Distribution and function of TRP ion channels in primary sensory neurons

It is frequently argued that cannabinoids exert part of their analgesic and anti-inflammatory effects via activation of the cannabinoid CB1 receptor located on TRPV1-expressing primary sensory nerve fibres in peripheral tissues. However, we find no evidence of CB1 receptor immunoreactivity on nerve fibres in rat or mouse hindpaw skin and mesenteric artery. The CB1 receptor agonists anandamide and HU210 also fail to inhibit TRPV1-mediated calcitonin gene-related peptide (CGRP) release from primary sensory neurons in rat hindpaw skin and mesenteric artery. Therefore, this study do not support the general view that the analgesic and anti-inflammatory effects of CB1 receptor agonists are due to direct inhibition of TRPV1-expressing primary sensory nerve terminals in the periphery. Garlic contains a number of organosulphur compounds, including allicin and diallyl disulfide (DADS), some of which may contribute to its pungent and vasodilator properties. Our results show that raw garlic extract, allicin and DADS activate TRPA1 ion channels on primary sensory neurons in culture and nerve fibres in the vascular system. These findings highlight TRPA1 as a novel ion channel in the vascular system and provide novel pharmacological tools for investigating the role of this ion channel. Whether activation of TRPA1 in the vascular system explains the beneficial antihypertensive effect observed by garlic treatment remains to be shown. This study also expands our understanding of how TRPA1 is regulated on a molecular basis, which is of importance for development of novel drug therapies for pain, inflammation and vascular disease. The skin is a major sensory organ that contains a large number of nerves. The TRP ion channels TRPV2 and TRPM8 are expressed in the somatosensory nervous system in animals and are therefore likely to be expressed in humans as well. Fluorescence immunohistochemistry was used to identify these channels and compare their expression and distribution patterns with known neuronal markers of the sensory nervous system in skin from healthy volunteers and from individuals with a mutation in the gene encoding nerve growth factor beta (NGF?) that causes Norrbottnian congenital insensitivity to pain. This study shows for the first time the presence of TRPV2 and TRPM8 in sensory nerves in the human skin. TRPV2 and TRPM8 as well as TRPV1 immunoreactive nerve fibres are present in unmyelinated nerve fibres in epidermis and papillary dermis, in nerve bundles, and around blood vessels and hair follicles. In contrast to TRPV1, TRPV2 and TRPM8 are found mainly in the papillary dermis and seem to be restricted to peptidergic nerve fibres, of which the majority contains the sensory neuropeptides CGRP or SP. There is a substantial loss of nerve fibres containing TRPV1, TRPV2 and TRPM8 in skin from individuals with Norrbottnian congenital insensitivity to pain. Insight into the role of TRPV2 and TRPM8 in human skin may open new avenues for treatment of neuropathic pain and inflammatory skin diseases

Duplex Sequencing Uncovers Recurrent Low-frequency Cancer-associated Mutations in Infant and Childhood KMT2A-rearranged Acute Leukemia

Infant acute lymphoblastic leukemia (ALL) with KMT2A-gene rearrangements (KMT2A-r) have few mutations and a poor prognosis. To uncover mutations that are below the detection of standard next-generation sequencing (NGS), a combination of targeted duplex sequencing and NGS was applied on 20 infants and 7 children with KMT2A-r ALL, 5 longitudinal and 6 paired relapse samples. Of identified nonsynonymous mutations, 87 had been previously implicated in cancer and targeted genes recurrently altered in KMT2A-r leukemia and included mutations in KRAS, NRAS, FLT3, TP53, PIK3CA, PAX5, PIK3R1, and PTPN11, with infants having fewer such mutations. Of identified cancer-associated mutations, 62% were below the resolution of standard NGS. Only 33 of 87 mutations exceeded 2% of cellular prevalence and most-targeted PI3K/RAS genes (31/33) and typically KRAS/NRAS. Five patients only had low-frequency PI3K/RAS mutations without a higher-frequency signaling mutation. Further, drug-resistant clones with FLT3 D835H or NRAS G13D/G12S mutations that comprised only 0.06% to 0.34% of diagnostic cells, expanded at relapse. Finally, in longitudinal samples, the relapse clone persisted as a minor subclone from diagnosis and through treatment before expanding during the last month of disease. Together, we demonstrate that infant and childhood KMT2A-r ALL harbor low-frequency cancer-associated mutations, implying a vast subclonal genetic landscape.publishedVersionPeer reviewe

