Cannabis and the brain IVERSEN, Leslie
Brain (London, England : 1878),
06/2003, Letnik:
126, Številka:
6
Journal Article
Recenzirano
Odprti dostop
The active compound in herbal cannabis, Δ9‐tetrahydrocannabinol, exerts all of its known central effects through the CB1 cannabinoid receptor. Research on cannabinoid mechanisms has been facilitated ...by the availability of selective antagonists acting at CB1 receptors and the generation of CB1 receptor knockout mice. Particularly important classes of neurons that express high levels of CB1 receptors are GABAergic interneurons in hippocampus, amygdala and cerebral cortex, which also contain the neuropeptides cholecystokinin. Activation of CB1 receptors leads to inhibition of the release of amino acid and monoamine neurotransmitters. The lipid derivatives anandamide and 2‐arachidonylglycerol act as endogenous ligands for CB1 receptors (endocannabinoids). They may act as retrograde synaptic mediators of the phenomena of depolarization‐induced suppression of inhibition or excitation in hippocampus and cerebellum. Central effects of cannabinoids include disruption of psychomotor behaviour, short‐term memory impairment, intoxication, stimulation of appetite, antinociceptive actions (particularly against pain of neuropathic origin) and anti‐emetic effects. Although there are signs of mild cognitive impairment in chronic cannabis users there is little evidence that such impairments are irreversible, or that they are accompanied by drug‐induced neuropathology. A proportion of regular users of cannabis develop tolerance and dependence on the drug. Some studies have linked chronic use of cannabis with an increased risk of psychiatric illness, but there is little evidence for any causal link. The potential medical applications of cannabis in the treatment of painful muscle spasms and other symptoms of multiple sclerosis are currently being tested in clinical trials. Medicines based on drugs that enhance the function of endocannabinoids may offer novel therapeutic approaches in the future.
Dopamine: 50 years in perspective Iversen, Susan D; Iversen, Leslie L
Trends in neurosciences (Regular ed.),
05/2007, Letnik:
30, Številka:
5
Journal Article
Recenzirano
The discovery of dopamine as a neurotransmitter in brain by Arvid Carlsson approximately 50 years ago, and the subsequent insight provided by Paul Greengard into the cellular signalling mechanisms ...triggered by dopamine, gained these researchers the Nobel Prize for Medicine in 2000. Dopamine research has had a greater impact on the development of biological psychiatry and psychopharmacology than work on any other neurotransmitter. Neuropsychological views of the role of dopamine in the CNS have evolved from that of a simple reward signal to a more complex situation in which dopamine encodes the importance or ‘salience’ of events in the external world. Hypofunctional dopamine states underlie Parkinson's disease and attention deficit hyperactivity disorder, and there is increasing evidence for dopamine hyperactivity in schizophrenia. Some of the medicines that are most widely used in psychiatry, such as L-DOPA, methylphenidate and neuroleptic drugs, act on dopaminergic mechanisms.
Summary
Background The JAK (Janus kinase)/STAT (signal transducer and activator of transcription) signalling pathway is known to play an important role in many cellular processes including ...inflammation. The activation of STAT1 is dependent on tyrosine 701 and serine 727 phosphorylation, which leads to the formation of the STAT dimer and modulation of STAT1 activity, respectively.
Objective To determine STAT1 expression and activation in psoriatic skin.
Methods Biopsies were collected from patients with psoriasis. mRNA expression was evaluated by quantitative polymerase chain reaction, whereas the protein and phosphorylation level of STAT1 were evaluated by Western blotting. STAT1 localization was determined by immunofluorescence analysis and STAT1‐induced transcriptional activity was analysed in cultured human keratinocytes using a reporter assay.
Results The expression of STAT1 was demonstrated to be significantly increased at both mRNA and protein level in lesional psoriatic skin. In addition, the phosphorylation level of STAT1(Tyr701) and STAT1(Ser727) was significantly increased in lesional compared with nonlesional psoriatic skin. Luciferase assays showed a significant induction of the STAT1‐induced transcriptional activity when cultured human keratinocytes were stimulated with either interferon (IFN)‐α or IFN‐γ. STAT1(Ser727) phosphorylation induced by IFN‐α, IFN‐γ or ultraviolet B was mediated by a protein kinase C (PKC)‐δ‐ and p38 mitogen‐activated protein kinase‐dependent mechanism in human keratinocytes, whereas IFN‐α‐induced STAT1(Tyr701) phosphorylation was mediated by a PKC‐δ‐dependent mechanism.
Conclusions This study demonstrates for the first time that the phosphorylation level of STAT1(Tyr701) and STAT1(Ser727) is increased in lesional psoriatic skin. In addition, specific signalling pathways leading to this phosphorylation have been identified. Together, our data indicate an important role of STAT1 in the pathogenesis of psoriasis.
What’s already known about this topic?
•
The expression of STAT1 is increased in lesional psoriatic skin.
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STAT1 has an increased nuclear expression in psoriatic epidermis.
•
STAT1 can be phosphorylated on two different phosphorylation sites: a tyrosine 701 site and a serine 727 site.
