Highlights Mitochondria are the hub of cellular oxidative homeostasis. Mitochondria are the major source of reactive oxygen species (ROS). Extracellular mitochondria are found in blood, in circulating platelets and vesicles. COVID-19 pathogenesis is aggravated by the hyper- inflammatory state. Inflammation activates events leading to microbiota & mitochondrial oxidative damage. Mitochondrial damage contributes to coagulopathy, ferroptosis & microbial dysbiosis. Blood & platelet mitochondria dysfunction may accelerate systemic coagulopathy events. Targeting mitochondria dysfunction may provide useful therapeutic strategies against COVID-19 pathogenesis.

The coronavirus 2 (SARS-CoV-2) pandemic is viciously spreading through the continents with rapidly increasing mortality rates. Current management of COVID-19 is based on the premise that respiratory failure is the leading cause of mortality. However, mounting evidence links accelerated pathogenesis in gravely ill COVID-19 patients to a hyper-inflammatory state involving a cytokine storm. Several components of the heightened inflammatory state were addressed as therapeutic targets. Another key component of the heightened inflammatory state is hyper-ferritinemia which reportedly identifies patients with increased mortality risk. In spite of its strong association with mortality, it is not yet clear if hyper-ferritinemia in COVID-19 patients is merely a systemic marker of disease progression, or a key modulator in disease pathogenesis. Here we address implications of a possible role for hyperferritinemia, and altered iron homeostasis in COVID-19 pathogenesis, and potential therapeutic targets in this regard.

A number of classification schemes for intracranial dural arteriovenous fistulas (AVFs) have been published that claim to predict which lesions will present in a benign or aggressive fashion based on radiological anatomy. We have tested the validity of two proposed classification schemes for the first time in a large single-institution study. A series of 102 intracranial dural AVFs in 98 patients assessed at a single institution was analyzed. All patients were classified according to two grading scales: the more descriptive schema of Cognard, et al. (Cognard) and that recently proposed by Borden, et al. (Borden). According to the Borden classification, 55 patients were Type I, 18 Type II, and 29 Type III. Using the Cognard classification, 40 patients were Type I, 15 Type IIA, eight Type IIB, 10 Type IIA+B, 13 Type III, 12 Type IV, and four Type V. Intracranial hemorrhage (ICH) or nonhemorrhagic neurological deficit was considered an aggressive presenting clinical feature. A total of 16 (16%) of 102 intracranial dural AVFs presented with hemorrhage. Eleven of these hemorrhages (69%) occurred in either anterior cranial fossa or tentorial lesions. When analyzed according to the Borden classification, none (0%) of 55 Type I intracranial dural AVFs, two (11%) of 18 Type II, and 14 (48%) of 29 Type III intracranial dural AVFs presented with hemorrhage (p < 0.0001). After exclusion of visual or cranial nerve deficits that were clearly related to cavernous sinus intracranial dural AVFs, nonhemorrhagic neurological deficits were a feature of presentation in one (2%) of 55 Type I, five (28%) of 18 Type II, and nine (31%) of 29 Type III patients (p < 0.0001). When combined, an aggressive clinical presentation (ICH or nonhemorrhagic neurological deficit) was seen most commonly in intracranial dural AVFs located in the tentorium (11 (79%) of 14) and the anterior cranial fossa (three (75%) of four), but this simply reflected the number of higher grade lesions in these locations. Aggressive clinical presentation strongly correlated with Borden types: one (2%) of 55 Type I, seven (39%) of 18 Type II, and 23 (79%) of 29 Type III patients (p < 0.0001). A similar correlation with aggressive presentation was seen with the Cognard classification: none (0%) of 40 Type I, one (7%) of 15 Type IIA, three (38%) of eight Type IIB, four (40%) of 10 Type IIA+B, nine (69%) of 13 Type III, 10 (83%) of 12 Type IV, and four (100%) of four Type V (p < 0.0001). No location is immune from harboring lesions capable of an aggressive presentation. Location itself only raises the index of suspicion for dangerous venous anatomy in some intracranial dural AVFs. The configuration of venous anatomy as reflected by both the Cognard and Borden classifications strongly predicts intracranial dural AVFs that will present with ICH or nonhemorrhagic neurological deficit.

