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Background: Brain perfusion is altered in both alcohol dependence and stimulant dependence. Although most substance users also abuse/depend on alcohol concurrently (polysubstance users; PSU), rigorous perfusion research in PSU is limited. Also, the relationships of perfusion abnormalities with cognition, impulsivity, or decision making are not well known. Methods: Arterial spin labeling MRI and neuropsychological measures assessed perfusion levels and neurocognition in 20 alcohol-dependent individuals with comorbid-stimulant dependence (PSU), 26 individuals dependent on alcohol only (ALC), and 31 light/non-drinking controls (LD). The patient groups included smokers and non-smokers. Results: ALC had lower perfusion than LD in subcortical and cortical brain regions including the brain reward/executive oversight system (BREOS). Contrary to our hypothesis, regional perfusion was generally not lower in PSU than ALC. However, smoking PSU had lower perfusion than smoking ALC in several regions, including BREOS. Lower BREOS perfusion related to greater drinking severity in smoking substance users and to greater smoking severity in smoking ALC. Lower regional perfusion in ALC and PSU correlated with worse performance in different cognitive domains; smoking status affected perfusion-cognition relationships in ALC only. Lower BREOS perfusion in both substance using groups related to higher impulsivity. Conclusion: Although regional perfusion was not decreased in PSU as a group, the combination of cigarette smoking and polysubstance use is strongly related to hypoperfusion in important cortical and subcortical regions. As lower perfusion relates to greater smoking severity, worse cognition and higher impulsivity, smoking cessation is warranted for treatment-seeking PSU and ALC.

Introduction: IgG4-related disease is an immune-mediated condition characterized by tissue infiltration of IgG4-positive plasma cells. Involvement of the spinal meninges results in hypertrophic spinal pachymeningitis (HSP), causing spinal cord and nerve root compression., Research Question and Case Description: In this review, we present a case of IgG4-related hypertrophic spinal pachymeningitis. Furthermore, we provide an updated literature review on IgG4-related HSP., Materials and Methods: We describe the case of a 45-year-old male presenting with cervical myelopathy. MR-imaging showed a ventrodorsal thickening of the meninges resulting in spinal cord compression. The patient underwent surgical decompression through laminectomy and excision of the dural thickening. The pathological findings demonstrated hypertrophic pachymeningitis with further examination showing large-scale dural infiltration of IgG4-positive lymphocytes. Adjuvant therapy with methylprednisolone and rituximab resulted in full neurological recovery with no signs of recurrence on MRI or clinically 12 months postoperatively.An updated review of the literature regarding IgG4-related HSP was performed according to PRISMA-guidelines. Relevant articles were searched from the PubMed, Web of Science and Embase databases. Patient characteristics, MRI- and histopathological findings, treatment modality and outcome were reviewed., Results: The literature review provided a summary of 52 available cases, which included the one cases from our centre. Progressive worsening of neurological impairment was observed in 28 patients (58%). The lesions involved the thoracic spine (n = 33, 62.2%), cervical spine (n = 35, 70%), lumbar spine (n = 10, 20%), and sacral spine (n = 1, 2.2%). The dural thickening typically appeared as striated, fusiform, or oval changes, with homogeneous and patterns being the most common. Surgical decompression followed by immunosuppressive treatment was the main choice of therapy. The disease proved fatal in one case., Discussion and Conclusion: IgG4-related HSP usually affects the cervical and thoracic dura and therefore often presents with myelopathy. Surgical decompression in cases of neurological deficits may prevent permanent neurological impairment. Immunosuppressive therapy constitutes the cornerstone in the treatment IgG4-related HSP., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors.)

Background and Objectives: Delayed cerebral ischemia (DCI) is one of the main contributing factors to poor clinical outcome after aneurysmal subarachnoid hemorrhage (SAH). Unsuccessful treatment can cause irreversible brain injury in the form of DCI-related infarction. We aimed to assess the association between the location, distribution, and size of DCI-related infarction in relation to clinical outcome., Methods: Consecutive patients with SAH treated at 2 university hospitals between 2014 and 2019 (Helsinki, Finland) and between 2006 and 2020 (Aachen, Germany) were included. Size of DCI-related infarction was quantitatively measured as absolute volume (in milliliters). In a semiquantitative fashion, infarction in 14 regions of interest (ROIs) according to a modified Alberta Stroke Program Early CT Score (ASPECTS) was noted. The association of infarction in these ROIs along predefined regions of eloquent brain, with clinical outcome, was assessed. For this purpose, 1-year outcome was measured by the Glasgow Outcome Scale (GOS) and dichotomized into favorable (GOS 4-5) and unfavorable (GOS 1-3)., Results: Of 1,190 consecutive patients with SAH, 155 (13%) developed DCI-related infarction. One-year outcome data were available for 148 (96%) patients. A median overall infarct volume of 103 mL (interquartile range 31-237) was measured. DCI-related infarction was significantly associated with 1-year unfavorable outcome (odds ratio [OR] 4.89, 95% CI 3.36-7.34, p < 0.001). In patients with 1-year unfavorable outcome, vascular territories more frequently affected were left middle cerebral artery (affected in 49% of patients with unfavorable outcome vs in 30% of patients with favorable outcome; p = 0.029), as well as left (44% vs 18%; p = 0.003) and right (52% vs 14%; p < 0.001) anterior cerebral artery supply areas. According to the ASPECTS model, the right M3 (OR 8.52, 95% CI 1.41-51.34, p = 0.013) and right A2 (OR 7.84, 95% CI 1.97-31.15, p = 0.003) regions were independently associated with unfavorable outcome., Discussion: DCI-related infarction was associated with a 5-fold increase in the odds of unfavorable outcome, after 1 year. Ischemic lesions in specific anatomical regions are more likely to contribute to unfavorable outcome., Trial Registration Information: Data collection in Aachen was registered in the German Clinical Trial Register (DRKS00030505); on January 3, 2023.

Background: Delayed cerebral ischemia (DCI) is one of the main contributors to poor clinical outcome after aneurysmal subarachnoid hemorrhage (SAH). Endovascular spasmolysis with intra-arterial nimodipine (IAN) may resolve angiographic vasospasm, but its effect on infarct prevention and clinical outcome is still unclear. We report the effect of IAN on infarction rates and functional outcome in a consecutive series of SAH patients., Methods: To assess the effectiveness of IAN, we collected functional outcome data of all SAH patients referred to a single tertiary center since its availability (2011-2020). IAN was primarily reserved as a last tier option for DCI refractory to induced hypertension (iHTN). Functional outcome was assessed after 12 months according to the Glasgow Outcome Scale (GOS, favorable outcome = GOS4-5)., Results: Out of 376 consecutive SAH patients, 186 (49.5%) developed DCI. Thereof, a total of 96 (25.5%) patients remained unresponsive to iHTN and received IAN. DCI-related infarction was observed in 44 (45.8%) of IAN-treated patients with a median infarct volume of 111.6 mL (Q 1 : 51.6 to Q 3 : 245.7). Clinical outcome was available for 84 IAN-treated patients. Of those, a total of 40 (47.6%) patients reached a favorable outcome after 1 year. Interventional complications were observed in 9 (9.4%) of the IAN-treated patients., Conclusion: Intra-arterial spasmolysis using nimodipine infusion was associated with low treatment specific complications. Despite presenting a subgroup of severely affected SAH patients, almost half of IAN-treated patients were able to lead an independent life after 1 year of follow-up., Trial Registration Number: German Clinical Trial Register DRKS00030505., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: This study evaluates the precision of a commercially available spine planning software in automatic spine labelling and screw-trajectory proposal., Methods: The software uses automatic segmentation and registration of the vertebra to generate screw proposals. 877 trajectories were compared. Four neurosurgeons assessed suggested trajectories, performed corrections, and manually planned pedicle screws. Additionally, automatic identification/labelling was evaluated., Results: Automatic labelling was correct in 89% of the cases. 92.9% of automatically planned trajectories were in accordance with G&R grade A + B. Automatic mode reduced the time spent planning screw trajectories by 7 s per screw to 20 s per vertebra. Manual mode yielded differences in screw-length between surgeons (largest distribution peak: 5 mm), automatic in contrast at 0 mm. The size of suggested pedicle screws was significantly smaller (largest peaks in difference between 0.5 and 3 mm) than the surgeon's choice., Conclusion: Automatic identification of vertebrae works in most cases and suggested pedicle screw trajectories are acceptable. So far, it does not substitute for an experienced surgeon's assessment., (© 2023 The Authors. The International Journal of Medical Robotics and Computer Assisted Surgery published by John Wiley & Sons Ltd.)

