Novel noninvasive identification of patient-specific epileptic networks in focal epilepsies: Linking single-photon emission computed tomography perfusion during seizures with resting-state magnetoencephalography dynamics.

Single-photon emission computed tomography (SPECT) during seizures and magnetoencephalography (MEG) during the interictal state are noninvasive modalities employed in the localization of the epileptogenic zone in patients with drug-resistant focal epilepsy (DRFE). The present study aims to investigate whether there exists a preferentially high MEG functional connectivity (FC) among those regions of the brain that exhibit hyperperfusion or hypoperfusion during seizures. We studied MEG and SPECT data in 30 consecutive DRFE patients who had resective epilepsy surgery. We parcellated each ictal perfusion map into 200 regions of interest (ROIs) and generated ROI time series using source modeling of MEG data. FC between ROIs was quantified using coherence and phase-locking value. We defined a generalized linear model to relate the connectivity of each ROI, ictal perfusion z score, and distance between ROIs. We compared the coefficients relating perfusion z score to FC of each ROI and estimated the connectivity within and between resected and unresected ROIs. We found that perfusion z scores were strongly correlated with the FC of hyper-, and separately, hypoperfused ROIs across patients. High interictal connectivity was observed between hyperperfused brain regions inside and outside the resected area. High connectivity was also observed between regions of ictal hypoperfusion. Importantly, the ictally hypoperfused regions had a low interictal connectivity to regions that became hyperperfused during seizures. We conclude that brain regions exhibiting hyperperfusion during seizures highlight a preferentially connected interictal network, whereas regions of ictal hypoperfusion highlight a separate, discrete and interconnected, interictal network.

Radiation necrosis or tumor progression? A review of the radiographic modalities used in the diagnosis of cerebral radiation necrosis.

PURPOSE: Cerebral radiation necrosis is a complication of radiation therapy that can be seen months to years following radiation treatment. Differentiating radiation necrosis from tumor progression on standard magnetic resonance imaging (MRI) is often difficult and advanced imaging techniques may be needed to make an accurate diagnosis. The purpose of this article is to review the imaging modalities used in differentiating radiation necrosis from tumor progression following radiation therapy for brain metastases. METHODS: We performed a review of the literature addressing the radiographic modalities used in the diagnosis of radiation necrosis. RESULTS: Differentiating radiation necrosis from tumor progression remains a diagnostic challenge and advanced imaging modalities are often required to make a definitive diagnosis. If diagnostic uncertainty remains following conventional imaging, a multi-modality diagnostic approach with perfusion MRI, magnetic resonance spectroscopy (MRS), positron emission tomography (PET), single photon emission spectroscopy (SPECT), and radiomics may be used to improve diagnosis. CONCLUSION: Several imaging modalities exist to aid in the diagnosis of radiation necrosis. Future studies developing advanced imaging techniques are needed.

18F-fluciclovine PET/CT to distinguish radiation necrosis from tumor progression for brain metastases treated with radiosurgery: results of a prospective pilot study.

PURPOSE: Distinguishing radiation necrosis from tumor progression among patients with brain metastases previously treated with stereotactic radiosurgery represents a common diagnostic challenge. We performed a prospective pilot study to determine whether PET/CT with 18F-fluciclovine, a widely available amino acid PET radiotracer, repurposed intracranially, can accurately diagnose equivocal lesions. METHODS: Adults with brain metastases previously treated with radiosurgery presenting with a follow-up tumor-protocol MRI brain equivocal for radiation necrosis versus tumor progression underwent an 18F-fluciclovine PET/CT of the brain within 30 days. The reference standard for final diagnosis consisted of clinical follow-up until multidisciplinary consensus or tissue confirmation. RESULTS: Of 16 patients imaged from 7/2019 to 11/2020, 15 subjects were evaluable with 20 lesions (radiation necrosis, n = 16; tumor progression, n = 4). Higher SUVmax statistically significantly predicted tumor progression (AUC = 0.875; p = 0.011). Lesion SUVmean (AUC = 0.875; p = 0.018), SUVpeak (AUC = 0.813; p = 0.007), and SUVpeak-to-normal-brain (AUC = 0.859; p = 0.002) also predicted tumor progression, whereas SUVmax-to-normal-brain (p = 0.1) and SUVmean-to-normal-brain (p = 0.5) did not. Qualitative visual scores were significant predictors for readers 1 (AUC = 0.750; p < 0.001) and 3 (AUC = 0.781; p = 0.045), but not for reader 2 (p = 0.3). Visual interpretations were significant predictors for reader 1 (AUC = 0.898; p = 0.012) but not for reader 2 (p = 0.3) or 3 (p = 0.2). CONCLUSIONS: In this prospective pilot study of patients with brain metastases previously treated with radiosurgery presenting with a contemporary MRI brain with a lesion equivocal for radiation necrosis versus tumor progression, 18F-fluciclovine PET/CT repurposed intracranially demonstrated encouraging diagnostic accuracy, supporting the pursuit of larger clinical trials which will be necessary to establish diagnostic criteria and performance.

