Blood Pressure Control Targets and Risk of Cardiovascular and Cerebrovascular Events After Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) survivors are at high risk for recurrent stroke and cardiovascular events. Blood pressure (BP) control represents the most potent intervention to lower these risks, but optimal treatment targets in this patient population remain unknown. We sought to determine whether survivors of ICH achieving more intensive BP control than current guideline recommendations (systolic BP <130 mmHg and diastolic BP <80 mmHg) were at lower risk of major adverse cardiovascular and cerebrovascular events and mortality. METHODS: We analyzed data for 1828 survivors of spontaneous ICH from 2 cohort studies. Follow-up BP measurements were recorded 3 and 6 months after ICH, and every 6 months thereafter. Outcomes of interest were major adverse cardiovascular and cerebrovascular events (recurrent ICH, incident ischemic stroke, myocardial infarction), vascular mortality (defined as mortality attributed to recurrent ICH, ischemic stroke, or myocardial infarction), and all-cause mortality. RESULTS: During a median follow-up of 46.2 months, we observed 166 recurrent ICH, 68 ischemic strokes, 69 myocardial infarction, and 429 deaths. Compared with survivors of ICH with systolic BP 120 to 129 mmHg, participants who achieved systolic BP <120 mmHg displayed reduced risk of recurrent ICH (adjusted hazard ratio [AHR], 0.74 [95% CI, 0.59-0.94]) and major adverse cardiovascular and cerebrovascular events (AHR, 0.69 [95% CI, 0.53-0.92]). All-cause mortality (AHR, 0.76 [95% CI, 0.57-1.03]) and vascular mortality (AHR, 0.68 [95% CI, 0.45-1.01]) did not differ significantly. Among participants aged >75 years or with modified Rankin Scale score 4 to 5, systolic BP <120 mmHg was associated with increased all-cause mortality (AHR, 1.38 [95% CI, 1.02-1.85] and AHR, 1.36 [95% CI, 1.03-1.78], respectively), but not vascular mortality. We found no differences in outcome rates between survivors of ICH with diastolic BP <70 versus 70 to 79 mmHg. CONCLUSIONS: Targeting systolic BP <120 mmHg in select groups of survivors of ICH could result in decreased major adverse cardiovascular and cerebrovascular events risk without increasing mortality. Our findings warrant investigation in dedicated randomized controlled trials.

Location-Specific Hematoma Volume Cutoff and Clinical Outcomes in Intracerebral Hemorrhage.

BACKGROUND: Major intracerebral hemorrhage (ICH) trials have largely been unable to demonstrate therapeutic benefit in improving functional outcomes. This may be partly due to the heterogeneity of ICH outcomes based on their location, where a small strategic ICH could be debilitating, thus confounding therapeutic effects. We aimed to determine the ideal hematoma volume cutoff for different ICH locations in predicting ICH outcomes. METHODS: We retrospectively analyzed consecutive ICH patients enrolled in the University of Hong Kong prospective stroke registry from January 2011 to December 2018. Patients with premorbid modified Rankin Scale score >2 or who underwent neurosurgical intervention were excluded. ICH volume cutoff, sensitivity, and specificity in predicting respective 6-month neurological outcomes (good [modified Rankin Scale score 0-2], poor [modified Rankin Scale score 4-6], and mortality) for specific ICH locations were determined using receiver operating characteristic curves. Separate multivariate logistic regression models were also conducted for each location-specific volume cutoff to determine whether these cutoffs were independently associated with respective outcomes. RESULTS: Among 533 ICHs, the volume cutoff for good outcome according to ICH location was 40.5 mL for lobar, 32.5 mL for putamen/external capsule, 5.5 mL for internal capsule/globus pallidus, 6.5 mL for thalamus, 17 mL for cerebellum, and 3 mL for brainstem. ICH smaller than the cutoff for all supratentorial sites had higher odds of good outcomes (all P<0.05). Volumes exceeding 48 mL for lobar, 41 mL for putamen/external capsule, 6 mL for internal capsule/globus pallidus, 9.5 mL for thalamus, 22 mL for cerebellum, and 7.5 mL for brainstem were at greater risk of poor outcomes (all P<0.05). Mortality risks were significantly higher for volumes that exceeded 89.5 mL for lobar, 42 mL for putamen/external capsule, and 21 mL for internal capsule/globus pallidus (all P<0.001). All receiver operating characteristic models for location-specific cutoffs had good discriminant values (area under the curve >0.8), except in predicting good outcome for cerebellum. CONCLUSIONS: ICH outcomes differed with location-specific hematoma size. Location-specific volume cutoff should be considered in patient selection for ICH trials.

Delays in Stroke Onset to Hospital Arrival Time During COVID-19.

