Background: Progranulin (PGRN) is a fundamental neurotrophic factor, and is also involved in inflammation and wound repair. PGRN may have pro- or anti-inflammatory properties, depending upon ...proteolysis of the anti-inflammatory parent PGRN protein and the generation of pro-inflammatory granulin peptides.
Objectives: Our objectives were as follows: (1) to evaluate the presence and distribution of PGRN in multiple sclerosis (MS) brain tissue, correlating it with demyelination and inflammation; (2) to evaluate cerebrospinal fluid (CSF) PGRN concentrations in patients with MS and controls, in relationship to the clinical features of the disease.
Methods: Our study involved the following: (1) neuropathological study of PGRN on post-mortem tissue of 19 MS and six control brains; (2) evaluation of PGRN CSF concentration in 40 MS patients, 15 non-inflammatory controls and five inflammatory controls (viral encephalitis).
Results: In active demyelinating lesions, PGRN was expressed on macrophages/microglia. In the normal-appearing white matter (NAWM), expression of PGRN was observed on activated microglia. PGRN was expressed by neurons and microglia in cortical lesions and in normal-appearing cortex. No expression of PGRN was observed in controls, except on neurons. PGRN CSF concentrations were significantly higher in patients with relapsing–remitting MS during relapses and in progressive MS patients, compared with relapsing–remitting MS patients during remissions and with non-inflammatory controls.
Conclusions: PGRN is strongly expressed in MS brains, by macrophages/microglia in active lesions, and by activated microglia in the NAWM; PGRN CSF concentrations in MS are correspondingly increased in conditions of enhanced macrophage/microglia activation, such as during relapses and in progressive MS.
Gray matter (GM) lesions are recognized as important components of the pathology of multiple sclerosis (MS), and involvement of the deep gray matter (DGM) is suggested by magnetic resonance imaging. ...The aims of this study were to determine the frequency and distribution of lesions and characterize the inflammatory and neurodegenerative changes in DGM of MS patients. Histochemistry, immunohistochemistry, and morphometry were performed on whole coronal sections of 14 MS and 12 control (6 normal, 6 from amyotrophic lateral sclerosis patients) brains. Demyelinating lesions were frequent in MS DGM; most often in the thalamus and caudate, but they were also seen in the putamen, pallidum, claustrum, amygdala, hypothalamus, and substantia nigra. Most DGM lesions involved both GM and white matter. Inflammation in active DGM lesions was similar to that in lesions only in white matter but was less intense, and there was a preponderance of activated microglia, scarce myelin-laden macrophages, and a lesser extent of axonal damage. Neuronal loss was observed both in DGM lesions and nondemyelinated DGM with neuron atrophy in nondemyelinated DGM. In conclusion, demyelination and neurodegenerative changes are common in MS DGM and may contribute to clinical impairment. Inflammation in DGM lesions is intermediate between the destructive inflammation of white matter lesions and the minimal inflammation of cortical lesions. We hypothesize that alterations of glutamate reuptake mechanisms may contribute to these differences.
Background
The Work Ability in Natalizumab-Treated MS Patients (WANT) study assessed work ability, quality of life, and cognitive processing speed during natalizumab treatment.
Methods
WANT was a ...1-year, prospective, multicenter observational study conducted in Italy. Inclusion criteria included relapsing-remitting multiple sclerosis (MS), natalizumab treatment, full-time worker status, and loss of working hours due to MS as measured by the Work Productivity and Activity Impairment Questionnaire for MS (WPAI:MS). The primary endpoint was change in WPAI:MS domain scores after 1 year on natalizumab. Secondary endpoints included change in annualized relapse rate (ARR), Multiple Sclerosis Impact Scale (MSIS-29) score, and Symbol Digit Modalities Test (SDMT) score.
Results
At enrollment, the 91 patients had a mean age of 38.3 (standard deviation SD, 9.0) years and a mean ARR of 1.5 (SD, 0.8). After 1 year, improvements were observed in all WPAI:MS domains, with significant reductions in Absenteeism (−4.2 SD, 26.0,
p
= 0.0190) and Work Productivity Loss (−7.2 SD, 28.6;
p
= 0.0456). These changes were accompanied by a low ARR (0.1), and 87.9% of patients were relapse free. Significant improvement was observed in MSIS-29 physical and psychological domains (reductions of 2.8 SD, 11.6;
p
= 0.0295 and 6.3 SD, 15.6;
p
= 0.0007, respectively) and SDMT score (increase of 2.4 SD, 7.9;
p
= 0.0006). Adverse events were reported in 32 of 104 patients (30.8%).
Conclusions
The reductions in Absenteeism and Work Productivity Loss and the improved physical and psychological functioning reported after 1 year of natalizumab treatment in real-world settings extend our understanding of natalizumab’s effects on patient-centric and health economics outcomes.
The effect of sub-chronic exposure of intraperitoneal (i.p.) injections of microcystin-LR (MC-LR) on microscopic tissue architecture, hepatic function and lipid peroxidation has been studied in liver ...and kidney of mice. Mice were treated i.p. with 25
μg of pure MC-LR/kg body weight or saline solution for 1 month (every 2 days) with the aim of producing an inflictive stage with evident damage. Histopathological analysis of dissected livers of mice showed a disrupted lobar architecture and the development of cytoplasmatic vacuoles. According to this, a significant increase in hepatic lipid content and in lipid peroxidation levels in liver and kidney was found in MC-LR-treated animals when compared with controls. Moreover, serum alkaline phosphatase and aspartate aminotransferase activities showed a significant alteration in MC-LR-treated animals. After damage, progression or recovery was studied for 1 and 2 months of wash-out. The recovery from liver damage was evident at the cytological and physiological level, only the recovery of lobar architecture was incomplete along the period investigated. In conclusion, the present study demonstrates the ability of hepatic tissue to recover from damage produced by sub-chronic MC-LR administration. The dynamic interplay between damage and tissue-repairing response in determining the ultimate outcome of toxicity should be considered in risk-assessment studies.
