Stress hyperglycaemia is associated with poor functional outcomes in patients with acute ischaemic stroke after intravenous thrombolysis.

BACKGROUND: Transient hyperglycaemia in the context of illness with or without known diabetes has been termed as 'stress hyperglycaemia'. Stress hyperglycaemia can result in poor functional outcomes in patients with acute ischaemic stroke (AIS) who underwent mechanical thrombectomy. We investigated the association between stress hyperglycaemia and clinical outcomes in AIS patients undergoing intravenous thrombolysis (IVT). METHODS: We examined 666 consecutive patients with AIS who underwent IVT from 2006 to 2018. All patients had a glycated haemoglobin level (HbA1c) and fasting venous blood glucose measured within 24 h of admission. Stress hyperglycaemia ratio (SHR) was defined as the ratio of the fasting glucose to the HbA1c. Univariate and multivariate analyses were employed to identify predictors of poor functional outcomes (modified Rankin Scale 3-6 at 3 months) after IVT. RESULTS: Three-hundred and sixty-one patients (54.2%) had good functional outcomes. These patients tended to be younger (60.7 ± 12.7 vs. 70 ± 14.4 years, P < 0.001), male (70.7% vs. 51.5%, P < 0.001), had lower prevalence of atrial fibrillation (13.0% vs. 20.7%, P = 0.008) and lower SHR (0.88 ± 0.20 vs. 0.99 ± 26, P < 0.001). Patients with high SHR (≥0.97) were slightly older than those with low SHR (<0.97) and were more likely to have diabetes mellitus. On multivariate analysis, higher SHR was independently associated with poor functional outcomes (adjusted odds ratio 3.85, 95% confidence interval 1.59-9.09, P = 0.003). CONCLUSION: SHR appears to be an important predictor of functional outcomes in patients with AIS undergoing IVT. This may have important implications on the role of glycaemic control in the acute management of ischaemic stroke.

Simultaneous cardio-cerebral infarction: a meta-analysis.

BACKGROUND/INTRODUCTION: Cardio-cerebral infarction (CCI), which involves the simultaneous occurrence of acute ischaemic stroke and acute myocardial infarction, has a reported incidence of 0.0009%. Treatment of CCI presents a dilemma to physicians as both conditions are time critical. Despite the need for standardized treatment protocols, published data are sparse. AIM: We aimed to summarize the reported cardio-cerebral infarction cases in the literature. DESIGN: Meta-analysis. METHODS: Four databases, Pubmed, Embase, Scopus and Google Scholar were searched until 25 August 2020. A title and abstract sieve, full-text review and extraction of data were conducted independently by three authors. RESULTS: A total of 44 cases of CCI were identified from 37 case reports and series; 15 patients (34.1%) were treated using percutaneous coronary intervention (PCI) with stent, 8 patients (18.2%) were treated with a PCI without stent, 10 patients (22.7%) were treated via a cerebral vessel thrombectomy and 8 patients (18.2%) were treated via a thrombectomy of a coronary vessel. For medications, 20 patients (45.5%) were treated with thrombolytics, 10 patients (22.7%) were treated with anticoagulants, 8 patients (18.2%) were treated with antiplatelets and 11 patients (25.0%) were treated with anticoagulants and antiplatelets. Of 44 patients, 10 patients died, and 9 of those were due to cardiac causes. Among the 44 patients, days to death was observed to be a median of 2.0 days (interquartile range (IQR): 1.5, 4.0). The modified Rankin Score was measured in nine patients, with a median score of 2.0 (IQR: 1.0, 2.5) being reported. DISCUSSION/CONCLUSION: The condition of CCI has substantial morbidity and mortality, and further studies are needed to examine the optimal diagnostic and treatment strategies of these patients.

Hepatitis B virus infection among children of hepatitis B surface antigen positive mothers in a Malaysian hospital.