BACKGROUND AND PURPOSE: The current coronavirus disease 2019 (COVID-19) pandemic represents a global public health crisis, disrupting emergency healthcare services. We determined whether COVID-19 has resulted in delays in stroke presentation and affected the delivery of acute stroke services in a comprehensive stroke center in Hong Kong. METHODS: We retrospectively reviewed all patients with transient ischemic attack and stroke admitted via the acute stroke pathway of Queen Mary Hospital, Hong Kong, during the first 60 days since the first diagnosed COVID-19 case in Hong Kong (COVID-19: January 23, 2020-March 24, 2020). We compared the stroke onset to hospital arrival (onset-to-door) time and timings of inpatient stroke pathways with patients admitted during the same period in 2019 (pre-COVID-19: January 23, 2019-March 24, 2019). RESULTS: Seventy-three patients in COVID-19 were compared with 89 patients in pre-COVID-19. There were no significant differences in age, sex, vascular risk factors, nor stroke severity between the 2 groups (P>0.05). The median stroke onset-to-door time was ≈1-hour longer in COVID-19 compared with pre-COVID-19 (154 versus 95 minutes, P=0.12), and the proportion of individuals with onset-to-door time within 4.5 hours was significantly lower (55% versus 72%, P=0.024). Significantly fewer cases of transient ischemic attack presented to the hospital during COVID-19 (4% versus 16%, P=0.016), despite no increase in referrals to the transient ischemic attack clinic. Inpatient stroke pathways and treatment time metrics nevertheless did not differ between the 2 groups (P>0.05 for all comparisons). CONCLUSIONS: During the early containment phase of COVID-19, we noted a prolongation in stroke onset to hospital arrival time and a significant reduction in individuals arriving at the hospital within 4.5 hours and presenting with transient ischemic attack. Public education about stroke should continue to be reinforced during the COVID-19 pandemic.

Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study.

BACKGROUND: The infliximab biosimilar CT-P13 was approved for use in Crohn's disease after clinical comparison with originator infliximab in ankylosing spondylitis and rheumatoid arthritis; however, concerns about such indication extrapolation have been expressed. This study investigated whether CT-P13 is non-inferior to infliximab in patients with Crohn's disease who were naive to biological therapy. METHODS: In this randomised, multicentre, double-blind, phase 3 non-inferiority study, we enrolled patients with active Crohn's disease who had not responded to, or were intolerant to, non-biological treatments. Patients were randomly assigned (1:1:1:1) to receive CT-P13 then CT-P13, CT-P13 then infliximab, infliximab then infliximab, or infliximab then CT-P13, with switching occurring at week 30. Patients received 5 mg/kg CT-P13 or infliximab at weeks 0, 2, 6, and then every 8 weeks up to week 54. The primary endpoint was the proportion of patients with a decrease of 70 points or more in Crohn's Disease Activity Index (CDAI) from baseline to week 6. A non-inferiority margin of -20% was set (CT-P13 was non-inferior to infliximab if the lower limit of the two-sided 95% CI for the treatment difference was greater than -20). This trial is registered with ClinicalTrials.gov, number NCT02096861, and is completed. FINDINGS: Between Aug 20, 2014, and Feb 15, 2017, 308 patients were assessed for eligibility, and 220 patients were enrolled: 111 were randomly assigned to initiate CT-P13 (56 to the CT-P13-CT-P13 group and 55 to the CT-P13-infliximab group) and 109 to initiate infliximab (54 to the infliximab-infliximab group and 55 to the infliximab-CT-P13 group). CDAI-70 response rates at week 6 were similar for CT-P13 (77 [69·4%, 95% CI 59·9 to 77·8] of 111) and infliximab (81 [74·3%, 95% CI 65·1 to 82·2] of 109; difference -4·9% [95% CI -16·9 to 7·3]), thereby establishing non-inferiority. Over the total study period, 147 (67%) patients experienced at least one treatment-emergent adverse event (36 [64%] in the CT-P13-CT-P13 group, 34 [62%] in the CT-P13-infliximab group, 37 [69%] in the infliximab-infliximab group, and 40 [73%] in the infliximab-CT-P13 group). INTERPRETATION: This study showed non-inferiority of CT-P13 to infliximab in patients with active Crohn's disease. Biosimilar CT-P13 could be a new option for the treatment of active Crohn's disease. FUNDING: Celltrion, Pfizer.

The relationship between postoperative opioid consumption and the incidence of hypoxemic events following total hip arthroplasty: a post hoc analysis.

