The microbial metabolite urolithin A reduces Clostridioides difficile toxin expression and toxin-induced epithelial damage.

Clostridioides difficile is a Gram-positive, anaerobic, spore-forming bacterium responsible for antibiotic-associated pseudomembranous colitis. Clostridioides difficile infection (CDI) symptoms can range from diarrhea to life-threatening colon damage. Toxins produced by C. difficile (TcdA and TcdB) cause intestinal epithelial injury and lead to severe gut barrier dysfunction, stem cell damage, and impaired regeneration of the gut epithelium. Current treatment options for intestinal repair are limited. In this study, we demonstrate that treatment with the microbial metabolite urolithin A (UroA) attenuates CDI-induced adverse effects on the colon epithelium in a preclinical model of CDI-induced colitis. Moreover, our analysis suggests that UroA treatment protects against C. difficile-induced inflammation, disruption of gut barrier integrity, and intestinal tight junction proteins in the colon of CDI mice. Importantly, UroA treatment significantly reduced the expression and release of toxins from C. difficile without inducing bacterial cell death. These results indicate the direct regulatory effects of UroA on bacterial gene regulation. Overall, our findings reveal a novel aspect of UroA activity, as it appears to act at both the bacterial and host levels to protect against CDI-induced colitis pathogenesis. This research sheds light on a promising avenue for the development of novel treatments for C. difficile infection.IMPORTANCETherapy for Clostridioides difficile infections includes the use of antibiotics, immunosuppressors, and fecal microbiota transplantation. However, these treatments have several drawbacks, including the loss of colonization resistance, the promotion of autoimmune disorders, and the potential for unknown pathogens in donor samples. To date, the potential benefits of microbial metabolites in CDI-induced colitis have not been fully investigated. Here, we report for the first time that the microbial metabolite urolithin A has the potential to block toxin production from C. difficile and enhance gut barrier function to mitigate CDI-induced colitis.

Gender differences in multifidus fatty infiltration, sarcopenia and association with preoperative pain and functional disability in patients with lumbar spinal stenosis.

BACKGROUND: In patients with lumbar spinal stenosis, female gender has been associated with higher pain and functional disability. Sarcopenia and multifidus atrophy have also been associated with symptomatic severity. PURPOSE: The purpose of this study was to determine if gender differences in sarcopenia and multifidus atrophy are associated with gender disparities in disease symptomatology. STUDY DESIGN: Prospectively collected medical records and imaging studies were retrospectively reviewed. PATIENT SAMPLE: We retrospectively reviewed medical records and imaging studies for 63 patients with clinically and radiologically defined lumbar spinal stenosis at L3/4 or L4/5 who underwent minimally invasive decompression. OUTCOME MEASURES: Pain and functional disability were measured using the Oswestry Disability Index (ODI) and visual analogue scores for back pain (VASB) and leg pain (VASL). METHODS: Multifidus total cross sectional area (tCSA), multifidus functional cross sectional area (fnCSA), multifidus fatty infiltration (FI), psoas tCSA, and psoas relative cross sectional area (rCSA) were evaluated by univariable and multivariable regression to identify gender linked and gender independent predictors of higher ODI, VASB, and VASL. RESULTS: Female gender was significantly associated with lower multifidus fnCSA (p < .001), higher multifidus FI (p < .001), lower psoas tCSA (p < .001), lower psoas rCSA (p = .002), and higher preoperative ODI (p = .008). Lower psoas rCSA (p = .044) and psoas tCSA in the lowest sex specific quartile (p = .034) were significantly associated with higher preoperative VASB and psoas rCSA less than the sex specific median (p = .050) was significantly associated with higher preoperative VASL after controlling for age and gender. Multifidus FI was significantly associated with preoperative ODI after adjusting for age (p = .048) but not after controlling additionally for gender (p = .651). CONCLUSIONS: Female patients with lumbar spinal stenosis may develop more severe and functionally significant multifidus atrophy, resulting in a more severe clinical course with higher functional disability. Sarcopenia was significantly associated with higher preoperative back pain and leg pain in both male and female patients with lumbar spinal stenosis.