Introduction: Elevated intracranial pressure (ICP) and blood components are the main trigger factors starting the complex pathophysiological cascade following subarachnoid hemorrhage (SAH). It is not clear whether they independently contribute to tissue damage or whether their impact cannot be differentiated from each other. We here aimed to establish a rat intracranial hypertension model that allows distinguishing the effects of these two factors and investigating the relationship between elevated ICP and hypoperfusion very early after SAH., Methods: Blood or four different types of fluids [gelofusine, silicone oil, artificial cerebrospinal fluid (aCSF), aCSF plus xanthan (CX)] were injected into the cisterna magna in anesthetized rats, respectively. Arterial blood pressure, ICP and cerebral blood flow (CBF) were continuously measured up to 6 h after injection. Enzyme-linked immunosorbent assays were performed to measure the pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) in brain cortex and peripheral blood., Results: Silicone oil injection caused deaths of almost all animals. Compared to blood, gelofusine resulted in lower peak ICP and lower plateau phase. Artificial CSF reached a comparable ICP peak value but failed to reach the ICP plateau of blood injection. Injection of CX with comparable viscosity as blood reproduced the ICP course of the blood injection group. Compared with the CBF course after blood injection, CX induced a comparable early global ischemia within the first minutes which was followed by a prompt return to baseline level with no further hypoperfusion despite an equal ICP course. The inflammatory response within the tissue did not differ between blood or blood-substitute injection. The systemic inflammation was significantly more pronounced in the CX injection group compared with the other fluids including blood., Discussion: By cisterna magna injection of blood substitution fluids, we established a subarachnoid space occupying rat model that exactly mimicked the course of ICP in the first 6 h following blood injection. Fluids lacking blood components did not induce the typical prolonged hypoperfusion occurring after blood-injection in this very early phase. Our study strongly suggests that blood components rather than elevated ICP play an important role for early hypoperfusion events in SAH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hao, Conzen-Dilger, Schmidt, Harder, Schöps, Clauser, Schubert and Lindauer.)

The pathophysiology of degenerative cervical myelopathy (DCM) is characterized by chronic compression-induced damage to the spinal cord leading to secondary harm such as disruption of the blood spinal cord barrier (BSCB). It is therefore the purpose of this study to analyze BSCB disruption in pre- and postoperative DCM patients and to correlate those with the clinical status and postoperative outcome. This prospectively controlled cohort included 50 DCM patients (21 female; 29 male; mean age: 62.9 ± 11.2 years). As neurological healthy controls, 52 (17 female; 35 male; mean age 61.8 ± 17.3 years) patients with thoracic abdominal aortic aneurysm (TAAA) and indication for open surgery were included. All patients underwent a neurological examination and DCM-associated scores (Neck Disability Index, modified Japanese Orthopaedic Association Score) were assessed. To evaluate the BSCB status, blood and cerebrospinal fluid (CSF) samples (lumbar puncture or CSF drainage) were taken preoperatively and in 15 DCM patients postoperatively (4 female; 11 male; mean age: 64.7 ± 11.1 years). Regarding BSCB disruption, CSF and blood serum were examined for albumin, immunoglobulin (Ig) G, IgA and IgM. Quotients for CSF/serum were standardized and calculated according to Reiber diagnostic criteria. Significantly increased preoperative CSF/serum quotients were found in DCM patients as compared to control patients: Albumin Q (p < .001), IgA Q (p < .001) and IgG Q (p < .001). IgM Q showed no significant difference (T = - 1.15, p = .255). After surgical decompression, neurological symptoms improved in DCM patients, as shown by a significantly higher postoperative mJOA compared to the preoperative score (p = .001). This neurological improvement was accompanied by a significant change in postoperative CSF/serum quotients for Albumin (p = .005) and IgG (p = .004) with a trend of a weak correlation between CSF markers and neurological recovery. This study further substantiates the previous findings, that a BSCB disruption in DCM patients is evident. Interestingly, surgical decompression appears to be accompanied by neurological improvement and a reduction of CSF/serum quotients, implying a BSCB recovery. We found a weak association between BSCB recovery and neurological improvement. A BSCB disruption might be a key pathomechanism in DCM patients, which could be relevant to treatment and clinical recovery., (© 2023. The Author(s).)

Many recent research projects have described typical chronic changes in the retinal vasculature for diverse neurovascular and neurodegenerative disorders such as stroke or Alzheimer's disease. Unlike cerebral vasculature, retinal blood vessels can be assessed non-invasively by retinal vessel analysis. To date, there is only a little information about potential simultaneous reactions of retinal and cerebral vessels in acute neurovascular diseases. The field of applications of retinal assessment could significantly be widened if more information about potential correlations between those two vascular beds and the feasibility of non-invasive retinal vessel analysis in acute neurovascular disease were available. Here, we present our protocol for the simultaneous assessment of retinal and cerebral vessels in an acute setting in anesthetized rats using a non-invasive retinal vessel analyzer and a superficial tissue imaging system for laser speckle contrast analysis via a closed bone window. We describe the experimental set-up in detail, outline the pitfalls of repeated retinal vessel analyses in an experimental set-up of several hours, and address issues that arise from the simultaneous use of two different assessment tools. Finally, we demonstrate the robustness and variability of the reactivity of retinal vessels to hypercapnia at baseline as well as their reproducibility over time using two anesthetic protocols common for neurovascular research. In summary, the procedures described in this protocol allow us to directly compare retinal and cerebral vascular beds and help to substantiate the role of the retina as a "window to the brain.", Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Warner, Bach-Hagemann, Schmidt, Pinkernell, Schubert, Clusmann, Albanna, Lindauer and Conzen-Dilger.)

Objective: Inflammation is increasingly recognized to be involved in the pathophysiology of aneurysmal subarachnoid hemorrhage (aSAH) and may increase the susceptibility to delayed cerebral ischemia (DCI). Macrophage migration inhibitory factor (MIF) has been shown to be elevated in serum and cerebrospinal fluid (CSF) after aSAH. Here, we determined MIF levels in serum, CSF and cerebral microdialysate (MD) at different time-points after aSAH and evaluated their clinical implications., Methods: MIF levels were measured in serum, CSF and MD obtained from 30 aSAH patients during early (EP d1-4 ), critical (CP d5-15 ) and late (LP d16-21 ) phase after hemorrhage. For subgroup analyses, patients were stratified based on demographic and clinical data., Results: MIF levels in serum increased during CP d5-15 and decreased again during LP d16-21 , while CSF levels showed little changes over time. MD levels peaked during EP d1-4 , decreased during CP d5-15 and increased again during LP d16-21 . Subgroup analyses revealed significantly higher serum levels in patients with aneurysms located in the anterior vs . posterior circulation during CP d5-15 (17.3 [15.1-21.1] vs . 10.0 [8.4-11.5] ng/ml, p = 0.009) and in patients with DCI vs . no DCI during CP d5-15 (17.9 [15.1-22.7] vs . 11.9 [8.9-15.9] ng/ml, p = 0.026) and LP d16-21 (17.4 [11.7-27.9] vs . 11.3 [9.2-12.2] ng/ml, p = 0.021). In addition, MIF levels in MD during CP d5-15 were significantly higher in patients with DCI vs . no DCI (3.6 [1.8-10.7] vs . 0.2 [0.1-0.7] ng/ml, p = 0.026), while CSF levels during the whole observation period were similar in all subgroups., Conclusion: Our findings in a small cohort of aSAH patients provide preliminary data on systemic, global cerebral and local cerebral MIF levels after aSAH and their clinical implications., Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT02142166., Competing Interests: FN was employed by Forschungszentrum Jülich GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Neumaier, Stoppe, Stoykova, Weiss, Veldeman, Höllig, Hamou, Temel, Conzen, Schmidt, Dogan, Wiesmann, Clusmann, Schubert, Haeren and Albanna.)