Neurovascular networks in epilepsy: Correlating ictal blood perfusion with intracranial electrophysiology.

Perfusion patterns observed in Subtraction Ictal SPECT Co-registered to MRI (SISCOM) assist in focus localization and surgical planning for patients with medically intractable focal epilepsy. While the localizing value of SISCOM has been widely investigated, its relationship to the underlying electrophysiology has not been extensively studied and is therefore not well understood. In the present study, we set to investigate this relationship in a cohort of 70 consecutive patients who underwent ictal and interictal SPECT studies and subsequent stereo-electroencephalography (SEEG) monitoring for localization of the epileptogenic focus and surgical intervention. Seizures recorded during SEEG evaluation (SEEG seizures) were matched to semiologically-similar seizures during the preoperative ictal SPECT evaluation (SPECT seizures) by comparing the semiological changes in the course of each seizure. The spectral changes of the ictal SEEG with respect to interictal ones over 7 traditional frequency bands (0.1 to 150Hz) were analyzed at each SEEG site. Neurovascular (SEEG/SPECT) relations were assessed by comparing the estimated spectral power density changes of the SEEG at each site with the perfusion changes (SISCOM z-scores) estimated from the acquired SISCOM map at that site. Across patients, a significant correlation (p<0.05) was observed between spectral changes during the SEEG seizure and SISCOM perfusion z-scores. Brain sites with high perfusion z-score exhibited higher increased SEEG power in theta to ripple frequency bands with concurrent suppression in delta and theta frequency bands compared to regions with lower perfusion z-score. The dynamics of the correlation of SISCOM perfusion and SEEG spectral power from ictal onset to seizure end and immediate postictal period were also derived. Forty-six (46) of the 70 patients underwent resective epilepsy surgery. SISCOM z-score and power increase in beta to ripple frequency bands were significantly higher in resected than non-resected sites in the patients who were seizure-free following surgery. This study provides for the first time concrete evidence that both hyper-perfusion and hypo-perfusion patterns observed in SISCOM maps have strong electrophysiological underpinnings, and that integration of the information from SISCOM and SEEG can shed light on the location and dynamics of the underlying epileptic brain networks, and thus advance our anatomo-electro-clinical understanding and approaches to targeted diagnostic and therapeutic interventions.

LncRNA DANCR upregulation induced by TUFT1 promotes malignant progression in triple negative breast cancer via miR-874-3p-SOX2 axis.

Triple negative breast cancer (TNBC) is a subtype of breast cancer with poorest survival outcome and is prone to metastasis. TUFT1 and the long non-coding RNA (lncRNA), DANCR, play vital roles in metastasis and progression of various cancers. However, the correlation between TUFT1 and DANCR in TNBC and their downstream molecular mechanisms are still undetermined. We demonstrated that upregulation of TUFT1 in TNBC was related to a worse survival in TNBC patients. The TNBC cells invasiveness was augmented by TUFT1 in a dose-dependent manner, while inhibiting TUFT1 repressed the invasiveness. Particularly, the expression of TUFT1 was positively correlated with the expression of DANCR in TNBC tissues. In addition, TUFT1 increased DANCR expression, while silencing DANCR ameliorated the invasiveness of TNBC cells induced by TUFT1. As demonstrated, TUFT1 interacted with miR-874-3p. Subsequently, qRT-PCR together with luciferase reporter further demonstrated that DANCR acted as competing endogenous (ceRNA) for miR-874-3p, thereby regulating the de-repression of SOX2 and advancing epithelial-mesenchymal transition (EMT) in TNBC. The present research shows that TUFT1 promotes the malignant development in TNBC via enhancing the expression of DANCR. The upregulation of DANCR may contribute to the progression and tumor invasiveness of TNBC, considering that DANCR functions as a miR-874-3p sponge, thus modulating SOX2 positively. Collectively, the present study explored the molecular mechanism underlying TUFT1 in TNBC, raising a TUFT1-mediated therapy for the treatment of patients with TNBC.