INTRODUCTION: There have been no published data on the transmission of hepatitis B virus (HBV) infection among children of hepatitis B surface antigen (HBsAg) positive mothers in Malaysia. METHODS: This is a cross-sectional study of all the children of HBsAg-positive mothers who delivered at the University of Malaya Medical Centre between 1993 and 2000. RESULTS: A total of 60 HBsAg-positive mothers and their 154 children participated in the study. HBsAg was detected in four children (2.6%) while IgG antibody to the hepatitis B core antigen (anti-HBc IgG) was detected in seventeen children (11.0%). The mother's age at childbirth was significantly lower in the children with detectable HBsAg (22.5±6.1 years vs. 29.7±4.5 years, p=0.043) and anti-HBc IgG (26.6±6.1 years vs. 30.0±4.3 years, p=0.004). Children born in the 1980s were significantly more likely to have detectable HBsAg (18.8% vs. 0.7%, p=0.004) and anti-HBc IgG (37.5% vs. 8.0%, p=0.000) compared with those born later. All children with detectable HBsAg were born via spontaneous vaginal delivery, and hepatitis B immunoglobulin was either not given or the administration status was unknown. The majority of mothers with chronic HBV infection (70.4%) were not under any regular follow-up for their chronic HBV infection and the main reason was the lack of awareness of the need to do so (47.4%). CONCLUSION: Transmission of HBV infection among children of HBsAg-positive mothers in Malaysia is low. However, attention needs to be given to the high rate of HBsAgpositive mothers who are not on any regular follow-up.

Disrupted topology of the resting state structural connectome in middle-aged APOE ε4 carriers.

The apolipoprotein E (APOE) ε4 allele is the best characterized genetic risk factor for Alzheimer's disease to date. Older APOE ε4 carriers (aged 60 + years) are known to have disrupted structural and functional connectivity, but less is known about APOE-associated network integrity in middle age. The goal of this study was to characterize APOE-related differences in network topology in middle age, as disentangling the early effects of healthy versus pathological aging may aid early detection of Alzheimer's disease and inform treatments. We performed resting state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) in healthy, cognitively normal, middle-aged adults (age 40-60; N = 76, 38 APOE ε4 carriers). Graph theoretical analysis was used to calculate local and global efficiency of 1) a whole brain rs-fMRI network; 2) a whole brain DTI network; and 3) the resting state structural connectome (rsSC), an integrated functional-structural network derived using functional-by-structural hierarchical (FSH) mapping. Our results indicated no APOE ε4-associated differences in network topology of the rs-fMRI or DTI networks alone. However, ε4 carriers had significantly lower global and local efficiency of the integrated rsSC compared to non-carriers. Furthermore, ε4 carriers were less resilient to targeted node failure of the rsSC, which mimics the neuropathological process of Alzheimer's disease. Collectively, these findings suggest that integrating multiple neuroimaging modalities and employing graph theoretical analysis may reveal network-level vulnerabilities that may serve as biomarkers of age-related cognitive decline in middle age, decades before the onset of overt cognitive impairment.

Brain connectome modularity in weight-restored anorexia nervosa and body dysmorphic disorder.

BACKGROUND: Anorexia nervosa (AN) and body dysmorphic disorder (BDD) frequently co-occur, and have several overlapping phenomenological features. Little is known about their shared neurobiology. The aim of the study was to compare modular organization of brain structural connectivity. METHOD: We acquired diffusion-weighted magnetic resonance imaging data on unmedicated individuals with BDD (n = 29), weight-restored AN (n = 24) and healthy controls (HC) (n = 31). We constructed connectivity matrices using whole-brain white matter tractography, and compared modular structures across groups. RESULTS: AN showed abnormal modularity involving frontal, basal ganglia and posterior cingulate nodes. There was a trend in BDD for similar abnormalities, but no significant differences compared with AN. In AN, poor insight correlated with longer path length in right caudal anterior cingulate and right posterior cingulate. CONCLUSIONS: Abnormal network organization patterns in AN, partially shared with BDD, may have implications for understanding integration between reward and habit/ritual formation, as well as conflict monitoring/error detection.

Time trends in upper gastrointestinal diseases and Helicobacter pylori infection in a multiracial Asian population--a 20-year experience over three time periods.

