Journal articles on the topic '822/.92'

ABSTRACT The gene encoding the DNA gyrase A subunit of Streptococcus pneumoniae was cloned and sequenced. The gyrA gene codes for a protein of 822 amino acids homologous to the gyrase A subunit of eubacteria. Translation of the gene in an Escherichia coli expression system revealed a 92-kDa polypeptide. A sequence-directed DNA curvature was identified in the promoter region of gyrA. The bend center was mapped and located between the −35 and −10 regions of the promoter. Primer extension analysis showed that gyrA transcription initiates 6 bp downstream of an extended −10 promoter. The possible implications of the bent DNA region as a regulatory element in the transcription of gyrAare discussed.

Neste trabalho, objetivou-se determinar a diversidade florística e a estrutura fitossociológica da vegetação arbórea em gradiente topográfico de Floresta Estacional Semidecidual Submontana (Mata do Mumbaça), município de Dionísio-MG (19º48'S e 42º31'W). Todos os indivíduos lenhosos com diâmetro ao nível do peito (1,3m) ≥ 10cm foram medidos em 1,2 ha distribuídos em 120 parcelas 10 × 10m de modo a contemplar quatro unidades topográficas (Rampa Baixa, Baixa Encosta, Alta Encosta e Topo). Foram amostrados 2990 indivíduos com um total de 132 espécies, pertencentes a 92 gêneros, representados em 38 famílias. As faixas Alta Encosta e Topo apresentaram maior número de indivíduos, 870 e 822, respectivamente. As faixas que apresentaram maiores valores de área basal foram Rampa Baixa 24,60 m²/ha-1 e Topo 19,36 m²/ha-1. Somente Casearia arborea e Anadenanthera peregrina estiveram presentes entre as dez espécies mais importantes nas quatro faixas, porém algumas espécies ocuparam posições de destaque nas diferentes áreas estudadas como Anadenanthera peregrina e Xylopia aromatica no Topo, Myrcia fallax e Dalbergia nigra na Alta Encosta, Tapirira guianensis e Hortia arborea na Baixa Encosta e Apuleia leiocarpa e Siparuna guianensis na Rampa Baixa.

952 ( ملم ونماذج مكعبات ×522× تقييم تاثير الحرق على سلوك نماذج سقوف خرسانية مسلحة بأبعاد ) 522 952 ( ملم وفق تصميم خلطة خرسانية بمقاومة انضغاط 42 ميكا باسكال. تم تعريضها إلى لهب ×952× بأبعاد ) 952 النار المباشر من السطح الأسفل لثلاثة مستويات من الح ا ررة ) 822،522،422 ( م° لمدة ساعة واحدة. بعد تبريد النماذج إلى درجة الح ا ررة الاعتيادية تم أج ا رء فحصين لا اتلافيين هما فحص الأمواج فوق الصوتية وفحص مطرقة شميدت المرتدة قبل وبعد الحرق. كما وتم تحديد عمق الطبقة التالفة لنماذج السقوف بعد الحرق.وقورنت النتائج مع نماذج المكعبات بعد تعرضها إلى نفس الظروف التي عرضت إليها نماذج السقوف الخرسانية المسلحة لغرض إيجاد التغيير في الوزن, مقاومة الانضغاط, سرعة الموجات و رقم الارتداد. واعتمادا على نتائج هذا البحث شهدت نتائج فحص الانضغاط انخفاضا بمقدار %22 ( في درجة ح ا ررة 422 مْ ،) 26 %( في درجة ح ا ررة 522 مْ ،) 46 %( في درجة ح ا ررة 822 مْ , وان مقدار الفقدان ( 9,1 9,5 (% على التوالي لمستويات درجات الح ا ررة أعلاه, وان - - - (،%)9,5 9,0(، %) بالوزن ظهر ) 2,55 2,5 62 60 (% على التوالي لمستويات - - - (،%)11 18(،%) الانخفاض في سرعة الموجات فوق الصوتية كان بمقدار ) 86 80 22 (% على التوالي لمستويات ( ,%)02( ,%) درجات الح ا ررة أعلاه, كذلك تبين انخفاض في رقم الارتداد وبمقدار ) 92 درجات الح ا ررة أعلاه.

To analyse the potential changes in soil characteristics and associated impacts on the land price, the region of South Moravia was selected, strongly threatened by erosion and by claiming the most valuable land in suburban territories due to industrial and housing expansion. For the detailed analysis of the impacts of erosion and land appropriation in the region of South Moravia, the model territories of Brno surroundings with the municipality of Dolní Heršpice and Hustopeče surroundings with the municipality of Starovice were selected. The price of land degraded by potential erosion in the South Moravian region fluctuates between 88 and 2 400 EUR/ha. In the past 180 years, 148 ha of agricultural land in the total value of 822 815 EUR have been used for construction in the location under study in Dolní Heršpice. Further growth of the municipality should involve additional appropriation of agricultural land in the value of 411 000 EUR. In the studied land block of 100.5 ha, located in the Starovice municipality area, water erosion caused degradation in the total value of 92 000 EUR in the period 1978–2013. Extensive losses of fertile agricultural land are to be expected in the future. Their main causes are continuing land appropriation and degradation processes – soil erosion.

To determine growth patterns of the lung and airways in adolescents, we analyzed maximal expiratory flow-volume curves, closing capacity, and residual volume. They were obtained every 6 mo for up to 7 yr in 430 boys and 125 girls (11–19 yr), of whom 143 boys and 36 girls were classified as symptomatic; symptoms were most often minor and limited to childhood. Development of flows vs. volumes was used to investigate growth of the airways relative to lung size. A model of isotropic growth of the airways and air spaces (J. Appl. Physiol. 65: 822–828, 1988) was modified for increasing elastic recoil pressure with growth. Growth of airways relative to volume occurred faster in teenage boys than in teenage girls and was compatible with isotropic growth in 92% of asymptomatic boys and in 44% of asymptomatic girls: dysanaptic growth in teenage girls seems to be a normal phenomenon and not a unique characteristic of symptomatic subjects. Subjects with respiratory symptoms in childhood and/or adolescence have lower flows for a given lung size and airway closure at a greater lung volume when they enter adulthood. However, no difference in patterns of lung growth was observed in association with the presence of respiratory symptoms.