The First Racemic Total Syntheses of the Antiplasmodials Watsonianones A and B and Corymbone B.

The first biomimetic total syntheses of three biologically meaningful acylphloroglucinols, watsonianones A and B and corymbone B, with potent antiplasmodial activity, were performed. Their total syntheses were carried out through a diversity-oriented synthetic strategy from congener 2,2,4,4-tetramethyl-6-(3-methylbutylidene)cyclohexane-1,3,5-trione with high step efficiency. The spontaneous enolization/air oxidation of the precursor 2,2,4,4-tetramethyl-6-(3-methylbutylidene)cyclohexane-1,3,5-trione through a singlet O2-induced Diels-Alder reaction pathway to assemble the key biosynthetic peroxide intermediate is also discussed.

Quantitative positron emission tomography-guided magnetic resonance imaging postprocessing in magnetic resonance imaging-negative epilepsies.

OBJECTIVE: Detection of focal cortical dysplasia (FCD) is of paramount importance in epilepsy presurgical evaluation. Our study aims at utilizing quantitative positron emission tomography (QPET) analysis to complement magnetic resonance imaging (MRI) postprocessing by a morphometric analysis program (MAP) to facilitate automated identification of subtle FCD. METHODS: We retrospectively included a consecutive cohort of surgical patients who had a negative preoperative MRI by radiology report. MAP was performed on T1-weighted volumetric sequence and QPET was performed on PET/computed tomographic data, both with comparison to scanner-specific normal databases. Concordance between MAP and QPET was assessed at a lobar level, and the significance of concordant QPET-MAP+ abnormalities was confirmed by postresective seizure outcome and histopathology. QPET thresholds of standard deviations (SDs) of -1, -2, -3, and -4 were evaluated to identify the optimal threshold for QPET-MAP analysis. RESULTS: A total of 104 patients were included. When QPET thresholds of SD = -1, -2, and -3 were used, complete resection of the QPET-MAP+ region was significantly associated with seizure-free outcome when compared with the partial resection group (P = 0.023, P < 0.001, P = 0.006) or the no resection group (P = 0.002, P < 0.001, P = 0.001). The SD threshold of -2 showed the best combination of positive rate (55%), sensitivity (0.68), specificity (0.88), positive predictive value (0.88), and negative predictive value (0.69). Surgical pathology of the resected QPET-MAP+ areas revealed mainly FCD type I. Multiple QPET-MAP+ regions were present in 12% of the patients at SD = -2. SIGNIFICANCE: Our study demonstrates a practical and effective approach to combine quantitative analyses of functional (QPET) and structural (MAP) imaging data to improve identification of subtle epileptic abnormalities. This approach can be readily adopted by epilepsy centers to improve postresective seizure outcomes for patients without apparent lesions on MRI.

Connectivity in ictal single photon emission computed tomography perfusion: a cortico-cortical evoked potential study.

