The adenosine modulation system mostly operates through inhibitory A1 (A1R) and facilitatory A2A receptors (A2AR) in the brain. The activity‐dependent release of adenosine acts as a brake of ...excitatory transmission through A1R, which are enriched in glutamatergic terminals. Adenosine sharpens salience of information encoding in neuronal circuits: high‐frequency stimulation triggers ATP release in the ‘activated’ synapse, which is locally converted by ecto‐nucleotidases into adenosine to selectively activate A2AR; A2AR switch off A1R and CB1 receptors, bolster glutamate release and NMDA receptors to assist increasing synaptic plasticity in the ‘activated’ synapse; the parallel engagement of the astrocytic syncytium releases adenosine further inhibiting neighboring synapses, thus sharpening the encoded plastic change. Brain insults trigger a large outflow of adenosine and ATP, as a danger signal. A1R are a hurdle for damage initiation, but they desensitize upon prolonged activation. However, if the insult is near‐threshold and/or of short‐duration, A1R trigger preconditioning, which may limit the spread of damage. Brain insults also up‐regulate A2AR, probably to bolster adaptive changes, but this heightens brain damage since A2AR blockade affords neuroprotection in models of epilepsy, depression, Alzheimer's, or Parkinson's disease. This initially involves a control of synaptotoxicity by neuronal A2AR, whereas astrocytic and microglia A2AR might control the spread of damage. The A2AR signaling mechanisms are largely unknown since A2AR are pleiotropic, coupling to different G proteins and non‐canonical pathways to control the viability of glutamatergic synapses, neuroinflammation, mitochondria function, and cytoskeleton dynamics. Thus, simultaneously bolstering A1R preconditioning and preventing excessive A2AR function might afford maximal neuroprotection.
The main physiological role of the adenosine modulation system is to sharp the salience of information encoding through a combined action of adenosine A2A receptors (A2AR) in the synapse undergoing an alteration of synaptic efficiency with an increased inhibitory action of A1R in all surrounding synapses. Brain insults trigger an up‐regulation of A2AR in an attempt to bolster adaptive plasticity together with adenosine release and A1R desensitization; this favors synaptotocity (increased A2AR) and decreases the hurdle to undergo degeneration (decreased A1R). Maximal neuroprotection is expected to result from a combined A2AR blockade and increased A1R activation.
This article is part of a mini review series: “Synaptic Function and Dysfunction in Brain Diseases”.
The main physiological role of the adenosine modulation system is to sharp the salience of information encoding through a combined action of adenosine A2A receptors (A2AR) in the synapse undergoing an alteration of synaptic efficiency with an increased inhibitory action of A1R in all surrounding synapses. Brain insults trigger an up‐regulation of A2AR in an attempt to bolster adaptive plasticity together with adenosine release and A1R desensitization; this favors synaptotocity (increased A2AR) and decreases the hurdle to undergo degeneration (decreased A1R). Maximal neuroprotection is expected to result from a combined A2AR blockade and increased A1R activation.
This article is part of a mini review series: “Synaptic Function and Dysfunction in Brain Diseases”.
Alzheimer's disease (AD) is the most common neurodegenerative disorder that affects the elderly. The increase of life-expectancy is transforming AD into a major health-care problem. AD is ...characterized by a progressive impairment of memory and other cognitive skills leading to dementia. The major pathogenic factor associated to AD seems to be amyloid-beta peptide (Aβ) oligomers that tend to accumulate extracellularly as amyloid deposits and are associated with reactive microglia and astrocytes as well as with degeneration of neuronal processes. The involvement of microglia and astrocytes in the onset and progress of neurodegenerative process in AD is becoming increasingly recognized, albeit it is commonly accepted that neuroinflammation and oxidative stress can have both detrimental and beneficial influences on the neural tissue. However, little is known about the interplay of microglia, astrocytes and neurons in response to Aβ, especially in the early phases of AD. This review discusses current knowledge about the involvement of neuroinflammation in AD pathogenesis, focusing on phenotypic and functional responses of microglia, astrocytes and neurons in this process. The abnormal production by glia cells of pro-inflammatory cytokines, chemokines and the complement system, as well as reactive oxygen and nitrogen species, can disrupt nerve terminals activity causing dysfunction and loss of synapses, which correlates with memory decline; these are phenomena preceding the neuronal death associated with late stages of AD. Thus, therapeutic strategies directed at controlling the activation of microglia and astrocytes and the excessive production of pro-inflammatory and pro-oxidant factors may be valuable to control neurodegeneration in dementia.
Fever of Unknown Origin: A Clinical Approach Cunha, Burke A., MD; Lortholary, Olivier, MD, PhD; Cunha, Cheston B., MD
The American journal of medicine,
10/2015, Letnik:
128, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Abstract Fevers of unknown origin remain one of the most difficult diagnostic challenges in medicine. Because fever of unknown origin may be caused by over 200 malignant/neoplastic, infectious, ...rheumatic/inflammatory, and miscellaneous disorders, clinicians often order non-clue-based imaging and specific testing early in the fever of unknown origin work-up, which may be inefficient/misleading. Unlike most other fever-of-unknown-origin reviews, this article presents a clinical approach. Characteristic history and physical examination findings together with key nonspecific test abnormalities are the basis for a focused clue-directed fever of unknown origin work-up.
