The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.

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The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

Pattern Recognition Receptors and Inflammation

Parkinson's disease: Mechanisms and models

Between the 1960s and 1980s, most life scientists focused their attention on studies of nucleic acids and the translation of the coded information. Protein degradation was a neglected area, conside...

The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction

The cause of Parkinson's disease (PD) is unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex I. We report that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and alpha-synuclein. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.

/pdf/chronic-systemic-pesticide-exposure-reproduces-features-of-11pdan5pm0.pdf

Chronic systemic pesticide exposure reproduces features of Parkinson's disease

Sirs: Damage of retina and/or optic nerve often cause dysfunction of color vision [1]. Sometimes this phenomenon appears as a side effect of various drugs, e. g. digitoxin [1]. One putative reason for impaired parkinsonian color vision is reduced dopamine levels in dopamine containing amacrine cells of the retina and/or other alterations of the visual pathway [1]. Accordingly dopaminergic substitution improves impaired parkinsonian color vision [2–4]. Known frequent and rare side effects of dopamine substituting drugs are nausea, hypotension, psychosis, sleep disturbances, edema, retroperitoneal fibrosis and rarely loss of visual acuity; however, a loss of color vision due to antiparkinsonian drugs is not reported in the literature to the best of our knowledge [5, 6]. Loss of color vision during long-term treatment with pramipexole in a parkinsonian patient prompted this report. The 72-year-old male parkinsonian patient (UPDRS total score 27, Hoehn and Yahr range II, diagnosis of PD: 1994) with known deuteranopia had a prior history of dysfunction of blue and yellow vision after increase of digitoxin from 0.07 mg to 0.1 mg (o. i.d), which disappeared after reduction of digitoxin to 0.07 mg (o. i. d.). Treatment with digitoxin was stopped in 1997 after weight reduction. We switched him to pramipexole because of the onset of ankle edema after increase of bromocriptine to 7.5 mg (t. i. d.) in September 1999. After the introduction of pramipexole 0.18 mg (t. i. d.) in October 1999, he complained of impairment of color vision and temporarily diplopia, which may hypothetically result from transient off-period like deterioration of the motor symptoms secondary to convergence insufficiency during the dopamine agonist switching period [7]. Within two weeks, black appeared to him as violet, white as yellow. Since pramipexole improved his motor symptoms, he accepted and tolerated these visual phenomena. Further deterioration of his parkinsonian motor symptoms resulted in a slow increase of pramipexole to 0.7 mg (t. i. d.) in April 2000. Within one week he complained a total loss of color vision. Unfortunately we did not perform an objective color vision testing at that time. Then we reduced pramipexole to 0.18 mg (t. i. d.). This improved his color vision to a certain extent within one week, but finally cessation of pramipexole in May 2000 reestablished the same quality of color vision compared with the one before the start of pramipexole application according to his subjective impression. Additional concomitant medication, consisting of l-thyroxine 100 μg (o. i. d.), acetylsalicylic acid 100 mg (o. i. d.), captopril 12.5 mg (four i. d.), furosemide 40 mg (o. i. d.), levodopa/benserazide 125 mg (five i. d.), retarded levodopa/carbidopa 125 mg (o. i. d.), retarded bezafibrate 400 mg (o. i. d.) remained stable during the whole period of pramipexole application, therefore an impact of all these concomitant drugs is unlikely. Pramipexole chemically resembles compounds like 2-amino–6trifluoromethoxy benzothiazole or 2-amino-6-trigluoromethoxy benzothiazole [8]. These agents interact with γ-amino-butyric acid (GABA) metabolism by blockade of its synaptic reuptake [9]. GABA is a major inhibitory transmitter in the retina [10]. GABA related vigabatrin, which irreversibly inhibits the enzyme GABA transaminase and thus catabolic inactivation of GABA, caused in an increasing dose dependent manner in albino but not in pigmented rats retinal disruption of the outer nuclear layer, which contains photoreceptor nuclei. These structures are looked upon as responsible for color vision [8, 10]. In view of our case report, we assume, that pramipexole induced loss of color vision in our subject with a known sensitivity to visual dysfunction in a dose dependent manner due to its putative negative impact on retinal function by synaptic increase of retinal GABA [10]. The patient’s previous deuteranopia hypothetically increased the retinal vulnerability to pramipexole exposure. Since bromocriptine with its predominant agonistic dopamine D2-receptor and weak D1-antagonostic receptor profile differs from the preponderant D2and D3-receptor agonistic receptor affinities of pramipexole, we also hypothesize, that applied dopamine agonists modulated retino-geniculate transmission due to their different dopamine receptor profile [11]. This could have caused a change of visual activity in a dose-dependent fashion additionally influenced by prior plastic changes of intracellular signal processing and D1-receptor internalization in postsynaptic dopaminergic retinal cells and/or downregulation of D1-receptor uptake sites mediated by prior longterm bromocriptine treatment [6, 11, 12]. Our case report can not exclude the possibility that an abnormality of color vision could also occur in any patient taking LETTER TO THE EDITORS

https://link.springer.com/content/pdf/10.1007/s00415-003-0915-5.pdf

Loss of color vision during long-term treatment with pramipexole.