Subtraction ictal and interictal single photon emission computed tomography can demonstrate complex ictal perfusion patterns. Regions with ictal hyperperfusion are suggested to reflect seizure onset and propagation pathways. The significance of ictal hypoperfusion is not well understood. The aim of this study was to verify whether ictal perfusion changes, both hyper- and hypoperfusion, correspond to electrically connected brain networks. A total of 36 subtraction ictal and interictal perfusion studies were analysed in 31 consecutive medically refractory focal epilepsy patients, evaluated by stereo-electroencephalography that demonstrated a single focal onset. Cortico-cortical evoked potential studies were performed after repetitive electrical stimulation of the ictal onset zone. Evoked responses at electrode contacts outside the stimulation site were used as a measure of connectivity. The evoked responses at these electrodes were compared to ictal perfusion values noted at these locations. In 67% of studies, evoked responses were significantly larger in hyperperfused compared to baseline-perfused areas. The majority of hyperperfused contacts also had significantly increased evoked responses relative to pre-stimulus electroencephalogram. In contrast, baseline-perfused and hypoperfused contacts mainly demonstrated non-significant evoked responses. Finally, positive significant correlations (P < 0.05) were found between perfusion scores and evoked responses in 61% of studies. When the stimulated ictal onset area was hyperperfused, 82% of studies demonstrated positive significant correlations. Following stimulation of hyperperfused areas outside seizure onset, positive significant correlations between perfusion changes and evoked responses could be seen, suggesting bidirectional connectivity. We conclude that strong connectivity was demonstrated between the ictal onset zone and hyperperfused regions, while connectivity was weaker in the direction of baseline-perfused or hypoperfused areas. In trying to understand a patient's epilepsy, one should consider the contribution of all hyperperfused regions, as these are likely not random, but represent an electrically connected epileptic network.

Whole-brain 320-detector row dynamic volume CT perfusion detected crossed cerebellar diaschisis after spontaneous intracerebral hemorrhage.

INTRODUCTION: The purpose of this study was to evaluate the value of 320-detector row CT used to detect crossed cerebellar diaschisis (CCD) in patients with unilateral supratentorial spontaneous intracerebral hemorrhage (SICH). METHODS: We investigated 62 of 156 patients with unilateral supratentorial SICH using 320-detector row CT scanning. Regional cerebral blood flow (rCBF), cerebral blood volume (rCBV), mean transit time (rMTT), and time to peak (rTTP) levels were measured in different regions of interest (ROIs) that were manually outlined on computed tomography perfusion (CTP) for the cerebrum, including normal-appearing brain tissue that surrounded the perilesional low-density area (NA) and the perihematomal low-density area (PA) in all patients and the cerebellum (ipsilateral and contralateral) in CCD-positive patients. RESULTS: Of 62 cases, a total of 14 met the criteria for CCD due to cerebellar perfusion asymmetry on CTP maps. In the quantitative analysis, significant differences were found in the perfusion parameters between the contralateral and ipsilateral cerebellum in CCD-positive cases. No significant differences were found between the CCD-positive group and the CCD-negative group according to the hematoma volume, NIHSS scores, and cerebral perfusion abnormality (each P > 0.05). The correlation analysis of the degree of NA, PA perfusion abnormality, and the degree of CCD severity showed negative and significant linear correlations (R, -0.66∼-0.56; P < 0.05). CONCLUSION: 320-detector row CT is a robust and practicable method for the comprehensive primary imaging work-up of CCD in unilateral supratentorial SICH patients.

[Trends and forecast of hepatocellular carcinoma in Nantong, China: mortality rates from 1999 to 2011].

OBJECTIVE: To investigate the mortality rates of hepatocellular carcinoma (HCC) in Nantong,China from 1999 to 2011, in order to uncover dynamic trends and provide reasoned advice on intervention strategies to decrease HCC incidence and mortality in Nantong in the future. METHODS: Versions 10 and 9 of the WHO International Classification of Diseases (ICD-10 and ICD-9) were used to determine the number of HCC deaths in Nantong,China for the study's range of years. Thex2 test was applied to compare the HCC mortality rates according to sex and age. The Grey system GM(1,1) model was used to predict the next-5-year HCC mortality for Nantong. RESULTS: Analysis of the standardized mortality in Nantong showed a slight decreasing trend from 1999 to 2011 (x2=57 545.98, P less than 0.001),with males showing a steeper decrease than females. The total mortality of HCC during these years was 53.41 per 100,000 people,with mortality among males being significantly higher than that among females (80.81 per 100,000 people vs. 26.94 per 100,000 people; x2=13 625.42, P less than 0.001). In general, HCC mortality increased with increase in age (general trend:x2=57 545.98, P less than 0.001; male trend: x2=39 878.8, P less than 0.001; female trend: x2=20 105.3, P less than 0.001). However,HCC mortality increased significantly in women after the age of 40 and in men after the age of 35. The GM(1,1) equation was: Yt=-1265.28e(-0.0375t)+1315.5, which predicted that the HCC mortality will decrease to 25.56 per 100,000 people in 2016. CONCLUSION: Although HCC mortality generally decreased from 1999 to 2011, the rate remained high. Public health intervention strategies may be more effective if they focus on males over the age of 35 and females over the age of 40.

