An unbiased and efficient assessment of excitability of sensory neurons for analgesic drug discovery

Alleviating chronic pain is challenging, due to lack of drugs that effectively inhibit nociceptors without off target effects on motor or central neurons. Dorsal root ganglia (DRG) contain nociceptive and non-nociceptive neurons. Drug screening on cultured DRG neurons, rather than cell lines, allows the identification of drugs most potent on nociceptors with no effects on non-nociceptors (as a proxy for unwanted side effects on CNS and motor neurons). However, screening using DRG neurons is currently a low-throughput process and there is a need for assays to speed this process for analgesic drug discovery. We previously showed that veratridine elicits distinct response profiles in sensory neurons. Here we show evidence that a veratridine-based calcium assay allows an unbiased and efficient assessment of a drug effect on nociceptors (targeted neurons) and non-nociceptors (non-targeted neurons). We confirmed the link between the oscillatory profile and nociceptors; and the slow-decay profile and non-nociceptors using three transgenic mouse lines of known pain phenotypes. We used the assay to show that blockers for Nav1.7 and Nav1.8 channels, which are validated targets for analgesics, affect non-nociceptors at concentrations needed to effectively inhibit nociceptors. However, a combination of low doses of both blockers had an additive effect on nociceptors without a significant effect on non-nociceptors, indicating that the assay can also be used to screen for combinations of existing or novel drugs for the greatest selective inhibition of nociceptors

One session laparoscopic management of Mirizzi syndrome: feasible and safe in specialist units

BACKGROUND:To evaluate the laparoscopic management of Mirizzi syndrome, seldom diagnosed preoperatively causing difficulty when performing cholecystectomy and increasing complication risks. METHODS:Analysis of a prospective single-surgeon database of 5700 laparoscopic cholecystectomies found 58 Mirizzi syndrome cases. They were managed with an intention to treat during the index admission according to protocol of single-session management of bile duct stones. RESULTS:38/58 patients were females (65.5%). The median age was 55 years. 53 cases were emergency admissions. 34 cases (58.6%) only had ultrasound scanning. Operative difficulty was Grade IV in 34 cases (58.6%) and Grade V in 20 (34.5%) (Nassar Scale). There were 33 Mirizzi Type IA, 7 Type IB, 16 Type II and one each of Type III and Type IV. Bile duct exploration was performed in 94.8% through choledochotomy/ transfistula in 58.6% or transcystic in 36.2%. Four cases required conversion to open. Postoperative morbidity occurred in 29%. Two 30-day mortalities occurred from pneumonia in two elderly patients who were late referrals. CONCLUSION:Although the utilization of the laparoscopic approach in managing bile duct stones is not currently widely practiced it was safer in this series than in reported series of open surgery in Mirizzi Syndrome. The optimal approach to Mirizzi Type II is via cholecystocholedochal fistula to explore the bile duct then drain with T-tube through the fistula. It is unnecessary to perform bilioenteric bypass in majority of cases, reducing the morbidity and mortality

Deletion of annexin 2 light chain p11 in nociceptors causes deficits in somatosensory coding and pain behavior

The S100 family protein p11 (S100A10, annexin 2 light chain) is involved in the trafficking of the voltage-gated sodium channel Na(V)1.8, TWIK-related acid-sensitive K+ channel (TASK-1), the ligand-gated ion channels acid-sensing ion channel 1a (ASIC1a) and transient receptor potential vanilloid 5/6 (TRPV5/V6), as well as 5-hydroxytryptamine receptor 1B (5-HT1B), a G-protein-coupled receptor. To evaluate the role of p11 in peripheral pain pathways, we generated a loxP-flanked (floxed) p11 mouse and used the Cre-loxP recombinase system to delete p11 exclusively from nociceptive primary sensory neurons in mice. p11-null neurons showed deficits in the expression of NaV1.8, but not of annexin 2. Damage-sensing primary neurons from these animals show a reduced tetrodotoxin-resistant sodium current density, consistent with a loss of membrane-associated NaV1.8. Noxious coding in wide-dynamic-range neurons in the dorsal horn was markedly compromised. Acute pain behavior was attenuated in certain models, but no deficits in inflammatory pain were observed. A significant deficit in neuropathic pain behavior was also apparent in the conditional-null mice. These results confirm an important role for p11 in nociceptor function

