Dominantly Inherited Amyotrophic Lateral Sclerosis (Motor Neuron Disease)

The term amyotrophic lateral sclerosis was first introduced by Charcot to describe cases with mixed upper and lower motor neuron signs without sensory impairment. Later the syndromes of progressive bulbar palsy (PBP) and progressive muscular atrophy (PMA) were recognized to be variations of the same pathological process, and ALS was used as an inclusive term to refer to these syndromes as well. Although some authors reserve the term ALS for the specific syndrome of mixed upper and lower motor neuron lesions and use the term “motor neuron disease” to refer to the constellation of syndromes, most of the literature on familial cases uses ALS as a generic title. We will adhere to this convention

Does the Meguma Terrane Extend into SW England?

The peri-Gondwanan Meguma terrane of southern Nova Scotia, Canada, is the only major lithotectonic element of the northern Appalachian orogen that has no clear correlatives elsewhere in the Appalachians and lacks firm linkages to the Caledonide and Variscan orogens of western and southern Europe. This characteristic is in contrast with its immediate peri-Gondwanan neighbor, Avalonia, which has features in common with portions of Carolinia in the southern Appalachians and has been traced from the Rhenohercynian Zone of southern Britain eastward around the Bohemian Massif to the Carpathians and western Pontides. At issue is the tendency in Europe to assign all peri-Gondwanan terranes lying outboard of the Rheic suture to Avalonia, characterized by relatively juvenile basement and detrital zircon ages that include Mesoproterozoic populations, and those inboard of the suture to Cadomia, characterized by a more evolved basement and detrital zircon ages that match Paleoproterozoic and older sources in the West African craton.    Although the unexposed basements of Avalonia and Meguma are thought to be isotopically very similar, the Meguma sedimentary cover contains scarce Mesoproterozoic zircon and is dominated instead by Neoproterozoic and Paleoproterozoic populations like those of Cadomia. Hence, felsic magma produced by crustal melting in the Meguma terrane (e.g. the ca. 370 Ma South Mountain Batholith) is isotopically more juvenile (eNd = –5 to –1, TDM = 1.3 Ga) than the rocks it intruded (eNd= –12 to –7, TDM = 1.7 Ga). By contrast, felsic magma produced by crustal melting in Avalonia (eNd = –1 to +6, TDM = 0.7–1.2 Ga) is isotopically similar to its host rocks (eNd = –3 to +4, TDM = 0.9–1.4).    The isotopic relationship shown by the Meguma terrane has also been recognized in the South Portuguese Zone of southern Spain, which is traditionally assigned to Avalonia. However, the Sierra Norte Batholith of the South Portuguese Zone (ca. 330 Ma; eNd = +1 to –3, TDM = 0.9–1.2 Ga) is on average more juvenile than the Late Devonian host rocks (eNd = –5 to –11) it intruded, suggesting instead an extension of the Meguma terrane into Europe. Available data for the Cornubian Batholith of SW England (ca. 275–295 Ma; eNd = –4 to –7, TDM = 1.3–1.8 Ga) and the Devonian–Carboniferous metasedimentary rocks it intruded (eNd = –8 to –11) suggests this may also be true of that part of the southern Britain (Rhenohercynian Zone) with which the South Portuguese Zone is traditionally correlated.SOMMAIRELe terrane péri-gondwanien de Meguma en Nouvelle-Écosse au Canada, est le seul grand élément lithotectonique de l’orogène des Appalaches du Nord qui n’ait pas de correspondant avéré ailleurs dans les Appalaches et qui ne montre aucun lien sûr avec les orogènes calédonienne et varisque de l’ouest et du sud de l’Europe.  Cette situation contraste avec celle de son voisin péri-gondwanien immédiat, l’Avalonie, qui partage certaines caractéristiques avec des portions de Carolinia des Appalaches du sud et qui a été suivi à partir de la zone rhénohercynienne dans le sud de la Grande-Bretagne vers l’est autour du massif bohémien jusqu’aux Carpates et l’ouest de la chaîne pontique.  Ce qui est en question ici c’est la tendance en Europe à assigner l’Avalonie à tous les terranes péri-gondwaniens situés à l’extérieur de la suture rhéïque lesquels sont caractérisés par un socle relativement juvénile et des âges de zircons détritiques qui comportent des populations mésoprotérozoïques, et ceux situés à l’intérieur de la suture à Cadomia, lesquels sont caractérisés par un socle plus évolué et des âges de zircons détritiques qui correspondent à des sources du craton ouest africain paléoprotérozoïques et plus anciennes.     Bien que l’on estime que les socles non-exposés des terranes d’Avalonie et de Meguma soient très similaires isotopiquement, le couvert sédimentaire de Meguma ne renferme que de rares zircons mésoprotérozoïques, et ce sont plutôt les populations de zircons néoprotérozoïques et paléoprotérozoïques qui dominent, comme c’est le cas pour Cadomia.  Il en ressort que le magma felsique produit par la fusion de croûte dans le terrane de Meguma (par ex. le batholite de South Mountain de 370 Ma env.) est isotopiquement plus jeune (eNd = –5 à –1, TDM = 1.3 Ga) que les roches qu’il recoupe (eNd= –12 à –7, TDM = 1.7 Ga).  Par opposition, le magma felsique produit par la fusion de la croûte dans le terrane d’Avalonie (eNd = –1 à +6, TDM = 0.7–1.2 Ga) est isotopiquement similaire aux roches de son encaissant (eNd = –3 à +4, TDM = 0.9–1.4).     Le profil isotopique du terrane de Meguma, traditionnellement assignée à l’Avalonie,  a aussi été détecté dans la Zone sud-portugaise du sud de l’Espagne.  Cependant, le batholite de Sierra Norte de la Zone sud-portugaise (ca. 330 Ma; eNd = +1 à –3, TDM = 0.9–1.2 Ga) est en moyenne plus jeune que l’encaissant du Dévonien moyen (eNd = –5 à –11) qu’il recoupe, ce qui permet de penser à une extension du terrane de Meguma en Europe.  Les données disponibles du batholite de Cornubian dans le S-O de l’Angleterre (ca. 275–295 Ma; eNd = –4 à –7, TDM = 1.3–1.8 Ga) et des roches métasédimentaires dévono-carbonifères qu’il recoupe (eNd = –8 to –11) permet de penser qu’il pourrait en être de même de cette portion du sud de la Grande-Bretagne (Zone rhénohercynienne) avec laquelle la Zone sud-portugaise est traditionnellement corrélée