BACKGROUND: Marked epidemiological changes in upper gastrointestinal diseases and Helicobacter pylori infection have taken place in the Asian Pacific region. In particular, differences with respect to race in the multiracial Asian population in Malaysia have been important and interesting. AIM: A time trend study of upper gastrointestinal disease and H. pylori infection in three time periods: 1989-1990, 1999-2000 and 2009-2010 spanning a period of 20 years was carried out. METHODS: Consecutive first time gastroscopies carried out on patients attending the University of Malaya Medical Center were studied. Diagnoses and H. pylori infection status were carefully recorded. RESULTS: A steady decline in prevalence of duodenal ulcer (DU) and gastric ulcer (GU) from 21.1% to 9.5% to 5.0% and from 11.9% to 9.4% to 9.9% while an increase in erosive oesophagitis (EO) from 2.0% to 8.4% to 9.5% (chi-square for trend; P < 0.001) for the periods 1989-1990, 1999-200 and 2009-2010 were observed. The overall prevalence of H. pylori had also decreased from 51.7% to 30.3% to 11.1% for the same periods of time. The proportion of H. pylori positive ulcers had also decreased: DU (90.1%-69.8%-28.9%) and GU (86.6-56.8%-18.9%) (P < 0.001). This was observed in Malays, Chinese and Indians but the difference over time was most marked in Malays. There was a steady decline in the proportion of patients with gastric and oesophageal cancers. CONCLUSIONS: Peptic ulcers have declined significantly over a 20-year period together with a decline in H. pylori infection. In contrast, a steady increase in erosive oesophagitis was observed. Gastric and oesophageal squamous cell cancers have declined to low levels.

MEASURING INTER-HEMISPHERIC INTEGRATION IN BIPOLAR AFFECTIVE DISORDER USING BRAIN NETWORK ANALYSES AND HARDI.

Bipolar disorder is characterized by extreme mood swings, including both manic and depressive episodes commonly accompanied by psychosis. Many imaging studies have investigated white matter changes in bipolar illness, and the results have suggested abnormal intra- and inter-hemispheric white matter structures, particularly in the fronto-limbic and callosal systems. However, some inconsistency remains in the literature, and no study to-date has utilized brain network analysis using graph theory. Here, we acquired 64-direction diffusion weighted imaging (DWI) on 25 euthymic bipolar I subjects and 25 gender/age matched healthy subjects. White matter integrity measures were computed and compared in 50 white matter ROIs. The results indicated impaired integrity in the corpus callosum. Guided by this, we constructed whole brain structural connectivity networks using graph theory. We devised brain network metrics (inter-hemispheric path length and efficiency) to further probe inter-hemispheric integration, and demonstrated relatively preserved intra-hemispheric but significantly impaired inter-hemispheric integration in our bipolar subjects.

Navigation-guided resection with immediate functional reconstruction for high-grade malignant parotid tumour at skull base.

The authors report a case of navigation-guided tumour ablation of a high-grade epithelial-myoepithelial carcinoma of the right parotid gland extending to the skull base. Immediate functional reconstruction of the mandible with a prosthetic temporomandibular joint and facial nerve was performed. Postoperative follow-up showed no evidence of local tumour recurrence or distant metastasis with satisfactory temporomandibular and facial nerve function.

The tensor distribution function.

Diffusion weighted magnetic resonance imaging is a powerful tool that can be employed to study white matter microstructure by examining the 3D displacement profile of water molecules in brain tissue. By applying diffusion-sensitized gradients along a minimum of six directions, second-order tensors (represented by three-by-three positive definite matrices) can be computed to model dominant diffusion processes. However, conventional DTI is not sufficient to resolve more complicated white matter configurations, e.g., crossing fiber tracts. Recently, a number of high-angular resolution schemes with more than six gradient directions have been employed to address this issue. In this article, we introduce the tensor distribution function (TDF), a probability function defined on the space of symmetric positive definite matrices. Using the calculus of variations, we solve the TDF that optimally describes the observed data. Here, fiber crossing is modeled as an ensemble of Gaussian diffusion processes with weights specified by the TDF. Once this optimal TDF is determined, the orientation distribution function (ODF) can easily be computed by analytic integration of the resulting displacement probability function. Moreover, a tensor orientation distribution function (TOD) may also be derived from the TDF, allowing for the estimation of principal fiber directions and their corresponding eigenvalues.