sex veckor med högintensiv intervallträning

Studien avser att undersöka utvecklingen av styrkeuthållighet och aerob förmåga efter sex veckors träningscamp med MIT-Fitness. Campet består av tre träningstillfällen med högintensiv intervallträning á 75 minuter i veckan. Deltagarna i studien var regelbundet fysisk aktiva kvinnor (n=4) som tidigare deltagit i MIT-Fitness träningscamp. Åstrands cykeltest användes för att undersöka förändringen av den maximala syreupptagningsförmågan (VO2max). Utvecklingen av styrkeuthållighet undersöktes genom dynamiska och statiska tester. De dynamiska testerna bestod av push-ups, hoppande squats, och sit-ups där maximalt antal repetitioner utfördes under 60 sekunder. De statiska testerna bestod av plankan och jägarvilan som utfördes på maximal tid. Testerna genomfördes före och efter träningscampet. För att kontrollera mätmetodernas reliabilitet användes en test-retestgrupp bestående av fysisk aktiva kvinnor (n=2) som inte deltog i MIT-Fitness träningscamp. Test-retestgruppen utförde samma tester som deltagarna i studien med en veckas intervall mellan för- och eftertester. Resultatet från test-retest visar att testerna är stabila över tid då det inte sker någon signifikant förbättring från en vecka till en annan. Testerna bedöms därför som tillförlitliga och att reproducerbarheten är hög. Resultatet i studien visar inte på någon förbättring av deltagarnas genomsnittliga VO2max i ml/kg/min, test 1: 44,75±3,30 (41-48), test 2: 43,75±5,25 (41-51). Förbättringar ses på styrkeuthålligheten där deltagarnas medelvärde för samtliga styrkeuthållighetstester ökade. En signifikant skillnad (P<0,05) noterades på hoppande squats och push-ups. Slutsatsen är att någon förbättring av VO2max inte kunnat ses efter sex veckors träning med MIT-Fitness medan förbättringar kunde ses på alla styrkeuthållighetstester

Från verklighet till "verklighet"

Examensarbetet har gjorts inom temat innovation. Syftet var att utifrån teorin se hur en innovationsprocess kan gå till inom en offentlig sektor och jämföra denna med hur Svenska institutet gick tillväga för att skapa Second House of Sweden. Frågor vi ställde oss var hur processen gick tilll och vilka konsekvenserna blev av den färdiga ambassaden. Efter en kvalitativ undersökning och en analys av det insamlade materialet kom vi fram till att en innovationsprocess inte behöver ha någon konkret början och slut. En innovation kan uppstå i ett samspel av adoptering- och genereringsprocessen. Second House of Sweden har skapat en ny form av effektivitet för Svenska institutet, samt gjort det möljligt att socialt interagera med en eftertraktad målgrupp

Obesity associates with increased all-cause and cardiovascular mortality in adults with asthma

Background: Asthma and obesity are prevalent conditions that are increasing worldwide. Asthma is characterized by airway inflammation and bronchial variability, while obesity is a complex metabolic disorder that poses significant morbidity and mortality risks. Obesity is a risk factor for asthma and a plethora of other non-communicable diseases. Objective: To compare all-cause and cause-specific mortality between obese, overweight and normal weight adults with asthma in a cohort with long-term follow-up. Methods: Individuals from a population-based adult asthma cohort recruited in Norrbotten county, Sweden, were clinically examined between 1986 and 2001 and grouped into body mass index (BMI) categories. Underlying causes of death until December 31st, 2020 were categorized as cardiovascular, respiratory, cancer and other mortality by linking cohort data to the Swedish National Board of Health and Welfare's National Cause of Death register. Hazard ratios (HR) with 95% confidence intervals (CI) for all-cause and cause-specific mortality associated with overweight and obesity were calculated via Cox proportional hazard models. Results: In total, 940 individuals were normal weight, 689 overweight and 328 obese while only 13 were underweight. Obesity increased the hazard for all-cause (HR 1.26, 95% CI 1.03–1.54) and cardiovascular mortality (HR 1.43, 95% CI 1.03–1.97). Obesity was not significantly associated with respiratory or cancer mortality. Overweight did not increase the hazard of all-cause or any cause-specific mortality category. Conclusion: Obesity, but not overweight, was significantly associated with increased hazard of all-cause and cardiovascular mortality in adults with asthma. Neither obesity nor overweight were associated with increased hazard of respiratory mortality

Quality-of-life after bile duct injury repaired by hepaticojejunostomy : a national cohort study.

