Transient disruption of functional connectivity and depression of neural fluctuations in a mouse model of acute septic encephalopathy.

Septic encephalopathy leads to major and costly burdens for a large percentage of admitted hospital patients. Elderly patients are at an increased risk, especially those with dementia. Current treatments are aimed at sedation to combat mental status changes and are not aimed at the underlying cause of encephalopathy. Indeed, the underlying pathology linking together peripheral infection and altered neural function has not been established, largely because good, acutely accessible readouts of encephalopathy in animal models do not exist. Behavioral testing in animals lasts multiple days, outlasting the time frame of acute encephalopathy. Here, we propose optical fluorescent imaging of neural functional connectivity (FC) as a readout of encephalopathy in a mouse model of acute sepsis. Imaging and basic behavioral assessment were performed at baseline, Hr8, Hr24, and Hr72 following injection of either lipopolysaccharide or phosphate buffered saline. Neural FC strength decreased at Hr8 and returned to baseline by Hr72 in motor, somatosensory, parietal, and visual cortical regions. Additionally, neural fluctuations transiently declined at Hr8 and returned to baseline by Hr72. Both FC strength and fluctuation tone correlated with neuroscore indicating this imaging methodology is a sensitive and acute readout of encephalopathy.

Atypical periprosthetic femoral fracture with stem breakage: a case report.

Although the American Society for Bone and Mineral Research definition of atypical femoral fracture excludes periprosthetic fractures, fractures around the prosthesis with clinical features of atypical femoral fractures have been reported in the literature. All fractures reported thus far have been distal to the prosthetic segment; however, we encountered a case of a stress fracture in the middle of the femoral component segment. An 86-year-old woman with a history of bisphosphonate osteoporosis treatment and revisional total hip arthroplasty visited our outpatient clinic complaining of pain in the left thigh and groin. We diagnosed an incomplete atypical femoral fracture around the hip prosthesis; medical treatment was implemented. Two months later, the patient visited the emergency department with a complete subtrochanteric fracture with stem breakage. Without revision of the broken stem, two plates were applied after reduction. In this case, we recognized the possibility of a stress fracture but overlooked the possibility of stem breakage in an atypical femoral fracture. Even if it is not evident on the radiograph before complete fracture, clinicians should be alert to the signs of stress fracture in the middle of the femoral component segment, as they may be clues to atypical periprosthetic femoral fracture with stem failure. Isolated medical treatment plans are not recommended for incomplete subtrochanteric atypical periprosthetic femoral fracture. Instead, concomitant prophylactic plate fixation is recommended.

Investigation of the optimal medium and application strategy for foot-and-mouth disease vaccine antigen production.

AIMS: For the effective production of 146S particles, which determines foot-and-mouth disease (FMD) vaccine efficacy, we aimed to identify the optimal medium that is easy-to-use, productive and economically affordable for the large-scale production of FMD vaccine. METHODS AND RESULTS: Nine combinations of cell growth media and replacement media were tested for virus propagation. Apart from the replacement strategy, we tested a simple addition strategy involving the addition of 30% v/v of fresh medium to the total spent medium using the Cellvento BHK-200 (Vento). Unlike other tested media that produced poor yields of 146S particles when the spent media were not eliminated, Vento exhibited high productivity with the 30% addition strategy. CONCLUSIONS: Considering its lower price and media consumption compared to those of other media that require media replacement, the 30% addition strategy of Vento is highly effective. Furthermore, owing to its simple application strategy, it makes the scale-up process easy and helps in saving the time and labour involved in spent media removal. SIGNIFICANCE AND IMPACT OF THE STUDY: Through the first comparative assessment of commercial media for the 146S particle recovery, this study suggests the best practical medium for the industrial-scale production of FMD vaccines.

Retrograde transvenous obliteration for the prevention of variceal rebleeding in patients with hepatocellular carcinoma: a multicentre retrospective study.