Horticultural Therapy Reduces Biomarkers of Immunosenescence and Inflammaging in Community-Dwelling Older Adults: A Feasibility Pilot Randomized Controlled Trial.

BACKGROUND: With the challenges that aging populations pose to health care, interventions that facilitate alleviation of age-related morbidities are imperative. A prominent risk factor for developing age-related morbidities is immunosenescence, characterized by increased chronic low-grade inflammation, resulting in T-cell exhaustion and senescence. Contact with nature and associated physical activities have been shown to boost immunity in older adults and may be promoted in the form of horticultural therapy (HT). We aimed to examine the effects of HT on immunosenescence. METHOD: We conducted a randomized controlled trial with 59 older adults assigned to either the HT intervention or waitlist control group. Older adults in the HT intervention group underwent HT intervention program over 6 months. Venous blood was drawn at baseline and at the third and sixth month from the commencement of this study. For participants who attended all 3 blood collection time points (HT: n = 22; waitlist: n = 24), flow cytometry analysis was performed on whole blood samples to evaluate the kinetics of lymphocyte subsets over the intervention period, revealing the composition of CD4+ and CD8+ subsets expressing exhaustion markers-CD57, CTLA4, and KLRG1. Enzyme-linked immunosorbent assays were employed to measure changes in plasma IL-6 levels. RESULTS: HT is associated with increased numbers of naive CD8+ T cells and fewer CTLA4-expressing terminally differentiated effector CD4+ and CD8+ memory T cells re-expressing CD45RA (TEMRA). Furthermore, IL-6 levels were reduced during HT, and the frequencies of naive and TEMRA CD8+ T cells were found to be associated with IL-6 levels. CONCLUSION: HT is associated with a reduction in the levels of biomarkers that measure the extent of T-cell exhaustion and inflammaging in older adults. The positive effects of HT on T-cell exhaustion were associated with the reduction of IL-6 levels.

Vertebroplasty for acute painful osteoporotic vertebral compression fractures: An update.

Vertebral compression fractures (VCFs) are a common cause of back pain and disability and are usually osteoporotic in nature. Therapy aims to adequately control pain and allow early mobilisation and return of function while preventing additional fractures. A proportion of patients do not achieve adequate pain relief using conservative measures alone. Unwanted adverse effects from medications may also ensue. Vertebroplasty represents an alternative treatment option for VCFs. Patients with acute VCFs (≤6 weeks old) may gain the most benefit from vertebroplasty as healed fractures are not as amenable to cement injection. High-quality studies have reported conflicting results regarding the use of vertebroplasty in the treatment of acute VCFs. Despite high-quality evidence, varying study designs and heterogenous patient cohorts make interpretation of this data difficult. Only one sham-controlled randomised controlled trial (RCT) has evaluated vertebroplasty exclusively in patients with acute VCFs, reporting favourable results. Pooled data from RCTs also suggest vertebroplasty to be safe. This article provides a concise and critical review of the current literature regarding vertebroplasty for the treatment of acute VCFs.

Hallmarks of improved immunological responses in the vaccination of more physically active elderly females.

Physical inactivity is one of the leading contributors to worldwide morbidity and mortality. The elderly are particularly susceptible since the features of physical inactivity overlap with the outcomes of natural aging - including the propensity to develop cardiovascular diseases, cancer, diabetes mellitus, sarcopenia and cognitive impairment. The age-dependent loss of immune function, or immunosenescence, refers to the progressive depletion of primary immune resources and is linked to the development of many of these conditions. Immunosenescence is primarily driven by chronic immune activation and physical activity interventions have demonstrated the potential to reduce the risk of complications in the elderly by modulating inflammation and augmenting the immune system. Since poor vaccination outcome is a hallmark of immunosenescence, the assessment of vaccine efficacy provides a window to study the immunological effects of regular physical activity. Using an accelerator-based study, we demonstrate in a Singaporean Chinese cohort that elderly women (n=56) who walk more after vaccination display greater post-vaccination expansion of monocytes and plasmablasts in peripheral blood. Active elderly female participants also demonstrated lower baseline levels of IP-10 and Eotaxin, and the upregulation of genes associated with monocyte/macrophage phagocytosis. We further describe postive correlations between the monocyte response and the post-vaccination H1N1 HAI titres of participants. Finally, active elderly women reveal a higher induction of antibodies against Flu B in their 18-month second vaccination follow-up. Altogether, our data are consistent with better immunological outcomes in those who are more physically active and highlight the pertinent contribution of monocyte activity.