Background: Postoperative opioid analgesia may cause respiratory depression. We assessed whether following total hip arthroplasty, placebo-adjusted reductions in morphine consumption at 48 hours with parecoxib (47.0%), propacetamol (35.1%) or parecoxib plus propacetamol (67.9%) translated into a reduction in hypoxemic events. Methods: This was a post hoc analysis of a randomized, placebo-controlled, noninferiority study. Patients were randomly assigned to receive intravenous parecoxib (40 mg twice daily), propacetamol (2 g 4 times daily), parecoxib plus propacetamol (40 mg twice daily + 2 g 4 times daily) or placebo. Dose, date and time of morphine administration via patient-controlled analgesia were monitored throughout the study. In patients not receiving supplemental oxygen, peripheral blood oxygenation was assessed continuously for 48 hours after surgery. Hypoxemia was defined as peripheral oxygen saturation less than 90%. The times and oximeter readings of hypoxemic events were recorded. Pearson correlation coefficient was used to assess for correlations between cumulative morphine consumption at 48 hours and mean number of hypoxemic events. Results: A significantly smaller proportion of patients who received the combined treatment with parecoxib and propacetamol had hypoxemia versus placebo (2.8% v. 13.2%, p < 0.05), and the mean number of hypoxemic events was significantly smaller for parecoxib (0.12), propacetamol (0.06) and parecoxib plus propacetamol (0.03) versus placebo (0.36; all p < 0.05). There was no correlation between the reduction in cumulative morphine consumption at 48 hours and the mean number of hypoxemic events in any treatment group (all p > 0.1). Conclusion: Following total hip arthroplasty, a greater than 70% reduction in morphine consumption may be necessary to translate into a corresponding reduction in hypoxemic events.

Contexte: L'utilisation d'analgésiques opioïdes en période postopératoire peut provoquer une dépression respiratoire. Nous avons voulu déterminer si, après une arthroplastie totale de la hanche, une réduction de la consommation de morphine à 48 heures par l'administration de parécoxib (47,0 %), de propacétamol (35,1 %) ou d'une combinaison des deux (67,9 %) ­ avec ajustement selon un groupe placebo ­ se traduirait par une réduction du nombre d'épisodes d'hypoxémie. Méthodes: Nous avons effectué une analyse post hoc d'une étude randomisée de non-infériorité avec témoins sous placebo. Après une répartition aléatoire, chaque patient a reçu par intraveineuse du parécoxib (40 mg 2 fois par jour), du propacétamol (2 g 4 fois par jour), une combinaison de parécoxib et de propacétamol (40 mg 2 fois par jour + 2 g 4 fois par jour) ou un placebo. Tout au long de l'étude, la dose, la date et le moment de l'administration de morphine contrôlée par le patient ont été notés. Chez les patients qui ne recevaient pas d'oxygène d'appoint, la saturation périphérique en oxygène a été surveillée de manière continue pendant les 48 heures suivant l'opération. L'hypoxémie a été définie comme une saturation inférieure à 90 %. Le moment et les données d'oxymétrie ont été notés pour chaque épisode d'hypoxémie. Le coefficient de corrélation de Pearson a été utilisé pour évaluer la présence de corrélations entre la consommation cumulative de morphine durant les premières 48 heures et le nombre moyen d'épisodes d'hypoxémie. Résultats: Une proportion significativement plus faible de patients ayant reçu le traitement combiné de parécoxib et de propacétamol ont connu des épisodes d'hypoxémie, comparativement aux patients qui avaient reçu le placebo (2,8 % c. 13,2 %, p < 0,05), et le nombre moyen d'épisodes d'hypoxémie était significativement plus faible dans le groupe ayant reçu du parécoxib (0,12), du propacétamol (0,06) ou une combinaison de parécoxib et de propacétamol (0,03), par rapport au groupe placebo (0,36, p < 0,05 pour tous). Aucune corrélation n'a été observée entre la réduction de la quantité totale de morphine consommée à 48 heures et le nombre moyen d'épisodes d'hypoxémie pour tous les groupes (p > 0,1 pour tous). Conclusion: Après une arthroplastie totale de la hanche, une réduction de la consommation de morphine de plus de 70 % pourrait être nécessaire pour obtenir une réduction correspondante du nombre d'épisodes d'hypoxémie.

Numeric simulation of occlusal interferences in molars restored with ultrathin occlusal veneers.

STATEMENT OF PROBLEM: Selecting material for a minimally invasive occlusal veneer reconstruction concept requires an understanding of how stresses are distributed during functional and parafunctional forces. PURPOSE: The purpose of this in vitro study was to investigate stress distribution in a maxillary molar restored with ultrathin occlusal veneers and subjected by an antagonistic mandibular molar to clenching and working and nonworking movements. MATERIAL AND METHODS: A maxillary first molar was modeled from microcomputed tomography (micro-CT) data, using medical image processing software, stereolithography editing/optimizing software, and finite element software. Simulated ultrathin occlusal veneer materials were used. The mandibular molar antagonist was a solid nondeformable geometric entity. Loads simulated clenching, working, and nonworking movements with loading of 500 N. The values of the maximum principal stress were recorded. RESULTS: In the clenching load situation, maximum tensile stresses were located at the occlusal veneer (52 MPa for composite resin versus 47 MPa for ceramic). In the working movement, significant additional tensile stresses were found on the palatal root (87 MPa for composite resin and 85 MPa for ceramic). In the nonworking movement, tensile stress on the ultrathin occlusal veneer increased to 118 MPa for composite resin and 143 MPa for ceramic veneers. Tensile stress peaks shifted to the mesiobuccal root (75 MPa for composite resin and 74 MPa for ceramic). CONCLUSIONS: The topography of stresses generated by the various occlusal interferences were clearly identified. Significant tensile stress concentrations were found within the restoration's occlusal topography and root, with the nonworking interference being the most harmful and also the most revealing of the difference between the composite resin and ceramic ultrathin occlusal veneers.