AIM: To evaluate the effectiveness and safety of retrograde transvenous obliteration (RTO) for the prevention of variceal rebleeding variceal rebleeding in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This multicentre retrospective study enrolled 79 patients with HCC who underwent RTO for the prevention of variceal rebleeding. Successful occlusion of the gastrorenal shunt and obliteration of the gastric varices were achieved in 74 patients, with a technical success rate of 93.7%. Of the remaining 74 patients (mean age, 64.9±10.3 years; 56 men), 66 (90.4%) had gastroesophageal varices and seven (9.6%) had isolated gastric varices. Thirty-two patients (43.8%) underwent balloon-occluded RTO, 40 patients (54.8%) underwent plug-assisted RTO, and one patient (1.4%) underwent coil-assisted RTO. No patients had major procedural complications. RESULTS: Rebleeding occurred in seven patients (9.6%) during the follow-up period. The 6-week and 1-year actuarial probabilities of patients remaining free of rebleeding were 90.8±3.6% and 88.6±4.1%, respectively. The median survival was 12.6 (95% confidence interval [CI] 8-17.3) months. The 6-week, 1-year, and 3-year actuarial probabilities of survival were 83.2±4.4%, 51.1±6.6%, and 32.7±7%, respectively. New or worsening ascites and oesophageal varices occurred in 12 (16.4%) and 13 patients (17.8%), respectively, during the follow-up period. Overt hepatic encephalopathy occurred in one patient (1.4%) during the follow-up period. The Child-Pugh score remained comparable to that at baseline at 1 and 3 months. CONCLUSION: RTO was effective and safe in preventing variceal rebleeding in patients with HCC.

The alternative complement pathway in ANCA-associated vasculitis: further evidence and a meta-analysis.

We compared the common pathway components C3a, C5a and membrane attack complex (MAC), also known as C5b-9, and the alternative pathway components factor B and properdin in patients with ANCA-associated vasculitis (AAV) and healthy controls, and conducted a meta-analysis of the available clinical evidence for the role of complement activation in the pathogenesis of AAV. Complement components were evaluated in 59 patients with newly diagnosed or relapsing granulomatosis with polyangiitis or microscopic polyangiitis and 36 healthy volunteers. In 28 patients, testing was repeated in remission. Next, we performed a meta-analysis by searching databases to identify studies comparing complement levels in AAV patients and controls. A random-effects model was used for statistical analyses. The median concentrations of MAC, C5a, C3a and factor B were higher in active AAV patients (P < 0·001). Achievement of remission was associated with reductions in C3a (P = 0·005), C5a (P = 0·035) and factor B levels (P = 0·045), whereas MAC and properdin levels did not change. In active AAV, there were no effects of ANCA specificity, disease phenotype, previous immunosuppression or disease severity on complement levels. A total of 1122 articles were screened, and five studies, including this report, were entered into the meta-analysis. Plasma MAC, C5a and factor B in patients with active AAV were increased compared to patients in remission (excluding factor B) and controls. Changes in C3a were of borderline significance. Our findings and the results of the meta-analysis support activation of the complement system predominantly via the alternative pathway in AAV patients.

The effect of cricoid and paralaryngeal force on upper oesophageal occlusion during induction of anaesthesia: a randomised, crossover study.

The aim of this study was to evaluate the effectiveness of cricoid and paralaryngeal force for oesophageal entrance occlusion during induction of anaesthesia. Seventy-four patients were included in this randomised, crossover study. The relative position of the glottis and outer anteroposterior diameter of the upper oesophageal entrance were assessed at baseline, after the application of 30 N cricoid and paralaryngeal force, and after induction of anaesthesia. The occlusion rate of the oesophageal entrance with cricoid and paralaryngeal force was assessed during direct laryngoscopy. The relative position of the upper oesophageal entrance to the glottis changed in 45 out of 74 patients after induction of anaesthesia and during direct laryngoscopy compared with the awake state. The application of cricoid and paralaryngeal force decreased the mean (SD) diameter of the upper oesophageal entrance to a similar degree in awake (8.5 (2.1) mm to 6.4 (1.7) mm and 6.5 (1.6) mm, respectively; p < 0.001) and anaesthetised (8.7 (2.2) mm to 6.5 (1.7) mm and (6.7 (1.9) mm, respectively; p < 0.001) states. During direct laryngoscopy, the occlusion rate of the oesophageal entrance was greater with cricoid compared with paralaryngeal force (46/74 vs. 26/74, respectively; p = 0.002). The relative position of the upper oesophageal entrance to the glottis may change after induction of anaesthesia and during direct laryngoscopy. Cricoid and paralaryngeal force both decrease the diameter of the upper oesophageal entrance in awake and anaesthetised states. Occlusion of the oesophageal entrance is achieved more frequently with cricoid force compared with paralaryngeal force during direct laryngoscopy.