Spine Trauma as a Component of Essential Neurosurgery: An Outcomes Analysis from Cambodia.

OBJECTIVE: In recent years, delivery of cost-effective "essential neurosurgery" in resource-limited communities has been recognized as an indispensable part of health care and a global health priority. The aim of this study was to review outcomes from operative management of spine trauma at a resource-limited government hospital in Phnom Penh, Cambodia, and to provide an epidemiologic report to guide prevention programs. METHODS: A retrospective review of a prospective neurosurgical database was performed to identify risk factors for spine trauma and severe spinal cord injury (American Spinal Injury Association A or American Spinal Injury Association B) and to evaluate the cost-effectiveness of surgery for patients treated at Preah Kossamak Hospital for subaxial and thoracolumbar spine trauma from 2013 to 2016. RESULTS: Surgical treatment was provided to 277 patients with cervical or thoracolumbar spine trauma, including 36 facet dislocations and 135 thoracolumbar burst fractures at a cost of $100-$280 per surgery. Six patients (2.2%) required treatment for postoperative wound infection. Reoperation was performed in 8 patients (2.9%) for wrong-level surgery. Failure of short-segment pedicle screw fixation was discovered in 4 patients (7.0%). Neurologic improvement was reported by 64 patients (65.3%) with incomplete spinal cord injury and available long-term follow-up. CONCLUSIONS: Affordable neurosurgical care can be provided in a safe and sustainable manner to patients with traumatic spine and spinal cord injuries in resource-limited communities. This supports the call for essential neurosurgery to be made available around the world to individuals from all socioeconomic strata.

Soluble Fms-Like Tyrosine Kinase 1 (sFlt-1) and Risk of Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: The molecular mechanisms underlying cerebral vasospasm and delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) are incompletely understood. We hypothesized that circulating antiangiogenic factors, such as soluble Fms-like tyrosine kinase 1 (sFlt-1) and soluble transforming growth factor ß coreceptor, soluble endoglin (sEng), are important markers of their pathophysiology. METHODS: We performed a prospective study in patients with aSAH and measured cerebrospinal fluid and serum levels of sFlt-1 and sEng on postbleed day 1 and 6 and correlated levels with incidence and severity of cerebral vasospasm and DCI. RESULTS: Twenty-seven patients with aSAH were enrolled in the study. Severe angiographic vasospasm was present in 14.8% of patients and DCI occurred in 33.3%. Serum sFlt1 levels were increased on postbleed day 6 in patients who developed vasospasm. However, on postbleed day 1, there were no differences in patients who developed vasospasm. Increased serum sFlt-1 levels on postbleed day 1 were found to predict the development of severe angiographic vasospasm with an area under the curve of 0.818 with an optimal cutoff value of 95 pg/mL. Alterations in sFlt1 were not associated with DCI. Serum and cerebrospinal fluid sEng levels did not correlate with vasospasm or DCI. CONCLUSIONS: Serum levels of sFlt-1 are increased in patients with aSAH who are at risk for severe vasospasm. Further studies with larger sample sizes are needed to evaluate whether sFlt-1 levels may predict onset of severe vasospasm and DCI.

Risk of Aneurysm Residual Regrowth, Recurrence, and de Novo Aneurysm Formation After Microsurgical Clip Occlusion Based on Follow-up with Catheter Angiography.