A self-assembling nanomaterial reduces acute brain injury and enhances functional recovery in a rat model of intracerebral hemorrhage.

There is no effective treatment for intracerebral hemorrhage (ICH). Intracerebral delivery of nanomaterials into the hemorrhagic lesion may be a new therapeutic strategy. In a rat model of ICH plus ultra-early hematoma aspiration, we found that locally delivered self-assembling peptide nanofiber scaffold (SAPNS) replaced the hematoma, reduced acute brain injury and brain cavity formation, and improved sensorimotor functional recovery. SAPNS serves as biocompatible material in the hemorrhagic brain cavity. Local delivery of this nanomaterial may facilitate the repair of ICH related brain injury and functional recovery. From the clinical editor: In a rat model of intracranial hemorrhage, these authors demonstrate that following ultra-early hematoma aspiration, local delivery of a self-assembling peptide nanofiber scaffold replaces the hematoma, reduces brain cavity formation, and improves sensorimotor functional recovery. Similar approaches would be welcome additions to the clinical treatment of this often devastating condition.

Preliminary evidence of the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) on swallowing functions in post-stroke individuals with chronic dysphagia.

BACKGROUND: There is growing evidence of potential benefits of repetitive transcranial magnetic stimulation (rTMS) in the rehabilitation of dysphagia. However, the site and frequency of stimulation for optimal effects are not clear. AIMS: The aim of this pilot study is to investigate the short-term effects of high-frequency 5 Hz rTMS applied to the tongue region of the motor cortex on swallowing functions and the quality of life of post-stroke individuals with dysphagia. METHODS & PROCEDURES: Two male and two female participants were assigned randomly to active and sham groups. The participants in the active group received 10 sessions of active rTMS for 2 weeks, whereas the sham participants received 10 sessions of sham rTMS for 2 weeks. Each participant received a total of 3000 pulses of 5 Hz active or sham rTMS per day for 10 days. Outcome measures were taken at baseline, 1 week and 1 month post-rTMS. OUTCOMES & RESULTS: Participants who received active rTMS had improved swallowing functions and swallowing-related quality of life at 1 week and 1 month post-stimulation. CONCLUSIONS & IMPLICATIONS: The study showed that excitatory rTMS applied over the tongue motor cortex is a feasible approach in individuals with chronic post-stroke dysphagia. Further investigation with larger sample population is warranted to support the benefit of this stimulation protocol.

Prediction of pregabalin-mediated pain response by severity of sleep disturbance in patients with painful diabetic neuropathy and post-herpetic neuralgia.

OBJECTIVE: To evaluate the predictive value of disturbed sleep on the ability of pregabalin to reduce pain associated with diabetic peripheral neuropathy (DPN) and post-herpetic neuralgia (PHN). DESIGN: A post-hoc analysis of data pooled from 16 placebo-controlled trials of pregabalin in patients with DPN or PHN. METHODS: Pain relief at endpoint was compared in patients with mild, moderate, or severe levels of baseline sleep disturbance. Sleep disturbance was based on a scale from 0-10 and scores <4, 4 to 7, and ≥7 were classified as mild, moderate, and severe, respectively. RESULTS: Pregabalin significantly reduced mean pain scores in the DPN (N = 3,056) and PHN (N = 1,471) cohorts (mean placebo-adjusted reductions were -0.73 and -1.08 for patients with DPN/PHN, respectively; both P < 0.05). The greatest extent of pain relief occurred in patients with severe sleep interference scores at baseline. Data analyses using the pooled DPN/PHN population identified a subset of patients (N = 707) exhibiting marked levels of pain relief at endpoint (mean placebo-adjusted reduction of -2.88), all of whom had severe sleep interference scores at baseline. Baseline sleep interference scores were a moderately good predictor of global patient improvement in response to pregabalin treatment in both patient cohorts. Finally, path analysis showed a high degree of association between improvements in sleep and pain relief in patients with DPN/PHN. CONCLUSION: Overall, these data suggest that the presence of comorbid sleep disturbance in patients with DPN/PHN might, in part, predict substantial pain relief in response to pregabalin treatment.

Melatonin at repeated doses alleviates hyperglycemia-exacerbated cerebral ischemia-reperfusion injury at 72 h via anti-inflammation and anti-apoptosis.