Short communication: Evaluation of an eating time sensor for use in pasture-based dairy systems.

The assessment of grazing behavior is important for research and practice in pasture-grazed dairy farm systems. However, few devices are available that enable assessment of cow grazing behavior at an individual animal level. This study investigated whether commercially available Smarttag "eating time" sensors (Nedap Livestock Management, Groenlo, the Netherlands) were suitable for recording the grazing time of cows. Smarttag sensors were mounted on the neck collars of multiparous Holstein-Friesian cows in a herd in Taranaki, New Zealand. Cows were randomly selected each observation day from the milking herd for 8 separate days across a 1-mo period. Trained observers conducted 90-min observation periods to evaluate the relationship between the sensor eating time measure and grazing time. A set of 5 defined cow behaviors (2 "head up" and 3 "head down" behaviors) were assessed. In total, observations of 37 cows were recorded in 14 sessions over 8 d in the study period, providing 55.5 total hours of observations. Observation data were aligned with sensor data according to the sensor time stamps and grouped into matching 15-min intervals. Interobserver reliability was assessed both before and after the main trial period, and the mean percentage eating time per observer had a coefficient of variation of 0.46% [mean 93.2, standard deviation (SD) 0.425] before and 0.07% (mean 96.3, SD 0.074) after. In the main trial, the relationship between observed (mean 70.8%) and sensor-derived (mean 69.3%) percentage eating time over the observation period gave a Pearson correlation coefficient of 0.971, concordance correlation coefficient 0.968, mean difference 1.50% points, and SD 5.8% points. Therefore, sensor-identified percentage "eating time" and observed percentage active grazing time were shown to be both very well correlated and concordant (in agreement, with high correlation and little bias). Therefore, the relationship between observed and sensor-derived data had a high degree of agreement for identifying cow grazing activity. In conclusion, Smarttag sensors are a valid and useful tool for estimating grazing activity at time periods of 1 h or more.

Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer.

BACKGROUND: Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic. In the primary analysis of this phase II study, combination cediranib/olaparib improved progression-free survival (PFS) compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. This updated analysis was conducted to characterize overall survival (OS) and update PFS outcomes. PATIENTS AND METHODS: Ninety patients were enrolled to this randomized, open-label, phase II study between October 2011 and June 2013 across nine United States-based academic centers. Data cut-off was 21 December 2016, with a median follow-up of 46 months. Participants had relapsed platinum-sensitive ovarian cancer of high-grade serous or endometrioid histology or had a deleterious germline BRCA1/2 mutation (gBRCAm). Participants were randomized to receive olaparib capsules 400 mg twice daily or cediranib 30 mg daily and olaparib capsules 200 mg twice daily until disease progression. RESULTS: In this updated analysis, median PFS remained significantly longer with cediranib/olaparib compared with olaparib alone (16.5 versus 8.2 months, hazard ratio 0.50; P = 0.007). Subset analyses within stratum defined by BRCA status demonstrated statistically significant improvement in PFS (23.7 versus 5.7 months, P = 0.002) and OS (37.8 versus 23.0 months, P = 0.047) in gBRCA wild-type/unknown patients, although OS was not statistically different in the overall study population (44.2 versus 33.3 months, hazard ratio 0.64; P = 0.11). PFS and OS appeared similar between the two arms in gBRCAm patients. The most common CTCAE grade 3/4 adverse events with cediranib/olaparib remained fatigue, diarrhea, and hypertension. CONCLUSIONS: Combination cediranib/olaparib significantly extends PFS compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. Subset analyses suggest this margin of benefit is driven by PFS prolongation in patients without gBRCAm. OS was also significantly increased by the cediranib/olaparib combination in this subset of patients. Additional studies of this combination are ongoing and should incorporate analyses based upon BRCA status. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT0111648.

Clinical relevance of amnestic versus non-amnestic mild cognitive impairment subtyping in Parkinson's disease.

