Non‐organ‐specific autoimmunity in adult 47,XXY Klinefelter patients and higher‐grade X‐chromosome aneuploidies

Current literature regarding systemic autoimmune diseases in X‐chromosome aneuploidies is scarce and limited to case reports. Our aim was to evaluate the frequency of anti‐nuclear (ANAs), extractable nuclear (ENA), anti‐double‐stranded DNA (dsDNAs), anti‐smooth muscle (ASMAs) and anti‐mitochondrial (AMAs) antibodies in a large cohort of adults with Klinefelter’s syndrome (KS, 47,XXY) and rare higher‐grade sex chromosome aneuploidies (HGAs) for the first time. Sera from 138 X‐chromosome aneuploid patients [124 adult patients with 47,XXY KS and 14 patients with HGA (six children, eight adults)] and 50 age‐matched 46,XY controls were recruited from the Sapienza University of Rome (2007–17) and tested for ANAs, ENAs, anti‐dsDNAs, ASMAs and AMAs. Non‐organ‐specific immunoreactivity was found to be significantly higher in patients with 47,XXY KS (14%) than in the controls (2%, p = 0.002). Among all the antibodies investigated, only ANAs were observed significantly more frequently in patients with 47,XXY KS (12.1%) than in the controls (2%, p = 0.004). No anti‐dsDNA immunoreactivity was found. Stratifying by testosterone replacement therapy (TRT), non‐organ‐specific autoantibody frequencies were higher in TRT‐naive (p = 0.01) and TRT‐treated groups than in controls. No patients with HGA were found positive for the various autoantibodies. Non‐organ‐specific autoantibodies were significantly present in 47,XXY adult patients. Conversely, HGAs did not appear to be target of non‐organ‐specific immunoreactivity, suggesting that KS and HGAs should be considered as two distinct conditions. The classification and diagnosis of systemic autoimmune diseases is frequently difficult. To support a correct clinical evaluation of KS disease and to prevent eventual secondary irreversible immune‐mediated damages, we highlight the importance of screening for non‐organ‐specific autoimmunity in Klinefelter’s syndrome.     

COVID‐19‐related neuropathology and microglial activation in elderly with and without dementia

The actual role of SARS‐CoV‐2 in brain damage remains controversial due to lack of matched controls. We aim to highlight to what extent is neuropathology determined by SARS‐CoV‐2 or by pre‐existing conditions. Findings of 9 Coronavirus disease 2019 (COVID‐19) cases and 6 matched non‐COVID controls (mean age 79 y/o) were compared. Brains were analyzed through immunohistochemistry to detect SARS‐CoV‐2, lymphocytes, astrocytes, endothelium, and microglia. A semi‐quantitative scoring was applied to grade microglial activation. Thal‐Braak stages and the presence of small vessel disease were determined in all cases. COVID‐19 cases had a relatively short clinical course (0–32 days; mean: 10 days), and did not undergo mechanical ventilation. Five patients with neurocognitive disorder had delirium. All COVID‐19 cases showed non‐SARS‐CoV‐2‐specific changes including hypoxic‐agonal alterations, and a variable degree of neurodegeneration and/or pre‐existent SVD. The neuroinflammatory picture was dominated by ameboid CD68 positive microglia, while only scant lymphocytic presence and very few traces of SARS‐CoV‐2 were detected. Microglial activation in the brainstem was significantly greater in COVID‐19 cases (p = 0.046). Instead, microglial hyperactivation in the frontal cortex and hippocampus was clearly associated to AD pathology (p = 0.001), regardless of the SARS‐CoV‐2 infection. In COVID‐19 cases complicated by delirium (all with neurocognitive disorders), there was a significant enhancement of microglia in the hippocampus (p = 0.048). Although higher in cases with both Alzheimer''s pathology and COVID‐19, cortical neuroinflammation is not related to COVID‐19 per se but mostly to pre‐existing neurodegeneration. COVID‐19 brains seem to manifest a boosting of innate immunity with microglial reinforcement, and adaptive immunity suppression with low number of brain lymphocytes probably related to systemic lymphopenia. Thus, no neuropathological evidence of SARS‐CoV‐2‐specific encephalitis is detectable. The microglial hyperactivation in the brainstem, and in the hippocampus of COVID‐19 patients with delirium, appears as a specific topographical phenomenon, and probably represents the neuropathological basis of the “COVID‐19 encephalopathic syndrome” in the elderly.     

