The goal of this study was to present the results of treatment of 100 chemically sensitive and chronically mold-exposed patients, who continued to be disabled even after decontamination of their ...houses or work places or they were physically removed from their sources of mold.
Molds were identified, serum anti-mold immunoglobulin G antibodies were measured, patients were skin-tested, immunologic abnormalities were recorded, and objective neurologic tests were performed in a subset of patients.
Patient sensitivities and exposures were confirmed by measuring serum immunoglobulin G anti-mold antibodies, intradermal skin testing, and trichothecene toxin breakdown products in the urine. Patients were positive (44%–98%) for individual molds. Abnormalities in T and B cells were found in >80% of patients. Respiratory signs were present in 64% of all patients, and physical signs and symptoms of neurologic dysfunction were present in 70%. Objective autonomic nervous system test results were abnormal in almost 100% of patients tested. Objective neuropsychological evaluations were conducted in 46 of the patients who exhibited symptoms of neurologic impairment and showed typical abnormalities in short-term memory, executive function/judgment, concentration, and hand/eye coordination. Patients (N = 100) with documented mold exposure were divided into 3 groups: (1) those who improved easily, with mold avoidance and antigen injections; (2) those who improved after desensitization to their mold antigens plus additional mycotoxin antigens; and (3) those who had their regular mold antigens, additional mycotoxin antigens, along with regimens that included sauna, oxygen therapy, and nutrients. Approximately 85% of all patients cleared completely; 14% had partial improvement, and 1% remained unchanged.
Exposure to molds has been increasingly recognized as a major reason for patients presenting with multiple organ symptoms that could not otherwise be explained. Early diagnosis and appropriate treatment could be very successful.
Much research on the health effects of outdoor air pollution has been published in the last decade. The goal of this review is to concisely summarize a wide range of the recent research on health ...effects of many types of outdoor air pollution. A review of the health effects of major outdoor air pollutants including particulates, carbon monoxide, sulfur and nitrogen oxides, acid gases, metals, volatile organics, solvents, pesticides, radiation and bioaerosols is presented. Numerous studies have linked atmospheric pollutants to many types of health problems of many body systems including the respiratory, cardiovascular, immunological, hematological, neurological and reproductive/ developmental systems. Some studies have found increases in respiratory and cardiovascular problems at outdoor pollutant levels well below standards set by such agencies as the US EPA and WHO. Air pollution is associated with large increases in medical expenses, morbidity and is estimated to cause about 800,000 annual premature deaths worldwide Cohen, A.J., Ross Alexander, H., Ostro, B., Pandey, K.D., Kryzanowski, M., Kunzail, N., et al., 2005. The global burden of disease due to outdoor air pollution. J Toxicol Environ Health A. 68: 1–7.. Further research on the health effects of air pollution and air pollutant abatement methods should be very helpful to physicians, public health officials, industrialists, politicians and the general public.
This study uses Monte Carlo experiments to produce new evidence on the performance of a wide range of panel data estimators. It focuses on estimators that are readily available in statistical ...software packages such as Stata and Eviews, and for which the number of cross-sectional units (N) and time periods (T) are small to moderate in size. The goal is to develop practical guidelines that will enable researchers to select the best estimator for a given type of data. It extends a previous study on the subject (Reed and Ye, Which panel data estimator should I use? 2011), and modifies their recommendations. The new recommendations provide a (virtually) complete decision tree: When it comes to choosing an estimator for efficiency, it uses the size of the panel dataset (N and T) to guide the researcher to the best estimator. When it comes to choosing an estimator for hypothesis testing, it identifies one estimator as superior across all the data scenarios included in the study. An unusual finding is that researchers should use different estimators for estimating coefficients and testing hypotheses. The authors present evidence that bootstrapping allows one to use the same estimator for both.
Objective
The first aim was to demonstrate a previously hypothesized increased sensitivity of corticostriatal glutamatergic terminals in the rodent with brain iron deficiency (BID), a pathogenetic ...model of restless legs syndrome (RLS). The second aim was to determine whether these putative hypersensitive terminals could constitute a significant target for drugs effective in RLS, including dopamine agonists (pramipexole and ropinirole) and α2δ ligands (gabapentin).