BACKGROUND AND PURPOSE: To clarify whether subtyping of amnestic and non-amnestic mild cognitive impairment (MCI) is clinically relevant in Parkinson's disease (PD) by analyzing patterns of neuroimaging and longitudinal cognitive changes. METHODS: We performed comparative analyses of cortical thickness, hippocampal volume, white matter integrity and resting-state functional connectivity between the patients with de-novo PD with amnestic MCI (PD-aMCI) (n = 50) and non-amnestic MCI (PD-naMCI) (n = 50) subtypes. Additionally, we assessed the longitudinal rate of cognitive decline in each cognitive domain over time and the rate of dementia conversion in patients with de-novo PD-aMCI (n = 125) and PD-naMCI (n = 61). RESULTS: The demographic data showed that scores in memory domains were lower in the PD-aMCI group compared with the PD-naMCI group. There were no significant differences in cortical thickness, hippocampal volume and white matter integrity between the two groups, although the PD-aMCI group exhibited more cortical thinning and hippocampal atrophy relative to the control group. The PD-aMCI group exhibited increased functional connectivity in the left posterior parietal region with the salience network relative to the PD-naMCI group. The longitudinal cognitive assessment demonstrated that patients with PD-aMCI exhibited a more rapid cognitive decline in frontal/executive function than those with PD-naMCI (P = 0.022). In addition, the PD-aMCI group had a higher risk of dementia conversion than the PD-naMCI group. CONCLUSIONS: This study suggests that the designation of PD-MCI subtypes based on memory function would highlight the heterogeneity of functional correlates as well as the longitudinal cognitive prognosis.

Entecavir and tenofovir reduce hepatitis B virus-related hepatocellular carcinoma recurrence more effectively than other antivirals.

Nucleos(t)ide analogues (NAs) have been shown to decrease the risk of hepatocellular carcinoma (HCC) recurrence. This study evaluated whether high-potency NAs (entecavir and tenofovir disoproxil fumarate [TDF]) reduce the risk of tumour recurrence more potently than low-potency NAs after curative treatment of hepatitis B virus (HBV)-related HCC. This study included 607 consecutive HBV-related HCC patients treated with surgical resection or radiofrequency ablation. The patients were categorized into three groups according to antiviral treatment: group A (no antiviral; n = 261), group B (low-potency NA; n = 90) and group C (high-potency NA; n = 256). The primary end-point was recurrence-free survival (RFS). During the duration of follow-up, the median RFS was 29.4, 25.1, and 88.2 months in groups A, B and C, respectively (P < .001, log-rank test). The multivariate Cox analysis indicated that group C had a significantly longer RFS than both group A (adjusted hazard ratio [HR] = 0.39, P < .001) and group B (adjusted HR = 0.47, P < .001). When baseline characteristics were balanced using inverse probability weighting, group C still had a significantly longer RFS than group A (adjusted HR = 0.46, P < .001) and group B (adjusted HR = 0.59, P = .007). Group C had significantly lower risk of viral breakthrough than group B (HR = 0.19, P < .001). Viral breakthrough was an independent risk factor for shorter RFS among groups B and C (adjusted HR = 2.03, P = .007, time-dependent Cox analysis). Antiviral agents with high genetic barrier to resistance (entecavir and TDF) reduced the risk of HCC recurrence compared with other antivirals and no antiviral treatment, especially in patients with high baseline viral load.

Comparison of overall survival between antiviral-induced viral suppression and inactive phase chronic hepatitis B patients.

Nucleot(s)ide analogues (NAs) reduce the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. However, the risk of HCC is reportedly higher for NA-treated patients than for patients in the inactive CHB phase. This study aimed to compare the long-term outcomes of CHB patients with NA-induced viral suppression and those of patients with inactive CHB. This retrospective study involved 1118 consecutive CHB patients whose HBV DNA level was continuously <2000 IU/mL during follow-up with/without antiviral agents. The patients were classified into inactive CHB (n = 373) or NA groups (n = 745). The primary endpoint was overall survival. Secondary endpoints included development of HCC and other liver-related events. The median duration of follow-up was 41.0 (interquartile range = 26.5-55.0) months. The difference in overall survival between the NA group vs. the inactive CHB group was not significant (hazard ratio [HR] = 0.78; 95% confidence interval [CI] = 0.33-1.85; P = .57). The NA group showed a significantly higher risk of HCC (HR = 3.44; 95% CI = 1.82-6.52; P < .01), but comparable risk for non-HCC liver-related events (HR = 1.02; 95% CI = 0.66-1.59; P = .93), compared with the inactive CHB group. Among patients with cirrhosis, the NA group showed a significantly lower risk of death (HR = 0.31; 95% CI = 0.097-0.998; P = .05) and non-HCC liver-related events (HR = 0.51; 95% CI = 0.31-0.83; P < .01), but a slightly higher risk of HCC (HR = 2.39; 95% CI = 0.85-6.75; P = .09), compared to the inactive CHB group. The overall survival of untreated patients with inactive CHB and of CHB patients achieving viral suppression with NA was comparable. However, NA treatment of cirrhotic patients was significantly associated with longer overall survival and lower risk of liver-related events.