INTRODUCTION: Established guidelines for radiologic surveillance after microsurgical treatment of intracranial aneurysms are lacking in the literature because of small sample sizes, poor definitions, and heterogeneous use of imaging modalities. We aimed to propose clinically meaningful definitions for postoperative aneurysm residual, recurrence, and de novo aneurysm formation and to analyze our long-term follow-up catheter angiography results in patients with microsurgically treated intracranial aneurysms. METHODS: A retrospective review of all aneurysms treated microsurgically in a consecutive, single-surgeon series from 1997 to present identified patients with long-term follow-up catheter angiography (>1 year after surgery). Clinical and radiologic data were collected for analysis. RESULTS: We identified 240 patients harboring 380 aneurysms (mean follow-up time, 6.0 ± 3.3 years per patient; range, 1.0-16.8 years). Postoperative residuals were present in 16 out of 346 clipped aneurysms (4.6%), of which only 3 were left unintentionally. Two out of 16 residual aneurysms (12.5%) demonstrated regrowth, with a regrowth risk of 2.1% per year from 93.6 patient-years of angiographic follow-up. Of 326 aneurysms with no postoperative residual, 5 (1.5%) demonstrated aneurysm recurrence, with a recurrence risk of 0.26% per year from 1931.9 patient-years of angiographic follow-up. Eight de novo aneurysms were identified in 240 patients (3.3%), with a risk of 0.6% per year from 1441.9 patient-years of angiographic follow-up. CONCLUSIONS: Microsurgically treated aneurysms have a very low risk of postoperative residuals and aneurysm recurrence. Growth of residuals and de novo aneurysm formation justify following up with catheter angiography 3 to 5 years after microsurgical clipping.

Clinical presentation, progression, and treatment outcomes of moyamoya disease in the elderly.

BACKGROUND: Moyamoya disease is a vascular disorder characterized by progressive stenosis of the internal carotid artery. The presentation, progression, treatment options, and post-operative clinical outcomes for elderly (60 and older) Moyamoya patients have never been reported. METHODS: A retrospective analysis of all patients who were diagnosed with Moyamoya disease by the senior authors between 1991 and 2016 was performed. Patients who were 60 years or older at the time of surgery or last follow-up were further evaluated. RESULTS: Seventy patients were diagnosed with probable or definite Moyamoya disease during the study period (1991-2016). Eight patients (11.4 %; six females: two males; median age 63; range, 60-71 years) were found to be 60 years or older at the time of surgery or last follow-up and were included in the study. All patients had a modified Rankin scale (mRS) of either one or two (median 1) pre-operatively. Six patients (75 %) underwent surgical treatment on a total on seven hemispheres. Post-surgery, one patient had an improved mRS score, three had no changes, and two had worsening in their mRS scores. Both patients who did not undergo surgical interventions suffered from intra-parenchymal hemorrhages post-diagnosis. CONCLUSIONS: Moyamoya disease is most commonly seen in young and middle-aged patients. Presentation in the elderly (defined as 60 years and older in this study) is rare, and has never been reported in the literature. In this study, both direct and indirect revascularization procedures demonstrated potential benefit in some of these patients, with stabilization of progressive symptoms.

Lazic Aneurysm Clip System for Microsurgical Clipping of Cerebral Aneurysms: Transition to a New Aneurysm Clip System in an Established Cerebrovascular Practice.

BACKGROUND: In an era of continued advancements in endovascular treatment of cerebral aneurysms, novel developments concerning microsurgical clipping are sparse. The Lazic aneurysm clip system represents such an advancement. The applier has a malleable shaft and is designed to minimally obstruct the view of the surgical field. The purpose of this study was to illustrate the transition to this new aneurysm clip system in an established cerebrovascular practice. METHODS: We retrospectively reviewed all aneurysms treated with microsurgical clipping using the Lazic aneurysm clip system in 1 cerebrovascular practice in the United States from January 2009 to June 2016. RESULTS: Between 2009 and 2016, a total of 973 aneurysms underwent surgical clipping. The Lazic clip system was used in 191 (19.6%) aneurysms (maximum diameter, 5.6 ± 3.8 mm) in 181 patients. The middle cerebral artery was the most frequent location (25.7%) followed by posterior communicating artery (20.9%). There was a continuous increase in the percentage of aneurysms treated with the Lazic clip system from 6% in 2009 to 98% in 2016. The proportion of posterior circulation aneurysms treated with Lazic clips decreased, whereas the middle cerebral artery location increased. There were a total of 11 complications (5.8%), but no instances of clip malfunction. CONCLUSIONS: In the largest series to date, the Lazic clip system proved to be safe and efficacious and presents an interesting alternative to established aneurysm clip systems. This study illustrates the transition of an established cerebrovascular practice to the Lazic clip system.

