The MRI technique has been used in diagnosis of manganism in humans and non-human primates. This cross-sectional study was designed to explore whether the pallidal signal intensity in T1-weighted MRI correlated with Mn levels in the blood compartment among Mn-exposed workers and to understand to what extent the MRI signal could reflect Mn exposure. A group of 18 randomly selected male Mn-exposed workers of which 13 were smelting workers with high exposure (mean of airborne Mn in work place: 1.26 mg/m 3 ; range: 0.31-2.93 mg/m 3 ), and 5 power distribution control workers with low exposure (0.66 mg/m 3 and 0.23-0.77 mg/m 3 ) from a ferroalloy factory, and another group of 9 male subjects as controls from a non-smelting factory who were office or cafeteria workers (0.01 mg/m 3 and 0-0.03 mg/m 3 ) were recruited for neurological tests, MRI examination, and analysis of Mn in whole blood (MnB), plasma (MnP) or red blood cells (MnRBC). No clinical symptoms and signs of manganism were observed among these workers. MRI data showed average increases of 7.4% (p < 0.05) and 16.1% (p < 0.01) in pallidal index (PI) among low-and high-exposed workers, respectively, as compared to controls. Fourteen out of 18 Mn-exposed workers (78%) had intensified PI values, while this proportion was even higher (85%) among the high Mn-exposed workers. Among exposed workers, the PI values were significantly associated with MnRBC (r = 0.55, p = 0.02). Our data suggest that the workers exposed to airborne Mn, but without clinical symptoms, display an exposure-related, intensified MRI signal. The MRI, as well as MnRBC, may be useful in early diagnosis of Mn exposure.

BackgroundExposure to excessive levels of manganese (Mn) is known to induce psychiatric and motor disorders, including parkinsonian symptoms. Therefore, finding a reliable means for early detection of Mn neurotoxicity is desirable.ObjectivesOur goal was to determine whether in vivo brain levels of γ-aminobutyric acid (GABA), N-acetylaspartate (NAA), and other brain metabolites in male smelters were altered as a consequence of Mn exposure.MethodsWe used T1-weighted magnetic resonance imaging (MRI) to visualize Mn deposition in the brain. Magnetic resonance spectroscopy (MRS) was used to quantify concentrations of NAA, glutamate, and other brain metabolites in globus pallidus, putamen, thalamus, and frontal cortex from a well-established cohort of 10 male Mn-exposed smelters and 10 male age-matched control subjects. We used the MEGA-PRESS MRS sequence to determine GABA levels in a region encompassing the thalamus and adjacent parts of the basal ganglia [GABA-VOI (volume of interest)].ResultsSeven of 10 exposed subjects showed clear T1-hyperintense signals in the globus pallidus indicating Mn accumulation. We found a significant increase (82%; p = 0.014) in the ratio of GABA to total creatine (GABA/tCr) in the GABA-VOI of Mn-exposed subjects, as well as a distinct decrease (9%; p = 0.04) of NAA/tCr in frontal cortex that strongly correlated with cumulative Mn exposure (R = −0.93; p < 0.001).ConclusionsWe demonstrated elevated GABA levels in the thalamus and adjacent basal ganglia and decreased NAA levels in the frontal cortex, indicating neuronal dysfunction in a brain area not primarily targeted by Mn. Therefore, the noninvasive in vivo MRS measurement of GABA and NAA may prove to be a powerful tool for detecting presymptomatic effects of Mn neurotoxicity.

Objective-Chronic manganese (Mn) intoxication induces syndromes resembling Parkinson disease. The clinical intervention has largely been unsuccessful. We report a 17-year follow-up study of effective treatment of occupational Mn parkinsonism with sodium para-aminosalicylic acid (PAS).Methods-The patient, female and aged 50 at the time of treatment, was exposed to airborne Mn for 21 years . The patient had palpitations, hand tremor, lower limb myalgia, hypermyotonia, and a distinct festinating gait. She received 6 g PAS per day through an intravenous drip infusion for 4 days and rested for 3 days as one therapeutic course. Fifteen such courses were carried out between March and June 1987.Results-At the end of PAS treatment, her symptoms were significantly alleviated, and handwriting recovered to normal. Recent follow-up examination at age 67 years (in 2004) showed a general normal presentation in clinical, neurologic, brain magnetic resonance imaging, and handwriting examinations with a minor yet passable gait.Conclusions-This case study suggests that PAS appears to be an effective drug for treatment of severe chronic Mn poisoning with a promising prognosis.Occupational exposure to manganese (Mn) takes place in ore extraction and processing, steel and alloy production, welding, chemical synthesis, ceramic production, and dry battery fabrication. Mn is also used in water purification, as bactericidal and fungicide agents, and recently used as an antiknock agent in gasoline. Neurotoxicities resulting from occupational

Intake of a Western diet (WD), which is high in saturated fat and sugar, is associated with deficits in hippocampal-dependent learning and memory processes as well as with markers of hippocampal pathology. In the present study, rats were trained to asymptote on hippocampal-dependent serial feature negative (FN) and hippocampal-independent simple discrimination problems. Performance was then assessed following 7 days on ad libitum chow and after 10, 24, 40, 60, and 90 days of maintenance on WD, on ketogenic (KETO) diet which is high in saturated fat and low in sugar and other carbohydrates, or continued maintenance on chow (CHOW). Confirming and extending previous findings, diet-induced obese (DIO) rats fed WD showed impaired FN performance, increased BBB permeability, and increased fasting blood glucose levels compared to CHOW controls and to diet resistant (DR) rats that did not become obese when maintained on WD. For rats fed the KETO diet, FN performance and BBB integrity was more closely associated with level of circulating ketone bodies than with obesity phenotype (DR or DIO) with higher levels of ketones appearing to provide a protective effect. The evidence also indicated that FN deficits preceded and predicted increased body weight and adiposity. This research (a) further substantiates previous findings of WD-induced deficits in hippocampal-dependent feature negative discriminations, (b) suggests that ketones may be protective against diet-induced cognitive impairment, and (c) provides evidence that diet-induced cognitive impairment precedes weight gain and obesity.