Ictal single photon emission computed tomography in epileptic auras.

OBJECTIVES: Little is known about whether ictal single photon emission computed tomography (SPECT) during an isolated aura can localize the epileptogenic zone (EZ). This study seeks to evaluate the yield of ictal SPECT injection in isolated epileptic auras. METHODS: We identified 20 patients with focal epilepsy studied during 26 isolated auras by ictal interictal subtraction SPECT coregistered to magnetic resonance imaging (SISCOM). Studies were rated by two readers who blindly scored the images for presence or absence of an area of dominant hyperperfusion and the lateralization and localization of ictal hyperperfusion; kappa statistics were calculated. Results are correlated with the localization or lateralization of the EZ, time of injection, and electroencephalography (EEG) findings during aura. RESULTS: Fourteen (53%) of 26 injections in 13 patients were rated by both readers as having an area of dominant hyperperfusion with poor interobserver agreement (k = 0.128). Nine of 26 injections in eight patients were correctly lateralized to the side of the EZ (κ = 0.46), but only one of 21 injections in one patient was correctly localized (κ = 0.146). No difference was found when comparing temporal and extratemporal cases. Studies obtained in auras with ictal EEG change were no more likely to be correctly localized than in ones without (p = 0.19). The timing of injection was not a predictor of success. SIGNIFICANCE: Ictal SPECT injection during an isolated aura has a low yield of correct localization of the EZ and cannot be relied on alone during presurgical evaluation. A repeat injection during a seizure with clinical signs and ictal EEG accompaniment is recommended.

Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke.

We describe an autosomal recessive condition characterized with cerebral vasculopathy and early onset of stroke in 14 individuals in Old Order Amish. The phenotype of the condition was highly heterogeneous, ranging from severe developmental disability to normal schooling. Cerebral vasculopathy was a major hallmark of the condition with a common theme of multifocal stenoses and aneurysms in large arteries, accompanied by chronic ischemic changes, moyamoya morphology, and evidence of prior acute infarction and hemorrhage. Early signs of the disease included mild intrauterine growth restriction, infantile hypotonia, and irritability, followed by failure to thrive and short stature. Acrocyanosis, Raynaud's phenomenon, chilblain lesions, low-pitch hoarse voice, glaucoma, migraine headache, and arthritis were frequently observed. The early onset or recurrence of strokes secondary to cerebral vasculopathy seems to always be associated with poor outcomes. The elevated erythrocyte sedimentation rate (ESR), IgG, neopterin, and TNF-α found in these patients suggested an immune disorder. Through genomewide homozygosity mapping, we localized the disease gene to chromosome (Chr) 20q11.22-q12. Candidate gene sequencing identified a homozygous mutation, c.1411-2A > G, in the SAMHD1 gene, being associated with this condition. The mutation appeared at the splice-acceptor site of intron 12, resulted in the skipping of exon 13, and gave rise to an aberrant protein with in-frame deletion of 31 amino acids. Immunoblotting analysis showed lack of mutant SAMHD1 protein expression in affected cell lines. The function of SAMHD1 remains unclear, but the inflammatory vasculopathies of the brain found in the patients with SAMHD1 mutation indicate its important roles in immunoregulation and cerebral vascular hemeostasis.

Atractylenolide II regulates the proliferation, ferroptosis, and immune escape of hepatocellular carcinoma cells by inactivating the TRAF6/NF-κB pathway.