Who is Likely to Present in Poor Neurologic Condition After Aneurysmal Subarachnoid Hemorrhage? Risk Factors and Implications for Treatment.

OBJECTIVE: Neurologic condition at presentation is the most important predictor of morbidity and mortality from aneurysmal subarachnoid hemorrhage (aSAH). To guide management, it is important to identify patients who are at risk of presenting in poor neurologic condition after aSAH. METHODS: We retrospectively reviewed medical records and imaging studies for 387 consecutive cases of aSAH that were managed at a major academic neurovascular center in the United States from January 2008 to December 2013. Clinically accessible patient and aneurysm characteristics were evaluated by univariable analysis and multivariable logistic regression to identify predictors of poor neurologic status at presentation. RESULTS: For all aneurysms, multivariable logistic regression identified age (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.00-1.04; P = 0.0129), aneurysm size (≥7 and <10 mm: OR, 1.78; 95% CI, 1.02-3.11; P = 0.0429; ≥10 mm: OR, 3.22; 95% CI, 1.82-5.70; P < 0.0001), and vertebrobasilar junction location (OR, 10.1; 95% CI, 1.93-52.5; P = 0.0060) as independent predictors of poor neurologic condition at presentation. For internal carotid artery (ICA) aneurysms, female gender (OR, 9.21; 95% CI, 1.54-55.1; P = 0.0151), hypertension (OR, 8.67; 95% CI, 1.80-41.7; P = 0.007), and size ≥7 mm (OR, 3.67; 95% CI, 0.852-15.8; P = 0.0807) were predictive of poor neurologic condition at presentation, with a C statistic of 0.842. No association was found between poor neurologic grade at presentation and smoking status or warfarin therapy. CONCLUSIONS: Independent predictors of poor neurologic grade were identified for all, ICA, anterior cerebral artery/anterior communicating artery, middle cerebral artery, and posterior circulation aneurysms. A risk prediction chart was constructed using clinically accessible patient and aneurysm characteristics for poor presenting neurologic condition after ICA aneurysm rupture. These factors should be considered when counseling patients with unruptured intracranial aneurysms.

Antifibrinolytic therapy in aneurysmal subarachnoid hemorrhage increases the risk for deep venous thrombosis: A case-control study.

OBJECTIVES: Aneurysm re-rupture is associated with significant morbidity and mortality in aneurysmal subarachnoid hemorrhage (aSAH). While antifibrinolytics reduce aneurysm re-rupture rates, they have been associated with hydrocephalus, delayed cerebral ischemia, and venous thrombosis. We performed a case-control study in patients enrolled in the Cerebral Aneurysm Renin Angiotensin System (CARAS) study to evaluate the impact of short course (<48 h) ɛ-aminocaproic acid (EACA) on deep venous thrombosis (DVT) rates. PATIENTS AND METHODS: A case-control study design was utilized to evaluate the effect of EACA on DVT formation. All cases and controls were obtained from the CARAS study, a prospective, blinded study assessing the association of polymorphisms in the renin angiotensin system and aSAH. RESULTS: One hundred and twenty-eight eligible patients were enrolled in CARAS. Overall, 48 (37.5%) patients were screened for DVT, 57 (44.5%) patients were treated with short course (<48 h) EACA, and 8 (6.3%) patients suffered a re-rupture (4 treated with EACA). Ten patients (7.8%) were diagnosed with DVT as evidenced by Doppler US and represent the cases. Twenty controls without evidence of a DVT matched for age, sex, race, tobacco history, Hunt-Hess score, Fisher grade, body mass index, and length of stay were identified from the remaining pool of 118 patients. EACA was found to significantly increase the risk of DVT formation in patients with aSAH (OR 8.49, CI 1.27-77.1). CONCLUSION: Short course (<48 h) administration of EACA in patients with aneurysmal subarachnoid hemorrhage is associated with an 8.5 times greater risk of DVT formation.