Introduction: Animal models for preclinical research of subarachnoid hemorrhage (SAH) are widely used as much of the pathophysiology remains unknown. However, the burden of these models inflicted on the animals is not well characterized. The European directive requires severity assessment-based allocation to categories. Up to now, the classification into predefined categories is rather subjective and often without underlying scientific knowledge. We therefore aimed at assessing the burden of rats after SAH or the corresponding sham surgery to provide a scientific assessment., Methods: We performed a multimodal approach, using different behavior tests, clinical and neurological scoring, and biochemical markers using the common model for SAH of intracranial endovascular filament perforation in male Wistar rats. Up to 7 days after surgery, animals with SAH were compared to sham surgery and to a group receiving only anesthesia and analgesia., Results: Sham surgery (n = 15) and SAH (n = 16) animals showed an increase in the clinical score the first days after surgery, indicating clinical deterioration, while animals receiving only anesthesia without surgery (n = 5) remained unaffected. Body weight loss occurred in all groups but was more pronounced and statistically significant only after surgery. The analysis of burrowing, open field (total distance, erections), balance beam, and neuroscore showed primarily an effect of the surgery itself in sham surgery and SAH animals. Only concerning balance beam and neuroscore, a difference was visible between sham surgery and SAH. The outcome of the analysis of systemic and local inflammatory parameters and of corticosterone in blood and its metabolites in feces was only robust in animals suffering from larger bleedings. Application of principal component analysis resulted in a clear separation of sham surgery and SAH animals from their respective baseline as well as from the anesthesia-only group at days 1 and 3, with the difference between sham surgery and SAH being not significant., Discussion/conclusion: To our knowledge, we are the first to publish detailed clinical score sheet data combined with advanced behavioral assessment in the endovascular perforation model for SAH in rats. The tests chosen here clearly depict an impairment of the animals within the first days after surgery and are consequently well suited for assessment of the animals' suffering in the model. A definitive classification into one of the severity categories named by the EU directive is yet pending and has to be performed in the future by including the assessment data from different neurological and nonneurological disease models., (The Author(s). Published by S. Karger AG, Basel.)

Background: Delayed cerebral ischemia (DCI) is one of the main determinants of clinical outcome after aneurysmal subarachnoid hemorrhage (SAH). The classical description of risk for DCI over time is currently based on the outdated concept of angiographic vasospasm. The goal of this study was to assess the temporal risk profile of DCI, defined by extended clinical and radiological criteria, as well as the impact the time point of DCI onset has on clinical outcome., Methods: All patients with aneurysmal SAH referred to a single tertiary care center between 2010 and 2018 were considered for inclusion. This study was designed as a retrospective cohort analysis and data were extracted from existing patient files. In conscious patients, DCI was diagnosed clinically, and in unconscious patients, diagnosis was based on perfusion computed tomography imaging and multimodal neuromonitoring. Extended Glasgow Outcome Scale scores were assessed after 12 months and compared between patients with early (< day 7) and late (≥ day 7) DCI onset., Results: The median delay from day of the hemorrhage (day 0) until detection of the first DCI event was 7.0 days, with an interquartile range of 5 days. The probability of DCI development over time demonstrated a bimodal distribution with a peak risk on day 5 (0.084; confidence interval 0.05.5-0.122) and a second peak on day 9 (0.077; confidence interval 0.045-0.120). A total of 27 patients (15.6%) suffered dominant hemispheric or severe bilateral DCI-related infarctions, resulting in the withdrawal of technical life support. Of those, the majority (20 patients, 22.2%) presented with early DCI onset (vs. late onset: 7 patients, 8.4%; p = 0.013)., Conclusions: The risk profile of DCI over time mirrors the description of angiographic vasospasm; however, it comes with an added timely delay of 1 to 2 days. Early occurrence of DCI (before day 7) is associated with a higher infarct load and DCI-related mortality. Although the exact causal relationship remains to be determined, the time point of DCI onset may serve as an independent prognostic criterion in decision-making., (© 2022. The Author(s).)

Background: Rescue treatment for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage can include induced hypertension (iHTN) and, in refractory cases, endovascular approaches, of which selective, continuous intraarterial nimodipine (IAN) is one variant. The combination of iHTN and IAN can dramatically increase vasopressor demand. In case of unsustainable doses, iHTN is often prioritized over IAN. However, evidence in this regard is largely lacking. We investigated the effects of a classical (iHTN+IAN) and modified (IAN only ) treatment protocol for refractory DCI in an observational study., Methods: Rescue treatment for DCI was initiated with iHTN (target >180 mm Hg systolic) and escalated to IAN in refractory cases. Until July 2018, both iHTN and IAN were offered in cases refractory to iHTN alone. After protocol modification, iHTN target was preemptively lowered to >120 mm Hg when IAN was initiated (IAN only ). Primary outcome was noradrenaline demand. Secondary outcomes included noradrenaline-associated complications, brain tissue oxygenation, DCI-related infarction and favorable 6-month outcome (Glasgow Outcome Scale 4-5)., Results: N=29 and n=20 patients were treated according to the classical and modified protocol, respectively. Protocol modification resulted in a significant reduction of noradrenaline demand (iHTN+IAN 0.70±0.54 µg/kg per minute and IAN only 0.26±0.20 µg/kg per minute, P <0.0001) and minor complications (15.0% versus 48.3%, unadjusted odds ratio, 0.19 [95% CI, 0.05-0.79]; P <0.05) with comparable rates of major complications (20.0% versus 20.7%, odds ratio, 0.96 [0.23-3.95]; P =0.95). Incidence of DCI-related infarction (45.0% versus 41.1%, odds ratio, 1.16 [0.37-3.66]; P =0.80) and favorable clinical outcome (55.6% versus 40.0%, odds ratio, 1.88 [0.55-6.39]; P =0.32) were similar. Brain tissue oxygenation was significantly higher with IANonly (26.6±12.8, 39.6±15.4 mm Hg; P <0.01)., Conclusions: Assuming the potential of iHTN to be exhausted in case of refractory hypoperfusion, additional IAN may serve as a last-resort measure to bridge hypoperfusion in the DCI phase. With close monitoring, preemptive lowering of pressure target after induction of IAN may be a safe alternative to alleviate total noradrenaline load and potentially reduce complication rate.

Background: The aim of this study was to report the overall survival and baseline factors associated with OS for breast, cervical and ovarian cancer in Florianópolis, Southern Brazil, a region with quality-of-life indicators comparable to high-income countries., Methods: Cohort study was performed from probabilistic record linkage of the Mortality Information System and the Population-based cancer registry of Florianópolis. It was included breasts, cervical and ovarian cancer diagnosis during the period of 2008-2012 with a follow up of 60 months. Cox regression and Kaplan-Meier method were used for associations with overall survival and risk factors., Findings: 1857 cases of the three malignancies were included in the analysis. We identified 202 deaths in breast cancer subjects, 53 for cervical cancer and 51 for ovarian cancer. Metastatic disease at diagnosis was present in 31%, 9.6%, and 55% of the cases, respectively. Overall survival was statistically correlated with age, educational level and stage for breast cancer; age and stage for cervical cancer; age and stage for ovarian cancer., Interpretation: Metastatic disease and age are the main prognostic factors for the malignancies studied, as they were associated with both overall survival and risk of death. Better screening and preventive tests for early diagnosis are needed., Funding: Support of Research and Innovation in the State of Santa Catarina, Research Program for the Unified Health System (FAPESC/MS-DECIT/CNPQ/SES-SC-PPSUS); the Brazilian National Research Council (CNPq); and the Coordination for the Improvement of Higher Education Personnel (CAPES)., Competing Interests: None., (© 2022 The Authors.)

Objective: To estimate the probability of survival and prognostic factors for tobacco-related neoplasms in a population-based cohort., Methods: This is a cohort with data from the Population-Based Cancer Registry of Florianópolis, southern Brazil, from 2008 to 2012. The Stata 16.0 software was used to estimate the probabilities of survival in five years after diagnosis, by the Kaplan Meier method, and the risk of death, by the Cox regression., Results: A total of 2,829 cancer records related to smoking were included, more prevalent among males, over 70 years of age, nine years or more of schooling, white, with a partner and metastatic diagnosis. The most frequent groupings were colon and rectum (28.7%), trachea, bronchi and lungs (18.6%) and stomach (11.8%). At follow-up, 1,450 died. Pancreatic cancer had the worst probability of survival (14.3%), followed by liver cancer (19.4%)., Conclusion: Risk factors for death and survival rates differ across the 13 types of tobacco-related cancers. Early diagnosis and primary prevention are strategies that must be improved to improve survival and decrease the burden related to these types of cancer.