Objective: We aimed to investigate how hyperglycemia would exacerbate cerebral ischemia-reperfusion injury (CIRI) in a rat model of type 1 diabetes mellitus (T1DM) and explore the beneficial effects of multiple doses of melatonin in T1DM induced CIRI. Method: The T1DM rat model was induced with streptozocin, and melatonin (10 mg/kg) was injected at 0.5 h before ischemia as well as at 24 and 48 h after reperfusion. Results: When compared to normoglycemic (NG) rats, T1DM rats had hyperglycemia with weight loss before CIRI. Despite comparable degrees of ischemia and initial reperfusion, T1DM rats tended to have greater weight loss and had worse neurological deficits and larger infarct volume than NG rats up to 72 h after CIRI. Persistent activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway but not of apoptosis or calpains was a crucial factor in T1DM-mediated exacerbation of CIRI at 72 h. Despite lacking effects on baseline hyperglycemia, ischemia and initial reperfusion, melatonin at multiple doses lessened post-CIRI weight loss, neurological deficits and infarct volume in T1DM rats at 72 h. when compared to vehicle-treated T1DM rats with CIRI. Beneficial effects of melatonin treatment included decreased activation of NF-κB pathway, apoptosis and calpains, leading to reduced expression of inducible nitric oxide synthase and enhanced neuronal density. Conclusion: Melatonin at multiple doses can alleviate T1DM-mediated exacerbation of CIRI at 72 h through anti-inflammation and anti-apoptosis.

Association of LDL-cholesterol <1.8 mmol/L and statin use with the recurrence of intracerebral hemorrhage.

BACKGROUND: Recent intensive low-density lipoprotein cholesterol (LDL-C) lowering trials, including FOURIER, ODYSSEY OUTCOMES, and Treat Stroke to Target (TST) trials, have mostly refuted the concern surrounding statin use, LDL-C lowering, and intracerebral hemorrhage (ICH) risk. However, the results from these trials may not be fully applied to ICH survivors, as the populations studied were mainly patients without prior ICH, in whom the inherent ICH risk is more than 10 times lower than that of ICH survivors. Although available literature on statin use after ICH has demonstrated no excess risk of recurrent ICH, other potential factors that may modify ICH risk, especially hypertension control and ICH etiology, have not generally been considered. Notably, data on LDL-C levels following ICH are lacking. AIMS: We aim to investigate the association between LDL-C levels and statin use with ICH risk among ICH survivors, and to determine whether the risk differed with patients' characteristics, especially ICH etiology. METHODS: Follow-up data of consecutive spontaneous ICH survivors enrolled in the University of Hong Kong prospective stroke registry from 2011 to 2019 were retrospectively analyzed. ICH etiology was classified as cerebral amyloid angiopathy (CAA) using the modified Boston criteria or hypertensive arteriopathy, while the mean follow-up LDL-C value was categorized as <1.8 or ⩾1.8 mmol/L. The primary endpoint was recurrent ICH. The association of LDL-C level and statin use with recurrent ICH was determined using multivariable Cox regression. Pre-specified subgroup analyses were performed, including based on ICH etiology and statin prescription. Follow-up blood pressure was included in all the regression models. RESULTS: In 502 ICH survivors (mean age = 64.2 ± 13.5 years, mean follow-up LDL-C = 2.2 ± 0.6 mmol/L, 28% with LDL-C <1.8 mmol/L), 44 had ICH recurrence during a mean follow-up of 5.9 ± 2.8 years. Statin use after ICH was not associated with recurrent ICH (adjusted hazard ratio (AHR) = 1.07, 95% confidence interval (CI) = 0.57-2.00). The risk of ICH recurrence was increased for follow-up LDL-C <1.8 mmol/L (AHR = 1.99, 95% CI = 1.06-3.73). This association was predominantly observed in ICH attributable to CAA (AHR = 2.52, 95% CI = 1.06-5.99) and non-statin users (AHR = 2.91, 95% CI = 1.08-7.86). CONCLUSION: The association between post-ICH LDL-C <1.8 mmol/L and recurrent ICH was predominantly observed in CAA patients and those with intrinsically low LDL-C (non-statin users). While statins can be safely prescribed in ICH survivors, LDL-C targets should be individualized and caution must be exercised in CAA patients.

Melatonin mitigates type 1 diabetes-aggravated cerebral ischemia-reperfusion injury through anti-inflammatory and anti-apoptotic effects.