Corrective spinal surgery may be protective against stroke in patients with blunt traumatic vertebral artery occlusion.

OBJECT Approximately 10% of patients with blunt traumatic extracranial cerebrovascular injury have a complete occlusion of the vertebral artery (VA). Ischemic stroke due to embolization of thrombus from an occluded VA following cervical spine surgery has been observed. The risk of ischemic stroke with cervical spine surgery in the presence of an occluded VA, however, has never been determined. METHODS A retrospective chart review of 52 patients with a VA occlusion following a blunt trauma was performed. Clinical and radiographic characteristics were collected and analyzed. RESULTS Ten patients (19.2%) suffered an ischemic stroke attributable to a traumatic VA occlusion. Univariate analysis demonstrated that patients with ischemic stroke were significantly older (p = 0.042) and had a lower rate of cervical spine surgery (p < 0.005). Multivariate analysis found cervical spine surgery to be protective against ischemic stroke (OR 0.049 [95% CI 0.014-0.167], p = 0.014); increasing age and bilateral VA injury (bilateral occlusion or unilateral occlusion with contralateral dissection) were risk factors for ischemic stroke (OR 1.05 [95% CI1.02-1.07], p = 0.065 and OR 13.2 [95% CI 2.98-58.9], p = 0.084, respectively). CONCLUSIONS Traumatic VA occlusion is associated with a risk of ischemic stroke and mortality. Corrective cervical spine surgery potentially decreases the risk of ischemic stroke by stabilizing the spine and thereby reducing motion across the occluded segment of the VA and preventing embolization of thrombus. While a high stoke risk may be inherent to the disease, novel therapies should be investigated.

Stratification of recanalization for patients with endovascular treatment of intracranial aneurysms.

BACKGROUND: With the increasing use of endovascular techniques in the treatment of both ruptured and unruptured intracranial aneurysms, the issue of obliteration efficacy has become increasingly important. OBJECTIVE: To systematically develop a comprehensive model for predicting retreatment with various types of endovascular treatment. METHODS: We retrospectively reviewed medical records that were prospectively collected for 305 patients who received endovascular treatment for intracranial aneurysms from 2007 to 2013. Multivariable logistic regression was performed on candidate predictors identified by univariable screening analysis to detect independent predictors of retreatment. A composite risk score was constructed based on the proportional contribution of independent predictors in the multivariable model. RESULTS: Size (>10 mm), aneurysm rupture, stent assistance, and posttreatment degree of aneurysm occlusion were independently associated with retreatment, whereas intraluminal thrombosis and flow diversion demonstrated a trend toward retreatment. The Aneurysm Recanalization Stratification Scale was constructed by assigning the following weights to statistically and clinically significant predictors: aneurysm-specific factors: size (>10 mm), 2 points; rupture, 2 points; presence of thrombus, 2 points. Treatment-related factors were stent assistance, -1 point; flow diversion, -2 points; Raymond Roy occlusion class 2, 1 point; Raymond Roy occlusion class 3, 2 points. This scale demonstrated good discrimination with a C-statistic of 0.799. CONCLUSION: Surgical decision making and patient-centered informed consent require comprehensive and accessible information on treatment efficacy. We constructed the Aneurysm Recanalization Stratification Scale to enhance this decision-making process. This is the first comprehensive model that has been developed to quantitatively predict the risk of retreatment after endovascular therapy.

An unruptured anterior communicating artery aneurysm with bilateral infraoptic anterior cerebral arteries. Case report and review of the literature.

Variations of the anterior cerebral artery-anterior communicating artery complex are commonly identified in aneurysm surgery. An infraoptic course of the anterior cerebral artery is exceedingly rare. Robison first described this anomaly from an anatomic dissection in 1959. A unilateral anomalous infraoptic anterior cerebral artery is more common than anomalies of bilateral infraoptic anterior cerebral arteries. We present the case of an unruptured aneurysm at the anterior communicating artery in a patient with bilateral infraoptic anterior cerebral arteries, identified by computed tomography angiography and verified during surgery. Implications for aneurysm formation and surgical treatment are discussed.