The worldwide spread of the COVID-19 pandemic in 2020 forced most countries to intervene with policies and actions—including lockdowns, social-distancing and smart working measures—aimed at ...mitigating the health system and socio-economic disruption risks. The electricity sector was impacted as well, with performance largely reflecting the changes in the industrial and commercial sectors operations and in the social behavior patterns. The most immediate consequences concerned the power demand profiles, the generation mix composition and the electricity price trends. As a matter of fact, the electricity sectors experienced a foretaste of the future, with higher renewable energy penetration and concerns for security of supply. This paper presents a systemic approach toward assessing the impacts of the COVID-19 pandemic on the power sector. This is aimed at supporting decision making—particularly for policy makers, regulators, and system operators—by quantifying shorter term effects and identifying longer term impacts of the pandemic waves on the power system. Various metrics are defined in different areas—system operation, security, and electricity markets—to quantify those impacts. The methodology is finally applied to the European power system to produce a comparative assessment of the effects of the lockdown in the European context.
Abstract
Context
The lack of syndrome-specific reference ranges for thyroid function tests (TFT) among pediatric patients with Down syndrome (DS) results in an overestimation of the occurrence of ...hypothyroidism in this population.
Objective
To (a) outline the age-dependent distribution of TFT among pediatric patients with DS; (b) describe the intraindividual variability of TFT over time; and (c) assess the role of elevated thyrotropin (TSH) in predicting the future onset of overt hypothyroidism.
Methods
In this retrospective, monocentric, observational analysis, we included 548 patients with DS (0-18 years) longitudinally assessed between 1992 and 2022. Exclusion criteria were abnormal thyroid anatomy, treatments affecting TFT, and positive thyroid autoantibodies.
Results
We determined the age-dependent distribution of TSH, FT3, and FT4 and outlined the relative nomograms for children with DS. Compared with non-syndromic patients, median TSH levels were statistically greater at any age (P < .001). Median FT3 and FT4 levels were statistically lower than controls (P < .001) only in specific age classes (0-11 for FT3, 11-18 years for FT4). TSH levels showed a remarkable fluctuation over time, with a poor (23%-53%) agreement between the TSH centile classes at 2 sequential assessments. Finally, the 75th centile was the threshold above which TSH values predicted future evolution into overt hypothyroidism with the best statistical accuracy, with a satisfactory negative predictive value (0.91), but poor positive predictive value (0.15).
Conclusion
By longitudinally assessing TFT in a wide pediatric DS population, we outlined the syndrome-specific reference nomograms for TSH, FT3, and FT4 and demonstrated a persistent upward shift of TSH compared to non-syndromic children.
Jatropha in Mexico Skutsch, Margaret; de los Rios, Emilio; Solis, Silvia ...
Ecology and society,
01/2011, Letnik:
16, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Three case studies from Mexico are presented in which the impacts of the recent introduction of jatropha cultivation for biodiesel production are examined. In Chiapas and Michoacan, local social and ...environmental impacts were assessed using interviews with key informants and questionnaires directed at three groups of stakeholders: jatropha cultivators, farmers in the same areas who are not cultivating jatropha, and laborers on jatropha farms. Results show that the farmers are primarily motivated to participate by the subsidies offered in a government program in the first 2 years, rather than any proven economic benefit. Our farm budget study indicated that profits would be marginal for these farmers. However, no cases of land alienation were involved, and impacts on food security and deforestation are currently not significant. Employment opportunities for landless laborers have increased in areas where jatropha is now grown. The program is only in its third year currently, so these outcomes would need to be reexamined as it develops. In Yucatan, production is mainly in the hands of commercial companies, using estates formerly under low-intensity grazing and secondary forest. A carbon balance analysis indicated that there may be a significant loss of carbon stocks associated with jatropha plantation establishment on these estates. Depending on the maturity of the forest regrowth and the intensity of jatropha production, the carbon payback period varies from 2 to 14 years, although, in some scenarios, the carbon debt may never be recovered.
dexamethasone has been demonstrated to elicit GH secretion in adults, but few data are available about its effectiveness as a provocative
in the diagnostic work-up of GH deficiency (GHD) in ...childhood.
to assess the clinical value of dexamethasone stimulation test (DST) as a diagnostic tool for pediatric GHD.
retrospective single-center analysis. The study population included 166 patients with a pathological response to arginine stimulation test (AST, first-line test) and subsequently tested with either insulin tolerance test (ITT) or DST as a second-line investigation between 2008 and 2019.
comparison between GH peaks and secretory curves induced by ITT and DST; degree of agreement between DST and AST
ITT and AST.
the pathological response to AST (GH peak < 8 ng/mL) was confirmed by an ITT in 80.2% (89/111) of patients and by a DST in 76.4% (42/55), with no statistical difference between the two groups (
value 0.69). Mean GH peaks achieved after ITT and DST were entirely comparable (6.59 ± 3.59
6.50 ± 4.09 ng/ml, respectively,
0.97) and statistically higher than those elicited by arginine (
< 0.01 for both), irrespectively of the average GH peaks recorded for each patient (Bland-Altman method). Dexamethasone elicited a longer lasting and later secretory response than AST and ITT. No side effects were recorded after DST.
DST and ITT confirmed GHD in a superimposable percentage of patients with a pathological first-line test. DST and ITT share a similar secretagogue potency, overall greater than AST.
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