Network analysis of α-synuclein pathology progression reveals p21-activated kinases as regulators of vulnerability.

α-Synuclein misfolding and progressive accumulation drives a pathogenic process in Parkinson's disease. To understand cellular and network vulnerability to α-synuclein pathology, we developed a framework to quantify network-level vulnerability and identify new therapeutic targets at the cellular level. Full brain α-synuclein pathology was mapped in mice over 9 months.

Exploring symbiont gene expression in two echinoid-associated shrimp species under host separation.

Symbiotic relationships are omnipresent and particularly diverse in the marine world. In the Western Indian Ocean, the sea urchin Echinometra mathaei associates with two obligate ectosymbiotic shrimp species, Tuleariocaris holthuisi and Arete indicus. These shrimps are known for their host-dependent nature.

Spatial transcriptomics reveals molecular dysfunction associated with cortical Lewy pathology.

A key hallmark of Parkinson's disease (PD) is Lewy pathology. Composed of α-synuclein, Lewy pathology is found both in dopaminergic neurons that modulate motor function, and cortical regions that control cognitive function. Recent work has established the molecular identity of dopaminergic neurons susceptible to death, but little is known about cortical neurons susceptible to Lewy pathology or molecular changes induced by aggregates.

Spatial transcriptomics reveals molecular dysfunction associated with Lewy pathology.

Lewy pathology composed of α-synuclein is the key pathological hallmark of Parkinson's disease (PD), found both in dopaminergic neurons that control motor function, and throughout cortical regions that control cognitive function. Recent work has investigated which dopaminergic neurons are most susceptible to death, but little is known about which neurons are vulnerable to developing Lewy pathology and what molecular changes an aggregate induces. In the current study, we use spatial transcriptomics to selectively capture whole transcriptome signatures from cortical neurons with Lewy pathology compared to those without pathology in the same brains.

-derived poly-GA DPRs undergo endocytic uptake in iAstrocytes and spread to motor neurons.

Dipeptide repeat (DPR) proteins are aggregation-prone polypeptides encoded by the pathogenic GGGGCC repeat expansion in the gene, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. In this study, we focus on the role of poly-GA DPRs in disease spread. We demonstrate that recombinant poly-GA oligomers can directly convert into solid-like aggregates and form characteristic β-sheet fibrils in vitro.

Dipeptide repeat derived from C9orf72 hexanucleotide expansions forms amyloids or natively unfolded structures in vitro.

The abnormal repetition of the hexanucleotide GGGGCC within the C9orf72 gene is the most common genetic cause of both Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Different hypothesis have been proposed to explain the pathogenicity of this mutation. Among them, the production of aberrant proteins called Dipeptide Repeat Proteins (DPR) from the repeated sequence.

Echinometra mathaei and its ectocommensal shrimps: the role of sea urchin spinochrome pigments in the symbiotic association.

Tuleariocaris holthuisi and Arete indicus are two ectocommensal shrimps closely associated with the tropical sea urchin Echinometra mathaei. This study provides a comparison of these two E. mathaei symbiotic crustaceans and particularly focuses on the relationship between T.

Identification and quantification of spinochromes in body compartments of 's coloured types.

Sea urchin pigmentation is mainly due to polyhydroxy-1,4-naphthoquinones called spinochromes. If their molecular structures are well known in test and spines of many species, their abundance and distribution in other body compartments remain unstudied. The aim of this study is to analyse the pigment composition in four body compartments (test/spines, digestive system, gonads and coelomic fluid) of four coloured types of the sea urchin .

The Roles of Spinochromes in Four Shallow Water Tropical Sea Urchins and Their Potential as Bioactive Pharmacological Agents.

Spinochromes are principally known to be involved in sea urchin pigmentation as well as for their potentially interesting pharmacological properties. To assess their biological role in sea urchin physiology, experiments are undertaken on crude extracts from four species and on four isolated spinochromes in order to test their antibacterial, antioxidant, inflammatory and cytotoxic activities. First, the antibacterial assays show that the use of crude extracts as representatives of antibacterial effects of spinochromes are inaccurate.

Design, synthesis and biological characterization of a new class of osteogenic (1H)-quinolone derivatives.

Smoothened (Smo) is the signal transducer of the Hedgehog (Hh) pathway and its stimulation is considered a potential powerful tool in regenerative medicine to treat severe tissue injuries. Starting from GSA-10, a recently reported Hh activator acting on Smo, we have designed and synthesized a new class of quinolone-based compounds. Modification and decoration of three different portions of the original scaffold led to compounds able to induce differentiation of multipotent mesenchymal cells into osteoblasts.

Effects of Holothuroid Ichtyotoxic Saponins on the Gills of Free-Living Fishes and Symbiotic Pearlfishes.

Several carapid fishes, known as pearlfishes, are endosymbiotic in holothuroids and asteroids. These echinoderms contain a strong concentration of saponins that are efficient membranolytic repellents to predators. We compared the effects of exposure to saponins from the sea cucumber body wall and from the Cuvierian tubules on the behavior and gill ultrastructure of pearlfishes and free-living fishes.

Can treatment success with 5% lidocaine medicated plaster be predicted in cancer pain with neuropathic components or trigeminal neuropathic pain?

An expert group of 40 pain specialists from 16 countries performed a first assessment of the value of predictors for treatment success with 5% lidocaine-medicated plaster in the management of cancer pain with neuropathic components and trigeminal neuropathic pain. Results were based on the retrospective analysis of 68 case reports (sent in by participants in the 4 weeks prior to the conference) and the practical experience of the experts. Lidocaine plaster treatment was mostly successful for surgery or chemotherapy-related cancer pain with neuropathic components.