Adaptive immune system in pulmonary sarcoidosis—Comparison of peripheral and alveolar biomarkers

Sarcoidosis is a multi‐systemic granulomatous disease of unknown origin. Recent research has focused upon the role of autoimmunity in its development and progression. This study aimed to determine and define the disturbance and distribution of T and B cell subsets in the alveolar and peripheral compartments. Thirteen patients were selected for the study [median age, interquartile range (IQR) = 57 years (48–59); 23% were male]. Twelve healthy controls [median age, IQR = 53 years (52–65); 16% male] were also enrolled into the study. Cellular and cytokine patterns were measured using the cytofluorimetric approach. Peripheral CD8 percentages were higher in sarcoidosis patients (SP) than healthy controls (HC) (p = 0.0293), while CD4 percentages were lower (p = 0.0305). SP showed low bronchoalveolar lavage (BAL) percentages of CD19 (p = 0.0004) and CD8 (p = 0.0035), while CD19⁺CD5⁺CD27⁻ percentages were higher (p = 0.0213); the same was found for CD4 (p = 0.0396), follicular regulatory T cells (T_reg) (p = 0.0078) and T_reg (p < 0.0001) cells. Low T helper type 17 (Th17) percentages were observed in BAL (p = 0.0063) of SP. Peripheral CD4⁺ C‐X‐C chemokine receptor (CXCR)5⁺CD45RA⁻) percentages and follicular T helper cells (Tfh)‐like Th1 (Tfh1) percentages (p = 0.0493 and p = 0.0305, respectively) were higher in the SP than HC. Tfh1 percentages and Tfh‐like Th2 percentages were lower in BAL than in peripheral blood (p = 0.0370 and p = 0.0078, respectively), while CD4⁺ C‐X‐C motif CXCR5⁺CD45RA⁻ percentages were higher (p = 0.0011). This is the first study, to our knowledge, to demonstrate a link between an imbalance in circulating and alveolar Tfh cells, especially CCR4‐, CXCR3‐ and CXCR5‐expressing Tfh subsets in the development of sarcoidosis. These findings raise questions about the pathogenesis of sarcoidosis and may provide new directions for future clinical studies and treatment strategies.     

Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change and microvascular pathologies in community‐dwelling older persons

Limbic‐predominant age‐related transactive response DNA‐binding protein 43 (TDP‐43) encephalopathy neuropathologic change (LATE‐NC) and microvascular pathologies, including microinfarcts, cerebral amyloid angiopathy (CAA), and arteriolosclerosis are common in old age. A relationship between LATE‐NC and arteriolosclerosis has been reported in some but not all studies. The objectives of this study were to investigate the frequency of co‐occurring LATE‐NC and microvascular pathologies and test the hypothesis that arteriolosclerosis, specifically, is related to LATE‐NC in brains from community‐dwelling older persons. Analyses included 749 deceased participants with completed data on LATE‐NC and microvascular pathology from 3 longitudinal clinical pathologic studies of aging. Given the specific interest in arteriolosclerosis, we expanded the examination of arteriolosclerosis to include not only the basal ganglia but also two additional white matter regions from anterior and posterior watershed territories. Ordinal logistic regression models examined the association of microvascular pathology with LATE‐NC. LATE‐NC was present in 409 (54.6%) decedents, of which 354 (86.5%) had one or multiple microvascular pathologies including 132 (32.3%) with moderate‐severe arteriolosclerosis in basal ganglia, 195 (47.6%) in anterior watershed, and 144 (35.2%) in posterior watershed; 170 (41.5%) with moderate‐severe CAA, and 150 (36.6%) with microinfarcts. In logistic regression models, only posterior watershed arteriolosclerosis, but not other regions of arteriolosclerosis was associated with a higher odds of more advanced LATE‐NC stages (Odds Ratio = 1.12; 95% Confidence Interval = 1.01–1.25) after controlling for demographics, AD, and other age‐related pathologies. Capillary CAA, but not the severity of CAA was associated with an increased odds of LATE‐NC burden (Odds Ratio = 1.71; 95% Confidence Interval = 1.13–2.58). Findings were unchanged in analyses controlling for APOE ε4, vascular risk factors, or vascular diseases. These findings suggest that LATE‐NC with microvascular pathology is a very common mixed pathology and small vessel disease pathology may contribute to LATE‐NC in the aging brain.     