Methods
A recently introduced in vivo optogenetic–microdialysis approach was used, which allows the measurement of the extracellular concentration of glutamate upon local light‐induced stimulation of corticostriatal glutamatergic terminals. The method also allows analysis of the effect of local perfusion of compounds within the same area being sampled for glutamate.
Results
BID rats showed hypersensitivity of corticostriatal glutamatergic terminals (lower frequency of optogenetic stimulation to induce glutamate release). Both hypersensitive and control glutamatergic terminals were significant targets for locally perfused pramipexole, ropinirole, and gabapentin, which significantly counteracted optogenetically induced glutamate release. The use of selective antagonists demonstrated the involvement of dopamine D4 and D2 receptor subtypes in the effects of pramipexole.
Interpretation
Hypersensitivity of corticostriatal glutamatergic terminals can constitute a main pathogenetic mechanism of RLS symptoms. Selective D4 receptor agonists, by specifically targeting these terminals, should provide a new efficient treatment with fewer secondary effects. Ann Neurol 2017;82:951–960
Histories of mold, pollen, dust, food, chemicals, and electromagnetic field (EMF) sensitivities are the major categories of triggers for chemical sensitivity. They are tied together by the coherence ...phenomenon, where each has its own frequencies and identifiable EMF; therefore, they can be correlated. The diagnosis of chemical sensitivity can be done accurately in a less-polluted, controlled environment, as was done in these studies. The principles of diagnosis and treatment depend on total environmental and total body pollutant loads, masking or adaptation, bipolarity of response, and biochemical individuality, among others. These principles make less-polluted, controlled conditions necessary. The clinician has to use less-polluted water and organic food with individual challenges for testing, including dust, mold, pesticide, natural gas, formaldehyde, particulates, and EMF testing, which needs to be performed in less-polluted copper-screened rooms. The challenge tests for proof of chemical sensitivity include inhaled toxics within a clean booth that is chemical- and particulate-free at ambient doses in parts per million (ppm) or parts per billion (ppb). Individual foods, both organic and commercial (that are contaminated with herbicides and pesticides), are used orally. Water testing and intradermal testing are performed in a less-polluted, controlled environment. These include specific dose injections of molds, dust, and pollen that are preservative-free, individual organic foods, and individual chemicals, i.e. methane, ethane, propane, butane, hexane, formaldehyde, ethanol, car exhaust, jet fuel exhaust, and prosthetic implants (metal plates, pacemakers, mesh, etc.). Normal saline is used as a placebo. EMF testing is performed in a copper-screened room using a frequency generator. In our experience, 80% of the EMF-sensitive patients had chemical sensitivity when studied under less-polluted conditions for particulates, controlled natural gas, pesticides, and chemicals like formaldehyde.
Resting-state magnetic resonance imaging (rsMRI) is thought to reflect ongoing spontaneous brain activity. However, the precise neurophysiological basis of rsMRI signal remains elusive. Converging ...evidence supports the notion that local field potential (LFP) signal in the high-frequency range correlates with fMRI response evoked by a task (e.g., visual stimulation). It remains uncertain whether this relationship extends to rsMRI. In this study, we systematically modulated LFP signal in the whisker barrel cortex (WBC) by unilateral deflection of rat whiskers. Results show that functional connectivity between bilateral WBC was significantly modulated at the 2 Hz, but not at the 4 or 6 Hz, stimulus condition. Electrophysiologically, only in the low-frequency range (<5 Hz) was the LFP power synchrony in bilateral WBC significantly modulated at 2 Hz, but not at 4- or 6-Hz whisker stimulation, thus distinguishing these 2 experimental conditions, and paralleling the findings in rsMRI. LFP power synchrony in other frequency ranges was modulated in a way that was neither unique to the specific stimulus conditions nor parallel to the fMRI results. Our results support the hypothesis that emphasizes the role of low-frequency LFP signal underlying rsMRI.