Fishing on the Sergipe State coast is usually daily but depends on the tide. The main fishing landing port of the municipality of Aracaju is the Aracaju Fishing Terminal (T.P. Aracaju), located in the city center and responsible for 85% of the fishing landings. Data on fishing landings are essential tools for fisheries management, including caught species, fleet size, fishing gear and marketing. Therefore, this study’s aim was to analyze the data collected in the monitoring years from 2010 until 2016 at the T.P. Aracaju observing the developments of fish landings. The Fisheries Landings Monitoring Project - PMPDP specifically monitored and recorded the data at the Terminal Pesqueiro de Aracaju. The results showed that during the monitoring years the landings of fish from 92 vessels, locally called “lancha”, were recorded, of which 50 vessels originated from T.P. Aracaju and the other 42 vessels from other municipalities of Sergipe and other states of Brazil. The total annual production of landed fish was 426t in 2010, 567t in 2011, 504t in 2012, 761t in 2013, 910t in 2014, 822 in 2015 and 737 in 2016. Annual revenue ranged from BRL 2,985,582.00 in 2010 to BRL 8,225,128.7 in 2016, demonstrating that the sale of fish varied little in the years monitored. The work’s results show the real production landed in T.P. Aracaju, on which public policies of fisheries management in the state of Sergipe are based.

Abstract Background In 2016, Candida auris was first reported in the United States, with 2 Illinois patients among the first cases. In response, the state and 3 Chicago-area health departments (HDs) investigated clinical cases and performed point prevalence surveys (PPSs) to identify colonized cases. Methods Clinical cases had positive C. auris cultures obtained for clinical care; colonized cases had positive surveillance cultures during PPSs. In August 2016–January 2018, PPSs were performed in Chicago-area acute care hospital (ACH) intensive care units, long-term acute-care hospitals (LTACHs), and high-acuity floors of skilled nursing facilities (SNFs) and SNFs caring for ventilated patients (vSNFs). Facility and HD staff obtained composite axilla/groin swabs from assenting patients to detect colonization. Facilities with an epidemiologic link to a clinical case or a shared patient population with a facility housing a clinical case were prioritized for PPSs. Results During May 2016–January 2018, Chicago-area facilities reported 24 clinical cases, including 10 bloodstream infections. HDs performed 33 PPSs at 20 facilities (5 ACHs, 5 LTACHs, 3 SNFs, and 7 vSNFs) during August 2016–January 2018. Of 1,364 patients screened, 92 (6.7%) were colonized with C. auris; 10 (50%) facilities had ≥1 colonized patient. A significantly higher proportion screened positive from September 2017 to January 2018 (84/822, 10.2%) than in August 2016–August 2017 (8/542, 1.5%; z-test P < 0.01). Prevalence of C. auris colonization was highest in vSNFs (median: 7.7%; range: 0%–43.3%), compared with ACHs (0%; 0%–6.3%), LTACHs (0%; 0%–14.3%), and SNFs (0%, 0%–1.5%). PPSs in vSNFs identified 91% (84/92) of colonized cases. Among 5 vSNFs with repeat PPSs, 4 had higher prevalence on repeat screening (median: 26.1%; range: 0%–43.3%) than at baseline (1.2%; 0%–17.0%). Conclusion C. auris has rapidly emerged in the Chicago area. Increasing prevalence of C. auris colonization during repeat PPSs indicates transmission and amplification within vSNFs. To prevent spread, state and local HDs provided infection control recommendations, disseminated health alerts, and recommended placing vSNF patients from high-acuity floors on transmission-based precautions. Disclosures All authors: No reported disclosures.

Background: Enteric fever, also known as typhoid fever, is a commonly diagnosed disease in Nepal. Globally, enteric fever affects 21.6 million people and causes 216500 deaths annually. Appropriate use of antibiotics is a key element in the successful treatment of enteric fever. Objective: The study was aimed to study antibiotic use and their appropriateness in the patient with Enteric Fever. Methods: A cross-sectional study was carried out in two tertiary-care hospitals viz. Manipal Teaching Hospital (MTH) and Western Regional Hospital (WRH) in western Nepal between Aug- September 2010. Appropriateness in this study was assessed using Medication Appropriateness Index (MAI) criteria which include indication, effectiveness, dosage, correct directions, practical directions, drug-drug interactions, drug-disease interactions, duplication, duration and expense. Results: Mean use of antibiotics in WRH (2.18±0.87) was not significantly different (P = 0.015) from MTH (2.13±1.11). The Cephalosporin group of antibiotics was used widely to treat enteric fever in both hospitals. On average 1.12 Cephalosporin per patient in MTH and 0.93 Cephalosporin per patient in WRH were used. On average, we found that 31.7% in MTH and 39.5% in WRH of patient’s treatments with antibiotics were inappropriate. Other common types of inappropriateness are expensive drugs [90% (MTH), 92% (WRH)] duplication of antibiotics [53% (MTH), 822% (WRH)], prescribing high generation antibiotics [80% (MTH), 89% (WRH)], and practical direction [17% (MTH), 33% (WRH)]. Conclusion: Conclusively, more than thirty percent of patients in both of hospitals treated for enteric fever received inappropriate antibiotics. Hence we recommend future education or managerial intervention to improve appropriateness. DOI: http://dx.doi.org/10.3126/nje.v3i1.8289 Nepal Journal of Epidemiology 2013;3 (1): 236-242

Introduction: Intraosseous (IO) and intravenous (IV) access to the vascular system for the delivery of fluid and medication is a component of advanced pediatric resuscitation. Data describing the use of IV or IO vascular access methods and outcomes of pediatric out-of-hospital cardiac arrest (OHCA) are limited. Methods: We analyzed prospectively collected data of non-traumatic OHCA of the Resuscitation Outcomes Consortium registry in Canada and the USA (2011-2015). We included patients 17 years of age and younger who were treated by emergency medical services (EMS). We described the vascular access routes utilized, and the success rate of these attempts. We performed a logistic regression model, to evaluate the association of vascular access route and survival, adjusting for age, sex, shockable initial rhythm, witnessed status, public location, EMS arrival interval and time from 911 call to vascular access. In this model, we excluded patients with failed, multiple site or no vascular access attempts during the resuscitation. Results: Of 1549 non-traumatic pediatric OHCA, 822/895 (92%) and 345/488 (71%) had successful IO and IV vascular access attempts, respectively. IO access was more common in younger cases. Of 761 cases included in the regression model, 30/601 (5%) of IO-treated cases survived to hospital discharge, in comparison to 40/160 (25%) of IV-treated cases. Intraosseous access was associated with a decreased survival to hospital discharge (adjusted OR 0.46; 95% CI 0.21 to 0.98). Conclusion: In pediatric patients with OHCA, intraosseous vascular access was more commonly successful than IV placement and more common among younger cases. However, in cases with successful vascular access, IO use was associated with lower survival to hospital discharge.