Effectiveness of low‐dose intravenous immunoglobulin therapy in minor primary antibody deficiencies: A 2‐year real‐life experience

Primary antibody deficiencies (PAD) are the most prevalent group of primary immunodeficiencies (PID) in adults and immunoglobulin replacement therapy (IRT) is the mainstay therapy to improve clinical outcomes. IRT is, however, expensive and, in minor PAD, clear recommendations concerning IRT are lacking. We conducted a retrospective real‐life study to assess the effectiveness of low‐dose IRT in minor PAD on 143 patients fulfilling European Society for Immunodeficiencies (ESID) diagnostic criteria for immunoglobulin (Ig)G subclass deficiency (IgGSD) or unclassified antibody deficiency (UAD). All patients were treated with intravenous low‐dose IRT (0.14 ± 0.06 g/kg/month). Immunoglobulin (Ig) classes and IgG subclasses were measured at baseline and after 1 year of IRT. The annual rate of total infections, upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI) and hospitalizations was measured at baseline and after 1 and 2 years of IRT. After 1 year of IRT significant improvement was demonstrated in: (a) serum IgG (787.9 ± 229.3 versus 929.1 ± 206.7 mg/dl; p < 0.0001); (b) serum IgG subclasses (IgG1 = 351.4 ± 109.9 versus 464.3 ± 124.1, p < 0.0001; IgG2 = 259.1 ± 140 versus 330.6 ± 124.9, p < 0.0001; IgG3 = 50.2 ± 26.7 versus 55.6 ± 28.9 mg/dl, p < 0.002); (c) annual rate of total infections (5.75 ± 3.87 versus 2.13 ± 1.74, p < 0.0001), URTI (1.48 ± 3.15 versus 0.69 ± 1.27; p < 0.005), LRTI (3.89 ± 3.52 versus 1.29 ± 1.37; p < 0.0001) and hospitalizations (0.37 ± 0.77 versus 0.15 ± 0.5; p < 0.0002). The improvement persisted after 2 years of IRT. No significant improvement in URTI annual rate was noted in UAD and in patients with bronchiectasis. In conclusion, low‐dose IRT can improve clinical outcomes in UAD and IgGSD patients, providing a potential economical advantage over the standard IRT dose.     

Non‐linear shrinkage of Batson's #17 resin during vascular corrosion casting

Many studies of cardiovascular function require a realistic representation of vascular geometry. Corrosion casting has been used to acquire such geometries for many decades. However, the fidelity with which this method reproduces vascular anatomy has not been completely determined. Here we report on the non‐linear shrinkage characteristics and exothermic properties of Batson''s #17, a widely used casting resin, in model systems and in aortas of rats and rabbits. The setting process was captured using high‐resolution photography. Shrinkage ranged from 3.4 ± 1.5% of the diameter in 1 ml plastic syringes (inner diameter 4.8 mm) to 19.6 ± 5.6% in the aorta of rats (diameter 1.5–2.6 mm). In addition, aortic curvature and branching angles changed during setting. These effects should be determined and corrected in studies of vascular geometry where high accuracy is required.     