This study aims to investigate the characteristics of patients with mild aneurysmal and non-aneurysmal perimesencephalic and non-perimesencephalic subarachnoid hemorrhage (aSAH, pmSAH, npmSAH) with emphasis on admission biomarkers, clinical course, and outcome. A prospective cohort of 115 patients with aSAH (Hunt and Hess 1-3) and of 35 patients without aneurysms (16 pmSAH and 19 npmSAH) admitted between January 2014 and January 2020 was included. Demographic data, blood samples on admission, complications (hydrocephalus, shunt dependency, delayed cerebral ischemia DCI, DCI-related infarction, and mortality), and outcome after 6 months were analyzed. Demographic data was comparable between all groups except for age (aSAH 55 [48-65] vs. npmSAH 60 [56-68] vs. pmSAH 52 [42-60], p = 0.032) and loss of consciousness (33% vs. 0% vs. 0%, p = 0.0004). Admission biomarkers showed poorer renal function and highest glucose levels for npmSAH patients. Complication rate in npmSAH was high and comparable to that of aSAH patients (hydrocephalus, shunt dependency, DCI, DCI-related infarction, mortality), but nearly absent in patients with pmSAH. Favorable outcome after 6 months was seen in 92.9% of pmSAH, 83.3% of npmSAH, and 62.7% of aSAH (p = 0.0264). In this prospective cohort of SAH patients, npmSAH was associated with a complicated clinical course, comparable to that of patients with aSAH. In contrast, such complications were nearly absent in pmSAH patients, suggesting fundamental differences in the pathophysiology of patients with different types of non-aneurysmal hemorrhage. Our findings underline the importance for a precise terminology according the hemorrhage etiology as a basis for more vigilant management of npmSAH patients. NCT02142166, 05/20/2014, retrospectively registered., (© 2021. The Author(s).)

Objective: Outcome after aneurysmal subarachnoid hemorrhage (aSAH) is highly variable and largely determined by early brain injury and delayed cerebral ischemia (DCI). Soluble urokinase plasminogen activator receptor (suPAR) represents a promising inflammatory marker which has previously been associated with outcome in traumatic brain injury and stroke patients. However, its relevance in the context of inflammatory changes after aSAH is unclear. Here, we aimed to characterize the role of circulating suPAR in both serum and cerebrospinal fluid (CSF) as a novel biomarker for aSAH patients., Methods: A total of 36 aSAH patients, 10 control patients with unruptured abdominal aneurysm and 32 healthy volunteers were included for analysis. suPAR was analyzed on the day of admission in all patients. In aSAH patients, suPAR was also determined on the day of DCI and the respective time frame in asymptomatic patients. One- and two-sample t -tests were used for simple difference comparisons within and between groups. Regression analysis was used to assess the influence of suPAR levels on outcome in terms of modified Rankin score., Results: Significantly elevated suPAR serum levels (suPAR-SL) on admission were found for aSAH patients compared to healthy controls, but not compared to vascular control patients. Disease severity as documented according to Hunt and Hess grade and modified Fisher grade was associated with higher suPAR CSF levels (suPAR-CSFL). In aSAH patients, suPAR-SL increased daily by 4%, while suPAR-CSFL showed a significantly faster daily increase by an average of 22.5% per day. Each increase of the suPAR-SL by 1 ng/ml more than tripled the odds of developing DCI (OR = 3.06). While admission suPAR-CSFL was not predictive of DCI, we observed a significant correlation with modified Rankin's degree of disability at discharge., Conclusion: Elevated suPAR serum level on admission as a biomarker for early inflammation after aSAH is associated with an increased risk of DCI. Elevated suPAR-CSFL levels correlate with a higher degree of disability at discharge. These distinct relations and the observation of a continuous increase over time affirm the role of inflammation in aSAH and require further study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schmidt, Albanna, Weiss, Veldeman, Conzen, Nikoubashman, Blume, Kluger, Clusmann, Loosen and Schubert.)

Helicobacter pylori ( H. pylori ) expresses the serine protease and chaperone High temperature requirement A (HtrA) that is involved in periplasmic unfolded protein stress response. Additionally, H. pylori -secreted HtrA directly cleaves the human cell adhesion molecule E-cadherin leading to a local disruption of intercellular adhesions during pathogenesis. HtrA-mediated E-cadherin cleavage has been observed in response to a broad range of pathogens, implying that it is a prevalent mechanism in humans. However, less is known whether E-cadherin orthologues serve as substrates for bacterial HtrA. Here, we compared HtrA-mediated cleavage of human E-cadherin with murine, canine, and simian E-cadherin in vitro and during bacterial infection. We found that HtrA targeted mouse and dog E-cadherin equally well, whereas macaque E-cadherin was less fragmented in vitro. We stably re-expressed orthologous E-cadherin (Cdh1) in a CRISPR/Cas9-mediated cdh1 knockout cell line to investigate E-cadherin shedding upon infection using H. pylori wildtype, an isogenic htrA deletion mutant, or complemented mutants as bacterial paradigms. In Western blot analyses and super-resolution microscopy, we demonstrated that H. pylori efficiently cleaved E-cadherin orthologues in an HtrA-dependent manner. These data extend previous knowledge to HtrA-mediated E-cadherin release in mammals, which may shed new light on bacterial infections in non-human organisms.

Objectives: The recommendation of induced hypertension for delayed cerebral ischemia treatment after aneurysmal subarachnoid hemorrhage has been challenged recently and ideal pressure targets are missing. A new concept advocates an individual cerebral perfusion pressure where cerebral autoregulation functions best to ensure optimal global perfusion. We characterized optimal cerebral perfusion pressure at time of delayed cerebral ischemia and tested the conformity of induced hypertension with this target value., Design: Retrospective analysis of prospectively collected data., Setting: University hospital neurocritical care unit., Patients: Thirty-nine aneurysmal subarachnoid hemorrhage patients with invasive neuromonitoring (20 with delayed cerebral ischemia, 19 without delayed cerebral ischemia)., Interventions: Induced hypertension greater than 180 mm Hg systolic blood pressure., Measurements and Main Results: Changepoint analysis was used to calculate significant changes in cerebral perfusion pressure, optimal cerebral perfusion pressure, and the difference of cerebral perfusion pressure and optimal cerebral perfusion pressure 48 hours before delayed cerebral ischemia diagnosis. Optimal cerebral perfusion pressure increased 30 hours before the onset of delayed cerebral ischemia from 82.8 ± 12.5 to 86.3 ± 11.4 mm Hg (p < 0.05). Three hours before delayed cerebral ischemia, a changepoint was also found in the difference of cerebral perfusion pressure and optimal cerebral perfusion pressure (decrease from -0.2 ± 11.2 to -7.7 ± 7.6 mm Hg; p < 0.05) with a corresponding increase in pressure reactivity index (0.09 ± 0.33 to 0.19 ± 0.37; p < 0.05). Cerebral perfusion pressure at time of delayed cerebral ischemia was lower than in patients without delayed cerebral ischemia in a comparable time frame (cerebral perfusion pressure delayed cerebral ischemia 81.4 ± 8.3 mm Hg, no delayed cerebral ischemia 90.4 ± 10.5 mm Hg; p < 0.05). Inducing hypertension resulted in a cerebral perfusion pressure above optimal cerebral perfusion pressure (+12.4 ± 8.3 mm Hg; p < 0.0001). Treatment response (improvement of delayed cerebral ischemia: induced hypertension+ [n = 15] or progression of delayed cerebral ischemia: induced hypertension- [n = 5]) did not correlate to either absolute values of cerebral perfusion pressure or optimal cerebral perfusion pressure, nor the resulting difference (cerebral perfusion pressure [p = 0.69]; optimal cerebral perfusion pressure [p = 0.97]; and the difference of cerebral perfusion pressure and optimal cerebral perfusion pressure [p = 0.51])., Conclusions: At the time of delayed cerebral ischemia occurrence, there is a significant discrepancy between cerebral perfusion pressure and optimal cerebral perfusion pressure with worsening of autoregulation, implying inadequate but identifiable individual perfusion. Standardized induction of hypertension resulted in cerebral perfusion pressures that exceeded individual optimal cerebral perfusion pressure in delayed cerebral ischemia patients. The potential benefit of individual blood pressure management guided by autoregulation-based optimal cerebral perfusion pressure should be explored in future intervention studies., Competing Interests: Dr. Wiesmann received funding from Stryker Neurovascular, Bracco Imaging, Medtronic, Penumbra, Siemens Healthcare, Abbott, AB Medica, Acandis, Asahi Intecc, Bayer, Bracco Imaging, B. Braun, Cerenovus, Codman Neurovascular, Dahlhausen, Kaneka Pharmaceuticals, Medtronic, Mentice AB, Microvention, Penumbra, Phenox, Philips Healthcare, Route 92, Siemens Healthcare, SilkRoad Medical, St. Jude, and Stryker Neurovascular. Dr. Park’s institution received funding from the National Institutes of Health (NIH, R21NS113055), and she received support for article research from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Fibrinogen is an important biomarker of inflammation, but findings from longitudinal studies that correlated fibrinogen with lung function in older adults are inconsistent., Aim: To investigate the relationship between fibrinogen plasma levels and lung function impairment later in life., Methods: Longitudinal analysis of 2,150 participants of the English Longitudinal Study of Ageing (ELSA) aged 50 years and older. Associations between changes in plasma fibrinogen between waves 2 (2004-05) and 4 (2008-09) and lung function in wave 6 (2012-13) were performed using multiple linear regression adjusted by potential confounders., Results: Regarding the fibrinogen profile, 18.5% of the participants presented higher levels in both waves. In the adjusted models, the maintenance of high fibrinogen levels was associated with a significant reduction of lung function only for men. FEV1 showed a reduction of 0.17L, FVC of 0.22L, and the percentages predicted were 5.16% for FEV1 and 6.21% for FVC compared to those that maintained normal levels of fibrinogen., Discussion: To the best of our knowledge, this was the first study investigating the relationship between changes in fibrinogen levels over a long follow-up period and lung function in older adults without pre-existing chronic diseases. ELSA has information on critical demographic and clinical parameters, which allowed to adjust for potential confounding factors., Conclusion: It was found that the persistence of high levels of plasma fibrinogen in older English men, but not women, is associated with lung function decline. Therefore, plasma fibrinogen showed to be an important biomarker of pulmonary dysfunction in this population., Competing Interests: The authors have delcared that no competing interests exist.