Hepatocellular carcinoma (HCC) is a common and lethal tumor worldwide. Atractylenolide II (AT-II) is a natural sesquiterpenoid monomer, with anti-tumor effect. To address the effect and mechanisms of AT-II on HCC. The role and mechanisms of AT-II were assessed through cell counting kit-8, flow cytometry, enzyme-linked immunosorbent assay, immunofluorescence, and western blot experiments in Hep3B and Huh7 cells. In vivo experiments were conducted in BALB/c nude mice using immunohistochemistry and western blot assays. AT-II decreased the cell viability of Hep3B and Huh7 cells with a IC50 of 96.43 µM and 118.38 µM, respectively. AT-II increased relative Fe2+ level, which was further promoted with the incubation of erastin and declined with the ferrostatin-1 in Hep3B and Huh7 cells. AT-II enhanced the level of ROS and MDA, but reduced the GSH level, and the expression of xCT and GPX4. AT-II elevated the percent of CD8+ T cells and the IFN-γ contents, and declined the IL-10 concentrations and the expression of PD-L1 in Hep3B and Huh7 cells. AT-II downregulated the relative protein level of TRAF6, p-p65/p-65, and p-IkBα/IkBα, which was rescued with overexpression of TRAF6. Upregulation of TRAF6 also reversed the effect of AT-II on proliferation, ferroptosis, and immune escape in Hep3B cells. In vivo, AT-II reduced tumor volume and weight, the level of GPX4, xCT, and PD-L1, and the expression of TRAF6, p-p65/p-65, and p-IkBα/IkBα, with the increased expression of CD8. AT-II modulated the proliferation, ferroptosis, and immune escape of HCC cells by downregulating the TRAF6/NF-κB pathway.

Measurable transitions during seizures in intracranial EEG: A stereoelectroencephalography and SPECT study.

OBJECTIVE: Ictal Single Photon Emission Computed Tomography (SPECT) and stereo-electroencephalography (SEEG) are diagnostic techniques used for the management of patients with drug-resistant focal epilepsies. While hyperperfusion patterns in ictal SPECT studies reveal seizure onset and propagation pathways, the role of ictal hypoperfusion remains poorly understood. The goal of this study was to systematically characterize the spatio-temporal information flow dynamics between differently perfused brain regions using stereo-EEG recordings. METHODS: We identified seizure-free patients after resective epilepsy surgery who had prior ictal SPECT and SEEG investigations. We estimated directional connectivity between the epileptogenic-zone (EZ), non-resected areas of hyperperfusion, hypoperfusion, and baseline perfusion during the interictal, preictal, ictal, and postictal periods. RESULTS: Compared to the background, we noted significant information flow (1) during the preictal period from the EZ to the baseline and hyperperfused regions, (2) during the ictal onset from the EZ to all three regions, and (3) during the period of seizure evolution from the area of hypoperfusion to all three regions. CONCLUSIONS: Hypoperfused brain regions were found to indirectly interact with the EZ during the ictal period. SIGNIFICANCE: Our unique study, combining intracranial electrophysiology and perfusion imaging, presents compelling evidence of dynamic changes in directional connectivity between brain regions during the transition from interictal to ictal states.

Optimizing SPECT SISCOM analysis to localize seizure-onset zone by using varying z scores.

PURPOSE: Subtraction ictal single photon emission computed tomography (SPECT) co-registered to magnetic resonance imaging (MRI) (SISCOM) is a useful modality to identify epileptogenic focus. Using this technique, several studies have generally considered the area of highest ictal hyperperfusion, as outlined by thresholding the difference images with a standard z score of 2, to be highly concordant to the epileptogenic focus. In clinical practice, several factors influence ictal hyperperfusion and using different SISCOM thresholds can be helpful. We aimed to systematically evaluate the localizing value of various z scores (1, 1.5, 2, and 2.5) in a seizure-free cohort following resective epilepsy surgery, and to examine the localizing information of perfusion patterns observed at each z score. METHODS: Twenty-six patients were identified as having ictal-interictal SPECT images, preoperative and postoperative MRI studies, and having remained seizure free for at least 6 months after temporal or extratemporal surgical resection. SISCOM analysis was performed using preoperative MRI studies, and then blindly reviewed for localization of hyperperfused regions. With the added information from postoperative, coregistered MRI, perfusion patterns were determined. KEY FINDINGS: Using pair-wise comparisons, we found that the optimal z score for SPECT-SISCOM localization of the epileptogenic zone was 1.5, not the commonly used z score of 2. The z score of 1.5 was 84.8% sensitive and 93.8% specific. The z score of 1.5 had a moderate interrater agreement (0.70). When an hourglass configuration hyperperfusion pattern was present, a trend toward correctly localizing the seizure onset region was suggested (100% of the 11 observed occurrences). Nonetheless this trend was not statistically significant, possibly reflecting the small number of occurrences in our study. SIGNIFICANCE: SISCOM is a useful modality in evaluating patients for epilepsy surgery. This study shows that the z score of 1.5 represents a highly sensitive and specific SISCOM threshold that should be examined in conjunction with the traditionally used z score of 2 to enhance the chances of correct localization. Further prospective investigations are needed to confirm this finding in large patient series.