Shape modelling of the oropharynx distinguishes associations with body morphology but not whiplash‐associated disorder

Characterization of the oropharynx, a subdivision of the pharynx between the soft palate and the epiglottis, is limited to simple measurements. Structural changes in the oropharynx in whiplash‐associated disorder (WAD) cohorts have been quantified using two‐dimensional (2D) and three‐dimensional (3D) measures but the results are inconsistent. Statistical shape modelling (SSM) may be a more useful tool for systematically comparing morphometric features between cohorts. This technique has been used to quantify the variability in boney and soft tissue structures, but has not been used to examine a hollow cavity such as the oropharynx. The primary aim of this project was to examine the utility of SSM for comparing the oropharynx between WAD cohorts and control; and WAD severity cohorts. The secondary aim was to determine whether shape is associated with sex, height, weight and neck length. Magnetic resonance (MR) T1‐weighted images were obtained from healthy control (n = 20), acute WAD (n = 14) and chronic WAD (n = 14) participants aged 18–39 years. Demographic, WAD severity (neck disability index) and body morphometry data were collected from each participant. Manual segmentation of the oropharynx was undertaken by blinded researchers between the top of the soft palate and tip of the epiglottis. Digital 3D oropharynx models were constructed from the segmented images and principal component (PC) analysis was performed with the PC weights normalized to z‐scores for consistency. Statistical analyses were undertaken using multivariate linear models. In the first statistical model the independent variable was group (acute WAD, chronic WAD, control); and in the second model the independent variable was WAD severity (recovered/mild, moderate/severe). The covariates for both models included height, weight, average neck length and sex. Shape models were constructed to visualize the effect of perturbing these covariates for each relevant mode. The shape model revealed five modes which explained 90% of the variance: mode 1 explained 59% of the variance and primarily described differences in isometric size of the oropharynx, including elongation; mode 2 (13%) primarily described lateral (width) and AP (depth) dimensions; mode 3 (8%) described retroglossal AP dimension; mode 4 (6%) described lateral dimensions at the retropalatal‐retroglossal junction and mode 5 (4%) described the lateral dimension at the inferior retroglossal region. There was no difference in shape (mode 1 p = 0.52; mode 2 p = 0.96; mode 3 p = 0.07; mode 4 p = 0.54; mode 5 p = 0.74) between control, acute WAD and chronic WAD groups. There were no statistical differences for any mode (mode 1 p = 0.12; mode 2 p = 0.29; mode 3 p = 0.56; mode 4 p = 0.99; mode 5 p = 0.96) between recovered/mild and moderate/severe WAD. Sex was not significant in any of the models but for mode 1 there was a significant association with height (p = 0.007), mode 2 neck length (p = 0.044) and in mode 3 weight (p = 0.027). Although SSM did not detect differences between WAD cohorts, it did detect associations with body morphology indicating that it may be a useful tool for examining differences in the oropharynx.     

Anti‐vimentin/cardiolipin IgA in the anti‐phospholipid syndrome: A new tool for ‘seronegative’ diagnosis

Anti‐phospholipid syndrome (APS) is a systemic autoimmune disorder defined by the simultaneous presence of vascular clinical events, pregnancy morbidity and anti‐phospholipid antibodies (aPL). In clinical practice, it is possible to find patients with APS who are persistently negative for the routine aPL tests (seronegative APS; SN‐APS). Recently, the identification of aPL immunoglobulin (Ig)A and/or anti‐β2‐glycoprotein‐I (β2‐GPI) IgA was shown to represent a further test in SN‐APS patients. In this study we analyzed the presence of anti‐vimentin/cardiolipin (aVim/CL) IgA in a large cohort of patients with SN‐APS, evaluating their possible association with clinical manifestations of the syndrome. This study includes 60 consecutive SN‐APS patients, 30 patients with APS and 40 healthy donors. aVim/CL IgA were detected by enzyme‐linked immunosorbent assay (ELISA). Results show that 12 of 30 APS patients (40%) and 16 of 60 SN‐APS patients (26.7%) resulted positive for aVim/CL IgA. Interestingly, SN‐APS patients who tested positive for aVim/CL IgA showed a higher prevalence of arterial thrombosis (p = 0.017, likelihood positive ratio = 5.7). This study demonstrates for the first time, to our knowledge, the presence of aVim/CL IgA in sera of patients with APS. In particular, they revealed a potential usefulness in identification of a significant proportion of SN‐APS patients. Moreover, as patients tested positive for aVim/CL IgA reported a high likelihood ratio to have the clinical features of APS, this test may be considered a suitable approach in the clinical evaluation of SN‐APS.     

