Background and Purpose— Inflammatory cells play a significant role in secondary injury after ischemic stroke. Recent studies have suggested that a lack of autophagy in myeloid cells causes augmented proinflammatory cytokine release and prolonged inflammation after tissue injury. In this study, we investigated the roles of myeloid cell autophagy in ischemic brain injury. Methods— Focal cerebral ischemia was induced via transient middle cerebral artery occlusion in mice with autophagy-deficient myeloid lineage cells (Atg5flox/flox LysMCre+) and in their littermate controls (Atg5flox/flox). Infarct volume, neurological function, inflammatory cell infiltration, and proinflammatory cytokine expression levels were evaluated. Results— Mice lacking autophagy in myeloid lineage cells had a lower survival rate for 14 days than control mice (20% versus 70%; P <0.05). Although there was no difference in infarct volume at 12 hours between the 2 groups, mice lacking autophagy in myeloid lineage cells had larger infarct volumes at later time points (3 and 7 days after reperfusion) with worse neurological deficit scores and lower grip test scores. There were a higher number of ionized calcium binding adaptor molecule 1-positive cells and cells expressing M1 marker CD16/32 in mice lacking autophagy in myeloid cells at the later time points. Moreover, these mice had higher expression levels of proinflammatory cytokines at later time points; however, there was no difference in ionized calcium binding adaptor molecule 1-positive cells or mRNA levels of proinflammatory cytokines at the earlier time point (12 hours after reperfusion). Conclusions— These data suggest that the lack of myeloid cell autophagy aggravates secondary injury by augmenting and prolonging inflammation after ischemic stroke without affecting the initial injury.
The cardiovascular effects of a new antihypertensive drug, bupicomide, were compared with those of hydralazine in 6 patients with mild to moderate hypertension. The mean supine arterial pressure of patients was reduced 15.2 mm Hg by bupicomide (900 to 2,000 mg/day) and 15.7 mm Hg by hydralaslne (300 to 600 mg/day). Heart rate increased an average of 11.3 bpm during bupicomide and 14.5 bpm by hydralaine. Neither drug was associated with a postural decrease in mean arterial pressure. The heart rate response during maximum tolerated treadmill exercise was not diminished by either drug. Cardiac index was increased during administration of both drugs. Bupicomide and hydralazine reduced forearm vascular resistance, while renal blood flow and renal vascular resistance were not significantly modified. Evidence of equivalent augmentation of sympathetic nervous activity during administration of both drugs consisted of equal and significant increases in heart rate and urinary norepinephrine excretion, and decreases in duration of the pre‐ejection period. The absolute values of these parameters were correlated with mean arterial pressure, which may indicate that the increase in sympathetic nervous activity was mediated by baroreceptor reflexes. Although bupicomide inhibits dopamine ß‐hydroxylase, our results suggest that it is acting as a direct vasodilator.
Activation of the formyl-peptide receptor-like (FPRL) 1 pathway has recently gained high recognition for its significance in therapy of inflammatory diseases. Agonism at FPRL1 affords a beneficial effect in animal models of acute inflammatory conditions, as well as in chronic inflammatory diseases. TIPMFVPESTSKLQKFTSWFM-amide (CGEN-855A) is a novel 21-amino acid peptide agonist for FPRL1 and also activates FPRL2. CGEN-855A was discovered using a computational platform designed to predict novel G protein-coupled receptor peptide agonists cleaved from secreted proteins by convertase proteolysis. In vivo, CGEN-855A displays anti-inflammatory activity manifested as 50% inhibition of polymorphonuclear neutrophil (PMN) recruitment to inflamed air pouch and provides protection against ischemia-reperfusion-mediated injury to the myocardium in both murine and rat models (36 and 25% reduction in infarct size, respectively). Both these activities are accompanied by inhibition of PMN recruitment to the injured organ. The secretion of inflammatory cytokines, including interleukin (IL)-6, IL-1beta, and tumor necrosis factor-alpha, was not affected upon incubation of human peripheral blood mononuclear cells with CGEN-855A, whereas IL-8 secretion was elevated up to 2-fold upon treatment with the highest CGEN-855A dose only. Collectively, these new data support a potential role for CGEN-855A in the treatment of reperfusion-mediated injury and in other acute and chronic inflammatory conditions.
Odontoid fractures are common cervical spine fractures and lead to atlantoaxial instability depending on their type. Fractures through the base of the odontoid neck are considered for surgery. While the management of these fractures is controversial and may include external immobilization or posterior fusion, an odontoid screw offers the advantages of directly crossing the fracture site while preserving motion at C1-2. Although intraoperative navigation is routinely utilized in spine surgery, there are few reports of navigated anterior odontoid screw placement. In this report, we describe the safe and accurate placement of two anterior odontoid screws using the O-arm navigation system in an octogenarian with a type II odontoid fracture. Details of the technical approach are also provided. The follow-up imaging at three months confirmed the healing of the fracture. Intraoperative navigation using the O-arm system allows for safe and accurate placement of two odontoid screws.