Objective: Test the association between the practice of physical activity (PA) according to the gestational trimesters and the occurrence of cesarean delivery, prematurity, and low birth weight in puerperal women assisted in the Unified Health System of Santa Catarina, Brazil., Methods: A cross-sectional study was conducted with a probabilistic sample of puerperal women who gave birth in public maternity hospitals in Santa Catarina from January to August 2019. The cesarean delivery outcome was self-reported, and information on premature birth (< 37 gestational weeks) and low birth weight (< 2,500 grams) were obtained from medical records. The practice of PA during pregnancy and according to each trimester was self-reported. Multivariate Logistic Regression analyses and interviews with 3,580 puerperal women were carried out., Results: PA practice during any period of pregnancy was reported by 20.6% of the sample, with a gradual reduction in prevalence according to the gestational trimester (16.2%, 15.4%, and 12.8%). The highest prevalences of outcomes concerning the total sample were observed in puerperal women who did not practice PA in the third trimester, with 43.9% for cesarean delivery, 7.7% for low birth weight, and 5.5% for premature birth. The odds of cesarean delivery (OR = 1.40; 95%CI 1.10-1.76) and low birth weight (OR = 1.99; 95%CI 1.04-3.79) were, respectively, 40% and 99% higher among puerperal women who did not practice PA in the third trimester of pregnancy when compared to those who practiced PA. There was no association between PA practice and prematurity., Conclusion: Puerperal women who did not practice PA in the third trimester of pregnancy were more likely to have cesarean delivery and low birth weight newborns.

Background: Good-grade aneurysmal subarachnoid hemorrhage (Hunt and Hess 1-2) is generally associated with a favorable prognosis. Nonetheless, patients may still experience secondary deterioration due to delayed cerebral ischemia (DCI), contributing to poor outcome. In those patients, neurological assessment is challenging and invasive neuromonitoring (INM) may help guide DCI treatment., Methods: An observational analysis of 135 good-grade SAH patients referred to a single tertiary care center between 2010 and 2018 was performed. In total, 54 good-grade SAH patients with secondary deterioration evading further neurological assessment, were prospectively enrolled for this analysis. The cohort was separated into two groups: before and after introduction of INM in 2014 (pre-INM SecD : n = 28; post-INM SecD : n = 26). INM included either parenchymal oxygen saturation measurement (p ti O 2 ), cerebral microdialysis or both. Episodes of DCI (p ti O 2  < 10 mmHg or lactate/pyruvate > 40) were treated via induced hypertension or in refractory cases by endovascular means. The primary outcome was defined as the extended Glasgow outcome scale after 12 months. In addition, we recorded the amount of imaging studies performed and the occurrence of silent and overall DCI-related infarction., Results: Secondary deterioration, impeding neurological assessment, occurred in 54 (40.0%) of all good-grade SAH patients. In those patients, a comparable rate of favorable outcome at 12 months was observed before and after the introduction of INM (pre-INM SecD 14 (50.0%) vs. post-INM SecD 16, (61.6%); p = 0.253). A significant increase in good recovery (pre-INM SecD 6 (50.0%) vs. post-INM SecD 14, (61.6%); p = 0.014) was observed alongside a reduction in the incidence of silent infarctions (pre-INM SecD 8 (28.6%) vs. post-INM SecD 2 (7.7%); p = 0.048) and of overall DCI-related infarction (pre-INM SecD 12 (42.8%) vs. post-INM SecD 4 (23.1%); p = 0.027). The number of CT investigations performed during the DCI time frame decreased from 9.8 ± 5.2 scans in the pre-INM SecD group to 6.1 ± 4.0 (p = 0.003) in the post-INM SecD group., Conclusions: A considerable number of patients with good-grade SAH experiences secondary deterioration rendering them neurologically not assessable. In our cohort, the introduction of INM to guide DCI treatment in patients with secondary deterioration increased the rate of good recovery after 12 months. Additionally, a significant reduction of CT scans and infarction load was recorded, which may have an underestimated impact on quality of life and more subtle neuropsychological deficits common after SAH., (© 2020. The Author(s).)

Objective: Delayed cerebral ischemia (DCI) is a common complication after aneurysmal subarachnoid hemorrhage (aSAH) and can lead to infarction and poor clinical outcome. The underlying mechanisms are still incompletely understood, but animal models indicate that vasoactive metabolites and inflammatory cytokines produced within the subarachnoid space may progressively impair and partially invert neurovascular coupling (NVC) in the brain. Because cerebral and retinal microvasculature are governed by comparable regulatory mechanisms and may be connected by perivascular pathways, retinal vascular changes are increasingly recognized as a potential surrogate for altered NVC in the brain. Here, we used non-invasive retinal vessel analysis (RVA) to assess microvascular function in aSAH patients at different times after the ictus. Methods: Static and dynamic RVA were performed using a Retinal Vessel Analyzer (IMEDOS Systems GmbH, Jena) in 70 aSAH patients during the early (d 0-4 ), critical (d 5-15 ), late (d 16-23 ) phase, and at follow-up (f/u > 6 weeks) after the ictus. For comparison, an age-matched cohort of 42 healthy subjects was also included in the study. Vessel diameters were quantified in terms of the central retinal arterial and venous equivalent (CRAE, CRVE) and the retinal arterio-venous-ratio (AVR). Vessel responses to flicker light excitation (FLE) were quantified by recording the maximum arterial and venous dilation (MAD, MVD), the time to 30% and 100% of maximum dilation (tMAD 30 , tMVD 30 ; tMAD, tMVD, resp.), and the arterial and venous area under the curve (AUC art , AUC ven ) during the FLE. For subgroup analyses, patients were stratified according to the development of DCI and clinical outcomes after 12 months. Results: Vessel diameter (CRAE, CRVE) was significantly smaller in aSAH patients and showed little change throughout the whole observation period ( p < 0.0001 vs. control for all time periods examined). In addition, aSAH patients exhibited impaired arterial but not venous responses to FLE, as reflected in a significantly lower MAD [2.2 (1.0-3.2)% vs. 3.6 (2.6-5.6)% in control subjects, p = 0.0016] and AUC art [21.5 (9.4-35.8)% * s vs. 51.4 (32.5-69.7)% * s in control subjects, p = 0.0001] on d 0-4 . However, gradual recovery was observed during the first 3 weeks, with close to normal levels at follow-up, when MAD and AUC art amounted to 3.0 [2.0-5.0]% ( p = 0.141 vs. control, p = 0.0321 vs. d 5-15 ) and 44.5 [23.2-61.1]% * s ( p = 0.138 vs . control, p < 0.01 vs. d 0-4 & d 5-15 ). Finally, patients with clinical deterioration (DCI) showed opposite changes in the kinetics of arterial responses during early and late phase, as reflected in a significantly lower tMAD 30 on d 0-4 [4.0 (3.0-6.8) s vs. 7.0 (5.0-8.0) s in patients without DCI, p = 0.022) and a significantly higher tMAD on d 16-23 (24.0 (21.0-29.3) s vs . 18.0 (14.0-21.0) s in patients without DCI, p = 0.017]. Conclusion: Our findings confirm and extend previous observations that aSAH results in sustained impairments of NVC in the retina. DCI may be associated with characteristic changes in the kinetics of retinal arterial responses. However, further studies will be required to determine their clinical implications and to assess if they can be used to identify patients at risk of developing DCI. Trial Registration: ClinicalTrials.gov Identifier: NCT04094155., Competing Interests: IMEDOS Systems GmbH provided the Retinal Vessel Analyzer for research purposes only. The company did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Albanna, Conzen, Weiss, Seyfried, Kotliar, Schmidt, Kuerten, Hescheler, Bruecken, Schmidt-Trucksäss, Neumaier, Wiesmann, Clusmann and Schubert.)