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We identified B. crassa-like infection in people in northeastern China that caused mild to moderate symptoms. The possibility of more severe disease in immunocompromised patients and of transmission through the blood supply due to asymptomatic infections justifies further investigation of this reported infection.

Owing to a sessile lifestyle in nature, plants are routinely faced with diverse hostile environments such as various abiotic and biotic stresses, which lead to accumulation of free radicals in cells, cell damage, protein denaturation, etc., causing adverse effects to cells. During the evolution process, plants formed defense systems composed of numerous complex gene regulatory networks and signal transduction pathways to regulate and maintain the cell homeostasis. Among them, ubiquitin-proteasome pathway (UPP) is the most versatile cellular signal system as well as a powerful mechanism for regulating many aspects of the cell physiology because it removes most of the abnormal and short-lived peptides and proteins. In this system, the ubiquitin-conjugating enzyme (E2) plays a critical role in transporting ubiquitin from the ubiquitin-activating enzyme (E1) to the ubiquitin-ligase enzyme (E3) and substrate. Nevertheless, the comprehensive study regarding the role of E2 enzymes in plants remains unexplored. In this review, the ubiquitination process and the regulatory role that E2 enzymes play in plants are primarily discussed, with the focus particularly put on E2 s regulation of biological functions of the cell. especially E3s (more than 1400 potential E3s are encoded in A. thaliana genome) and E2s (37 E2s are encoded in A. thaliana genome) [8,21]. Therefore, it will be an important task for future research to uncover the role of these enzymes. UbiquitinUbiquitin, a small protein of 76 amino acids acting as a tag in post-translational modification of proteins, is absolutely conserved in vertebrates and higher plants, and only two or three amino acid residues are different even among animals, plants, and fungi [22]. The high conservatism renders ubiquitin interchangeable and universal in different species [23]. Ubiquitin is a β-grasp fold protein consisting of a 3.5-turn α-helix, a short 3 10 helix against a five-strand mixed β-sheet and seven reverse turns [24]. Ubiquitin possesses two hydrophobic surfaces. One surface consists of Ile44, Leu8, Val70, and His68 [25], and the other focuses on Ile36 that can be recognized by HECT (Homology to E6-AP C terminus) E3s, DUBs (Deubiquitinating enzymes), and UBDs (Ubiquitin binding domains) [26][27][28]. Ubiquitin contains seven lysine residues, including Lys-6, Lys-11, Lys-27, Lys-29, Lys-33, Lys-48, Lys-63 (K6, K11, K27, K29, K33, K48, and K63, respectively) [29,30]. Six of the seven Lys linkages (with a preference for Lys-48>Lys-63>Lys-11>>>Lys-33/Lys-29/Lys-6) were detected in A. thaliana [31,32]. Any one of the seven lysine residues or N-terminal Met1 residues in ubiquitin is likely to be involved in ubiquitin chain formation in vivo, and different ubiquitin linkages lead to the formation of different types of ubiquitin chains and induce diverse molecular signals in the cell [29,[33][34][35][36]. Different ways of linking ubiquitin chains and substrates result in distinct fates of the substrates. It is well-known that K48-linked chains are mediators signaling proteasom...

Regulation of cellular copper (Cu) homeostasis involves Cu-transporting ATPases (Cu-ATPases), i.e., ATP7A and ATP7B. The question as to how these Cu-ATPases in brain barrier systems transport Cu, i.e., toward brain parenchyma, cerebrospinal fluid (CSF), or blood, remained unanswered. This study was designed to characterize roles of Cu-ATPases in regulating Cu transport at the blood-brain barrier (BBB) and blood-CSF barrier (BCB) and to investigate how exposure to toxic manganese (Mn) altered the function of Cu-ATPases, thereby contributing to the etiology of Mn-induced parkinsonian disorder. Studies by quantitative real-time RT-PCR (qPCR), Western blot, and immunocytochemistry revealed that both Cu-ATPases expressed abundantly in BBB and BCB. Transport kinetic studies by in situ brain infusion and ventriculo-cisternal (VC) perfusion in Sprague Dawley rat suggested that the BBB was a major site for Cu entry into brain, whereas the BCB was a predominant route for Cu efflux from the CSF to blood. Confocal evidence showed that the presence of excess Cu or Mn in the choroid plexus cells led to ATP7A relocating toward the apical microvilli facing the CSF, but ATP7B toward the basolateral membrane facing blood. Mn exposure inhibited the production of both Cu-ATPases. Collectively, these data suggest that Cu is transported by the BBB from the blood to brain, which is mediated by ATP7A in brain capillary. By diffusion, Cu ions move from the interstitial fluid into the CSF, where they are taken up by the BCB. Within the choroidal epithelial cells, Cu ions are transported by ATP7B back to the blood. Mn exposure alters these processes, leading to Cu dyshomeostasis-associated neuronal injury.