Postconditioning (postcon) protects the heart from ischemia reperfusion (IR) injury. Protease activated receptor1 (PAR1) inhibition has protective effects after IR. Therefore, we hypothesize that if postcon and pharmacological PAR1 inhibition target the same pathway, and the combination of postcon and PAR1 inhibition may not have additive protective effect. Methods In anesthetized open‐chest rats, the left coronary artery (LCA) was occluded for 30 min and reperfused for 3 hours. Rats were randomly assigned to1) Control: saline; 2) PAR1 antagonist (BMS 226001) 1mg/Kg was administered 5 min before R; 3) Postcon with 3 cycles of 10 s R and 10 s re‐occlusion and 4) BMS 1 mg/Kg plus postcon. Results Area at risk (36%–39%) was comparable among 4 groups. Compared to control, infarct size (TTC staining) was significantly less in BMS, postcon and the combination groups. The combination of BMS and postcon did not further significantly reduce infarct size compared to either intervention alone. Conclusions Inhibition of PAR1 and postcon alone at reperfusion are cardioprotective in vivo; however, concomitant PAR1 inhibition does not enhance the cardioprotection of postcon. Group N AAR/LV (%) An/AAR (%) Control 7 37.9 ± 2.4 57.0 ± 2.1 BMS 8 38.1 ± 2.5 42.5 ± 2.5 * Postcon 7 39.3 ± 2.1 39.1 ± 2.3 * BMS + Postcon 7 35.6 ± 1.4 39.9 ± 3.0 * Values are expressed as mean ± S.E.M. P < 0.05 vs. values in control.
The incidences of intracranial aneurysm and aneurysmal subarachnoid hemorrhage are high in postmenopausal women. Although population-based studies suggest that hormone replacement therapy is beneficial for postmenopausal women with intracranial aneurysms, estrogen replacement may no longer be recommended for the prevention of chronic diseases given its association with adverse outcomes, such as cancer and ischemic stroke. The isoflavone daidzein and its intestinal metabolite equol are bioactive phytoestrogens and potent agonists of estrogen receptors. Given their estrogenic properties, we investigated whether the isoflavones daidzein and equol are protective against the formation and rupture of intracranial aneurysms in a mouse model of the postmenopausal state.We induced intracranial aneurysms in ovariectomized adult female mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. We fed the mice with an isoflavone-free diet with/without daidzein supplementation, or in a combination of intraperitoneal equol, or oral vancomycin treatment. We also used estrogen receptor beta knockout mice.Both dietary daidzein and supplementation with its metabolite, equol, were protective against aneurysm formation in ovariectomized mice. The protective effects of daidzein and equol required estrogen receptor-β. The disruption of the intestinal microbial conversion of daidzein to equol abolished daidzein’s protective effect against aneurysm formation. Mice treated with equol had lower inflammatory cytokines in the cerebral arteries, suggesting that phytoestrogens modulate inflammatory processes important to intracranial aneurysm pathogenesis.Our study establishes that both dietary daidzein and its metabolite, equol, protect against aneurysm formation in ovariectomized female mice through the activation of estrogen receptor-β and subsequent suppression of inflammation. Dietary daidzein’s protective effect required the intestinal conversion to equol. Our results indicate the potential therapeutic value of dietary daidzein and its metabolite, equol, for the prevention of the formation of intracranial aneurysms and related subarachnoid hemorrhage.
OBJECTIVE Moyamoya is a progressive arteriopathy that predisposes patients to stroke due to stenosis of the intracranial internal carotid arteries and their proximal branches. Despite the morbidity caused by this condition, the ability to accurately predict prognosis for individual patients remains challenging. The goal of this study was to develop a systematic scoring method based on parenchymal findings on preoperative brain MRI to predict long-term outcomes for surgically treated pediatric patients with moyamoya. METHODS A retrospective surgical cohort of pediatric patients (≤ 18 years of age at the time of the initial surgery) with moyamoya from a single center were studied. Radiological variables with existing correlations between outcomes in moyamoya or other vascular diseases were chosen to score preoperative MRI based on easily defined parenchymal findings that could be rapidly assessed and used to make a numeric score. Calculated scores were correlated with clinical outcome measures using the Pearson correlation coefficient and area under the receiver operating characteristic curve (AUROC). RESULTS A total of 35 children with moyamoya disease or moyamoya syndrome were included in the study, with a median follow-up time of 2.6 years from the time of surgery. The pediatric moyamoya MRI score (PMMS) consists of ischemic changes (0–2; 0 = none, 1 = focal, 2 = diffuse), encephalomalacia (0–2; 0 = none, 1 = focal, 2 = diffuse), and hemorrhage (0–1; 0 = not present, 1 = present). PMMSs were highly correlated with pediatric modified Rankin Scale scores at the last follow-up (r = 0.7, 95% CI 0.44–0.84; p < 0.001) as a six-point scale, and when dichotomized (AUROC = 0.85). CONCLUSIONS The PMMS was found to be a simple tool based on preoperative MRI data that could be quickly and easily calculated and correlated with disability. This scoring method may aid future development of predictive models of outcomes for children with moyamoya disease and moyamoya syndrome.