Background Clinical guidelines recommend annual chlamydia tests for all sexually active people aged 15–29 years. This study measured adherence to these guidelines and compared testing rates to the projected levels required to reduce chlamydia prevalence. Methods: All chlamydia tests conducted in Tasmania during 2012–13, for residents aged 15–29 years, were linked. Data linkage allowed individuals who had multiple tests across different healthcare settings to be counted only once each year in analyses. Rates of testing and test positivity by age, sex, rebate status and socioeconomic indicators were measured. Results: There were 31 899 eligible tests conducted in 24 830 individuals. Testing coverage was higher in females (21%, 19 404/92 685) than males (6%, 5426/98 123). Positivity was higher in males (16%, 862/5426) than females (10%, 1854/19 404). Most tests (81%, 25 803/31 899) were eligible for a rebate. Positivity was higher in females with non-rebatable tests (12%, 388/3116 compared with those eligible for a rebate (9%, 1466/16 285). More testing occurred in areas of middle disadvantage (10%, 9688/93 678) compared with least (8%, 1680/21 670) and most (10%, 7284/75 460) (both P < 0.001) disadvantaged areas. Higher test positivity was found in areas of most-disadvantage (11%, 822/7284) compared with middle- (10%, 983/9688) and least- (8%, 139/1680) disadvantaged areas. Conclusions: Chlamydia testing rates are lower than recommended levels. Sustaining the current testing rates in females aged 20–24 years may reduce population prevalence within 10 years. This study meets key priorities of national strategies for chlamydia control by providing a method of monitoring testing coverage and evidence to evaluate prevention programs.

Object Patients with trigeminal neuralgia due to multiple sclerosis (TN-MS) and idiopathic TN (ITN) who underwent glycerol rhizotomy (GR) and radiofrequency thermocoagulation with glycerol rhizotomy (RFTC-GR) were compared to investigate the effectiveness of these percutaneous ablative procedures in the TN-MS population. Methods Between 1998 and 2010, 822 patients with typical TN were evaluated; 63 (8%) had TN-MS and 759 (92%) had ITN. Pain relief comparisons were made between 22 GR procedures in patients with TN-MS and 470 GR procedures in patients with ITN; 50 RFTC-GR procedures in patients with TN-MS and 287 RFTC-GR procedures in patients with ITN were compared. Analysis of time to recurrence included only procedures that achieved complete pain relief without medications. Results After 15 of the GR procedures (68%) in patients with TN-MS and 315 of the procedures (67%) in those with ITN, the patients were pain free without medications (p = 0.736). After 36 of the RFTC-GR procedures (72%) in patients with TN-MS and 210 of the procedures (73%) in those with ITN, the patients were pain free without medications (p = 0.657). The difference in pain relief between GR and RFTC-GR for patients with TN-MS was not significant (p = 0.447). The median time to failure of GR was 20 months in patients with TN-MS compared with 25 months in those with ITN (p = 0.403). The median time to failure of RFTC-GR was 26 months in the TN-MS population compared with 21 months in the ITN population (p = 0.449). Patients with TN-MS experienced similar times to recurrence whether they were treated with GR or RFTC-GR (p = 0.431). Conclusions Pain relief and durability of relief outcomes of GR and RFTC-GR were similar in patients with TN-MS and ITN, reinforcing their use as preferred treatments of TN-MS. The GR and RFTC-GR achieved comparable outcomes in patients with TN-MS, suggesting that both can be used to good effect.

e15106 Background: Immune-checkpoint inhibitors (ICIs) are increasingly used to treat a variety of cancers. Immune-related adverse events (irAEs) have been reported. Oral manifestations of irAEs include stomatitis, oral ulcers, and xerostomia. However, the trajectory and frequency of oral irAEs remain unclear. This study aims to evaluate the prevalence, trajectory and nature of oral irAEs and their association with primary cancer diagnosis and other irAEs. Methods: A retrospective electronic chart review using the Partners Research Patient Data was performed for all patients treated with ICIs at Partners Healthcare hospitals and the Dana-Farber Cancer Institute between 12/2011 and 9/2019. Keywords specific to oral irAE such as oral mucositis, stomatitis or mouth sore were used. We collected data on demographics, cancer features, treatments, and characteristics of oral irAEs. Results: 822 of 4683 patients who received ICIs therapy were identified by keyword filtering. Lung cancer, gastrointestinal cancer, and skin cancer (including melanoma) were the most common types of primary malignancies with a frequency of 35.5%, 12.4 % and 11.7%, respectively. Oral irAEs were identified in 106 patients with the median age of 69 (range: 29-92) years and the female to male ratio of 1:1. 57.5% (n = 61) presented with symptomatic oral mucosal lesions. 47.2% (n = 50) had xerostomia and 17.0% (n = 18) had dysgeusia. The median time from the date of ICIs initiation to the date of oral irAE onset was 105 days (range: 2-631 days) in patients presented with oral mucosal lesions, 103 days (2-860 days) in xerostomia patients, and 156 days (range: 5-836 days) in dysgeusia patients. Melanoma was the most common cancer seen in oral irAE patients (30.2%), followed by lung cancer (26.4%) and oral/oropharyngeal cancer (12.3%). 60, 42, and 12 patients received pembrolizumab, nivolumab, and ipilimumab, respectively. 86.8% of oral irAE patients received only one type of ICIs therapy. Concomitant cutaneous, intestinal, and rheumatological irAEs were commonly reported with a frequency of 19.4%, 15.3%, and 12.2%, respectively in those patients. Conclusions: Oral irAEs can present with both acute and chronic onset in patients with ICIs therapy but are not as common as oral AEs associated with conventional cytotoxic regimens. While data relative to capturing oral irAEs is still preliminary, the current provides insight into their nature and course. Prospective studies focused on assessing the impact of ICI on oral irAEs are likely to provide additional insight into the character, course and impact of these conditions.

e15576 Background: Patients with unresectable mCRC can achieve long-term overall survival (OS) thanks to modern systemic treatment and subsequent lines of therapy. With effective 1st, 2nd and next lines of therapy, their condition often allows further lines of treatment. Since publication of RECOURSE study, one of the most frequently used drugs in the 3rd or 4th line is trifluridine/tipiracyl (FTD/TPI). There is limited data on optimal selection of patients in order to obtain the greatest therapeutic gain with the least toxicity. The aim of this study was to find and define groups of patients who would benefit most from this treatment in a real-world mCRC patient population. Methods: Consecutive patients with unresectable or metastatic colorectal cancer (mCRC) started treatment with FTD/TPI between 1/Sep/2019 and 31/Dec/2023. Clinical factors including age, gender, primary location of colorectal cancer, BRAF, RAS and MSI-H status, ECOG performance status, baseline CEA level, location of metastases, response to treatment and AEs occurrence were analyzed. Survival analyses were performed using the Kaplan-Meier method, Log-rank and chi-square tests were used for comparison between groups. Data cut-off was 31/Jan/2024. Results: 822 medical records of patients with mCRC were analyzed. In total 261 patients treated with FTD/TPI were enrolled. 204 (78%) patients were treated with FTD/TPI in 3rd line (L3) and 57 (22%) in the 4th line (L4). Patients with RASmt were statistically more numerous in the L3 group; no other statistically significant differences in baseline characteristics was found between L3 and L4 groups. Estimated median OS (mOS) was 10.2 and 14.4 months in L3 and L4 group, respectively; no statistical significance was found between them (p = 0.0866; HR = 1.34, Cl 95% 0.9-1.9). Estimated median PFS (mPFS) was 7.4 and 4.6 months in L3 and L4 group, respectively, and statistically significant differences in mPFS was found in the L3 group in comparison to L4 (p = 0.0079; HR = 0.65, Cl 95% 0.5-0.9). Disease progression (PD) was found in 187 (92%) and 50 (88%) patients in the L3 and L4 group, respectively. PD was most common reason for discontinuing therapy. Most frequent serious AEs of grade 3 or higher were diarrhea, neutropenia and weakness. There were no grade 5 AEs and toxicity rarely led to discontinuation of FTD/TPI therapy. 102 (39%) patients were qualified for next line sequential systemic treatment after L3 or L4. Conclusions: Patients with mCRC who were treated with FTD/TPI in the 3rd line had better PFS than patients treated in 4th line, but mOS was statistically non-significantly better in L4 than L3, which requires further analysis. FTD/TPI is an effective therapy in subsequent lines of treatment for mCRC patients with acceptable toxicity.

