Intraarterial anti-leptin therapy via ICA protects ipsilateral CA1 neurons subjected to ischemia and reperfusion

Background Brain reperfusion following an ischemic event is essential for tissue viability, however, it also involves processes that promote neuronal cell death. We have recently shown that local expression of the hormone leptin in cardiovascular organs drives deleterious remodeling. As cerebral ischemia-reperfusion (IR) lesions derive expression of both the leptin hormone and its receptor, we hypothesized that blocking leptin activity in the injured brain area will reduce the deleterious effects of IR injury. Methods C57BL6 male mice underwent bilateral common carotid artery and external carotid artery ligation. The right hemisphere was reperfused after 12 minutes, followed by intraarterial injection of either a low-dose leptin antagonist or saline solution via the ipsilateral ICA. The left common carotid artery remained ligated. Fifteen IR/leptin antagonist-injected and fourteen IR/saline-injected mice completed the experiment. Five days after surgery brains were collected and samples of the hippocampal CA1 region were analyzed for cell viability (H&E) and apoptosis (TUNEL and caspase3), for neuroinflammation (Iba1), and for signaling pathways of pSTAT3 and pSmad2. Results The right hemisphere hippocampal CA1 region subjected to IR and saline injection exhibited increased apoptosis and necrosis of pyramidal cells. Also, increased density of activated microglia/macrophages was evident around the CA1 region. Comparatively, leptin antagonist treatment at reperfusion reduced apoptosis and necrosis of pyramidal cells, as indicated by increased number of viable cells (p < 0.01), and reduced TUNEL (p < 0.001) and caspase3-positive cells (p<0.05). Furthermore, this treatment reduced the density of activated microglia/macrophages (p < 0.001) in the CA1 region. Signaling pathway analysis revealed that while pSTAT3 and pSmad2-positive cells were found surrounding the stratum pyramidal in saline-treated animals, pSTAT3 signal was undetected and pSmad2 was greatly reduced in this territory following leptin antagonist treatment (p < 0.01). Conclusions Inhibition of leptin activity in hemispheric IR injury preserved the viability of ipsilateral hippocampal CA1 neurons, likely by preventing apoptosis and local inflammation. These results indicate that intraarterial anti-leptin therapy may have clinical potential in reducing hemispheric brain IR injury.

Case of Mycotic Pseudoaneurysm of the Common Carotid Artery due to Salmonella typhi Bacteremia

Aneurysm of the extracranial carotid artery is a rare disease, mycotic pseudoaneurysms being even less common. They are a life-threatening complication of systemic infection and atherosclerosis. Immunocompromised people, including patients with HIV, uncontrolled diabetes melltus, those on immunosuppressants like high-dose steroids, and chemotherapy, are at a higher risk for development of mycotic pseudoaneurysms. Due to the high risk of potential complications like rupture and thromboembolic events, mycotic aneurysms always require surgical management. Early detection followed by restoration of blood flow is critical to minimize a fatal outcome. Here we report the case of a 52-year-old man with a past history of hypertension and dyslipidemia who presented with a pulsatile painful neck swelling. On evaluation, the patient was diagnosed to have Salmonella typhi bacteremia, HIV infection, and a mycotic aneurysm of the left common carotid artery.

The content of ATP Synthase in Cerebral Ischemia of Varying Severity Comparative Analysis

Objective. Evaluation of changes in the content of ATP synthase in the parietal cortex and hippocampus of the brain of rats with ischemia of varying severity in a comparative aspect. Methods. The experiments were performed on 88 male outbred white rats weighing 260 ± 20 g. Brain ischemia was modeled under conditions of intravenous thiopental anesthesia (40-50 mg / kg). Total cerebral ischemia was modeled by decapitation of animals. The brain sampling was carried out 1 hour and 24 hours after decapitation - to study tissue respiration of mitochondria, as well as 1 hour later to determine the content of ATP synthase. Subtotal cerebral ischemia was modeled by simultaneous ligation of both common carotid arteries. The material was taken after 1 hour to determine the content of ATP synthase. Stepwise subtotal cerebral ischemia was performed by sequential ligation of both common carotid arteries with an interval of 7 days. The sampling was carried out 1 hour after ligation of the second common carotid artery in each of the subgroups. Partial cerebral ischemia was modeled by ligation of one common carotid artery on the right. The sampling was carried out 1 hour after the operation. Determination of the content of ATP synthase was carried out by immunohistochemical method using monoclonal antibodies. For this purpose, after decapitation, the brain was quickly removed from the rats, pieces of the cerebral cortex were fixed in zinc-ethanol-formaldehyde at + 4 ° C (overnight), then embeddedвinвparaffin. Results. In the group of stepwise subtotal cerebral ischemia, the smallest decrease in the content of ATP synthase was observed in the 1st subgroup with an interval between dressings of 7 days, while the greatest decrease in the content of the enzyme was noted in the 3rd subgroup with the minimum interval between the dressings of the common carotid artery (1 day). Modeling of more severe types of ischemic damage led to pronounced morphological changes in neurons in the parietal cortex and hippocampus of the rat brain - a decrease in their size, deformation of the perikarya, an increase in the degree of neuronal chromatophilia with their simultaneous wrinkling and subsequent death. These disorders were most pronounced in the 3rd subgroup of stepwise subtotal cerebral ischemia with the shortest interval between dressings, which was 1 day, and in the group of total cerebral ischemia. Conclusion. Thus, the most pronounced decrease in the content of ATP synthase was observed in the groups of total cerebral ischemia, subtotal cerebral ischemia and in the 3rd subgroup of stepwise subtotal cerebral ischemia, with a minimal time interval between the ligation of the common carotid artery. In stepwise subtotal cerebral ischemia with an interval between ligation of the common carotid artery of 7 days, the suppression of the ATP synthase content was not so significant.