OBJECT Cushing's disease (CD) can lead to significant morbidity secondary to hormonal sequelae or mass effect from the pituitary tumor. A transsphenoidal approach to resection of the adrenocorticotropic hormone (ACTH)–secreting pituitary adenoma is the first-line treatment. However, in the setting in which patients are unable to undergo surgery, have acute hypercortisolism, or have recurrent disease, medical therapy can play an important role. The authors performed a systematic review to highlight the efficacy of medical treatment of CD and discuss novel molecular insights that could guide the development of future medical treatments of CD. METHODS A search on current medical therapies for CD was performed. After individual medical therapeutic agents for CD were identified, each agent underwent a formal systematic search. The phrase “(name of agent) and Cushing's” was used as a search term in PubMed for all years up to 2014. The abstract of each article was reviewed for studies that evaluated the efficacy of medical treatment of CD. Only studies that enrolled at least 20 patients were included in the review. RESULTS A total of 11 articles on 6 individual agents were included in this review. Specific medical therapies were categorized based on the level of action: pituitary directed (cabergoline and pasireotide), adrenal/steroidogenesis directed (ketoconazole, metyrapone, and mitotane), and end-tissue directed/cortisol receptors (mifepristone). The studies identified consisted of a mix of retrospective reviews and small clinical trials. Only pasireotide and mifepristone have undergone Phase III clinical trials, from which they garnered FDA approval for the treatment of patients with CD. Overall, agents targeting ACTH secretion and steroidogenesis were found to be quite effective in reducing urine free cortisol (UFC) to levels near normal. A significant reduction in UFC was observed in 45%–100% of patients and a majority of patients gained clinical improvement. Similarly, inhibition at the end-tissue level led to clinical improvement in 87% of patients. However, side-effect rates associated with these drugs are high (up to 88%). Ketoconazole has been shown to enhance tumor appearance on MRI to facilitate pituitary resection. Promising molecular targets have been identified, including epidermal growth factor receptor, retinoic acid receptors, and cyclin dependent kinases. These pathways have been linked to the regulation of pro-opiomelanocortin expression, ACTH secretion, and tumor growth. CONCLUSIONS Despite encouraging Phase III clinical trials leading to FDA approval of 2 agents for treatment of patients with CD, no agent has yet produced results comparable to resection. As a result, the molecular insights gained into CD pathogenesis will need to continue to be expanded until they can lead to the development of medical therapies for CD with a favorable side-effect profile and efficacy comparable to resection. Ideally these agents should also reduce tumor size, which could potentially permit their eventual discontinuation.
Healthcare disparities are widely described in adults, but barriers affecting access to care for pediatric patients with moyamoya disease (MMD) are unknown. Understanding socioeconomic factors impacting hospital access and outcomes is necessary to address pediatric healthcare disparities.In this cross-sectional observational study, the Kids' Inpatient Database was used to identify patients admitted with a primary diagnosis of MMD from 2003 to 2016. Patients ≤ 18 years with a primary diagnosis of MMD based on International Classification of Diseases (ICD) codes were included. Hospital admissions were queried for use of cerebral revascularization based on ICD procedure codes.Query of the KID yielded 1449 MMD hospitalizations. After multivariable regression, Hispanic ethnicity (OR 0.52 [95% CI 0.33-0.81], p = 0.004) was associated with lack of surgical revascularization. Private insurance (OR 1.56 [95% CI 1.15-2.13], p = 0.004), admissions at medium- and high-volume centers (OR 2.01 [95% CI 1.42-2.83], p < 0.001 and OR 2.84 [95% CI 1.95-4.14], p < 0.001, respectively), and elective hospitalization (OR 3.37 [95% CI 2.46-4.64], p < 0.001) were positively associated with revascularization. Compared with Caucasian race, Hispanic ethnicity was associated with increased mean (± SEM) length of stay by 2.01 ± 0.70 days (p = 0.004) and increased hospital charges by $24,333.61 ± $7918.20 (p = 0.002), despite the decreased utilization of surgical revascularization. Private insurance was associated with elective admission (OR 1.50 [95% CI 1.10-2.05], p = 0.01) and admission to high-volume centers (OR 1.90 [95% CI 1.26-2.88], p = 0.002). African American race was associated with the development of in-hospital complications (OR 2.52 [95% CI 1.38-4.59], p = 0.003).Among pediatric MMD hospitalizations, multiple socioeconomic factors were associated with access to care, whether surgical treatment is provided, and whether in-hospital complications occur. These results suggest that socioeconomic factors are important drivers of healthcare disparities in children with MMD and warrant further study.