T-cell production of matrix metalloproteinases and inhibition of parasite clearance by TIMP-1 during chronic Toxoplasma infection in the brain

Chronic infection with the intracellular protozoan parasite Toxoplasma gondii leads to tissue remodelling in the brain and a continuous requirement for peripheral leucocyte migration within the CNS (central nervous system). In the present study, we investigate the role of MMPs (matrix metalloproteinases) and their inhibitors in T-cell migration into the infected brain. Increased expression of two key molecules, MMP-8 and MMP-10, along with their inhibitor, TIMP-1 (tissue inhibitor of metalloproteinases-1), was observed in the CNS following infection. Analysis of infiltrating lymphocytes demonstrated MMP-8 and -10 production by CD4+ and CD8+ T-cells. In addition, infiltrating T-cells and CNS resident astrocytes increased their expression of TIMP-1 following infection. TIMP-1-deficient mice had a decrease in perivascular accumulation of lymphocyte populations, yet an increase in the proportion of CD4+ T-cells that had trafficked into the CNS. This was accompanied by a reduction in parasite burden in the brain. Taken together, these findings demonstrate a role for MMPs and TIMP-1 in the trafficking of lymphocytes into the CNS during chronic infection in the brain

Association Between Chronic Hepatitis C Virus Infection and Myocardial Infarction Among People Living With HIV in the United States.

Hepatitis C virus (HCV) infection is common among people living with human immunodeficiency virus (PLWH). Extrahepatic manifestations of HCV, including myocardial infarction (MI), are a topic of active research. MI is classified into types, predominantly atheroembolic type 1 MI (T1MI) and supply-demand mismatch type 2 MI (T2MI). We examined the association between HCV and MI among patients in the Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems, a US multicenter clinical cohort of PLWH. MIs were centrally adjudicated and categorized by type using the Third Universal Definition of Myocardial Infarction. We estimated the association between chronic HCV (RNA+) and time to MI while adjusting for demographic characteristics, cardiovascular risk factors, clinical characteristics, and history of injecting drug use. Among 23,407 PLWH aged ≥18 years, there were 336 T1MIs and 330 T2MIs during a median of 4.7 years of follow-up between 1998 and 2016. HCV was associated with a 46% greater risk of T2MI (adjusted hazard ratio (aHR) = 1.46, 95% confidence interval (CI): 1.09, 1.97) but not T1MI (aHR = 0.87, 95% CI: 0.58, 1.29). In an exploratory cause-specific analysis of T2MI, HCV was associated with a 2-fold greater risk of T2MI attributed to sepsis (aHR = 2.01, 95% CI: 1.25, 3.24). Extrahepatic manifestations of HCV in this high-risk population are an important area for continued research

Poorly Controlled HIV Infection: An Independent Risk Factor for Liver Fibrosis

Liver disease is a major cause of mortality among HIV-infected persons. There is limited information about the extent to which HIV disease severity impacts liver disease progression