INTRODUCTION: Cerebral ischemia and diabetes mellitus (DM) are common diseases that often coexist and interact with each other. DM doubles the risk of ischemic stroke, and cerebral ischemia causes stress-induced hyperglycemia. Most experimental stroke studies used healthy animals. Melatonin is neuroprotective against cerebral ischemia-reperfusion injury (CIRI) in non-DM, normoglycemic animals through anti-oxidant effect, anti-inflammation, and anti-apoptosis. Previous studies have also reported a negative correlation between hyperglycemia and urinary melatonin metabolite. OBJECTIVES: The present study investigated the effects of type 1 DM (T1DM) on CIRI in rats and the role of melatonin against CIRI in T1DM animals. RESULTS: Our results revealed that T1DM aggravated CIRI, leading to greater weight loss, increased infarct volume, and worse neurological deficit. T1DM aggravated the post-CIRI activation of nuclear factor kappa B (NF-κB) pathway and increase in pro-apoptotic markers. A single intraperitoneal injection of melatonin at 10 mg/kg given 30 min before ischemia onset attenuated CIRI in T1DM rats, resulting in less weight loss, decreased infarct volume, and milder neurological deficit when compared with the vehicle group. Melatonin treatment achieved anti-inflammatory and anti-apoptotic effects with reduced NF-κB pathway activation, reduced mitochondrial cytochrome C release, decreased calpain-mediated spectrin breakdown product (SBDP), and decreased caspase-3-mediated SBDP. The treatment also led to fewer iNOS+ cells, milder CD-68+ macrophage/microglia infiltration, decreased TUNEL+ apoptotic cells, and better neuronal survival. CONCLUSIONS: T1DM aggravates CIRI. Melatonin treatment is neuroprotective against CIRI in T1DM rats via anti-inflammatory and anti-apoptotic effects.

Inhibitory dysfunction may cause prospective memory impairment in temporal lobe epilepsy (TLE) patients: an event-related potential study.

Introduction: Prospective memory (PM) is the ability to remember future intentions, and PM function is closely related to independence in daily life, particularly in patients with temporal lobe epilepsy (TLE). As PM involves various cognitive components of attention, working memory, inhibition and other executive functions, this study investigated how TLE may affect PM components and the underlying neural mechanisms. Methods: Sixty-four subjects were recruited, including 20 refractory TLE patients, 18 well-controlled TLE patients and 26 age-matched healthy controls. A set of neuropsychological tests was administered to assess specific brain functions. An event-related potential (ERP) task was used to further explore how PM and its components would be differentially affected in the two TLE types. Results: Our findings revealed that: (1) refractory TLE patients scored lower than the healthy controls in the digit span, Verbal Fluency Test and Symbol Digit Modalities Test; (2) refractory TLE patients exhibited impaired PM performance and reduced prospective positivity amplitudes over the frontal, central and parietal regions in ERP experiments when compared to the healthy controls; and (3) decreased P3 amplitudes in the nogo trials were observed over the frontal-central sites in refractory but not in well-controlled TLE patients. Discussion: To our knowledge, this is the first ERP study on PM that has specifically identified PM impairment in refractory but not in well-controlled TLE patients. Our finding of double dissociation in PM components suggests that inhibition dysfunction may be the main reason for PM deficit in refractory TLE patients. The present results have clinical implications for neuropsychological rehabilitation in TLE patients.

Identification of the human cerebral cortical hemodynamic response to passive whole-body movements using near-infrared spectroscopy.

The human vestibular system is crucial for motion perception, balance control, and various higher cognitive functions. Exploring how the cerebral cortex responds to vestibular signals is not only valuable for a better understanding of how the vestibular system participates in cognitive and motor functions but also clinically significant in diagnosing central vestibular disorders. Near-infrared spectroscopy (NIRS) provides a portable and non-invasive brain imaging technology to monitor cortical hemodynamics under physical motion. Objective: This study aimed to investigate the cerebral cortical response to naturalistic vestibular stimulation induced by real physical motion and to validate the vestibular cerebral cortex previously identified using alternative vestibular stimulation. Approach: Functional NIRS data were collected from 12 right-handed subjects when they were sitting in a motion platform that generated three types of whole-body passive translational motion (circular, lateral, and fore-and-aft). Main results: The study found that different cortical regions were activated by the three types of motion. The cortical response was more widespread under circular motion in two dimensions compared to lateral and fore-and-aft motions in one dimensions. Overall, the identified regions were consistent with the cortical areas found to be activated in previous brain imaging studies. Significance: The results provide new evidence of brain selectivity to different types of motion and validate previous findings on the vestibular cerebral cortex.

Long-Term Blood Pressure Variability and Major Adverse Cardiovascular and Cerebrovascular Events After Intracerebral Hemorrhage.

Background Survivors of intracranial hemorrhage (ICH) are at increased risk for major adverse cardiovascular and cerebrovascular events (MACCE), in the form of recurrent stroke and myocardial Infarction. We investigated whether long-term blood pressure (BP) variability represents a risk factor for MACCE after ICH, independent of average BP. Methods and Results We analyzed data from prospective ICH cohort studies at Massachusetts General Hospital and the University of Hong Kong. We captured long-term (ie, visit-to-visit) BP variability, quantified as individual participants' variation coefficient. We explored determinants of systolic and diastolic BP variability and generated survival analyses models to explore their association with MACCE. Among 1828 survivors of ICH followed for a median of 46.2 months we identified 166 with recurrent ICH, 68 with ischemic strokes, and 69 with myocardial infarction. Black (coefficient +3.8, SE 1.3) and Asian (coefficient +2.2, SE 0.4) participants displayed higher BP variability. Long-term systolic BP variability was independently associated with recurrent ICH (subhazard ratio [SHR], 1.82; 95% CI, 1.19-2.79), ischemic stroke (SHR, 1.62; 95% CI, 1.06-2.47), and myocardial infarction (SHR, 1.54; 95% CI, 1.05-2.24). Average BP during follow-up did not modify the association between long-term systolic BP variability and MACCE. Conclusions Long-term BP variability is a potent risk factor for recurrent hemorrhage, ischemic stroke, and myocardial infarction after ICH, even among survivors with well-controlled hypertension. Our findings support the hypothesis that combined control of average BP and its variability after ICH is required to minimize incidence of MACCE.