Ostéogenèse imparfaite type III de découverte tardive: à propos d’un cas

Patient âgé de 52 ans, était admis dans notre établissement pour des polyarthralgies chroniques, plutôt mécaniques, touchant spécialement lesarticulations du membre inférieur. L’interrogatoire retrouvait l’antécédent de fractures répétées depuis l’enfance, pour des traumatismes minimes,suite à des chutes par glissement. Les signes cliniques et radiologiques, notamment, les fractures récurrentes, sclérotiques bleues, hyperlaxitéligamentaire, dentinogenèse imparfaite, syndrome dysmorphique, ostéoporose densitométrique importante, plaidaient tous en faveur d’uneostéogénèse imparfaite type III. Le patient a initié le traitement, par prise régulière du calcium (1g/jour), supplémentation en vitamine D et il estprogrammé pour perfusion de Bisphosphonate (Pamidronate 60mg). Ce cas illustre une forme rare de découverte tardive d’ostéogénèse imparfaitetype III.Key words: Ostéogenèse imparfaite, fractures, pathologie hétérogène, bisphosphonates, ostéodensitométrie

Prevalence of functional bowel disorders and faecal incontinence: an Australian primary care survey

Accepted Article online 30 October 2014. The copyright line for this article was changed on 14 February, 2017 after original online publication.Aim: Interest in functional bowel disorders (FBDs) and faecal incontinence (FI) has increased amongst coloproctologists. The study aimed to assess the prevalence of FBDs and FI (including its severity) among Australian primary healthcare seekers using objective criteria. Method: A cross-sectional survey was conducted in a primary care setting in Sydney, Australia. A self-administered questionnaire was used to collect demographic information and diagnose FBDs (irritable bowel syndrome, constipation, functional bloating and functional diarrhoea) based on Rome III criteria. The severity of FI was determined using the Vaizey incontinence score. Associations with medical/surgical history and healthcare utilization were assessed. Results: Of 596 subjects approached, 396 (66.4%) agreed to participate. Overall, 33% had FBD and/or FI. Irritable bowel syndrome was present in 11.1% and these participants were more likely to report anxiety/depression (P 8). Participants with FI were more likely to have irritable bowel syndrome, urinary incontinence and previous anal surgery (P < 0.01). Conclusion: FBDs and FI are prevalent conditions amongst primary healthcare seekers and the needs of those affected appear to be complex given their coexisting symptoms and conditions. Currently, the majority do not reach colorectal services, although increased awareness by primary care providers could lead to sufferers being referred for specialist management.K.-S. Ng, N. Nassar, K. Hamd, A. Nagarajah and M. A. Gladma

Dynamics and controls of urban heat sink and island phenomena in a desert city:development of a local climate zone scheme using remotely-sensed inputs

This study aims to determine the dynamics and controls of Surface Urban Heat Sinks (SUHS) and Surface Urban Heat Islands (SUHI) in desert cities, using Dubai as a case study. A Local Climate Zone (LCZ) schema was developed to subdivide the city into different zones based on similarities in land cover and urban geometry. Proximity to the Gulf Coast was also determined for each LCZ. The LCZs were then used to sample seasonal and daily imagery from the MODIS thermal sensor to determine Land Surface Temperature (LST) variations relative to desert sand. Canonical correlation techniques were then applied to determine which factors explained the variability between urban and desert LST. Our results indicate that the daytime SUHS effect is greatest during the summer months (typically ∼3.0 °C) with the strongest cooling effects in open high-rise zones of the city. In contrast, the night-time SUHI effect is greatest during the winter months (typically ∼3.5 °C) with the strongest warming effects in compact mid-rise zones of the city. Proximity to the Arabian Gulf had the largest influence on both SUHS and SUHI phenomena, promoting daytime cooling in the summer months and night-time warming in the winter months. However, other parameters associated with the urban environment such as building height had an influence on daytime cooling, with larger buildings promoting shade and variations in airflow. Likewise, other parameters such as sky view factor contributed to night-time warming, with higher temperatures associated with limited views of the sky

Identifying and Explaining Public Preferences for Renewable Energy Sources in Qatar

As a major natural gas and oil producer, Qatar has made significant strides towards its energy transition. This paper uses a survey research design with statistical tests to investigate citizens’ preferences for a wide range of energy resources. In this study, participants were asked to prioritize energy sources based on their environmental impact, price, benefits to Qatar’s economy, support of energy security, and ability to create jobs. The results showed that approximately two-thirds of the sample (n = 354) preferred renewable energy sources, particularly solar, which ranks first. Renewable energy sources were more likely to be favored by the group with greater knowledge of energy sources than those with limited knowledge, except for solar energy, which was preferred by both groups. Additionally, both natural gas and wind rank second in terms of preference, followed by hydropower. In contrast, nuclear power was not ranked, indicating a strong opposition to this type of energy. The study provides an evidence-based example of the tendency of citizens in a hydrocarbon-rich country to prefer renewable energy sources and natural gas. The energy policymakers need to collaborate with local communities so that citizens can participate in important future energy discussions to develop a personal connection to climate solutionsOpen Access funding provided by the Qatar National Library