IgG4-related Mikulicz's disease is a multiorgan lymphoproliferative disease distinct from Sjögren's syndrome: a Caucasian patient and literature review.

OBJECTIVES: This paper aims to report a case of IgG4-related Mikulicz's disease with a systematic review. METHODS: The relevant English literature was searched using the keywords 'Mikulicz's disease' and 'IgG4'. Original and review articles were reviewed, and the clinical scenarios were exemplified with a case report. RESULTS: A 49-year-old Caucasian man presented with axillary lymphadenopathy and bilateral parotid/submandibular enlargement. A chest computerized tomography showed mediastinal lymphadenopathy, with low metabolic activity on the position emission tomography. A histopathological study showed an IgG4/IgG ratio of 75% in the plasma cells of the submandibular glands, associated with high levels of total serum IgG and IgG4. He had dry mouth, but minor salivary gland biopsy was negative without xerophthalmia. He had nasal obstruction and dyspnea, notably with supine position/cervical rotation, which substantially improved with glucocorticoid treatment. He had newly diagnosed diabetes mellitus with hyperlipasaemia and diffuse pancreatic swelling supportive of autoimmune pancreatitis. CONCLUSIONS: Our case report supports the literature that there are similarities between IgG4-related Mikulicz's disease and Sjögren's syndrome, but the differences are significant. IgG4-related Mikulicz's disease is a multi-organ lymphoproliferative disease distinct from Sjögren's syndrome.

Spatiotemporal biocontrol and rhizosphere microbiome analysis of Fusarium wilt of banana.

The soil-borne fungus Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4) causes Fusarium wilt of banana (FWB), which devastates banana production worldwide. Biocontrol is considered to be the most efficient approach to reducing FWB. Here we introduce an approach that spatiotemporally applies Piriformospore indica and Streptomyces morookaensis strains according to their respective strength to increase biocontrol efficacy of FWB. P. indica successfully colonizes banana roots, promotes lateral root formation, inhibits Foc TR4 growth inside the banana plants and reduces FWB. S. morookaensis strain Sm4-1986 secretes different secondary compounds, of which xerucitrinin A (XcA) and 6-pentyl-α-pyrone (6-PP) show the strongest anti-Foc TR4 activity. XcA chelates iron, an essential nutrient in pathogen-plant interaction that determines the output of FWB. 6-PP, a volatile organic compound, inhibits Foc TR4 germination and promotes banana growth. Biocontrol trials in the field demonstrated that application of S. morookaensis lead to improvement of soil properties and increase of rhizosphere-associated microbes that are beneficial to banana growth, which significantly reduces disease incidence of FWB. Our study suggests that optimal utilization of the two biocontrol strains increases efficacy of biocontrol and that regulating iron accessibility in the rhizosphere is a promising strategy to control FWB.

The Effect of Different Milling Methods on the Physicochemical and In Vitro Digestibility of Rice Flour.

Preparation methods have been found to affect the physical and chemical properties of rice. This study prepared Guichao rice flour with wet, dry, semi-dry, and jet milling techniques. Differences in the particle size distribution of rice flour were investigated in order to assess their impact on pasting, thermal, gel, starch digestibility, and crystalline structure using an X-ray diffractometer (XRD) and a Rapid Visco Analyzer (RVA) across in vitro digestibility experiments. The results showed that semi-dry-milled rice flour (SRF) and wet-milled rice flour (WRF) were similar in damaged starch content, crystalline structure, and gelatinization temperature. However, compared with dry-milled rice flour (DRF) and jet-milled rice flour (JRF), SRF had less damaged starch, a higher absorption enthalpy value, and a higher gelatinization temperature. For starch digestibility, the extended glycemic index (eGI) values of WRF (85.30) and SRF (89.97) were significantly lower than those of DRF (94.47) and JRF (99.27). In general, the physicochemical properties and starch digestibility of WRF and SRF were better than those of DRF and JRF. SRF retained the advantages of WRF while avoiding the high energy consumption, high water consumption, and microbial contamination disadvantages of WRF and was able to produce better rice flour-associated products.