Longitudinal cortical thinning and cognitive decline in patients with early- versus late-stage subcortical vascular mild cognitive impairment.

BACKGROUND AND PURPOSE: Biomarker changes in cognitively impaired patients with small vessel disease are largely unknown. The rate of amyloid/lacune progression, cortical thinning and cognitive decline were evaluated in subcortical vascular mild cognitive impairment (svMCI) patients. METHODS: Seventy-two svMCI patients were divided into early stage (ES-svMCI, n = 39) and late stage (LS-svMCI, n = 33) according to their Clinical Dementia Rating Sum of Boxes score. Patients were annually followed up with neuropsychological tests and brain magnetic resonance imaging for 3 years, and underwent a second [11 C] Pittsburgh compound B (PiB) positron emission tomography scan within a mean interval of 32.4 months. RESULTS: There was no difference in the rate of increase in PiB uptake or lacune number between the ES-svMCI and LS-svMCI. However, LS-svMCI showed more rapid cortical thinning and cognitive decline than did the ES-svMCI. CONCLUSIONS: We suggest that, whilst the rate of change in pathological burden did not differ between ES-svMCI and LS-svMCI, cortical thinning and cognitive decline progressed more rapidly in the LS-svMCI.

Electroencephalographic markers of brain development during sevoflurane anaesthesia in children up to 3 years old.

BACKGROUND: General anaesthetics generate spatially defined brain oscillations in the EEG that relate fundamentally to neural-circuit architecture. Few studies detailing the neural-circuit activity of general anaesthesia in children have been described. The study aim was to identify age-related changes in EEG characteristics that mirror different stages of early human brain development during sevoflurane anaesthesia. METHODS: Multichannel EEG recordings were performed in 91 children aged 0-3 yr undergoing elective surgery. We mapped spatial power and coherence over the frontal, parietal, temporal, and occipital cortices during maintenance anaesthesia. RESULTS: During sevoflurane exposure: (i) slow-delta (0.1-4 Hz) oscillations were present in all ages, (ii) theta (4-8 Hz) and alpha (8-12 Hz) oscillations emerge by ∼4 months, (iii) alpha oscillations increased in power from 4 to 10 months, (iv) frontal alpha-oscillation predominance emerged at ∼6 months, (v) frontal slow oscillations were coherent from birth until 6 months, and (vi) frontal alpha oscillations became coherent ∼10 months and persisted in older ages. CONCLUSIONS: Key developmental milestones in the maturation of the thalamo-cortical circuitry likely generate changes in EEG patterns in infants undergoing sevoflurane general anaesthesia. Characterisation of anaesthesia-induced EEG oscillations in children demonstrates the importance of developing age-dependent strategies to monitor properly the brain states of children receiving general anaesthesia. These data have the potential to guide future studies investigating neurodevelopmental pathologies involving altered excitatory-inhibitory balance, such as epilepsy or Rett syndrome.

A simulation impact evaluation of a cigarette excise tax increase on licit and illicit cigarette consumption and tax revenue in 36 European countries.