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STAT1 is involved in the regulation of interferon‐responsive genes.
What does this study add?
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The phosphorylation level of STAT1(Tyr701) and STAT1(Ser727) is increased in lesional psoriatic skin.
•
The two kinases, p38 mitogen‐activated protein kinase and protein kinase C‐δ, are involved in the phosphorylation of STAT1 in cultured human keratinocytes.
Unlike in land plants, photosynthesis in many aquatic plants relies on bicarbonate in addition to carbon dioxide (CO
) to compensate for the low diffusivity and potential depletion of CO
in water. ...Concentrations of bicarbonate and CO
vary greatly with catchment geology. In this study, we investigate whether there is a link between these concentrations and the frequency of freshwater plants possessing the bicarbonate use trait. We show, globally, that the frequency of plant species with this trait increases with bicarbonate concentration. Regionally, however, the frequency of bicarbonate use is reduced at sites where the CO
concentration is substantially above the air equilibrium, consistent with this trait being an adaptation to carbon limitation. Future anthropogenic changes of bicarbonate and CO
concentrations may alter the species compositions of freshwater plant communities.
Summary
Background
Drug survival (time to drug discontinuation) has recently emerged as an important parameter reflecting the long‐term therapeutic performance in a real‐life setting. Biologic drug ...survival in psoriasis is mainly limited by a gradual loss of efficacy over time. Previous studies have been limited by small patient population size and short observation times and yielded discrepant survival times for different biologics.
Objectives
To calculate the long‐term drug survival for adalimumab, etanercept, infliximab and ustekinumab in a large cohort of real‐life patients with psoriasis vulgaris and to analyse the factors that influence drug survival.
Patients and methods
Data were extracted from the prospective registry DERMBIO covering all patients with psoriasis vulgaris treated with biologic agents in the academic centres in Denmark. Drug survival was analysed using the Kaplan–Meier method. The influence of different covariates on drug survival was analysed by Cox regression.
Results
Included in the analysis were 1867 treatment series (adalimumab n = 774, etanercept n = 449, infliximab n = 253, ustekinumab n = 391) administered in 1277 patients for up to 10 years. Drug survival was significantly longer for ustekinumab than for anti‐tumour necrosis factor (TNF)‐α agents (P < 0·001). Etanercept had the shortest survival time median survival 30 months, 95% confidence interval (CI) 25·1–34·9 whereas adalimumab and infliximab had comparable survival rates (59 months, 95% CI 45·6–72·4; 44 months, 95% CI 33–54·9, respectively). Survival was longer in men odds ratio (OR) 1·51, 95% CI 1·31–1·74 vs. women and in patients who had not previously received any biologic agent (OR 1·24, 95% CI 1·05–1·46). Loss of efficacy accounted for 67% of all drug discontinuations.
Conclusions
Ustekinumab has a significantly longer drug survival than the anti‐TNF‐α agents. Switching from one biologic to another is associated with an impairment of drug survival. Preventing loss of efficacy is a major area of medical need in the biologic therapy of psoriasis and the strategies that improve drug survival should be further investigated.
What's already known about this topic?
Gradual loss of efficacy of biologic agents has been observed during long‐term treatment of psoriasis.
Previous studies have had limited numbers of patients and short observation times and showed conflicting data.
What does this study add?
This is the largest study to date, comprising 1277 patients followed for up to 10 years.
Long‐term drug survival depends on the drug (ustekinumab > adalimumab = infliximab > etanercept), sex (men > women) and previous exposure to another biologic.
Freshwater ecosystems are among the most endangered habitats on Earth, with thousands of animal species known to be threatened or already extinct. Reliable monitoring of threatened organisms is ...crucial for data‐driven conservation actions but remains a challenge owing to nonstandardized methods that depend on practical and taxonomic expertise, which is rapidly declining. Here, we show that a diversity of rare and threatened freshwater animals—representing amphibians, fish, mammals, insects and crustaceans—can be detected and quantified based on DNA obtained directly from small water samples of lakes, ponds and streams. We successfully validate our findings in a controlled mesocosm experiment and show that DNA becomes undetectable within 2 weeks after removal of animals, indicating that DNA traces are near contemporary with presence of the species. We further demonstrate that entire faunas of amphibians and fish can be detected by high‐throughput sequencing of DNA extracted from pond water. Our findings underpin the ubiquitous nature of DNA traces in the environment and establish environmental DNA as a tool for monitoring rare and threatened species across a wide range of taxonomic groups.