Sickle cell anemia (SCA) is associated with an increased hypoxic response from anemia and vaso-occlusion-impaired tissue perfusion. The effects of hypoxia are mediated by hypoxia transcription factors (HIFs). Chuvash erythrocytosis (CE) is an inherited condition due to homozygosity for the missense mutation in VHL gene (VHLR200W) that impairs interactions of VHL with HIF-α subunits, thereby augmenting transcription of HIF-regulated genes. CE and SCA share increased expression of erythropoietin (EPO) and other HIF target genes. As HIF-regulation of transcription is tissue and differentiation-stage specific, in this study we used reticulocytes, which are easily accessible and purified peripheral blood erythroid cells. We compared the transcriptomes of SCA and CE reticulocytes to differentiate HIF-mediated dysregulation from non-hypoxic dysregulation of SCA transcripts. Our study revealed reticulocyte gene expression changes that are common to both diseases as well as SCA-specific changes. The reticulocytes were purified from 5 HbSS and 5 age- and gender-matched HbAA African-American individuals, and from 17 VHLR200W homozygotes from Chuvashia and 13 wild type Chuvash individuals. Total RNA was depleted of ribosomal RNA and globin transcripts, and reverse transcribed. Strand-specific libraries were constructed for 100 or 125 bp paired-end sequencing to 30-45 million reads using Illumina HiSeq 2500 or 4000 platform. The sequencing data were mapped to human reference genome version GRCh37 using the splice-aware aligner STAR and analyzed using DESeq2. In separate analyses of the two diseases, we identified 1435 genes differentially expressed in SCA among 6965 analyzed genes, 848 increased and 587 decreased in SCA relative to control individuals. We also identified 1498 genes differentially expressed in CE among 8989 analyzed genes, 862 increased and 636 decreased in CE relative to control individuals. Across all analyzed genes, there was a moderate correlation (r=0.30) of expression changes between the two diseases. Among genes differentially expressed, 258 up-regulated and 155 down-regulated genes overlapped between the two diseases, representing a 1.4-fold enrichment. In a combined analysis of the two diseases, we identified 1228 genes among 6924 analyzed genes that shared altered regulation in both diseases. The 693 genes increased in both diseases were enriched (adjusted P < 0.05) in multiple metabolic, inflammatory, and oxidative pathways. The 535 genes decreased in both diseases were enriched in a cell cycle pathway. Among the commonly increased genes, the expression level of ERFE encoding erythroferrone was increased by 9.4-fold in CE and by 4.3-fold in SCA, suggesting markedly altered iron regulation in CE and SCA. This would be expected as both SCA and CE share upregulated erythropoiesis that is associated with augmented erythroferrone. Among the commonly decreased genes, RPL3L encoding Ribosomal Protein L3 Like was decreased by 68% in CE and by 93% in SCA. These common expression changes reflect hypoxic regulation related to chronic anemia in SCA. To assess disease-specific gene expression change, we tested the disease (SCA versus CE) by genotype (mutation versus wildtype) interaction effect. We identified 822 genes that showed disease-specific expression changes among 6924 analyzed genes. Of these disease-specific genes, 304 were increased and 153 decreased in SCA (adjusted P <0.05) but not in CE (nominal P >0.05). For example, SLC16A1, encoding Solute Carrier Family 16 Member 1 and associated with an erythrocyte lactate transporter defect, was increased in SCA by 11-fold whereas PPBP encoding Pro-Platelet Basic Protein was decreased in SCA by 92%; both genes showing no change in CE. The 304 genes with SCA-specific increased expression were enriched in "Thyroid hormone signaling" (5.1 fold) and "Glioma" (7.0-fold) pathways. The 153 genes with SCA-specific decreased expression were enriched in "Ribosome" (12-fold) pathway. Among the disease-specific genes, only 34 increased and 28 decreased in CE but not in SCA. Our study demonstrates high HIF transcriptional activity in both CE and SCA reticulocytes but also reveals hypoxia-independent gene expression changes in SCA reticulocytes. These results suggest that HIF might be a therapeutic target of SCA. These data also shed light on the different molecular mechanisms underlying SCA complications. Disclosures Gordeuk: Pfizer: Research Funding; Modus Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Emmaus: Consultancy, Honoraria; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding; Inctye: Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Ironwood: Research Funding; Imara: Research Funding.