Fluid registration of diffusion tensor images using information theory.

We apply an information-theoretic cost metric, the symmetrized Kullback-Leibler (sKL) divergence, or J-divergence, to fluid registration of diffusion tensor images. The difference between diffusion tensors is quantified based on the sKL-divergence of their associated probability density functions (PDFs). Three-dimensional DTI data from 34 subjects were fluidly registered to an optimized target image. To allow large image deformations but preserve image topology, we regularized the flow with a large-deformation diffeomorphic mapping based on the kinematics of a Navier-Stokes fluid. A driving force was developed to minimize the J-divergence between the deforming source and target diffusion functions, while reorienting the flowing tensors to preserve fiber topography. In initial experiments, we showed that the sKL-divergence based on full diffusion PDFs is adaptable to higher-order diffusion models, such as high angular resolution diffusion imaging (HARDI). The sKL-divergence was sensitive to subtle differences between two diffusivity profiles, showing promise for nonlinear registration applications and multisubject statistical analysis of HARDI data.

Reconstructive treatment following resection of high-grade soft-tissue sarcomas of the lower limb.

PURPOSE: To review the role of free tissue transfer in reconstructive surgery following resection of high-grade soft-tissue sarcomas of the lower limb. METHODS: Medical records of all consecutive patients with high-grade soft-tissue sarcomas of the lower limbs between August 1997 and September 2003 were reviewed. RESULTS: Of 8 patients (6 women and 2 men) aged between 19 and 65 years, 4 had malignant fibrous histiocytoma, one had malignant peripheral nerve sheath tumour, one had synovial sarcoma, one had recurrent liposarcoma, and one had epitheloid sarcoma. The tumour sizes ranged from 132 cm(2) to 483 cm(2). The soft-tissue defects following tumour extirpation ranged from 153 cm(2) to 896 cm(2). The flaps used were 3 free latissimus dorsi flaps, 2 free osteoseptocutaneous fibula flaps (one vascularised fibula flap and one 'double barrel' fibula flap), one free rectus abdominis flap, 2 free mini-transverse rectus abdominis flaps, and one pedicled rectus abdominis flap. Five patients did not have local recurrence and systemic metastases. CONCLUSION: Tissue transfer allows early adjuvant therapy facilitating the multimodal approach for the high-grade soft-tissue sarcomas of the lower extremity.

Brain structural mapping using a novel hybrid implicit/explicit framework based on the level-set method.

This paper presents a novel approach to feature-based brain image warping, by using a hybrid implicit/explicit framework, which unifies many prior approaches in a common framework. In the first step, we develop links between image warping and the level-set method, and we formulate the fundamental mathematics required for this hybrid implicit/explicit approach. In the second step, we incorporate the large-deformation models into these formulations, leading to a complete and elegant treatment of anatomical structure matching. In this latest approach, exact matching of anatomy is achieved by comparing the target to the warped source structure under the forward mapping and the source to the warped target structure under the backward mapping. Because anatomy is represented nonparametrically, a path is constructed linking the source to the target structure without prior knowledge of their point correspondence. The final point correspondence is constructed based on the linking path with the minimal energy. Intensity-similarity measures can be naturally incorporated in the same framework as landmark constraints by combining them in the gradient descent body forces. We illustrate the approach with two applications: (1) tensor-based morphometry of the corpus callosum in autistic children; and (2) matching cortical surfaces to measure the profile of cortical anatomic variation. In summary, the new mathematical techniques introduced here contribute fundamentally to the mapping of brain structure and its variation and provide a framework that unites feature and intensity-based image registration techniques.

Displacement of linker for activation of T cells from the plasma membrane due to redox balance alterations results in hyporesponsiveness of synovial fluid T lymphocytes in rheumatoid arthritis.