The influence of HLA‐DRB1*15 on the relationship between microglia and neurons in multiple sclerosis normal appearing cortical grey matter

Cortical tissue injury is common in multiple sclerosis (MS) and associates with disability progression. We have previously shown that HLA‐DRB1*15 genotype status associates with the extent of cortical inflammatory pathology. In the current study, we sought to examine the influence of HLA‐DRB1*15 on relationships between inflammation and neurodegeneration in MS. Human post‐mortem MS cases (n = 47) and controls (n = 10) were used. Adjacent sections of motor cortex were stained for microglia (Iba1+, CD68+, TMEM119+), lymphocytes (CD3+, CD8+), GFAP+ astrocytes, and neurons (NeuN+). A subset of MS cases (n = 20) and controls (n = 7) were double‐labeled for neurofilament and glutamic acid decarboxylase 65/67 (GAD+) to assess the extent of the inhibitory synaptic loss. In MS cases, microglial protein expression positively correlated with neuron density (Iba1+: r = 0.548, p < 0.001, CD68+: r = 0.498, p = 0.001, TMEM119+ r = 0.437, p = 0.003). This finding was restricted to MS cases not carrying HLA‐DRB1*15. Evidence of a 14% reduction in inhibitory synapses in MS was detected (MS: 0.299 ± 0.006 synapses/μm² neuronal membrane versus control: 0.348 ± 0.009 synapses/μm² neuronal membrane, p = 0.005). Neurons expressing inhibitory synapses were 24% smaller in MS cases compared to the control (MS: 403 ± 15 μm² versus control: 531 ± 29 μm², p = 0.001), a finding driven by HLA‐DRB1*15+ cases (15+: 376 ± 21 μm² vs. 15−: 432 ± 22 μm², p = 0.018). Taken together, our results demonstrate that HLA‐DRB1*15 modulates the relationship between microglial inflammation, inhibitory synapses, and neuronal density in the MS cortex.     

Neuropathological profile of long‐duration amyotrophic lateral sclerosis in military Veterans

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both the upper and lower motor neurons. Although ALS typically leads to death within 3 to 5 years after initial symptom onset, approximately 10% of patients with ALS live more than 10 years after symptom onset. We set out to determine similarities and differences in clinical presentation and neuropathology in persons with ALS with long vs. those with standard duration. Participants were United States military Veterans with a pathologically confirmed diagnosis of ALS (n = 179), dichotomized into standard duration (<10 years) and long‐duration (≥10 years). The ALS Functional Rating Scale‐Revised (ALSFRS‐R) was administered at study entry and semi‐annually thereafter until death. Microglial density was determined in a subset of participants. long‐duration ALS occurred in 76 participants (42%) with a mean disease duration of 16.3 years (min/max = 10.1/42.2). Participants with long‐duration ALS were younger at disease onset (P = 0.002), had a slower initial ALS symptom progression on the ALSFRS‐R (P < 0.001) and took longer to diagnose (P < 0.002) than standard duration ALS. Pathologically, long‐duration ALS was associated with less frequent TDP‐43 pathology (P < 0.001). Upper motor neuron degeneration was similar; however, long‐duration ALS participants had less severe lower motor neuron degeneration at death (P < 0.001). In addition, the density of microglia was decreased in the corticospinal tract (P = 0.017) and spinal cord anterior horn (P = 0.009) in long‐duration ALS. Notably, many neuropathological markers of ALS were similar between the standard and long‐duration groups and there was no difference in the frequency of known ALS genetic mutations. These findings suggest that the lower motor neuron system is relatively spared in long‐duration ALS and that pathological progression is likely slowed by as yet unknown genetic and environmental modifiers.     