Introdução: O manejo no atendimento odontológico infantil torna-se fatigante quando não há cooperação por parte da criança e/ou dos responsáveis. A fim de minimizar esses quadros, quando não existe sucesso das técnicas de abordagem comportamental tradicionais, métodos terapêuticos alternativos têm sido amplamente estudados, em especial a sedação consciente com óxido nitroso associada ou não a fármacos sedativos. Objetivo: Dessa forma, objetivou-se realizar uma revisão crítica da literatura norteando o cirurgião-dentista sobre o uso do óxido nitroso e sua associação a fármacos, esclarecendo suas indicações, vantagens e desvantagens. Métodos: Foi realizada uma busca integrativa da literatura nacional e internacional, entre 2004 a 2019, nas bases Bireme e PubMed, utilizando os descritores: sedação consciente, ansiedade no tratamento odontológico e óxido nitroso. Resultados: No total, 43 artigos foram incluídos nesse estudo. O óxido nitroso tem sido bastante utilizado na odontologia, especialmente na odontopediatria. Este atua no sistema nervoso, promovendo uma leve depressão do córtex cerebral e não deprime o centro respiratório, sendo considerado seguro. A técnica pode ser combinada a outros fármacos, como Midazolam e Prometazina, sendo que cada abordagem medicamentosa apresenta suas indicações e vantagens específicas. Conclusão: A sedação consciente mostra-se como um método viável, e quando bem indicada é considerada segura. Seu papel na Odontologia vem sendo consolidado com o tempo, em decorrência dos inúmeros benefícios encontrados. No entanto, ainda existe certa resistência na utilização da mesma, tanto por parte dos responsáveis como também de alguns profissionais. Descritores: Sedação Consciente; Ansiedade ao Tratamento Odontológico; Óxido Nitroso. Referências Jain S. Sedation: A Primerfor Pediatricians. Pediatr Ann. 2018;47(6):254-58. Ashley PF, Chaudhary M, Lourenço-Matharu L. 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RESUMEN:El objetivo del artículo es aproximarnos a la controvertida biografía del comisario Manuel Brabo Portillo. El trabajo está basado en fuentes primarias y secundarias. El método utilizado es empírico. En el imaginario del mundo sindicalista revolucionario, Brabo Portillo era el policía más odiado, la reencarnación de la cara más turbia del Estado. Fue, así mismo, un espía alemán relacionado con el hundimiento de barcos españoles, el asesinato del empresario e ingeniero Barret y el primer jefe de los terroristas vinculados a la patronal barcelonesa. La conflictividad que afectó a España en el período de la Primera Guerra Mundial es fundamental para entender los orígenes del terrorismo vinculado al pistolerismo, que marcó la historia político social española del primer tercio del siglo XX.PALABRAS CLAVE: Brabo Portillo, pistolerismo, espionaje, sindicalismo, Primera Guerra Mundial.ABSTRACT:The objective of the article is an approach to the controversial biography of Police Chief Manuel Brabo Portillo. The work is based on primary and secondary sources. The method used is empirical. In the imagery of the revolutionary syndicalist world, Brabo Portillo was the most hated policeman, the reincarnation of the murkiest face of the state. He was also a German spy connected with the sinking of Spanish ships, the murder of businessman and engineer Josep Barret and the first head of the terrorists linked to Barcelona employers. 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Six CMS lines and nine restorers ofsunflower were used in a Line × Tester mating design at Zonal Agricultural Research Station, Bengaluru to determine the combining ability and mode of gene action. The traits studied were days to 50 % flowering, plant height, head diameter, stem diameter, seed yield/plant, 100 seed weight, volume weight and oil content. The gca and sca effects were not significant for all the traits. The SCA variance were greater than GCA variance for the traits viz., plant height, head diameter, seed yield/plant, stem diameter and 100 seed weight, which showed greater manifestation of non-additive gene action. Among the CMS line, BCB-43A andamong the testers, LTRR-822, RHA-95C-1 and RHA-95C-2 were good general combiners for most ofthe traits. The cross combinations BCB-171A × RHA 95C-2, BCB-44A × RHA-92, BCB-44A × RHA-95C-1, BCB-43A × GKVK-2 and BCB-170A × LTRR-822 showed higher sca for seed yield/plant.

Purpose: To compare training characteristics and aerobic power (VO2max) between the most successful junior and senior seasons of world-class cross-country (XC) skiers and to identify differences between sexes and among sprint and distance skiers.Methods: Retrospective analysis was conducted on self-reported training and VO2max tests of ten male and seven female world-class XC-skiers, collectively holding 38 Olympic medals. Training was categorized by form (endurance, strength, speed, other) and mode (specific, unspecific) and was divided into low- (LIT), moderate- (MIT), and high-intensity training (HIT).Results: Total training increased by 203 ± 130 h (35% ± 31%, p &lt; .001, large effect) and 78 ± 69 sessions (21% ± 24%, p &lt; .001, very large effect). Junior training volume (658 ± 107 h) did not correlate with senior volume (861 ± 74 h) but correlated negatively with changes in volume (r = −.822, p &lt; .001). No sex differences were observed related to total volume, but distance skiers increased their total volume more than sprint skiers (p = .037, large effect). Endurance training increased by 197 ± 117 h (p &lt; .001; large effect) tied to increased low-intensity training (186 ± 115 h, p &lt; .001; large effect) and moderate-intensity training (13 ± 7 h, p &lt; .001; large effect). Training intensity distribution (% LIT/MIT/HIT) was 91/3/6 in junior and 92/4/4 in senior season. Women demonstrated greater increase of unspecific modes (100 ± 58 vs. 37 ± 44 h, p = .022; large effect) and strength training (25 ± 23 vs. −3 ± 17 h, p = .010, large effect). Men improved absolute (8% ± 5%; p = .009; large effect) and relative VO2max (6% ± 4%; p = .016; large effect) from junior to senior, while women only increased relative VO2max (7% ± 5%, p = .012; large effect).Conclusion: This study provides novel information regarding changes in training characteristics and aerobic power from junior to senior age in world-class XC-skiers. Overall, the enhanced training volume during this transition was primarily driven by increased LIT and MIT and the exceptionally high relative VO2max at junior age further increased in both sexes.

Background: In hypertrophic cardiomyopathy (HCM), late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) is an in vivo marker of replacement fibrosis with a continuous relationship between amount of LGE and both risk for sudden death and development of endstage disease. Cost and accessibility can limit routine utilization of CMR. In contrast, electrocardiogram (ECG) is an inexpensive readily available test and identifies patients with myocardial scarring in ischemic heart disease. Its ability to identify presence and extent of LGE in HCM is unknown. Methods: 1983 consecutive HCM patients were included; 62% male, average wall thickness 18 ± 3mm, and 36% with resting LV outflow tract obstruction ≥ 30mmHg. ECGs were analyzed for LV hypertrophy, T wave abnormalities, ST-segment depression or elevations, abnormal Q waves, conduction disease, atrial enlargement and QTc prolongation. Extent of LGE was quantified and expressed as a proportion of total LV myocardium. Results: 822 (41%) had no LGE, while 1161 (59%) had LGE, including 687 (35%) with <5%, 299 (15%) with 5-9%, 92 (5%) with 10-14%, and 83 (4%) with ≥ 15%. Compared to no LGE, Patients with LGE were more likely to have pathologic T wave inversions (55% vs. 36%, p<0.01), positive T waves in aVR (34% vs. 20%, p<0.01), and ST-depressions (29% vs. 21%, p<0.01), with no difference in LV hypertrophy, bundle branch block, pathologic Q waves, first degree AV block, QTc prolongation ≥ 480ms, or ST-elevations (p>0.05). Notably, as extent of LGE increased there was a corresponding progressive increase in the prevalence of both positive T waves in aVR (20% in no LGE to 42% in ≥ 15% LGE, p<0.01) and pathologic T wave inversions (36% in no LGE to 61% in ≥ 15% LGE, p<0.01) but with no incremental differences in ST depressions (p>0.05). In contrast, 43% of patients with LGE did not have either positive T waves in aVR or pathologic T wave inversions, including 34% with ≥ 15% LGE. Conclusion: Most ECG findings including pathologic Q waves have no relation to presence or extent of LGE. While positive T waves in aVR and pathologic T wave inversions are associated with LGE, they have limited sensitivity. These finding support that routinely evaluated ECG abnormalities do not predict presence or extent of scarring in HCM.