Carotid Intima-Media Thickness in Patients with Subclinical Hypothyroidism: A Prospective Controlled Study

Purpose: The association between subclinical hypothyroidism (SCH) and cardiovascular risk, particularly with a TSH <10 µIU/ml, remains controversial. The objective of our study was to assess the association between SCH and cardiovascular risk through carotid intima-media thickness, and alternatively, to evaluate its change after treatment with levothyroxine. Methods: A total of 54 individuals were included in the study: 18 with SCH; 18 with overt hypothyroidism (OH); and 18 healthy controls (HC). The carotid intima-media thickness was measured in each group. In SCH, follow-up was performed at three and six months after the start of levothyroxine treatment. Results: The mean age of the total population at baseline was 35.8 years. The median TSH in SCH was 6.15 µIU/ml. The carotid intima-media thickness (mean and standard deviation) was greater in SCH in comparison to the HC group: right common carotid artery (RCCA), 0.486 ± 0.106 mm and 0.413 ± 0.075 mm in SCH and HC, respectively, p=0.01 and left common carotid artery (LCCA), 0.511 ± 0.144 mm and 0.427 mm ± 0.090 in SCH and HC, respectively, p=0.03). In patients with SCH, there was a decrease in the carotid intima-media thickness after treatment with levothyroxine (RCCA and LCCA, p <0.05 at three and six months). Conclusions: There was an association between increased carotid intima-media thickness in patients with SCH in comparison with HC, even with a TSH <10 µIU/ml. The increase was reversed with levothyroxine therapy. The association of this increased thickness with important cardiovascular outcomes remains uncertain and should be evaluated in future studies.

Retinal Degeneration in a Murine Model of Retinal Ischemia by Unilateral Common Carotid Artery Occlusion

Retinal degeneration is a progressive retinal damage in ocular vascular diseases. There are several reasons for this, such as occlusion of arteries or veins, diabetic retinopathy, or hereditary retinal diseases. To study pathological mechanisms of retinal degeneration, it is required to develop experimentally reproducible and clinically relevant models. In our previous studies, we developed a murine model of retinal hypoperfusion by unilateral common carotid artery occlusion (UCCAO) which mimics the pathophysiology of ocular ischemic syndrome (OIS) in humans, and described broad pathological mechanisms in the retina after UCCAO. However, there still remain missing pieces of the ocular pathologic process by UCCAO. In this study, we examined those unfound mechanisms. UCCAO was performed on adult mice. Ocular dysfunctions, histological deficits, and inflammation were examined after UCCAO, compared with sham-operated mice. Evaluation values were analyzed by electrophysiological, histological, and molecular biological methods. Eyelid drooping was permanently seen after UCCAO. Induction time point of acute reversible cataract under anesthesia was shortened. Retinal/visual dysfunctions were detected 2-4 weeks after UCCAO. Specifically, scotopic b-wave was more affected than a-wave, with the dysfunction of photopic b-wave. Impaired oscillatory potentials and visual evoked potential were constantly observed. Pathological Müller gliosis/inflammation was featured with NeuN-positive cell loss in the ganglion cell layer. Axial length, intraocular pressure, pupillary light reflex, and retinal pigment epithelium/choroidal thickness were not changed by UCCAO. A murine model of retinal ischemia by UCCAO can be useful for studying a series of degenerative process in the ischemic retina.