The T lymphocytes that reside in the synovium of the inflamed joints in patients with rheumatoid arthritis display severe hyporesponsiveness upon antigenic stimulation, which is probably due to their constant subjection to high levels of oxidative stress. Here we report that the synovial fluid T lymphocytes exert severely impaired phosphorylation of the adaptor protein linker for activation of T cells (LAT), a crucial component of the TCR-mediated signaling pathways. In healthy T lymphocytes, LAT is a membrane-bound protein and becomes phosphorylated by zeta-associated protein of 70 kDa (ZAP-70) upon TCR engagement. The molecular basis underlying the deficient phosphorylation of LAT and consequently the hyporesponsiveness of the synovial fluid T lymphocytes lies in the membrane displacement of LAT. We demonstrate that the subcellular localization of LAT is sensitive to changes in the intracellular levels of the antioxidant glutathione. The membrane anchorage of LAT, and consequently the phosphorylation of LAT and the cellular activation of the synovial fluid T lymphocytes upon TCR engagement, is restored in synovial fluid T lymphocytes after supplementation of the intracellular glutathione levels with N-acetyl-l -cysteine. These data suggest a role for the membrane displacement of LAT in the hyporesponsiveness of the synovial fluid T lymphocytes as a consequence of oxidative stress.

Expression of the thioredoxin-thioredoxin reductase system in the inflamed joints of patients with rheumatoid arthritis.

OBJECTIVE: To examine the expression of the thioredoxin (TRX)-thioredoxin reductase (TR) system in patients with rheumatoid arthritis (RA) and patients with other rheumatic diseases. METHODS: Levels of TRX in plasma and synovial fluid (SF) were measured using enzyme-linked immunosorbent assay. Cellular distribution of TRX was determined by flow cytometry and histochemistry. Cellular expression of TR was studied by in situ messenger RNA (mRNA) hybridization. The effect of oxidative stress and tumor necrosis factor alpha (TNF alpha) on TRX expression by cultured rheumatoid fibroblast-like synoviocytes was studied. RESULTS: Significantly increased TRX levels were found in the SF from 22 patients with RA, when compared with plasma levels in the same patients (P < 0.001) and compared with SF TRX levels in 15 patients with osteoarthritis (P < 0.001), 13 patients with gout (P < 0.05), and 9 patients with reactive arthritis (P < 0.0001). The presence of TRX could be demonstrated within the SF-derived mononuclear cells and synovial tissue (ST) of RA patients. Concordantly, expression of TR mRNA was observed in the ST of these patients. Stimulation of synovial fibroblast-like synoviocytes with either H2O2 or TNF alpha induced an increase in the production of TRX. CONCLUSION: The data demonstrate significantly increased concentrations of TRX in the SF and ST of RA patients when compared with the levels in patients with other joint diseases. Evidence is presented that the local environment in the rheumatic joint contributes to increased TRX production. Based on its growth-promoting and cytokine-like properties, it is proposed that increased expression of TRX contributes to the disease activity in RA.

Treatment with monoclonal anti-tumor necrosis factor alpha antibody results in an accumulation of Th1 CD4+ T cells in the peripheral blood of patients with rheumatoid arthritis.

OBJECTIVE: In rheumatoid arthritis (RA), treatment with tumor necrosis factor alpha (TNFalpha) binding agents has proven to be highly effective. Downregulation of the proinflammatory cytokine cascade and a reduced migration of leukocytes into the joints have been proposed as modes of action of TNFalpha blockade. We investigated whether alterations in the number of circulating pro- and antiinflammatory T cell subsets contribute to the therapeutic effect of monoclonal antibodies (mAb) against TNFalpha in RA patients. METHODS: Phenotypic analysis of peripheral blood T cell subsets was performed on blood from RA patients before and after treatment with an anti-TNFalpha mAb. RESULTS: An accumulation of primed CD45RA- T cells of both the CD4+ and the CD8+ T cell population was seen shortly after treatment. Most notably, within the CD4+,CD45RA- T cell subset, the number of interferon-gamma-producing T cells was significantly increased after anti-TNFalpha mAb treatment, resulting in a significant rise in the Th1:Th2 ratio. In addition, an increase in the number of CD4+ T cells expressing the homing receptor CD49d in high density was observed after treatment, which correlated positively with the increase in the Th1:Th2 ratio. Conclusion. We show that the Th1:Th2 ratio in the peripheral blood is raised by anti-TNFalpha mAb treatment.