The Himalayan Orogen is a typical continental collision orogenic belt that formed during India-Asia collision. The orogeny involved a transition in tectonic regime, which led to E-W−trending extension during the middle Miocene. At the same time, widespread post-collisional adakitic magmatism occurred in southern Tibet, particularly in the Lhasa Terrane, and these rocks provide a valuable record of the collisional geodynamic processes within the lithosphere. Few studies have focused on the middle Miocene adakitic rocks of the Himalayan Orogen, so further research is required to constrain their origin and geodynamics. This study presents new geochronological and geochemical data, including the whole rock Sr-Nd and zircon Hf isotopic compositions from the Mayum pluton in the Mayum-Gong Tso area, Northern Himalaya. Zircon U-Pb ages show that the Mayum granodiorite porphyries crystallized at 16.67 ± 0.14 Ma (mean square weighted deviation [MSWD] = 0.82, n = 29) and 16.68 ± 0.16 Ma (MSWD = 1.13, n = 28), indicating that they formed during the middle Miocene. The major and trace element characteristics are as follows: SiO2 = 65.79−67.31 wt%, Al2O3 = 15.28−16.00 wt%, MgO = 1.77−1.89 wt%, Y = 12.0−13.5 ppm, Yb = 0.11−0.99 ppm, Sr = 719−822 ppm, (La/Yb)N = 21.89−27.02, Sr/Y = 56.1−65.5, and the rocks have weak negative Eu anomalies (Eu/Eu* = 0.76−0.85), indicating that they are adakitic rocks and show high Sr-Ba granite affinity. The Mayum granodiorite porphyries have high K2O contents (3.42−3.65 wt%), Na2O (3.76−4.04 wt%), and K2O/Na2O ratios of 0.91−0.95, indicating a high-K calc-alkaline affinity. All samples are enriched in large-ion lithophile elements and depleted in high field strength elements. The initial 87Sr/86Sr ratios are 0.709262−0.709327 and εNd(t) values are −6.36 to −7.07, which correspond to two-stage Nd model ages [TDM2(Nd)] of 1405−1348 Ma. In situ zircon Lu-Hf isotopic compositions are variable, with 176Hf/177Hf ratios of 0.2823845−0.282824, εHf(t) values of −13.37 to +2.17, and two-stage Hf model ages [TDM2(Hf)] of 1704−841 Ma. These geochemical and Sr-Nd-Hf isotopic characteristics indicate that the Mayum granodiorite porphyries may be derived from partial melting of the subducted Indian thickened ancient mafic lower crust (∼92%) mixed with depleted mid-ocean ridge basalt mantle material input (∼8%) slightly. Crust-mantle interaction was induced by asthenospheric upwelling followed by the underplating of the Himalayan lower crust beneath Southern Tibet during the middle Miocene in response to significant changes in the geodynamics of the India-Asia collisional orogen. These deep geodynamic processes reflect the break-off or rollback of the subducted Indian continental slab, which caused asthenospheric upwelling, the input of juvenile heat, and the addition of depleted mantle material. This study indicates that the middle Miocene Himalayan adakitic rocks, which include the Miocene Yardoi two-mica granite, Gyangzê granite porphyry dike, Bendui two-mica granite, Langkazi enclave, Kuday dacitic dike, Lasa pluton, and Mayum pluton, form a belt of adakitic rocks in the Northern Himalaya to the south of the Indus-Tsangpo Suture Zone. These adakitic rocks have similar temporal and spatial distributions, geochemical features, and Sr-Nd isotopic compositions, indicating that their petrogenesis and geodynamic settings were similar. At that time there was widespread initiation of N-S−trending rifting, exhumation of central Himalayan eclogites, and large changes in the compositions of Himalayan leucogranites in the Himalayan Orogen. These can be attributed to significant changes in the characteristics of the subducted Indian continental lithosphere during the middle Miocene. The middle Miocene Himalayan adakitic rocks provide valuable insights into this transition in the tectonic regime and deep geodynamic processes.

BackgroundPatients who are unable to eat normally can be provided with enteral nutrition (tube feeding) via several routes, including percutaneous endoscopic gastronomy (PEG)and nasogastric (NG) tubes. In this retrospective cohort study, we examined the relationship between PEG and NG tube placement and three outcomes: mortality, complication, and discharge location, controlling for demographic covariates that have been associated with health disparities. We also examined the relationship between demographic covariates and types of tube placement.MethodsWe use delectronic medical record data to identify patients (n=3416) receiving enteralnutrition (PEG n=2321; NG n=1095) during 2013–2015 in a large urban hospital. ICD‐9 codes were used to assess complications. Mortality and complication were binary variables and a binary variable for discharge location was calculated to represent patients who were discharged to an attended setting or an unattended(e.g., home) setting. Relationships between enteral access type and outcomes were analyzed using logistic regression. Demographic covariates were race, coded as non‐White and White; insurance, coded as Medicaid, Medicare, orprivate; age, and sex.ResultsTube type was not found to be significantly associated with mortality, with or without adjustment for covariates. Odds of having a complication in patients with PEG tubes was 59.6 times more than those with NG tubes, adjusted for covariates (p<0.0001). The odds of being sent to an unattended discharge location (ie, home) following hospital treatment was 92% less likely for patients with PEG than those with NG tubes, adjusted for covariates (OR=0.08; p<0.0001). Having a PEG placed was 1.19 times more likely in non‐Whites than in Whites (p=.0196), 2.2 times greater among patients with Medicare (p<0.0001), and 1.4 times greater among patients with Medicaid (p=.0019), compared to patients with private insurance. Sex was not significantly associated with tube type.ConclusionsMortality was not found to be associated with tube type. However, the complication ratio was heavily skewed toward those with PEG devices. Those with PEG devices were much more likely to be sent to an attended care facility compared to those with NG tubes. Non‐Whites and those with government insurance were also more likely to have a PEG device. This may beconfounded by patient comorbidities or factors relating to PEGs and the healthcare system like length of stay or costs. The risk of complication with PEG compared to NG tubes and the impact patient demographics have on these outcomes should be examined in future studies to clarify the role of health disparities in artificial nutrition.Support or Funding InformationThis study was funded by National Institutes of Health Training Grant #HL007343 Descriptivestatistics and sample outcome compositions Composition Covariates PEG (n=2321) NGT (n=1095) Sex Male 1192 (68.31%) 553 (31.69%) Female 1129 (67.56%) 542 (32.44%) Insurance (SES) Medicaid (low) 461 (63.94%) 260 (36.06%) Medicare (gov't) 1477 (73.52%) 532 (26.48%) Private 383 (55.83%) 303 (44.17%) Age Mean: 62.4 year Mean: 66.7 years Ethnicity Non‐White 1499 (69.37%) 662 (30.63%) White 822 (65.50%) 433 (34.50%) Outcomes Mortality Yes (expired) 223 (71.47%) 89 (28.53% No 2098 (67.59%) 1006 (32.41%) Complication Yes 120 (99.17%) 1 (0.83% No 2201 (66.80%) 1094 (33.20%) Discharge Location (Unattended vs Attended) Unattended 134 (22.64%) 458 (77.36%) Attended 1964 (78.18%) 548 (21.82%) Univariate predictors of tube type among potentialconfounders Composition Logistic Regression results PEG (n=2321) NGT (n=1095) β parameter Odds Ratio P‐value Sex Male 1192 (68.31%) 553 (31.69%) 0.0342 1.035 0.6408 Female 1129 (67.56%) 542 (32.44%) 0 (ref) ‐‐‐ ‐‐‐ Insurance (SES) Medicaid (low) 461 (63.94%) 260 (36.06%) 0.3385 1.403 0.0019 Medicare (gov't) 1477 (73.52%) 532 (26.48%) 0.7869 2.197 <.0001 Private 383 (55.83%) 303 (44.17%) 0 (ref) ‐‐‐ ‐‐‐ Age Mean: 62.4 year Mean: 66.7 years 0.0124 1.012 <.0001 Ethnicity Non‐White 1499 (69.37%) 662 (30.63%) 0.1763 1.193 0.0196 White 833 (65.50%) 433 (34.50%) 0 (ref) ‐‐‐ ‐‐‐ Power analysis >0.999 Multivariate logistic regression adjusted forpotential confounders sex, SES, age, and ethnicity Outcome Predictor ORcrude ORadjusted 95% CI Adj P‐value Adj Mortality PEG 1.201 1.154 0.889, 1.499 0.2829 NGT 1.0 1.0 ‐‐‐ ‐‐‐ Complication PEG 59.589 55.159 7.7, 395.124 <0.0001 NGT 1.0 1.0 ‐‐‐ ‐‐‐ Discharge Location (Unattended vs Attended ) PEG 0.082 0.080 0.064, 0.101 <0.0001 NGT 1.0 1.0 ‐‐‐ ‐‐‐