See also the Perspective by Lodge et al
Patients with moderate to severe psoriasis are undertreated. To solve this persistent problem, the consensus programme was performed to define goals for treatment of plaque psoriasis with systemic ...therapy and to improve patient care. An expert consensus meeting and a collaborative Delphi procedure were carried out. Nineteen dermatologists from different European countries met for a face-to-face discussion and defined items through a four-round Delphi process. Severity of plaque psoriasis was graded into mild and moderate to severe disease. Mild disease was defined as body surface area (BSA) ≤10 and psoriasis area and severity index (PASI) ≤10 and dermatology life quality index (DLQI) ≤10 and moderate to severe psoriasis as (BSA > 10 or PASI > 10) and DLQI > 10. Special clinical situations may change mild psoriasis to moderate to severe including involvement of visible areas or severe nail involvement. For systemic therapy of plaque psoriasis two treatment phases were defined: (1) induction phase as the treatment period until week 16; however, depending on the type of drug and dose regimen used, this phase may be extended until week 24 and (2) maintenance phase for all drugs was defined as the treatment period after the induction phase. For the definition of treatment goals in plaque psoriasis, the change of PASI from baseline until the time of evaluation (ΔPASI) and the absolute DLQI were used. After induction and during maintenance therapy, treatment can be continued if reduction in PASI is ≥75%. The treatment regimen should be modified if improvement of PASI is <50%. In a situation where the therapeutic response improved ≥50% but <75%, as assessed by PASI, therapy should be modified if the DLQI is >5 but can be continued if the DLQI is ≤5. This programme defines the severity of plaque psoriasis for the first time using a formal consensus of 19 European experts. In addition, treatment goals for moderate to severe disease were established. Implementation of treatment goals in the daily management of psoriasis will improve patient care and mitigate the problem of undertreatment. It is planned to evaluate the implementation of these treatment goals in a subsequent programme involving patients and physicians.
It is unknown whether comorbidity interacts with colorectal cancer (CRC) to increase the rate of mortality beyond that explained by the independent effects of CRC and comorbid conditions.
We ...conducted a cohort study (1995-2010) of all Danish CRC patients (n=56963), and five times as many persons from the general population (n=271670) matched by age, gender, and specific comorbidities. To analyse comorbidity, we used the Charlson Comorbidity Index (CCI) scores. We estimated standardised mortality rates per 1000 person-years, and calculated interaction contrasts as a measure of the excess mortality rate not explained by the independent effects of CRC or comorbidities.
Among CRC patients with a CCI score=1, the 0-1 year mortality rate was 415 out of 1000 person-years (95% confidence interval (CI): 401, 430) and the interaction accounted for 9.3% of this rate (interaction contrast=39 out of 1000 person-years, 95% CI: 22, 55). For patients with a CCI score of 4 or more, the interaction accounted for 34% of the mortality (interaction contrast=262 out of 1000 person-years, 95% CI: 215, 310). The interaction between CRC and comorbidities had limited influence on mortality beyond 1 year after diagnosis.
Successful treatment of the comorbidity is pivotal and may reduce the mortality attributable to comorbidity itself, and also the mortality attributable to the interaction.
The Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO-CBRND) began development of a broad-spectrum antiviral countermeasure against deliberate use of ...high-consequence viral hemorrhagic fevers (VHFs) in 2016. The effort featured comprehensive preclinical research, including laboratory testing and rapid advancement of lead molecules into nonhuman primate (NHP) models of Ebola virus disease (EVD). Remdesivir (GS-5734, Veklury, Gilead Sciences) was the first small molecule therapeutic to successfully emerge from this effort. Remdesivir is an inhibitor of RNA-dependent RNA polymerase, a viral enzyme that is essential for viral replication. Its robust potency and broad-spectrum antiviral activity against certain RNA viruses including Ebola virus and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) led to its clinical evaluation in randomized, controlled trials (RCTs) in human patients during the 2018 EVD outbreak in the Democratic Republic of the Congo (DRC) and the ongoing Coronavirus Disease 2019 (COVID-19) pandemic today. Remdesivir was recently approved by the US Food and Drug Administration (FDA) for the treatment of COVID-19 requiring hospitalization. Substantial gaps remain in improving the outcomes of acute viral infections for patients afflicted with both EVD and COVID-19, including how to increase therapeutic breadth and strategies for the prevention and treatment of severe disease. Combination therapy that joins therapeutics with complimentary mechanisms of action appear promising, both preclinically and in RCTs. Importantly, significant programmatic challenges endure pertaining to a clear drug and biological product development pathway for therapeutics targeting biodefense and emerging pathogens when human efficacy studies are not ethical or feasible. For example, remdesivir's clinical development was facilitated by outbreaks of Ebola and SARS-CoV-2; as such, the development pathway employed for remdesivir is likely to be the exception rather than the rule. The current regulatory licensure pathway for therapeutics targeting rare, weaponizable VHF agents is likely to require use of FDA's established Animal Rule (21 CFR 314.600-650 for drugs; 21 CFR 601.90-95 for biologics). The FDA may grant marketing approval based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drug is safe and likely to produce clinical benefit in humans. In practical terms, this is anticipated to include a series of rigorous, well-documented, animal challenge studies, to include aerosol challenge, combined with human safety data. While small clinical studies against naturally occurring, high-consequence pathogens are typically performed where possible, approval for the therapeutics currently under development against biodefense pathogens will likely require the Animal Rule pathway utilizing studies in NHPs. We review the development of remdesivir as illustrative of the effort that will be needed to field future therapeutics against highly lethal, infectious agents.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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