Plasma Interleukin-6 (IL-6), Angiopoietin-2, and C-Reactive Protein Levels Predict Subsequent Type 1 Myocardial Infarction in Persons With Treated HIV Infection

BackgroundHIV infection leads to endothelial activation, promoting platelet adhesion, and accelerating atherosclerosis. Our goal was to determine whether biomarkers of endothelial activation and hemostasis/thrombosis were elevated in people with treated HIV (PWH) before myocardial infarction (MI).MethodsIn a case-control study nested within the CFAR Network of Integrated Clinical Systems (CNICS) cohort, we compared 69 adjudicated cases with type 1 MI with 138 controls matched for antiretroviral therapy regimen. We measured angiopoietin-1, angiopoietin-2 (ANG-2), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), von Willebrand factor, C-reactive protein (CRP), interleukin-6 (IL-6), plasminogen activation inhibitor-1, P-selectin, serum amyloid-A, soluble CD14, and apolipoprotein A1 in stored plasma. Conditional logistic regression identified associations with subsequent MI, with and without adjustment for Atherosclerotic Cardiovascular Disease (ASCVD) and Veterans Aging Cohort Study (VACS) scores.ResultsHigher IL-6 was associated with MI after adjustment for ASCVD score (adjusted odds ratio [AOR] 1.51, 95% confidence interval [95% CI]: 1.05 to 2.17 per standard-deviation-scaled log 2 increment). In a separate model adjusting for VACS score, higher ANG-2 (AOR 1.49, 95% CI: 1.04 to 2.14), higher CRP (AOR 1.45, 95% CI: 1.06 to 2.00), and higher IL-6 (AOR 1.68, 95% CI: 1.17 to 2.41) were associated with MI. In a sensitivity analysis excluding PWH with viral load ≥400 copies/mL, higher IL-6 remained associated with MI after adjustment for ASCVD score and after adjustment for VACS score.ConclusionsAmong PWH, higher levels of plasma IL-6, CRP, and ANG-2 predict subsequent type 1 MI, independent of conventional risk scores. IL-6 had the most consistent associations with type 1 MI, regardless of viral load suppression

Recent Incarceration, Substance Use, Overdose, and Service Use Among People Who Use Drugs in Rural Communities

Importance: Drug use and incarceration have a substantial impact on rural communities, but factors associated with the incarceration of rural people who use drugs (PWUD) have not been thoroughly investigated. Objective: To characterize associations between recent incarceration, overdose, and substance use disorder (SUD) treatment access among rural PWUD. Design, setting, and participants: For this cross-sectional study, the Rural Opioid Initiative research consortium conducted a survey in geographically diverse rural counties with high rates of overdose across 10 US states (Illinois, Wisconsin, North Carolina, Oregon, Kentucky, West Virginia, Ohio, Massachusetts, New Hampshire, and Vermont) between January 25, 2018, and March 17, 2020, asking PWUD about their substance use, substance use treatment, and interactions with the criminal legal system. Participants were recruited through respondent-driven sampling in 8 rural US regions. Respondents who were willing to recruit additional respondents from their personal networks were enrolled at syringe service programs, community support organizations, and through direct community outreach; these so-called seed respondents then recruited others. Of 3044 respondents, 2935 included participants who resided in rural communities and reported past-30-day injection of any drug or use of opioids nonmedically via any route. Data were analyzed from February 8, 2022, to September 15, 2023. Exposure: Recent incarceration was the exposure of interest, defined as a report of incarceration in jail or prison for at least 1 day in the past 6 months. Main outcomes and measures: The associations between PWUD who were recently incarcerated and main outcomes of treatment use and overdose were examined using logistic regression. Results: Of 2935 participants, 1662 (56.6%) were male, 2496 (85.0%) were White; the mean (SD) age was 36 (10) years; and in the past 30 days, 2507 (85.4%) reported opioid use and 1663 (56.7%) reported injecting drugs daily. A total of 1224 participants (41.7%) reported recent incarceration, with a median (IQR) incarceration of 15 (3-60) days in the past 6 months. Recent incarceration was associated with past-6-month overdose (adjusted odds ratio [AOR], 1.38; 95% CI, 1.12-1.70) and recent SUD treatment (AOR, 1.62; 95% CI, 1.36-1.93) but not recent medication for opioid use disorder (MOUD; AOR, 1.03; 95% CI, 0.82-1.28) or currently carrying naloxone (AOR, 1.02; 95% CI, 0.86-1.21). Conclusions and relevance: In this cross-sectional study of PWUD in rural areas, participants commonly experienced recent incarceration, which was not associated with MOUD, an effective and lifesaving treatment. The criminal legal system should implement effective SUD treatment in rural areas, including MOUD and provision of naloxone, to fully align with evidence-based SUD health care policies.</p