The TRP superfamily of channels (nomenclature as agreed by NC-IUPHAR [159, 997]), whose founder member is the Drosophila Trp channel, exists in mammals as six families; TRPC, TRPM, TRPV, TRPA, TRPP and TRPML based on amino acid homologies. TRP subunits contain six putative TM domains and assemble as homo- or hetero-tetramers to form cation selective channels with diverse modes of activation and varied permeation properties (reviewed by [679]). Established, or potential, physiological functions of the individual members of the TRP families are discussed in detail in the recommended reviews and in a number of books [371, 635, 1064, 236]. The established, or potential, involvement of TRP channels in disease is reviewed in [412, 634] and [637], together with a special edition of Biochemica et Biophysica Acta on the subject [634]. Additional disease related reviews, for pain [585], stroke [1050], sensation and inflammation [919], itch [117], and airway disease [284, 977], are available. The pharmacology of most TRP channels has been advanced in recent years. Broad spectrum agents are listed in the tables along with more selective, or recently recognised, ligands that are flagged by the inclusion of a primary reference. See Rubaiy (2019) for a review of pharmacological tools for TRPC1/C4/C5 channels [751]. Most TRP channels are regulated by phosphoinostides such as PtIns(4,5)P2 although the effects reported are often complex, occasionally contradictory, and likely to be dependent upon experimental conditions, such as intracellular ATP levels (reviewed by [939, 638, 747]). Such regulation is generally not included in the tables.When thermosensitivity is mentioned, it refers specifically to a high Q10 of gating, often in the range of 10-30, but does not necessarily imply that the channel's function is to act as a 'hot' or 'cold' sensor. In general, the search for TRP activators has led to many claims for temperature sensing, mechanosensation, and lipid sensing. All proteins are of course sensitive to energies of binding, mechanical force, and temperature, but the issue is whether the proposed input is within a physiologically relevant range resulting in a response. TRPA (ankyrin) familyTRPA1 is the sole mammalian member of this group (reviewed by [268]). TRPA1 activation of sensory neurons contribute to nociception [382, 829, 555]. Pungent chemicals such as mustard oil (AITC), allicin, and cinnamaldehyde activate TRPA1 by modification of free thiol groups of cysteine side chains, especially those located in its amino terminus [529, 51, 336, 531]. Alkenals with α, β-unsaturated bonds, such as propenal (acrolein), butenal (crotylaldehyde), and 2-pentenal can react with free thiols via Michael addition and can activate TRPA1. However, potency appears to weaken as carbon chain length increases [23, 51]. Covalent modification leads to sustained activation of TRPA1. Chemicals including carvacrol, menthol, and local anesthetics reversibly activate TRPA1 by non-covalent binding [391, 470, 1005, 1004]. TRPA1 is not mechanosensitive under physiological conditions, but can be activated by cold temperatures [392, 193]. The electron cryo-EM structure of TRPA1 [688] indicates that it is a 6-TM homotetramer. Each subunit of the channel contains two short ‘pore helices’ pointing into the ion selectivity filter, which is big enough to allow permeation of partially hydrated Ca2+ ions. TRPC (canonical) familyMembers of the TRPC subfamily (reviewed by [261, 726, 15, 4, 84, 410, 687, 60]) fall into the subgroups outlined below. TRPC2 is a pseudogene in humans. It is generally accepted that all TRPC channels are activated downstream of Gq/11-coupled receptors, or receptor tyrosine kinases (reviewed by [713, 887, 997]). A comprehensive listing of G-protein coupled receptors that activate TRPC channels is given in [4]. Hetero-oligomeric complexes of TRPC channels and their association with proteins to form signalling complexes are detailed in [15] and [411]. TRPC channels have frequently been proposed to act as store-operated channels (SOCs) (or compenents of mulimeric complexes that form SOCs), activated by depletion of intracellular calcium stores (reviewed by [689, 15, 718, 764, 1037, 141, 675, 55, 142]). However, the weight of the evidence is that they are not directly gated by conventional store-operated mechanisms, as established for Stim-gated Orai channels. TRPC channels are not mechanically gated in physiologically relevant ranges of force. All members of the TRPC family are blocked by 2-APB and SKF96365 [319, 318]. Activation of TRPC channels by lipids is discussed by [60]. Important progress has been recently made in TRPC pharmacology [751, 571, 400, 92]. TRPC channels regulate a variety of physiological functions and are implicated in many human diseases [270, 61, 825, 958]. TRPC1/C4/C5 subgroup TRPC1 alone may not form a functional ion channel [210]. TRPC4/C5 may be distinguished from other TRP channels by their potentiation by micromolar concentrations of La3+. TRPC2 is a pseudogene in humans, but in other mammals appears to be an ion channel localized to microvilli of the vomeronasal organ. It is required for normal sexual behavior in response to pheromones in mice. It may also function in the main olfactory epithelia in mice [1034, 672, 673, 1035, 496, 1075, 1030].TRPC3/C6/C7 subgroup All members are activated by diacylglycerol independent of protein kinase C stimulation [319].TRPM (melastatin) familyMembers of the TRPM subfamily (reviewed by [252, 318, 689, 1062]) fall into the five subgroups outlined below. TRPM1/M3 subgroupIn darkness, glutamate released by the photoreceptors and ON-bipolar cells binds to the metabotropic glutamate receptor 6 , leading to activation of Go . This results in the closure of TRPM1. When the photoreceptors are stimulated by light, glutamate release is reduced, and TRPM1 channels are more active, resulting in cell membrane depolarization. Human TRPM1 mutations are associated with congenital stationary night blindness (CSNB), whose patients lack rod function. TRPM1 is also found melanocytes. Isoforms