OBJECTIVES: To assess the impact of a simulated 10% tax-induced cigarette price increase on licit and illicit consumption and tax revenues in 36 European countries. METHODS: Employing panel data for licit and illicit cigarette consumption, fixed effects regression models were applied for different income clusters. RESULTS: Total cigarette consumption dropped by about 3.1% as a result of the simulated tax-induced price increase. Annual illicit cigarette consumption increased by 1.52%, (95% confidence interval: 0.21, 2.83), while annual licit cigarette consumption decreased by 4.61% (95% confidence interval: -6.51, -2.72) in the observed 36 European countries. With total consumption decreasing by about 8%, the Czech Republic, Latvia, Lithuania, Poland and Slovakia were affected the most by the price hike. More specifically, licit consumption in these countries decreased by 18.43% (95% confidence interval: -19.91, -16.95) while illicit use increased by 10.99% (95% confidence interval: 6.01, 15.96). Moreover, the overall annual tobacco tax revenue increased by US$14.69 billion in the simulation. CONCLUSION: Results of the study suggest that European policy makers continue to implement tobacco taxation policies to control smoking prevalence and national health care expenditures. At the same time, efforts to kerb contraband activities along EU Eastern borders should be intensified.

Adenovirus-mediated Foxp3 expression in lung epithelial cells ameliorates acute radiation-induced pneumonitis in mice.

Forkhead transcription factor 3 (Foxp3) has a critical role in regulatory T cells (Treg). There are an increasing number of researches concerning the functions of Foxp3 in other cells, including lung epithelial cells besides Treg. However, the roles of Foxp3 in lung epithelial cells remain poorly understood. To examine the potential therapeutic benefits of Foxp3 for lung inflammation, this study investigates the effect of adenovirus-mediated Foxp3 overexpression in a radiation-induced lung damage model. Foxp3-EGFP expressing adenovirus was administered by intratracheal injection three times over 14 days after focal X-ray irradiation. To evaluate effects of Foxp3 overexpression in radiation-induced lung inflammation, immune cell profiles of bronchoalveolar lavage (BAL) fluid were analyzed. Foxp3 gene-delivered mice showed significant inhibition of immune cell infiltration, such as eosinophils, lymphocytes, macrophages and neutrophils in BAL fluid. Histopathological analysis also showed that Foxp3 overexpression inhibits inflammatory cell recruitment and collagen deposition in lung tissues. In addition, expression of inflammatory and fibrosis-related genes was decreased in the Foxp3 expression adenovirus-infected group. These results suggest that Foxp3 expression in lungs holds considerable therapeutic potential for attenuating inflammation and fibrosis in radiation-induced lung injury.

Diffusion tensor imaging of normal-appearing white matter in patients with neuromyelitis optica spectrum disorder and multiple sclerosis.

BACKGROUND AND PURPOSE: The occult changes in normal-appearing white matter (NAWM) were investigated and compared amongst patients with neuromyelitis optica spectrum disorder (NMOSD), patients with multiple sclerosis (MS) and healthy controls (HCs) by applying tract-based spatial statistics to diffusion tensor imaging (DTI) data. METHODS: Diffusion tensor imaging was performed with a 3-T scanner in 93 patients with NMOSD, 53 patients with MS and 43 HCs. Voxel-wise statistical analyses of the DTI data were performed using tract-based spatial statistics. RESULTS: Compared to HCs, patients with NMOSD had significantly lower mean global fractional anisotropy, higher mean diffusivity and radial diffusivity, and no significant differences in axial diffusivity in their NAWM. Patients with MS demonstrated significantly lower mean global fractional anisotropy and higher mean diffusivity, axial diffusivity and radial diffusivity in the NAWM than did patients with NMOSD and HCs. Compared to patients with NMOSD, patients with MS had NAWM damage that was more extensive, particularly in the inferior cerebellar peduncle, external capsule, cingulum, superior fronto-occipital fasciculus and uncinate fasciculus. CONCLUSIONS: Using DTI, widespread occult damage was demonstrated in the NAWM of patients with NMOSD. However, the NAWM was less affected in patients with NMOSD than it was in patients with MS; specifically, the axonal injuries and diffusion abnormalities in the association fibers were more severe in patients with MS than they were in patients with NMOSD.

Volumetric analysis of the cerebellum in patients with progressive supranuclear palsy.