Central amplification and fibromyalgia: disorder of pain processing.

Fibromyalgia (FM), a complex chronic pain disorder affecting a heterogeneous patient population, is an area of active basic and clinical research. Although diagnostic criteria for FM have been available for 2 decades, there remains no definitive diagnostic and no consensus regarding its etiology. Accumulating evidence suggests the underlying cause of FM pain results from abnormal pain processing particularly in the central nervous system rather than from dysfunction in peripheral tissues where pain is perceived. In this review, we examine recent studies investigating abnormalities in central pain processing as a component of FM in both preclinical models of generalized muscle hypersensitivity and clinical research in patients with FM. We focus our discussion on two areas where strong evidence exists for abnormalities in sensory signaling: the reduction of descending control, including suppression of descending inhibitory pathways and/or enhancement of descending facilitatory pathways, and changes in key neurotransmitters associated with central sensitization. Finally, we discuss currently available pharmacological treatments indicated for the management of pain in FM patients, based on their proposed mechanism of action and efficacy.

Evaluation of the Cognitive Performance of Hypertensive Patients with Silent Cerebrovascular Lesions.

Evidence accumulated from the last decade has proven that silent cerebrovascular lesions (SCLs) and their underlying pathogenic processes contribute to cognitive decline in the elderly. However, the distinct effects of each type of the lesions on cognitive performance remain unclear. Moreover, research data from Chinese elderly with SCLs is scarce. In this study, 398 otherwise healthy hypertensive elderly subjects (median age 72 years) were included and assessed. All participates were required to complete a battery of structured neuropsychological assessment, including forward and backward digit span tests, symbol digit modalities test, Stroop test, verbal fluency test and Montreal Cognitive Assessment. These tests were used to assess attention, executive function, information processing speed, language, memory and visuospatial function. A multi-sequence 3T MRI scanning was arranged within one month of the neuropsychological assessment to evaluate the burden of SCLs. SCLs were rated visually. Cerebral microbleeds (CMBs) and silent lacunes (SLs) were identified as strictly lobar CMBs and SLs or deep CMBs and SLs according to their locations, respectively. Similarly, white matter hyperintensities (WMHs) were separated into periventricular WMHs (PVHs) and deep WMHs (DWMHs). A series of linear regression models were used to assess the correlation between each type of SCLs and individual cognitive function domain. The results showed that CMBs tend to impair language-related cognition. Deep SLs affect executive function, but this association disappeared after controlling for other types of SCLs. PVHs, rather than DWMHs, are associated with cognitive decline, especially in executive function and processing speed. It is concluded that different aspects of SCLs have differential impact on cognitive performance in hypertensive elderly Chinese.

Burden of comorbid anxiety and depression in patients with inflammatory bowel disease: a systematic literature review.

INTRODUCTION: Patients with inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, often have comorbid anxiety and depression that affects their quality of life (QoL) and management of their IBD. AREAS COVERED: A systematic literature review (SLR) was conducted to identify articles and conference abstracts on comorbid anxiety and depression in IBD patients using MEDLINE® and Embase® (January 2003 - June 2018). The impact of these psychological comorbidities on QoL and economic burden was examined. Non-pharmacologic interventions and disease-specific unmet clinical needs associated with these comorbidities were also evaluated. EXPERT OPINION: There is evidence that individual and group-based cognitive behavioral therapy can reduce rates of anxiety and depression in adults and adolescents with IBD. Patients with IBD and anxiety or depression had an increased risk of hospitalization, emergency department visits, readmission, and used outpatient services more often than people without these conditions. Several disease-specific unmet clinical needs for IBD patients were identified. These included lack of reimbursement for mental-health care, inconsistent screening for psychological comorbidities and patients not consulting mental-health professionals when needed. IBD patients may benefit from integrated medical and psychological treatment, and should be considered for behavioral treatment.Plain Language Summary. BACKGROUND: People with IBD may have mental-health conditions, such as anxiety and depression. These conditions can affect people's quality of life and how they manage their IBD. WHAT DID THIS REVIEW LOOK AT?: We found 79 publications on anxiety or depression in people with IBD, published between January 2003 and June 2018. In people with IBD and anxiety or depression, researchers looked at: the impact on health-related quality of life and healthcare utilization, including access to and reimbursement for mental-health services how effective interventions that do not involve the use of medicines were (known as non-pharmacologic therapy). WHAT WERE THE MAIN FINDINGS FROM THIS REVIEW?: People with IBD and anxiety or depression were more likely to be admitted to hospital and visit emergency departments than people without these conditions. Access to mental-health care varied and some people with IBD were not screened for depression.Individual and group-based talking therapy (known as cognitive behavioral therapy) reduced rates of anxiety and depression in some people with IBD. WHAT WERE THE MAIN CONCLUSIONS FROM THIS REVIEW?: We found evidence that people with IBD and anxiety or depression may benefit from certain non-pharmacologic interventions. However, many people with IBD and anxiety or depression did not have access to mental-health services. Healthcare professionals should address gaps in patient care to improve outcomes in people with IBD and anxiety or depression.See Additional file 1 for an infographic plain language summary.