Serotonin transporter in the temporal lobe,hippocampus and amygdala in SUDEP

Several lines of evidence link deficient serotonin function and SUDEP. Chronic treatment with serotonin reuptake inhibitors (SRIs) reduces ictal central apnoea, a risk factor for SUDEP. Reduced medullary serotonergic neurones, modulators of respiration in response to hypercapnia, were reported in a SUDEP post‐mortem series. The amygdala and hippocampus have high serotonergic innervation and are functionally implicated in seizure‐related respiratory dysregulation. We explored serotonergic networks in mesial temporal lobe structures in a surgical and post‐mortem epilepsy series in relation to SUDEP risk. We stratified 75 temporal lobe epilepsy patients with hippocampal sclerosis (TLE/HS) into high (N = 16), medium (N = 11) and low risk (N = 48) groups for SUDEP based on generalised seizure frequency. We also included the amygdala in 35 post‐mortem cases, including SUDEP (N = 17), epilepsy controls (N = 10) and non‐epilepsy controls (N = 8). The immunohistochemistry labelling index (LI) and axonal length (AL) of serotonin transporter (SERT)‐positive axons were quantified in 13 regions of interest with image analysis. SERT LI was highest in amygdala and subiculum regions. In the surgical series, higher SERT LI was observed in high risk than low risk cases in the dentate gyrus, CA1 and subiculum (p < 0.05). In the post‐mortem cases higher SERT LI and AL was observed in the basal and accessory basal nuclei of the amygdala and peri‐amygdala cortex in SUDEP compared to epilepsy controls (p < 0.05). Patients on SRI showed higher SERT in the dentate gyrus (p < 0.005) and CA4 (p < 0.05) but there was no difference in patients with or without a psychiatric history. Higher SERT in hippocampal subfields in TLE/HS cases with SUDEP risk factors and higher amygdala SERT in post‐mortem SUDEP cases than epilepsy controls supports a role for altered serotonergic networks involving limbic regions in SUDEP. This may be of functional relevance through reduced 5‐HT availability.     

A novel temporal‐predominant neuro‐astroglial tauopathy associated with TMEM106B gene polymorphism in FTLD/ALS‐TDP

Polymorphisms in TMEM106B, a gene on chromosome 7p21.3 involved in lysosomal trafficking, correlates to worse neuropathological, and clinical outcomes in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) with TDP‐43 inclusions. In a small cohort of C9orf72 expansion carriers, we previously found an atypical, neuroglial tauopathy in cases harboring a TMEM106B rs1990622 A/A genotype. To test whether TMEM106B genotype affects the risk of developing atypical tauopathy under a recessive genotype model (presence versus absence of two major alleles: A/A vs. A/G and G/G). We characterized the atypical tauopathy neuropathologically and determined its frequency by TMEM106B rs1990622 genotypes in 90 postmortem cases with a primary diagnosis of FTLD/ALS‐TDP [mean age at death 65.5 years (±8.1), 40% female]. We investigated the effect of this new atypical tauopathy on demographics and clinical and neuropsychological metrics. We also genotyped TMEM106B in an independent series with phenotypically similar cases. Sixteen cases (16/90, 17.7 %) showed the temporal‐predominant neuro‐astroglial tauopathy, and 93.7% of them carried an A/A genotype (vs. ~35% in a population cohort). The odds ratio of FTLD/ALS‐TDP individuals with the A/A genotype showing neuro‐astroglial tauopathy was 13.9. Individuals with this tauopathy were older at onset (p = 0.01). The validation cohort had a similarly high proportion of rs1990622 A/A genotype. TDP‐43 and tau changes co‐occur in a subset of neurons. Our data add to the growing body of evidence that TMEM106B polymorphisms may modulate neurodegeneration. A distinctive medial temporal predominant, 4‐repeat, neuro‐astroglial tauopathy strongly correlates to TMEM106B A/A genotype in FTLD/ALS‐TDP cases.     

