenotype. Conclusions and Implications H4 receptor blockade was detrimental in EAE. Given the interest in the development of H4 receptor antagonists as anti-inflammatory compounds, it is important to understand the role of H4 receptors in immune diseases to anticipate clinical benefits and also predict possible detrimental effects. Linked Articles This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/ 10.1111/bph.2013.170.issue-1

Objective. To study histamine transport and metabolism of salivary gland (SG) epithelial cells in healthy controls and SS patients. Methods. Enzymes and transporters involved in histamine metabolism were analysed in cultured human submandibular salivary gland (HSG) epithelial cells and tissue sections using quantitative real-time PCR and immunostaining. HSG cells were used to study [ 3 H]histamine uptake [(±1-methyl-4-phenylpyridinium (MPP)] and efflux by liquid scintillation counting. Results. mRNA levels of L-histidine decarboxylase (HDC) and histamine-N-methyltransferase (HNMT) were similar in the control and SS glands, but diamine oxidase was not expressed at all. Organic cation transporter 3 (OCT3) in healthy SG was localized in the acinar and ductal cells, whereas OCT2 was restricted to the myoepithelial cells. Both transporters were significantly decreased in SS at mRNA and protein levels. OCT3-mRNA levels in HSG cells were significantly higher than those of the other studied transporters. Uptake of [ 3 H]histamine was inhibited by MPP in a time-dependent manner, whereas [ 3 H]histamine-preloaded HSG cells released it. Conclusion. Ductal epithelial cells are non-professional histamine-producing cells able to release histamine via OCTs at the resting state up to � 100 nM, enough to excite H3R/H4R + epithelial cells, but not H1R, which requires burst release from mast cells. At the stimulated phase, 5060mM histamine passes from the interstitial fluid through the acinar cells to saliva, whereas uptake by ductal cells leads to intracellular degradation by HNMT. OCT3/histamine/H4R-mediated cell maintenance and down-regulation of high histamine levels fail in SS SGs.

The focus of this chapter is the visible and noninvisible near infrared electromagnetic frequency spectrum. We explore the biological and neurophysiological impact generated by visible and near infrared light frequencies with specific attention to therapeutic applications in the treatment of neurodegenerative and neuropsychiatric disorders.