OBJECTIVES: Reports on quality-of-life (QoL) after bile duct injury (BDI) show conflicting results. The aim of this cohort study was to evaluate QoL stratified according to type of treatment. METHODS: QoL assessment using the SF-36 (36-item short form health survey) questionnaire. Patients with post-cholecystectomy BDI needing hepaticojejunostomy (HJ) were compared to all other treatments (BDI repair) and to patients without BDI at cholecystectomy (controls). RESULTS: Patients needing a HJ after BDI reported reduced long-term QoL irrespective of time for diagnosis and repair in both the physical (PCS; p &lt; .001) and mental (MCS; p &lt; .001) domain compared to both controls and patients with less severe BDI. QoL was comparable for BDI repair (n = 86) and controls (n = 192) in both PCS (p = .171) and MCS (p = .654). As a group, patients with BDI (n = 155) reported worse QoL than controls, in both the PCS (p &lt; .001) and MCS (p = .012). Patients with a BDI detected intraoperatively (n = 124) reported better QoL than patients with a postoperative diagnosis. Patients with an immediate intraoperative repair (n = 99), including HJ, reported a better long-term QoL compared to patients subjected to a later procedure (n = 54). CONCLUSIONS: Patients with postoperative diagnosis and patients with BDIs needing biliary reconstruction with HJ both reported reduced long-term QoL

Distribution and Function of the Hydrogen Sulfide-Sensitive TRPA1 Ion Channel in Rat Urinary Bladder

OBJECTIVES: To investigate the distribution of the transient receptor potential (TRP) A1 ion channel in the rat urinary bladder, and to study the effects of hydrogen sulfide (H(2)S) and known TRPA1 activators on micturition in conscious rats and on heterologously expressed ion channels. METHODS: The expression of TRPA1 in urinary bladder was studied with fluorescence immunohistochemistry and real-time PCR in female Sprague-Dawley rats. Cystometric investigations were performed in conscious animals subjected to intravesical administration of sodium hydrogen sulfide (NaHS, donor of H(2)S), allyl isothiocyanate (AI), and cinnamaldehyde (CA). Fluorometric calcium imaging was used to study the effect of NaHS on human and mouse TRPA1 expressed in CHO cells. RESULTS: TRPA1 immunoreactivity was found on unmyelinated nerve fibres within the urothelium, suburothelial space, and muscle layer as well as around blood vessels throughout the bladder. All TRPA1 immunoreactive nerves fibres also expressed TRPV1 immunoreactivity and vice versa. TRPA1 was also detected in urothelial cells at both transcriptional and protein levels. AI increased micturition frequency and reduced voiding volume. CA and NaHS produced similar changes in urodynamic parameters after disruption of the urothelial barrier with protamine sulfate. NaHS also induced calcium responses in TRPA1-expressing CHO cells, but not in untransfected cells. CONCLUSIONS: The expression of TRPA1 on C-fibre bladder afferents and urothelial cells together with the finding that intravesical TRPA1 activators initiate detrusor overactivity indicate that TRPA1 may have a role in sensory transduction in this organ. The study also highlights H(2)S as a TRPA1 activator potentially involved in inflammatory bladder disease

Pungent products from garlic activate the sensory ion channel TRPA1

Garlic belongs to the Allium family of plants that produce organosulfur compounds, such as allicin and diallyl disulfide (DADS), which account for their pungency and spicy aroma. Many health benefits have been ascribed to Allium extracts, including hypotensive and vasorelaxant activities. However, the molecular mechanisms underlying these effects remain unknown. Intriguingly, allicin and DADS share structural similarities with allyl isothiocyanate, the pungent ingredient in wasabi and other mustard plants that induces pain and inflammation by activating TRPA1, an excitatory ion channel on primary sensory neurons of the pain pathway. Here we show that allicin and DADS excite an allyl isothiocyanate-sensitive subpopulation of sensory neurons and induce vasodilation by activating capsaicin-sensitive perivascular sensory nerve endings. Moreover, allicin and DADS activate the cloned TRPA1 channel when expressed in heterologous systems. These and other results suggest that garlic excites sensory neurons primarily through activation of TRPA1. Thus different plant genera, including Allium and Brassica, have developed evolutionary convergent strategies that target TRPA1 channels on sensory nerve endings to achieve chemical deterrence