BACKGROUND AND PURPOSE: Although early cerebellar symptoms are one of the exclusive criteria in the diagnosis of progressive supranuclear palsy (PSP), cerebellar involvement in PSP is evident both clinically and pathologically. However, structural analysis focusing on the cerebellum has not been previously studied in patients with PSP. We aimed to evaluate cerebellar involvement in PSP using a magnetic resonance imaging-based segmental volumetric analysis. METHODS: We retrospectively enrolled 48 patients with PSP composed of 25 patients with PSP-Richardson's syndrome (RS) and 23 patients with pure akinesia with gait freezing, 39 patients with Parkinson's disease (PD) and 34 healthy controls. Data on both the whole and segmented cerebellar volumes were analyzed using a fully automated procedure. RESULTS: A general linear model showed that whole cerebellar volume in patients with PSP was significantly smaller compared with that of patients with PD or controls after controlling for age, sex and intracranial volume (P = 0.34). In addition, patients with PSP exhibited decreased regional volume in the crus I, lobule VIIIa and lobule VIIIb, which play roles as secondary representations of motor tasks, compared with patients with PD or controls. In subgroup analysis of PSP, volume loss in the whole and segmental cerebellum was more pronounced in patients with PSP-RS than in those with pure akinesia with gait freezing, PD or control subjects. CONCLUSION: These data demonstrate that cerebellar atrophy is evident in patients with PSP and is especially prominent in the PSP-RS group. These findings increase understanding of the clinicopathological basis of cerebellar involvement in PSP.

Deep gray matter atrophy in neuromyelitis optica spectrum disorder and multiple sclerosis.

BACKGROUND AND PURPOSE: We investigated changes in deep gray matter (DGM) volume and its relationship to cognition and clinical factors in a large cohort of patients with neuromyelitis optica spectrum disorder (NMOSD) and compared them with results from multiple sclerosis (MS). METHODS: Brain magnetic resonance imaging (3 Tesla) and clinical data from 91 patients with NMOSD, 52 patients with MS and 44 healthy controls (HCs) were prospectively evaluated. Differences in DGM volumes were compared among groups. The relationships between DGM atrophy and clinical variables were also analysed. RESULTS: Patients with NMOSD exhibited significantly reduced thalamic volumes compared with HCs (P = 0.029), although this atrophy was less severe than that seen in patients with MS (P < 0.001). DGM atrophy was restricted to the thalamus in NMOSD, but it was broadly distributed in MS. Patients with NMOSD with cognitive impairment (CI) exhibited more severe thalamic atrophy than those with cognitive preservation (P = 0.017) and HCs (P = 0.003), whereas patients with MS with CI revealed DGM atrophy across the entire structure, with the exception of the bilateral pallidum, left hippocampus and amygdala, relative to HCs. The Expanded Disability Status Scale score was correlated with thalamic atrophy in both NMOSD and MS. Patients with NMOSD with brain lesions demonstrated more severe thalamic atrophy than did those without brain lesions and HCs (P < 0.001). CONCLUSIONS: The DGM atrophy was less severe and more selectively distributed in NMOSD than in MS. Thalamic atrophy was associated with clinical disability, including CI, in both NMOSD and MS.

Testosterone effects on pain and brain activation patterns.

BACKGROUND: This study investigated whether pain and pain-related unpleasantness ratings were altered by blood testosterone levels. We also investigated whether activation of brain regions that represent pain intensity [primary somatosensory cortex (S1)] and pain-related unpleasantness [perigenual ACC (pACC) and orbitofrontal cortex (OFC)] were affected by blood testosterone levels. METHODS: Twenty-six healthy men were recruited. Blood testosterone levels were measured before fMRI scanning. The participants were classified into two groups (high vs. low testosterone) according to their blood testosterone level (each group n = 13). The middle finger was immersed in a 50°C water bath (50°C, 30 s, five times) to induce identical noxious stimulation in all participants. RESULTS: The low testosterone group showed statistically significantly higher pain (P = 0.047), unpleasantness (P = 0.047), anxiety (P = 0.015), and fear ratings (P = 0.01) than the high testosterone group. Fear rating increased as pain rating rose and as testosterone level decreased (P < 0.001). When participants received noxious stimulation, the pACC and OFC were more highly activated in the low testosterone group compared to the high testosterone group. Activation of S1, a region related to pain intensity, did not differ between both groups. CONCLUSION: Compared to the high testosterone group, the low testosterone group had significant activation in the pACC and OFC, regions that represent pain-related unpleasantness, but not in S1 that represents pain intensity, leading to higher pain ratings. These findings emphasize the importance of considering the effects of testosterone levels when treating patients.