■ Abstract Insidious onset of mild, unspecific, sensitive, vegetative, psychopathological, cognitive and perceptive disturbances, i. e., visual and olfactory dysfunction, with a resulting change of personal behavior, i. e., reduced stress tolerance, precede the initially intermittently occurring motor symptoms in patients with Parkinson's disease (PD). Novel neuropathological findings suggest an expansion pattern of the neurodegenerative process beyond the nigral dopaminergic neurons with the initial event located outside the brain. This underlines the clinical concept of an initial premotor phase, which starts in non-dopaminergic areas in PD. Moreover a more global general understanding of chronic neurodegeneration enables the performance of clinical trials on neuro-protection, since there is increasing evidence that diagnosis of PD at the threshold of onset of motor symptoms or cognitive symptoms in Alzheimer's disease is too late. Such an earlier diagnosis of chronic neurodegeneration will allow a more convincing demonstration of the efficacy of a neuroprotective or disease modifying compound. It will also support the concept of a clinically effective pharmacological intervention on a disease process, which is also more and more demanded by the health authorities for drug approval.

Diagnostic aspects of early Parkinson's disease.

Despite the importance of gas/liquid/solid multiphase systems in the production of chemicals on an industrial scale, measuring the concentration of gases dissolved in the liquid phasea prerequisite for determining basic reaction data such as rate and adsorption constantsremains challenging. Recently, a new permeation probe became available, which allows in situ measurement of gas concentrations in liquids. To evaluate potential applications, the probe was used to follow the concentration of dissolved hydrogen during the cobalt-catalyzed reduction of an aliphatic dinitrile to the corresponding diamine. The changes in the hydrogen saturation level during the reaction were compared to the gas−liquid (G−L) mass transfer characteristics of the reactor as determined by kLa measurements. Under the reaction conditions used, G−L mass transfer became the rate-determining step when the stirring speed was decreased. The permeation probe allowed for evaluating the significance of G−L mass transfer in a straightforward...

In Situ Measurement of Dissolved Hydrogen during the Liquid-Phase Hydrogenation of Dinitriles-Method and Case Study

The dwindling of fossil resources has prompted producers of fuels, fine chemicals, and polymers to switch from fossil carbon sources and search for renewable feedstock. Biomass holds one of the keys to this transition to a circular economy. In this context, biodiesel obtained by transesterification of natural oils with alcohols is gaining importance in the fuel sector. Various reactor concepts have been developed for the transesterification reaction. Depending on the scale of the biodiesel production plant, reactors with varying designs are operated in the batch, semi-batch mode, or continuously. In this chapter, the optimal reactor technologies are analyzed with respect to the stages the chemical conversion runs through. The initial reaction mixture of natural oil and methanol, the most common alcohol in biodiesel production, is characterized by a liquid–liquid two-phase system. The high polarity difference of natural oil and methanol leads to a mixability gap and formation of a natural oil-rich phase and a methanol-rich phase. The mass transfer of the reagents across the phase boundary is slow relative to the chemical reaction, thereby resulting in diffusion limitations. Various mixing technologies, such as sonication, and the use of microreactors are explored to overcome these diffusion limitations. Once the reaction is 15–20% complete, the reaction mixture becomes homogeneous, reducing the need for intensive mixing. As the reaction continues and higher conversions are obtained, the fatty acid methyl ester separates from glycerin. The two phases are separated and purified. Recent technologies for process intensification aim at enhancing mass and heat transfer at all stages of the reaction.

Biodiesel Production Systems: Reactor Technologies

Consensus could be reached that there is overwhelming evidence of preclinical neuroprotection. However, the evidence of neuroprotection/neurorescue under clinical conditions is limited. Lessons from clinical trials designed to show neuroprotection (selegiline, amantadine, dopamine agonists) demonstrate that with the drugs available neuroprotection/neurorescue has to start as early as possible. A PET-controlled clinical trial with ropinirole shows that there seems to be a good chance for neuroprotection in the early phase of Parkinson's disease in patients treated from the very beginning of the disease while there is no such benefit in patients with a late start of a neuroprotective therapeutic strategy. Also long-term neuroprotection cannot be reached. Complicating factors to demonstrate clinical neuroprotection are discussed.

Thomas Müller

Papers

Loss of color vision during long-term treatment with pramipexole.

Diagnostic aspects of early Parkinson's disease.

In Situ Measurement of Dissolved Hydrogen during the Liquid-Phase Hydrogenation of Dinitriles-Method and Case Study

Biodiesel Production Systems: Reactor Technologies

Workshop II: "neuroprotection"--the Lugano consensus.