Background: Intraoperative computed tomography (iCT) navigated dorsal instrumentation has been successfully introduced as a new clinical standard. The proximity of vital anatomic structures makes cervical spine instrumentation an especially delicate task. Therefore, navigated approaches might prove to be beneficial. In this study, the accuracy of conventional instrumentation was compared with iCT navigated dorsal cervical spine instrumentation with focus on cervical pedicle screws (CPSs) versus lateral mass screws (LMSs) and pathologies., Methods: We analyzed a prospective consecutive series of patients undergoing cervical dorsal instrumentation with iCT and spinal navigation and retrospectively analyzed a cohort that received conventional cervical instrumentation with C-arm fluoroscopy (control group). Accuracy was assessed with a modified Gertzbein-Robbins classification. Underlying pathologies were taken into account regarding accuracy in different entities., Results: Fifty-nine patients were treated using iCT (357 screws: 238 CPSs, 119 LMSs), and 98 patients underwent conventional instrumentation (632 screws: 69 CPSs, 563 LMSs). We achieved an initial accuracy of 93.28% (n = 220 screws) in the iCT group and 80.9% (n = 511 screws) in the control group (P < 0.001). Significant differences were found regarding the accuracy of CPS placement in cases of degenerative disorders (iCT vs. control; 94% vs. 63%; P < 0.001) and trauma (iCT vs. control; 88% vs. 72%; P < 0.05). iCT yielded favorable precision rates in regard to LMS placement (iCT vs. control; 94.2% vs. 82%; P < 0.05)., Conclusions: Accuracy of iCT navigated instrumentation was significantly higher than conventional instrumentation. An overall tendency toward the use of CPSs with iCT navigation is evident, increasing the mechanical properties of the construct. iCT appears to be especially beneficial in elective surgery cases of degenerative spinal disorders., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The presence of multimorbidity patterns has been related to functional disability in basic activities (BADLs) and instrumental activities of daily living (IADLs), which are essential for elder individuals' self-care and autonomy. The study thus aimed to estimate the association between multimorbidity patterns and presence of functional disability in elderly Brazilians. This was a cross-sectional study using data from the Brazilian National Health Survey (PNS 2013) in a sample of elderly Brazilians (≥ 60 years). The measures of functional disability were from self-completed questionnaires, categorized in basic activities of daily living (BADLs) and instrumental activities of daily living (IADLs). The multimorbidity patterns analyzed here were: (1) cardiorespiratory; (2) vascular-metabolic; and (3) mental-musculoskeletal. The adjustment variables included age, sex, schooling, and region of Brazil. Multivariate logistic regression analyses were performed, estimating crude and adjusted odds ratios (OR) with Stata 16.0. Elderly individuals classified in the mental-musculoskeletal patterns showed the highest odds of disability in BADLs (OR = 2.72; 95%CI: 2.33; 3.18), while those with the cardiopulmonary pattern showed the highest odds of disability in IADLs (OR = 2.65; 95%CI: 1.95; 3.60), compared to those without the same patterns. All the multimorbidity patterns analyzed here were associated with disability in BADLs and IADLs and should thus be considered when planning measures to prevent disabilities in elderly individuals with multimorbidity.

Objective: The current definition of delayed cerebral ischemia (DCI) is based on clinical characteristics precluding its use in patients with poor-grade subarachnoid hemorrhage (SAH). Additional concepts to evaluate the unconscious patient are required. Invasive neuromonitoring (INM) may allow timely detection of metabolic and oxygenation crises before irreversible damage has occurred., Methods: The authors present a cohort analysis of all consecutive SAH patients referred to a single tertiary care center between 2010 and 2018. The cohort (n = 190) was split into two groups: one before (n = 96) and one after (n = 94) the introduction of INM in 2014. A total of 55 poor-grade SAH patients were prospectively monitored using parenchymal oxygen saturation measurement and cerebral microdialysis. The primary outcome was the Glasgow Outcome Scale-Extended (GOSE) score after 12 months., Results: With neuromonitoring, the first DCI event was detected earlier (mean 2.2 days, p = 0.002). The overall rate of DCI-related infarctions decreased significantly (from 44.8% to 22.3%; p = 0.001) after the introduction of invasive monitoring. After 12 months, a higher rate of favorable outcome was observed in the post-INM group, compared to the pre-INM group (53.8% vs 39.8%), with a significant difference in the GOSE score distribution (OR 4.86, 95% CI -1.17 to -0.07, p = 0.028)., Conclusions: In this cohort analysis of poor-grade SAH patients, the introduction of INM and the extension of the classic DCI definition toward a functional dimension resulted in an earlier detection and treatment of DCI events. This led to an overall decrease in DCI-related infarctions and an improvement in outcome.

Identification of neural correlates of relapse to alcohol after treatment is clinically important as it may inform better substance abuse treatment. Few studies have specifically analyzed the white matter microstructure in treatment seekers as it might relate to relapse risk versus long-term abstinence. Using 4 Tesla diffusion tensor imaging, we compared two groups of one-month-abstinent treatment-seekers, who were classified based on their drinking status between six and nine months after treatment initiation. We hypothesized that subsequent relapsers had greater white matter microstructural deficits in specific brain regions than long-term abstainers. At one month of abstinence, 37 future relapsers versus 25 future abstainers had lower fractional anisotropy (a measure of axonal organization and membrane integrity) in the corpus callosum and right stria terminalis/fornix, higher diffusivity in the genu of the corpus callosum, left and right stria terminalis/fornix, and lower diffusivity in left anterior corona radiata. These differences existed despite similar lifetime and recent drinking and smoking histories in the groups. Longer smoking duration in relapsers was associated with lower fractional anisotropy in right stria terminalis/fornix. The study identified specific microstructural biomarkers of alcohol relapse risk in adults, contributing to the definition of a neurobiological relapse risk profile in alcohol use disorder., (Copyright © 2018. Published by Elsevier B.V.)