Primary closure with a filleted hallux flap after transmetatarsal amputation of the big toe for osteomyelitis in the diabetic foot: a short series of four cases.

In the diabetic foot, osteomyelitis of the first metatarsal head adjacent to a malum perforans may require resection of the metatarsophalangeal joint. This results in a dysfunctional great toe and large tissue defects that take a long time to heal. The authors postulated that transmetatarsal amputation followed by primary closure with a filleted hallux flap would be feasible in selected cases.

[Leptomeningeal meningitis related to breast cancer overexpressing HER2: is there a place for a more specific treatment?].

Leptomeningeal metastases are very commonly associated with breast cancer. The prognosis is very poor in the short term with an overall median survival less than 6 months. Based on pragmatic and historical considerations intrathecal chemotherapy (IT) are considered to be the adequate treatment.

Outcome predictors for treatment success with 5% lidocaine medicated plaster in low back pain with neuropathic components and neuropathic pain after surgical and nonsurgical trauma.

Five percent lidocaine medicated plaster has been proven efficacious for the symptomatic relief of neuropathic pain in diverse pain conditions which might be attributed to a common localized symptomatology in these indications, possibly with common predictors of treatment success. To discuss potential symptoms and other factors predicting response to treatment with lidocaine plaster for the indications of low back pain with neuropathic components and neuropathic pain after surgical and nonsurgical trauma, 44 pain specialists from 17 countries attended a two-day conference meeting in December 2009. Discussions were based on the retrospective analysis of case reports (sent in by participants in the four weeks prior to the meeting) and the practical experience of the participants.

Cancer-related symptom assessment in France: validation of the French M. D. Anderson Symptom Inventory.

This multicenter study was intended to validate the French version of the M. D. Anderson Symptom Inventory (MDASI-Fr) in French cancer patients (n=162) with solid tumors or hematological malignancies.

[Pain and bone metastases].

Average 20% of the cancer patients will have bone metastasis most of time painful and with variable clinical expressions. Due to animal models, the bone metastasis pain is better known and it explains the different treatments mechanisms. After a suitable evaluation of the pain, several therapeutic approaches can be suggested.

Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia.

Non-invasive unilateral repetitive transcranial magnetic stimulation (rTMS) of the motor cortex induces analgesic effects in focal chronic pain syndromes, probably by modifying central pain modulatory systems. Neuroimaging studies have shown bilateral activation of a large number of structures, including some of those involved in pain processing, suggesting that such stimulation may induce generalized analgesic effects. The goal of this study was to assess the effects of unilateral rTMS of the motor cortex on chronic widespread pain in patients with fibromyalgia.

Are oral cannabinoids safe and effective in refractory neuropathic pain?

Although cannabinoids have anti-hyperalgesic effects in animal models of nerve injury, there are currently very few prospective trials of the efficacy of cannabinoids in neuropathic pain in humans. This open label prospective study investigated the safety, tolerability and analgesic benefit of oral Delta-9-tetrahydrocannabinol (THC) titrated to a maximal dosage of 25 mg/day in 8 consecutive patients with chronic refractory neuropathic pain. Spontaneous ongoing and paroxysmal pain, allodynia and paresthesias were assessed.

Systemic lidocaine in pain due to peripheral nerve injury and predictors of response.

Objective: To investigate the effects of IV lidocaine on spontaneous and evoked pain (allodynia and hyperalgesia) due to peripheral nerve injury (postherpetic neuralgia or nerve trauma) using quantitative sensory testing.

Method: The authors randomized 22 patients to receive lidocaine 5 mg/kg IV during 30 minutes or placebo in a double-blind crossover design and 16 patients subsequently received mexiletine on an open basis titrated from 400 to 1,000 mg per day (mean 737 mg/day).

Results: Lidocaine induced a significant decrease in ongoing pain for up to 6 hours with a peak effect 60 to 120 minutes postinjection.

[Pain in kidney disease].

There are little data concerning the prevalence of pain and its intensity in the population suffering from kidney diseases. However, according to number of pathologies with a kidney impact, the sequellae of the kidney disease itself and the technology in this area, there is a risk for a high prevalence rate of either acute and/or chronic pain. This can be responsible for some degree of psychologic disturbances as a major impact on the quality of life.

Long term effects of oral sustained release morphine on neuropsychological performance in patients with chronic non-cancer pain.

Morphine is increasingly used in patients with chronic non-cancer pain, but a major concern associated with chronic use relates to possible cognitive side-effects. The aim of this long-term prospective study was to evaluate the cognitive impact of oral sustained release morphine in patients with non-cancer pain. A battery of neuropsychological tests to explore attention, psychomotor speed and memory was administered.

[The therapeutic use of D9-tetrahydrocannabinol (dronabinol) in refractory neuropathic pain].

Introduction: Despite the recent discovery of the potential mechanisms underlying the analgesic effects of cannabis, few clinical studies have so far assessed its analgesic effects, notably in the treatment of chronic non-malignant pain. All the studies used administration of cannabis alone. The aim of this open, pilot, study was to assess the efficacy and side effect profile of oral dronabinol (tetrahydrocannabinol - THC) in the treatment of refractory neuropathic pain.

Effects of IV morphine in central pain: a randomized placebo-controlled study.

Objective: To investigate the effects of IV morphine on central pain syndromes through quantitative sensory testing and to assess the long-term benefit of oral morphine.

Methods: After an initial open titration phase aiming to determine the maximal tolerated dosage of IV morphine, the efficacy of morphine infusion (9-30 mg; mean dosage, 16 mg) was assessed in a double-blind, placebo-controlled and crossover fashion in 15 patients with poststroke- (6 patients) or spinal cord injury- (9 patients) related pain. All of the patients subsequently received sustained oral morphine.