Synchronized low-frequency spontaneous fluctuations of the functional MRI (fMRI) signal have recently been applied to investigate large-scale neuronal networks of the brain in the absence of specific ...task instructions. However, the underlying neural mechanisms of these fluctuations remain largely unknown. To this end, electrophysiological recordings and resting-state fMRI measurements were conducted in α-chloralose-anesthetized rats. Using a seed-voxel analysis strategy, region-specific, anesthetic dose-dependent fMRI resting-state functional connectivity was detected in bilateral primary somatosensory cortex (S1FL) of the resting brain. Cortical electroencephalographic signals were also recorded from bilateral S1FL; a visual cortex locus served as a control site. Results demonstrate that, unlike the evoked fMRI response that correlates with power changes in the γ bands, the resting-state fMRI signal correlates with the power coherence in low-frequency bands, particularly the δ band. These data indicate that hemodynamic fMRI signal differentially registers specific electrical oscillatory frequency band activity, suggesting that fMRI may be able to distinguish the ongoing from the evoked activity of the brain.
Abstract
The two highly homologous subtypes of stimulatory G proteins Gαs (Gs) and Gαolf (Golf) display contrasting expression patterns in the brain. Golf is predominant in the striatum, while Gs is ...predominant in the cortex. Yet, little is known about their functional distinctions. The dopamine D
1
receptor (D1R) couples to Gs/olf and is highly expressed in cortical and striatal areas, making it an important therapeutic target for neuropsychiatric disorders. Using novel drug screening methods that allow analysis of specific G-protein subtype coupling, we found that, relative to dopamine, dihydrexidine and N-propyl-apomorphine behave as full D1R agonists when coupled to Gs, but as partial D1R agonists when coupled to Golf. The Gs/Golf-dependent biased agonism by dihydrexidine was consistently observed at the levels of cellular signaling, neuronal function, and behavior. Our findings of Gs/Golf-dependent functional selectivity in D1R ligands open a new avenue for the treatment of cortex-specific or striatum-specific neuropsychiatric dysfunction.
Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide ...evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R-OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target σ1 receptor (σ1R) also associates with the CRF1R-OX1R heteromer. Cocaine binding to the σ1R-CRF1R-OX1R complex promotes a long-term disruption of the orexin-A-CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking.
The symptomatology of Restless Legs Syndrome (RLS) includes periodic leg movements during sleep (PLMS), dysesthesias, and hyperarousal. Alterations in the dopaminergic system, a presynaptic ...hyperdopaminergic state, seem to be involved in PLMS, while alterations in glutamatergic neurotransmission, a presynaptic hyperglutamatergic state, seem to be involved in hyperarousal and also PLMS. Brain iron deficiency (BID) is well-recognized as a main initial pathophysiological mechanism of RLS. BID in rodents have provided a pathogenetic model of RLS that recapitulates the biochemical alterations of the dopaminergic system of RLS, although without PLMS-like motor abnormalities. On the other hand, BID in rodents reproduces the circadian sleep architecture of RLS, indicating the model could provide clues for the hyperglutamatergic state in RLS. We recently showed that BID in rodents is associated with changes in adenosinergic transmission, with downregulation of adenosine A
receptors (A1R) as the most sensitive biochemical finding. It was hypothesized that A1R downregulation leads to hypersensitive striatal glutamatergic terminals and facilitation of striatal dopamine release. Hypersensitivity of striatal glutamatergic terminals was demonstrated by an optogenetic-microdialysis approach in the rodent with BID, indicating that it could represent a main pathogenetic factor that leads to PLMS in RLS. In fact, the dopaminergic agonists pramipexole and ropinirole and the α
δ ligand gabapentin, used in the initial symptomatic treatment of RLS, completely counteracted optogenetically-induced glutamate release from both normal and BID-induced hypersensitive corticostriatal glutamatergic terminals. It is a main tenet of this essay that, in RLS, a single alteration in the adenosinergic system, downregulation of A1R, disrupts the adenosine-dopamine-glutamate balance uniquely controlled by adenosine and dopamine receptor heteromers in the striatum and also the A1R-mediated inhibitory control of glutamatergic neurotransmission in the cortex and other non-striatal brain areas, which altogether determine both PLMS and hyperarousal. Since A1R agonists would be associated with severe cardiovascular effects, it was hypothesized that inhibitors of nucleoside equilibrative transporters, such as dipyridamole, by increasing the tonic A1R activation mediated by endogenous adenosine, could represent a new alternative therapeutic strategy for RLS. In fact, preliminary clinical data indicate that dipyridamole can significantly improve the symptomatology of RLS.
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