Impact of Uncontrolled Hypertension at 3 Months After Intracerebral Hemorrhage.

Background Survivors of intracerebral hemorrhage (ICH) are at high risk for recurrent stroke, which is associated with blood pressure control. Because most recurrent stroke events occur within 12 to 18 months of the index ICH, rapid blood pressure control is likely to be crucial. We investigated the frequency and prognostic impact of uncontrolled short-term hypertension after ICH. Methods and Results We analyzed data from Massachusetts General Hospital (n=1305) and the University of Hong Kong (n=523). We classified hypertension as controlled, undertreated, or treatment resistant at 3 months after ICH and determined the following: (1) the risk factors for uncontrolled hypertension and (2) whether hypertension control at 3 months is associated with stroke recurrence and mortality. We followed 1828 survivors of ICH for a median of 46.2 months. Only 9 of 234 (4%) recurrent strokes occurred before 3 months after ICH. At 3 months, 713 participants (39%) had controlled hypertension, 755 (41%) had undertreated hypertension, and 360 (20%) had treatment-resistant hypertension. Black, Hispanic, and Asian race/ethnicity and higher blood pressure at time of ICH increased the risk of uncontrolled hypertension at 3 months (all P<0.05). Uncontrolled hypertension at 3 months was associated with recurrent stroke and mortality during long-term follow-up (all P<0.05). Conclusions Among survivors of ICH, >60% had uncontrolled hypertension at 3 months, with undertreatment accounting for the majority of cases. The 3-month blood pressure measurements were associated with higher recurrent stroke risk and mortality. Black, Hispanic, and Asian survivors of ICH and those presenting with severe acute hypertensive response were at highest risk for uncontrolled hypertension.

Celecoxib, but not rofecoxib or naproxen, attenuates cardiac hypertrophy and fibrosis induced in vitro by angiotensin and aldosterone.

1. Cyclo-oxygenase (COX)-2 inhibitors and other non-steroidal anti-inflammatory drugs (NSAIDs) have been implicated in increased cardiovascular events. However, the direct effects of these drugs on cardiac function have not been explored extensively. Given the important role of the renin-angiotensin-aldosterone system (RAAS) in cardiac remodelling, we sought to determine the effect of COX-2 inhibitors and non-specific (NS-) NSAIDs on RAAS-induced cardiac hypertrophy and fibrosis in neonatal rat cardiac myocytes (NCM) and fibroblasts (NCF) isolated from 1-2-day-old Sprague-Dawley rat pups. 2. The NCM were pretreated for 2 h with COX-2 inhibitors (celecoxib or rofecoxib) or NS-NSAIDs (naproxen; all at 0.1-10 micromol/L) before being stimulated with 10 micromol/L aldosterone for 72 h or with 0.1 micromol/L angiotensin (Ang) II for 60 h. Hypertrophy of NCM was assessed by [3H]-leucine incorporation. 3. The NCF were pretreated with COX-2 inhibitors or naproxen as described for NCM before being stimulated with 0.1 micromol/L AngII for 48 h. Collagen synthesis was subsequently assayed by [3H]-proline incorporation. 4. Pooled cryopreserved male and female rat hepatocytes were treated with or without COX-2 inhibitors for 1 h before 1 nmol/L aldosterone ( approximately 540 pg/mL) was added to all wells. Cells were incubated for a further 60 min and culture media harvested by centrifugation. Human hepatic HepG2 cells were treated with compounds with or without serum starvation for 48 h. All cells were pretreated with COX-2 inhibitors for 2 h before the addition of aldosterone. Cell culture media were harvested after a further 3, 18, 24 or 48 h incubation. Aldosterone concentrations in the culture media were determined by enzyme immunoassay. 5. Aldosterone- and AngII-stimulated NCM hypertrophy was inhibited by celecoxib, but not by rofecoxib or naproxen. In NCF, AngII-stimulated collagen synthesis was inhibited by celecoxib and, to a lesser extent, by rofecoxib, whereas naproxen had no effect. The COX-2 inhibitors inhibited aldosterone uptake and/or metabolism by rat hepatocytes, but had no effect in human hepatic HepG2 cells. 6. These results demonstrate a potential antiremodelling effect of selective COX-2 inhibitors in the setting of RAAS stimulation in cardiac cells, whereas naproxen has no effect.