ABSTRACT
Drought is the natural disaster that impacts the greatest number of people and produces the most significant economic losses. This work presents a quantitative assessment of drought events ...occurred in the Semiarid region of Northeast Brazil during 1981–2016. The purpose of this study is to provide an overview of drought intensity for the last 36 years, analysing their severity, frequency and duration, considering hydro‐meteorological and agricultural aspects. To evaluate these two aspects, the 12‐month standardized precipitation index and the vegetation health index were considered to investigate drought characteristics. The definition of drought event for both these indices was performed regarding start and end month. In this context, drought duration is considered equal to the number of months of event, drought frequency is the number of events per time period and the drought severity is the absolute value of integral area below zero. Results show that the most severe and prolonged drought occurred in 2011–2016. In a clear contrast to previous droughts in past decades, during these last 5‐years period drought were more frequent, severe and affected a larger area with significant impacts for population, as well as economical activities.
Most severe and prolonged drought occurred in last 5 years (2011–2016).
The percentage of area affected by drought in the last 36 years exhibits an increasing linear trend.
The methodology presented in this study proved to be suitable for identification of drought events.
Drought frequency map (number of events in period) from October 1981 to May 2016, according to standardized precipitation index data.
Background
Locoregional extension of intrahepatic cholangiocarcinoma (ICC) at the time of diagnosis results in a low resectability rate and poor prognosis. The aim of this retrospective study was to ...assess the efficacy of neoadjuvant chemotherapy for locally advanced ICC.
Methods
All consecutive patients with ICC between 2000 and 2013 were included prospectively in a single‐centre database and analysed retrospectively. Patients with locally advanced ICC considered as initially unresectable received primary chemotherapy, followed by surgery in those with secondary resectability. Results of patients who underwent surgery for locally advanced ICC were compared with those of patients with initially resectable ICC treated by surgery alone.
Results
A total of 186 patients were included in the study. Of 74 patients with locally advanced ICC, 39 (53 per cent) underwent secondary resection after a median of six chemotherapy cycles. Patients in this group were younger (P = 0·030) and had more advanced disease than those who had surgery alone, and presented more frequently with lymphadenopathy (P = 0·010) and vascular invasion (P = 0·010). Postoperative morbidity and mortality were no different between the groups. The median survival of patients who had surgery after chemotherapy was 24·1 months, and that of patients who had surgery alone was 25·7 months (P = 0·391).
Conclusion
Patients with locally advanced ICC treated by surgery following neoadjuvant chemotherapy had similar short‐ and long‐term results to patients with initially resectable ICC who had surgery alone. Neoadjuvant chemotherapy as a first‐line treatment for locally advanced ICC may be an effective downstaging option, facilitating secondary resectability in patients with initially unresectable disease.
Option to increase resectability
Summary Since first identified in early 1977, bacteria of the genus Legionella are recognised as a common cause of community-acquired pneumonia and a rare cause of hospital-acquired pneumonia. ...Legionella bacteria multisystem manifestations mainly affect susceptible patients as a result of age, underlying debilitating conditions, or immunosuppression. Water is the major natural reservoir for Legionella , and the pathogen is found in many different natural and artificial aquatic environments such as cooling towers or water systems in buildings, including hospitals. The term given to the severe pneumonia and systemic infection caused by Legionella bacteria is Legionnaires' disease. Over time, the prevalence of legionellosis or Legionnaires' disease has risen, which might indicate a greater awareness and reporting of the disease. Advances in microbiology have led to a better understanding of the ecological niches and pathogenesis of the condition. Legionnaires' disease is not always suspected because of its non-specific symptoms, and the diagnostic tests routinely available do not offer the desired sensitivity. However, effective antibiotics are available. Disease notification systems provide the basis for initiating investigations and limiting the scale and recurrence of outbreaks. This report reviews our current understanding of this disease.
After more than two decades of preclinical and clinical studies, on August 27, 2019, the US Food and Drug Administration (FDA) approved the adenosine A
2A
receptor antagonist Nourianz® ...(istradefylline) developed by Kyowa Hakko Kirin Inc., Japan, as an add-on treatment to levodopa in Parkinson’s disease (PD) with “OFF” episodes. This milestone achievement is the culmination of the decade-long clinical studies of the effects of istradefylline in more than 4000 PD patients. Istradefylline is the first non-dopaminergic drug approved by FDA for PD in the last two decades. This approval also provides some important lessons to be remembered, namely, concerning disease-specific adenosine signaling and targeting subpopulation of PD patients. Importantly, this approval paves the way to foster entirely novel therapeutic opportunities for adenosine A
2A
receptor antagonists, such as neuroprotection or reversal of mood and cognitive deficits in PD and other neuropsychiatric diseases.
ATP is released in an activity-dependent manner from different cell types in the brain, fulfilling different roles as a neurotransmitter, neuromodulator, in astrocyte-to-neuron communication, ...propagating astrocytic responses and formatting microglia responses. This involves the activation of different ATP P2 receptors (P2R) as well as adenosine receptors upon extracellular ATP catabolism by ecto-nucleotidases. Notably, brain noxious stimuli trigger a sustained increase of extracellular ATP, which plays a key role as danger signal in the brain. This involves a combined action of extracellular ATP in different cell types, namely increasing the susceptibility of neurons to damage, promoting astrogliosis and recruiting and formatting microglia to mount neuroinflammatory responses. Such actions involve the activation of different receptors, as heralded by neuroprotective effects resulting from blockade mainly of P2X7R, P2Y1R and adenosine A2A receptors (A2AR), which hierarchy, cooperation and/or redundancy is still not resolved. These pleiotropic functions of ATP as a danger signal in brain damage prompt a therapeutic interest to multi-target different purinergic receptors to provide maximal opportunities for neuroprotection.
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