CD28 co-stimulation is intact and contributes to prolonged ex vivo survival of hyporesponsive synovial fluid T cells in rheumatoid arthritis.

In rheumatoid arthritis (RA), T cells in the inflamed joint are considered to play a crucial role in the pathogenesis. However, despite the fact that synovial T cells have an activated memory phenotype, they are functionally suppressed upon combined CD3 and CD28 stimulation. Here, we analyzed the contribution of both CD3 and CD28 to the hyporesponsiveness of synovial T cells in RA. In contrast to the low CD3 responsiveness of synovial fluid (SF) T cells compared to peripheral blood (PB) T cells, the CD28 co-stimulatory response was observed to be unaffected. Hyporesponsiveness of SF T cells has previously been associated with decreased levels of intracellular glutathione (GSH), an antioxidant and regulator of the intracellular redox state. Treatment of SF T cells with N-acetylcysteine, an antioxidant and replenisher of GSH, selectively improved CD3-induced responses, while leaving CD28 responsiveness unaffected. These data show that the CD3 pathway is highly sensitive to intracellular GSH alterations, whereas CD28 responsiveness is relatively refractory. Furthermore, in support for a functional role of CD28 co-stimulation, it was demonstrated that CD28 ligation acted in synergy with the IL-2 receptor gamma chain signaling cytokine IL-15 in the enhancement of the ex vivo survival of SF T cells. These data indicate that CD28 co-stimulatory capacity of SF T cells, in contrast to CD3 stimulation, remains intact despite an altered intracellular redox state. Thereby, CD28 stimulation may contribute to the persistence of T cells at the site of inflammation, which might be of relevance in the pathogenesis of RA.

Yersinia enterocolitica: a cause of chronic polyarthritis.

To investigate the role of Yersinia persistence in chronic undifferentiated arthritis, two patients who had chronic undifferentiated polyarthritis and circulating IgA and IgG antibodies to Yersinia outer proteins were studied. Immunofluorescence using antibodies directed against Yersinia adhesin A was performed on colonic and synovial tissue. Synovial tissue T cells were cloned aspecifically and screened for their proliferative responses to Yersinia enterocolitica. Furthermore, a Yersinia-specific polymerase chain reaction (PCR) was performed on synovial tissue. Both patients were found to have Yersinia antigens in colonic and synovial tissue. Y. enterocolitica-positive T-cell clones were grown from the synovial tissue: 4 CD4+ clones of 37 clones from patient 1 and 6 CD4+ clones of 53 clones from patient 2. Yersinia-specific PCR products were not detected in the synovial tissue specimens. The results support the hypothesis that an immune-mediated response to Yersinia antigens may play an important role in the pathogenesis of chronic undifferentiated arthritis.

Joint-derived T cells in rheumatoid arthritis proliferate to antigens present in autologous synovial fluid.

The histopathological features of rheumatoid joint-inflammation suggest that an antigen-driven activation of T cells plays a central role in the onset and/or perpetuation of the inflammatory process. However, the disease-associated antigens responsible for the activation of T cells in the joint are unknown. In this project we study the response of IL-2 expanded T-cell lines from the synovial fluid (SF) of rheumatoid arthritis (RA) patients against autologous SF in a proliferation assay. Sixteen out of 32 RA patients were found to have CD4+ T cells that proliferate in response to autologous SF. The presence of T cells able to respond to SF antigens in inflamed joints suggests that these T cells play an active role in the pathogenesis of RA. T cell clones reactive to autologous SF were isolated from SF-derived T-cell lines of two RA patients. All clones were of the CD4+, CD8-, alpha/beta+ phenotype. SF-reactivity of T-cell clones from the DR4/DR12-positive RA patient was restricted via the Dw4 subtype of DR4. SF reactivity of T cells of the DR12/DR15 patient was DP-restricted. Some of the T-cell clones responded specifically to autologous and not to allogeneic SF, whereas others revealed responsiveness against a limited number of allogeneic SF samples. The (restricted) specificity of T cells towards autologous SF antigens is indicative for heterogeneity of the epitopes recognized and argues against ubiquitous nonpolymorphic joint constituents as the relevant antigens recognized by the SF-autoreactive T cells.