The recently proposed classification scheme of Borden, Wu, and Shucart (Borden*) should have the ability to identify those intracranial dural arteriovenous fistulae (ICDAVF) which will continue to behave in a benign fashion. We examine for the first time the natural history of benign ICDAVF, including the predictive ability of this grading scale, and the implications for lesion management. A cohort of 55 Borden* grade I lesions was selected from a heterogeneous series of 102 consecutive ICDAVF seen at one institution between 1984 and 1995. Data were collected prospectively from 1991. Grade I lesions were those whose nidus drained directly into a dural venous sinus (DVS) or meningeal vein. The absence of retrograde leptomeningeal venous drainage (RLVD) was an important feature. Intracranial haemorrhage (ICH), non haemorrhagic neurological deficit (NHND), and death were considered aggressive features. There were 23 cavernous sinus, 2 foramen magnum, 1 middle cranial fossa, and 29 transverse sinus lesions. One patient received obliterative surgical treatment. Thirty-two lesions were observed only, and 22 patients developed symptoms or signs requiring palliative embolisation. Two minor complications occurred following embolisation: transient pulmonary aedema (1), and an asymptomatic pericallosal artery embolus (1). Follow-up was available on 48 (89%) patients for a total of 133 patient years (mean 33 months). This included 26 of the 32 patients observed and all 22 of the patients embolised. Aggressive interval behavior was seen in only one patient. Symptom improvement or resolution was observed in the majority of patients, whether observed only [21/26 (81%)], or whether they required embolisation for symptom palliation [19/22 (86%)]. Overall, 53 of the 54 (98%) of ICDAVF behaved in a benign fashion in the follow-up period. The predictable benign natural history of patients identified as Borden* grade I at presentation mandates a conservative approach to these ICDAVF. In some patients, when symptom severity demands, palliative embolisation is an effective and safe therapy.

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SALEH, JUMANA, KATHERINE CIANFLONE, TAQDEES CHAUDHARY, HAMED AL-RIYAMI, ABDUL-RAHEEM AL-ABRI, AND RIAD BAYOUMI. Increased plasma acylation-stimulating protein correlates with hyperlipidemia at late gestation. Obesity. 2007;15:646 -652. Objectives: Obesity is often associated with negative consequences, including hyperlipidemia and insulin resistance. Weight gain during pregnancy is also associated with major lipid alterations. Fat storage is enhanced in early pregnancy. At late gestation, hyperlipidemia becomes a major manifestation. The acylation-stimulating protein (ASP) is a potent lipogenic adipocytokine that correlates with postprandial triglyceride (TG) clearance in vivo and has been linked to hyperlipidemic disorders. The role of ASP during a normal pregnancy is unknown. The objective of this study was to investigate plasma ASP levels in correlation with the lipid profile during late gestation. Research Methods and Procedures: Seventy healthy women at late gestation and 60 non-pregnant controls of similar age and prepregnancy BMI were included in a cross-sectional study. Fasting plasma ASP levels and the lipid profile of all of the women were measured. Results: ASP levels were markedly elevated in the pregnant women (66%, p Ͻ 0.001). ASP levels correlated strongly with the elevated levels of TGs (r ϭ 0.608, p Ͻ 0.000), apolipoprotein B (0.519, p Ͻ 0.000), and low-density lipoprotein-cholesterol (r ϭ 0.405, p Ͻ 0.000). Multivariate analysis adjusting for BMI and age showed that changes in ASP levels at late gestation were best predicted by TG and apoB levels, accounting for 53.8% of plasma ASP variation. For the controls, ASP strongly correlated with BMI, which was the only significant predictor of ASP levels. Discussion: Gestational hormone alterations during pregnancy may affect ASP function as a lipogenic factor. Increased plasma ASP levels at late gestation and their strong correlation with parameters reflecting very low-density lipoprotein accumulation are suggestive of ASP resistance, which may further contribute to the hyperlipidemic state, shifting energy in the form of TGs to the rapidly growing fetus.