Neuroimaging of opiate-dependent individuals indicates both altered brain structure and function. Magnetic resonance-based arterial spin labeling has been used to measure noninvasively cerebral blood flow (i.e. perfusion) in alcohol, tobacco and stimulant dependence; only one arterial spin labeling paper in opiate-dependent individuals demonstrated frontal and parietal perfusion deficits. Additional research on regional brain perfusion in opiate dependence and its relationship to cognition and self-regulation (impulsivity, risk taking and decision making) may inform treatment approaches for opiate-dependent individuals. Continuous arterial spin labeling magnetic resonance imaging at 4 T and neuropsychological measures assessed absolute brain perfusion levels, cognition and self-regulation in 18 cigarette smoking opiate-dependent individuals (sODI) stable on buprenorphine maintenance therapy. The sODI were compared with 20 abstinent smoking alcohol-dependent individuals (a substance-dependent control group), 35 smoking controls and 29 nonsmoking controls. sODI had lower perfusion in several cortical and subcortical regions including regions within the brain reward/executive oversight system compared with smoking alcohol-dependent individuals and nonsmoking controls. Perfusion was increased in anterior cingulate cortex and globus pallidus of sODI. Compared with all other groups, sODI had greater age-related declines in perfusion in most brain reward/executive oversight system and some other regions. In sODI, lower regional perfusion related to greater substance use, higher impulsivity and weaker visuospatial skills. Overall, sODI showed cortical and subcortical hypoperfusion and hyperperfusion. Relating to neuropsychological performance and substance use quantities, the frontal perfusion alterations are clinically relevant and constitute potential targets for pharmacological and cognitive-based therapeutic interventions to improve treatment outcome in opiate dependence., (© 2017 Society for the Study of Addiction.)

Background: We previously reported widespread microstructural deficits of brain white matter in alcohol-dependent individuals (ALC) compared to light drinkers in a small 1.5T diffusion tensor imaging study employing tract-based spatial statistics. Using a larger dataset acquired at 4T, the present study is an extension that investigated the effects of alcohol consumption, abstinence from alcohol, and comorbid cigarette smoking on white matter microstructure., Methods: Tract-based spatial statistics were performed on 20 1-week-abstinent ALC, 52 1-month-abstinent ALC, and 30 controls. Regional measures of fractional anisotropy (FA) and mean diffusivity (MD) in the significant clusters were compared by Analysis of Covariance. The metrics were correlated with substance use history and behavioral measures., Results: 1-week-abstinent ALC showed lower FA than controls in the corpus callosum, right cingulum, external capsule, and hippocampus. At 1 month of abstinence, only the FA in the body of the corpus callosum of ALC remained significantly different from controls. Some regional FA deficits correlated with more severe measures of drinking and smoking histories but only weakly with mood and impulsivity measures., Conclusion: White matter microstructure is abnormal during early abstinence in alcohol dependent treatment seekers and recovers into the normal range within about four weeks. The compromised white matter was related to substance use severity, mood, and impulsivity. Our findings suggest that ALC may benefit from interventions that facilitate normalization of DTI metrics to maintain abstinence, via smoking cessation, cognitive-based therapy, and perhaps pharmacology to support remyelination., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Intact neurocognition and early cognitive recovery during abstinence are important for substance use treatment outcome. Yet, little is known about them in the largest group of treatment seekers today, individuals with polysubstance use disorders (PSU). This study primarily contrasted PSU and individuals with an alcohol use disorder (AUD) on neurocognitive and inhibitory control measures and, secondarily, measured changes during abstinence in PSU., Method: At one month of abstinence from all substances except tobacco, 36 PSU and 69 AUD completed neurocognitive assessments of executive function, general intelligence, auditory-verbal learning/memory, visuospatial learning/memory/skills, processing speed, working memory, fine motor skills, and cognitive efficiency. The groups were also assessed on inhibitory control measures of self-reported impulsivity, risk-taking, and decision-making. Seventeen PSU repeated the assessments after approximately four months of abstinence. All cross-sectional and longitudinal analyses included smoking status as a possible confound., Results: At baseline, PSU performed significantly worse than AUD on auditory-verbal memory and on an inhibitory control measure of impulsivity. Polysubstance users showed trends to worse performance than AUD on general intelligence, auditory-verbal learning, and a decision-making task. Between one and four months of abstinence, PSU showed significant improvements on several neurocognitive and inhibitory control measures., Conclusions: Polysubstance users exhibit distinct differences in neurocognition and inhibitory control compared to AUD. Between one and four months of abstinence, neurocognition and inhibitory control improve in PSU. This neurocognitive recovery in some domains of abstinent PSU is influenced by smoking status. These results underscore the clinical value of select methods to augment neurocognitive recovery in PSU through appropriate interventions., Competing Interests: The authors have no financial or any other personal conflicts with this study.

Highly organized intercellular tight and adherens junctions are crucial structural components for establishing and maintenance of epithelial barrier functions, which control the microbiota and protect against intruding pathogens in humans. Alterations in these complexes represent key events in the development and progression of multiple infectious diseases as well as various cancers. The gastric pathogen Helicobacter pylori exerts an amazing set of strategies to manipulate these epithelial cell-to-cell junctions, which are implicated in changing cell polarity, migration and invasive growth as well as pro-inflammatory and proliferative responses. This chapter focuses on the H. pylori pathogenicity factors VacA, CagA, HtrA and urease, and how they can induce host cell signaling involved in altering cell-to-cell permeability. We propose a stepwise model for how H. pylori targets components of tight and adherens junctions in order to disrupt the gastric epithelial cell layer, giving fresh insights into the pathogenesis of this important bacterium.

The recently described 'gasomediator' hydrogen sulfide (H 2 S) has been involved in pain mechanisms, but its effect on pruritus, a sensory modality that similarly to pain acts as a protective mechanism, is poorly known and controversial. The effects of the slow-releasing (GYY4137) and spontaneous H 2 S donors (Na 2 S and Lawesson's reagent, LR) were evaluated in histamine and compound 48/80 (C48/80)-dependent dorsal skin pruritus and inflammation in male BALB/c mice. Animals were intradermally (i.d.) injected with C48/80 (3μg/site) or histamine (1μmol/site) alone or co-injected with Na 2 S, LR or GYY4137 (within the 0.3-100nmol range). The involvement of endogenous H 2 S and K ATP channel-dependent mechanism were also evaluated. Pruritus was assessed by the number of scratching bouts, whilst skin inflammation was evaluated by the extravascular accumulation of intravenously injected 125 I-albumin (plasma extravasation) and myeloperoxidase (MPO) activity (neutrophil recruitment). Histamine or C48/80 significantly evoked itching behavior paralleled by plasma extravasation and increased MPO activity. Na 2 S and LR significantly ameliorated histamine or C48/80-induced pruritus and inflammation, although these effects were less pronounced or absent with GYY4137. Inhibition of endogenous H 2 S synthesis increased both Tyrode and C48/80-induced responses in the skin, whereas the blockade of K ATP channels by glibenclamide did not. H 2 S-releasing donors significantly attenuate C48/80-induced mast cell degranulation either in vivo or in vitro. We provide first evidences that H 2 S donors confer protective effect against histamine-mediated acute pruritus and cutaneous inflammation. These effects can be mediated, at least in part, by stabilizing mast cells, known to contain multiple mediators and to be primary initiators of allergic processes, thus making of H 2 S donors a potential alternative/complementary therapy for treating inflammatory allergic skin diseases and related pruritus., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The serine proteases HtrA/DegP secreted by the human gastrointestinal pathogens Helicobacter pylori (H. pylori) and Campylobacter jejuni (C. jejuni) cleave the mammalian cell adhesion protein E-cadherin to open intercellular adhesions. A wide range of bacteria also expresses the HtrA/DegP homologs DegQ and/or DegS, which significantly differ in structure and function., Methods: E-cadherin shedding was investigated in infection experiments with the Gram-negative pathogens H. pylori, enteropathogenic Escherichia coli (EPEC), Salmonella enterica subsp. Enterica (S. Typhimurium), Yersinia enterocolitica (Y. enterocolitica), and Proteus mirabilis (P. mirabilis), which express different combinations of HtrAs. Annotated wild-type htrA/degP, degQ and degS genes were cloned and proteolytically inactive mutants were generated by a serine-to-alanine exchange in the active center. All HtrA variants were overexpressed and purified to compare their proteolytic activities in casein zymography and in vitro E-cadherin cleavage experiments., Results: Infection of epithelial cells resulted in a strong E-cadherin ectodomain shedding as reflected by the loss of full length E-cadherin in whole cell lysates and formation of the soluble 90 kDa extracellular domain of E-cadherin (NTF) in the supernatants of infected cells. Importantly, comparing the caseinolytic and E-cadherin cleavage activities of HtrA/DegP, DegQ and DegS proteins revealed that DegP and DegQ homologs from H. pylori, S. Typhimurium, Y. enterocolitica, EPEC and P. mirabilis, but not activated DegS, cleaved E-cadherin as a substrate in vitro., Conclusions: These data indicate that E-cadherin cleavage is confined to HtrA/DegP and DegQ proteins representing an important prevalent step in bacterial pathogenesis.