A single dose of ketamine relieves fentanyl-induced-hyperalgesia by reducing inflammation initiated by the TLR4/NF-κB pathway in rat spinal cord neurons.

A large amount of clinical evidence has revealed that ketamine can relieve fentanyl-induced hyperalgesia. However, the underlying mechanism is still unclear. In the current study, a single dose of ketamine (5 mg/kg or 10 mg/kg), TAK-242 (3 mg/kg), or saline was intraperitoneally injected into rats 15 min before four subcutaneous injections of fentanyl. Results revealed that pre-administration of ketamine alleviated fentanyl-induced hyperalgesia according to hind paw-pressure and paw-withdrawal tests. High-dose ketamine can reverse the expression of toll-like receptor-dimer (d-TLR4), phospho- nuclear factor kappa-B (p-NF-κB, p-p65), cyclooxygenase-2 (COX-2), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) 1 d after fentanyl injection in the spinal cord. Moreover, fentany-linduced-hyperalgesia and changes in the expression of the aforementioned proteins can be attenuated by TAK-242, an inhibitor of TLR4, as well as ketamine. Importantly, TLR4, p-p65, COX-2, and IL-1ß were expressed in neurons but not in glial cells in the spinal cord 1 d after fentanyl injection. In conclusion, results suggested that a single dose of ketamine can relieve fentanyl-induced-hyperalgesia via the TLR4/NF-κB pathway in spinal cord neurons.

Intestinal ischemia/reperfusion enhances microglial activation and induces cerebral injury and memory dysfunction in rats.

OBJECTIVE: The mortality of critically ill patients associated with intestinal ischemia/reperfusion remains very high, which results from multiorgan dysfunction or failure due to intestinal injury induced by intestinal ischemia/reperfusion. This study was carried out to investigate whether intestinal ischemia/reperfusion can cause cerebral injury and concomitant memory dysfunction, and explore the potential mechanisms. DESIGN: Prospective, controlled, and randomized animal study. SETTING: University research laboratory. SUBJECTS: Male, adult Sprague-Dawley rats (weighing 250-300 g). INTERVENTIONS: Intestinal ischemia/reperfusion was established by clamping the superior mesenteric artery for 90 mins followed by different reperfusion durations (2, 6, 12, 24, or 48 hrs). The sham surgical preparation including isolation of the superior mesenteric artery without occlusion was performed as control. MEASUREMENTS AND MAIN RESULTS: In comparison with sham control, intestinal ischemia/reperfusion caused severe intestinal injury, accompanied by notable cerebral damage evidenced by increased wet-to-dry brain weight ratio reflecting brain edema and neuronal cell apoptosis manifested by increased apoptotic cell number and cleaved caspase-3 protein expressions. All these changes were concomitant with reduced survival rates as well as impaired memory function determined by Morris water maze test at 24 and 48 hrs after reperfusion. In addition, intestinal ischemia/reperfusion resulted in significant increases in the levels of tumor necrosis factor-α and interleukin-6 both in the serum and in cortices and hippocampal Cornu Ammonis area 1 regions, concomitant with the activation of microglia, a key cellular mediator involved in neuroinflammation and neurodegeneration, which was evidenced by increased protein expressions of ionized calcium binding adaptor molecule 1. Furthermore, the releases of reactive oxygen species evidenced by increased malondialdehyde levels and decreased superoxide dismutase activities in cortices and hippocampal Cornu Ammonis area 1 regions were found after reperfusion. CONCLUSIONS: These findings indicate that intestinal ischemia/reperfusion-induced intestinal injury can lead to cerebral damage and memory dysfunction partly via microglia activation which further facilitates oxidative injury, inflammatory response, and neuronal cell apoptosis.