of TRPM1 may present in melanocytes, melanoma, brain, and retina. In melanoma cells, TRPM1 is prevalent in highly dynamic intracellular vesicular structures [368, 657]. TRPM3 (reviewed by [663]) exists as multiple splice variants which differ significantly in their biophysical properties. TRPM3 is expressed in somatosensory neurons and may be important in development of heat hyperalgesia during inflammation (see review [876]). TRPM3 is frequently coexpressed with TRPA1 and TRPV1 in these neurons. TRPM3 is expressed in pancreatic beta cells as well as brain, pituitary gland, eye, kidney, and adipose tissue [662, 875]. TRPM3 may contribute to the detection of noxious heat [947].TRPM2TRPM2 is activated under conditions of oxidative stress (respiratory burst of phagocytic cells) and ischemic conditions. However, the direct activators are ADPR(P) and calcium. As for many ion channels, PIP2 must also be present (reviewed by [1018]). Numerous splice variants of TRPM2 exist which differ in their activation mechanisms [219]. The C-terminal domain contains a TRP motif, a coiled-coil region, and an enzymatic NUDT9 homologous domain. TRPM2 appears not to be activated by NAD, NAAD, or NAADP, but is directly activated by ADPRP (adenosine-5'-O-disphosphoribose phosphate) [900]. TRPM2 is involved in warmth sensation [788], and contributes to neurological diseases [66]. Recent study shows that 2'-deoxy-ADPR is an endogenous TRPM2 superagonist [253]. TRPM4/5 subgroupTRPM4 and TRPM5 have the distinction within all TRP channels of being impermeable to Ca2+ [997]. A splice variant of TRPM4 (i.e.TRPM4b) and TRPM5 are molecular candidates for endogenous calcium-activated cation (CAN) channels [301]. TRPM4 is active in the late phase of repolarization of the cardiac ventricular action potential. TRPM4 deletion or knockout enhances beta adrenergic-mediated inotropy [546]. Mutations are associated with conduction defects [374, 546, 819]. TRPM4 has been shown to be an important regulator of Ca2+ entry in to mast cells [924] and dendritic cell migration [43]. TRPM5 in taste receptor cells of the tongue appears essential for the transduction of sweet, amino acid and bitter stimuli [494] TRPM5 contributes to the slow afterdepolarization of layer 5 neurons in mouse prefrontal cortex [471]. Both TRPM4 and TRPM5 are required transduction of taste stimuli [226].TRPM6/7 subgroupTRPM6 and 7 combine channel and enzymatic activities (‘chanzymes’). These channels have the unusual property of permeation by divalent (Ca2+, Mg2+, Zn2+) and monovalent cations, high single channel conductances, but overall extremely small inward conductance when expressed to the plasma membrane. They are inhibited by internal Mg2+ at ~0.6 mM, around the free level of Mg2+ in cells. Whether they contribute to Mg2+ homeostasis is a contentious issue. When either gene is deleted in mice, the result is embryonic lethality. The C-terminal kinase region is cleaved under unknown stimuli, and the kinase phosphorylates nuclear histones. TRPM7 is responsible for oxidant- induced Zn2+ release from intracellular vesicles [3] and contributes to intestinal mineral absorption essential for postnatal survival [574]. TRPM8Is a channel activated by cooling and pharmacological agents evoking a ‘cool’ sensation and participates in the thermosensation of cold temperatures [54, 161, 205] reviewed by [941, 516, 420, 599]. TRPML (mucolipin) familyThe TRPML family [729, 1047, 723, 1008, 173] consists of three mammalian members (TRPML1-3). TRPML channels are probably restricted to intracellular vesicles and mutations in the gene (MCOLN1) encoding TRPML1 (mucolipin-1) cause the neurodegenerative disorder mucolipidosis type IV (MLIV) in man. TRPML1 is a cation selective ion channel that is important for sorting/transport of endosomes in the late endocytotic pathway and specifically, fission from late endosome-lysosome hybrid vesicles and lysosomal exocytosis [765]. TRPML2 and TRPML3 show increased channel activity in low extracellular sodium and are activated by similar small molecules [293]. A naturally occurring gain of function mutation in TRPML3 (i.e. A419P) results in the varitint waddler (Va) mouse phenotype (reviewed by [729, 639]). TRPP (polycystin) familyThe TRPP family (reviewed by [197, 195, 275, 986, 345]) or PKD2 family is comprised of PKD2 (PC2), PKD2L1 (PC2L1), PKD2L2 (PC2L2), which have been renamed TRPP1, TRPP2 and TRPP3, respectively [997]. It should also be noted that the nomenclature of PC2 was TRPP2 in old literature. However, PC2 has been uniformed to be called TRPP2 [317]. PKD2 family channels are clearly distinct from the PKD1 family, whose function is unknown. PKD1 and PKD2 form a hetero-oligomeric complex with a 1:3 ratio. [843]. Although still being sorted out, TRPP family members appear to be 6TM spanning nonselective cation channels. TRPV (vanilloid) familyMembers of the TRPV family (reviewed by [926]) can broadly be divided into the non-selective cation channels, TRPV1-4 and the more calcium selective channels TRPV5 and TRPV6.TRPV1-V4 subfamilyTRPV1 is involved in the development of thermal hyperalgesia following inflammation and may contribute to the detection of noxius heat (reviewed by [710, 822, 858]). Numerous splice variants of TRPV1 have been described, some of which modulate the activity of TRPV1, or act in a dominant negative manner when co-expressed with TRPV1 [786]. The pharmacology of TRPV1 channels is discussed in detail in [303] and [945]. TRPV2 is probably not a thermosensor in man [684], but has recently been implicated in innate immunity [503]. TRPV3 and TRPV4 are both thermosensitive. There are claims that TRPV4 is also mechanosensitive, but this has not been established to be within a physiological range in a native environment [114, 488].TRPV5/V6 subfamily TRPV5 and TRPV6 are highly expressed in placenta, bone, and kidney. Under physiological conditions, TRPV5 and TRPV6 are calcium selective channels involved in the absorption and reabsorption of calcium across intestinal and kidney tubule epithelia (reviewed by [982, 185, 601, 248]).