Objective: Proton magnetic resonance spectroscopy (1H MRS) in opiate dependence showed abnormalities in neuronal viability and glutamate concentration in the anterior cingulate cortex (ACC). Metabolite levels in dorsolateral prefrontal cortex (DLPFC) or orbitofrontal cortex (OFC) and their neuropsychological correlates have not been investigated in opiate dependence., Methods: Single-volume proton MRS at 4 Tesla and neuropsychological testing were conducted in 21 opiate-dependent individuals (OD) on buprenorphine maintenance therapy. Results were compared to 28 controls (CON) and 35 alcohol-dependent individuals (ALC), commonly investigated treatment-seekers providing context for OD evaluation. Metabolite concentrations were measured from ACC, DLPFC, OFC and parieto-occipital cortical (POC) regions., Results: Compared to CON, OD had lower concentrations of N-acetylaspartate (NAA), glutamate (Glu), creatine +phosphocreatine (Cr) and myo-Inositol (mI) in the DLPFC and lower NAA, Cr, and mI in the ACC. OD, ALC, and CON were equivalent on metabolite levels in the POC and γ-aminobutyric acid (GABA) concentration did not differ between groups in any region. In OD, prefrontal metabolite deficits in ACC Glu as well as DLPFC NAA and choline containing metabolites (Cho) correlated with poorer working memory, executive and visuospatial functioning; metabolite deficits in DLPFC Glu and ACC GABA and Cr correlated with substance use measures. In the OFC of OD, Glu and choline-containing metabolites were elevated and lower Cr concentration related to higher nonplanning impulsivity. Compared to 3 week abstinent ALC, OD had significant DLPFC metabolite deficits., Conclusion: The anterior frontal metabolite profile of OD differed significantly from that of CON and ALC. The frontal lobe metabolite abnormalities in OD and their neuropsychological correlates may play a role in treatment outcome and could be explored as specific targets for improved OD treatment.

Background: The cell adhesion and tumor suppressor protein E-cadherin is an important factor in the establishment and maintenance of epithelial integrity. E-cadherin is a single transmembrane protein, which consists of an intracellular domain (IC), a transmembrane domain (TD), and five extracellular domains (EC). EC domains form homophilic interactions in cis and trans that require calcium binding to the linker region between the EC domains. In our previous studies, we identified the serine protease high temperature requirement A (HtrA) from the human pathogen and class-I carcinogen Helicobacter pylori (H. pylori) as a bacterial E-cadherin-cleaving protease that targets the linker region of the EC domains, thereby disrupting gastric epithelial integrity. However, it remains unclear how calcium binding to the E-cadherin linker regions affects HtrA-mediated cleavage., Results: Investigating the influence of calcium on the HtrA-mediated cleavage of recombinant E-cadherin (rCdh1) in vitro, we tested different concentrations of calcium ions and the calcium chelator ethylenediaminetetraacetic acid (EDTA). Calcium efficiently reduced HtrA-mediated E-cadherin fragmentation. Conversely, the addition of EDTA strongly increased cleavage, resulting in a ladder of defined E-cadherin fragments. However, calcium ions did not affect HtrA oligomerization and protease activity as monitored by degradation of the universal protease substrate casein. Finally, addition of ethyleneglycol-bis-tetraacetic acid (EGTA) slightly enhanced E-cadherin cleavage during H. pylori infection of gastric epithelial cells., Conclusions: Our results suggest that calcium blocks HtrA-mediated cleavage by interfering with the accessibility of calcium-binding regions between the individual EC domains, which have been identified as cleavage sites of HtrA.

The cell adhesion protein and tumour suppressor E-cadherin exhibits important functions in the prevention of gastric cancer. As a class-I carcinogen, Helicobacter pylori (H. pylori) has developed a unique strategy to interfere with E-cadherin functions. In previous studies, we have demonstrated that H. pylori secretes the protease high temperature requirement A (HtrA) which cleaves off the E-cadherin ectodomain (NTF) on epithelial cells. This opens cell-to-cell junctions, allowing bacterial transmigration across the polarised epithelium. Here, we investigated the molecular mechanism of the HtrA-E-cadherin interaction and identified E-cadherin cleavage sites for HtrA. Mass-spectrometry-based proteomics and Edman degradation revealed three signature motifs containing the [VITA]-[VITA]-x-x-D-[DN] sequence pattern, which were preferentially cleaved by HtrA. Based on these sites, we developed a substrate-derived peptide inhibitor that selectively bound and inhibited HtrA, thereby blocking transmigration of H. pylori. The discovery of HtrA-targeted signature sites might further explain why we detected a stable 90 kDa NTF fragment during H. pylori infection, but also additional E-cadherin fragments ranging from 105 kDa to 48 kDa in in vitro cleavage experiments. In conclusion, HtrA targets E-cadherin signature sites that are accessible in in vitro reactions, but might be partially masked on epithelial cells through functional homophilic E-cadherin interactions.

HtrA proteases and chaperones exhibit important roles in periplasmic protein quality control and stress responses. The genetic inactivation of htrA has been described for many bacterial pathogens. However, in some cases such as the gastric pathogen Helicobacter pylori, HtrA is secreted where it cleaves the tumour-suppressor E-cadherin interfering with gastric disease development, but the generation of htrA mutants is still lacking. Here, we show that the htrA gene locus is highly conserved in worldwide strains. HtrA presence was confirmed in 992 H. pylori isolates in gastric biopsy material from infected patients. Differential RNA-sequencing (dRNA-seq) indicated that htrA is encoded in an operon with two subsequent genes, HP1020 and HP1021. Genetic mutagenesis and complementation studies revealed that HP1020 and HP1021, but not htrA, can be mutated. In addition, we demonstrate that suppression of HtrA proteolytic activity with a newly developed inhibitor is sufficient to effectively kill H. pylori, but not other bacteria. We show that Helicobacter htrA is an essential bifunctional gene with crucial intracellular and extracellular functions. Thus, we describe here the first microbe in which htrA is an indispensable gene, a situation unique in the bacterial kingdom. HtrA can therefore be considered a promising new target for anti-bacterial therapy., (© 2015 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.)

Sustained identification of innovative chemical entities is key for the success of chemical biology and drug discovery. We report the fragment-based, computer-assisted de novo design of a small molecule inhibiting Helicobacter pylori HtrA protease. Molecular binding of the designed compound to HtrA was confirmed through biophysical methods, supporting its functional activity in vitro. Hit expansion led to the identification of the currently best-in-class HtrA inhibitor. The results obtained reinforce the validity of ligand-based de novo design and binding-kinetics-guided optimization for the efficient discovery of pioneering lead structures and prototyping drug-like chemical probes with tailored bioactivity., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Brain perfusion is altered in both alcohol dependence and stimulant dependence. Although most substance users also abuse/depend on alcohol concurrently (polysubstance users; PSU), rigorous perfusion research in PSU is limited. Also, the relationships of perfusion abnormalities with cognition, impulsivity, or decision making are not well known., Methods: Arterial spin labeling MRI and neuropsychological measures assessed perfusion levels and neurocognition in 20 alcohol-dependent individuals with comorbid-stimulant dependence (PSU), 26 individuals dependent on alcohol only (ALC), and 31 light/non-drinking controls (LD). The patient groups included smokers and non-smokers., Results: ALC had lower perfusion than LD in subcortical and cortical brain regions including the brain reward/executive oversight system (BREOS). Contrary to our hypothesis, regional perfusion was generally not lower in PSU than ALC. However, smoking PSU had lower perfusion than smoking ALC in several regions, including BREOS. Lower BREOS perfusion related to greater drinking severity in smoking substance users and to greater smoking severity in smoking ALC. Lower regional perfusion in ALC and PSU correlated with worse performance in different cognitive domains; smoking status affected perfusion-cognition relationships in ALC only. Lower BREOS perfusion in both substance using groups related to higher impulsivity., Conclusion: Although regional perfusion was not decreased in PSU as a group, the combination of cigarette smoking and polysubstance use is strongly related to hypoperfusion in important cortical and subcortical regions. As lower perfusion relates to greater smoking severity, worse cognition and higher impulsivity, smoking cessation is warranted for treatment-seeking PSU and ALC., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)