Heterogeneity of cellular inflammatory responses in ageing white matter and relationship to Alzheimer’s and small vessel disease pathologies

White matter lesions (WML) are common in the ageing brain, often arising in a field effect of diffuse white matter abnormality. Although WML are associated with cerebral small vessel disease (SVD) and Alzheimer’s disease (AD), their cause and pathogenesis remain unclear. The current study tested the hypothesis that different patterns of neuroinflammation are associated with SVD compared to AD neuropathology by assessing the immunoreactive profile of the microglial (CD68, IBA1 and MHC‐II) and astrocyte (GFAP) markers in ageing parietal white matter (PARWM) obtained from the Cognitive Function and Ageing Study (CFAS), an ageing population‐representative neuropathology cohort. Glial responses varied extensively across the PARWM with microglial markers significantly higher in the subventricular region compared to either the middle‐zone (CD68 p = 0.028, IBA1 p < 0.001, MHC‐II p < 0.001) or subcortical region (CD68 p = 0.002, IBA1 p < 0.001, MHC‐II p < 0.001). Clasmatodendritic (CD) GFAP⁺ astrocytes significantly increased from the subcortical to the subventricular region (p < 0.001), whilst GFAP⁺ stellate astrocytes significantly decreased (p < 0.001). Cellular reactions could be grouped into two distinct patterns: an immune response associated with MHC‐II/IBA1 expression and CD astrocytes; and a more innate response characterised by CD68 expression associated with WML. White matter neuroinflammation showed weak relationships to the measures of SVD, but not to the measures of AD neuropathology. In conclusion, glial responses vary extensively across the PARWM with diverse patterns of white matter neuroinflammation. Although these findings support a role for vascular factors in the pathogenesis of age‐related white matter neuroinflammation, additional factors other than SVD and AD pathology may drive this. Understanding the heterogeneity in white matter neuroinflammation will be important for the therapeutic targeting of age‐associated white matter damage.     

Mesenteric traction syndrome in pigs: A single‐blinded,randomized controlled trial

BackgroundMesenteric traction syndrome is commonly observed in patients undergoing upper abdominal surgery and is associated with severe postoperative complications. A triad of hypotension, tachycardia, and facial flushing seems provoked by prostacyclin (PGI₂) release from the gut in response to mesenteric traction. The administration of nonsteroidal anti‐inflammatory drugs (NSAID) inhibits PGI₂ release, stabilizing the hemodynamic response. Here, we examined the effect of mesenteric traction on splanchnic blood flow in pigs randomized to NSAID or placebo treatment.Materials and MethodsTwenty pigs were allocated to either ketorolac or placebo treatment. Five minutes of manual mesenteric traction was applied. Plasma 6‐keto‐PGF1_α, a stable metabolite of PGI₂, hemodynamic variables, and regional blood flow (laser speckle contrast imaging) to the liver, stomach, small intestine, upper lip, and snout (laser Doppler flowmetry) were recorded prior to traction and 5 and 30 minutes thereafter.ResultsBoth groups of pigs presented a decrease in systemic vascular resistance (P = .01), mean arterial blood pressure (P = .001), and blood flow in the gastric antrum (P = .002). Plasma 6‐keto‐PGF1_α did not increase in either group (P = .195), and cardiac output, heart rate, central venous pressure, and blood flow to the liver, small intestine, upper lip, and snout remained unchanged.ConclusionMesenteric traction resulted in cardiovascular depression, including reduced blood flow in the gastric antrum. Plasma 6‐keto‐PGF1_α did not increase, and ketorolac administration did not alter the response to mesenteric traction. Furthers studies are needed to identify which substance is responsible for eliciting the cardiovascular response to mesenteric traction in pigs.     

A pilot study on reparixin,a CXCR1/2 antagonist,to assess safety and efficacy in attenuating ischaemia–reperfusion injury and inflammation after on-pump coronary artery bypass graft surgery

Reparixin, a CXCR 1/2 antagonist, has been shown to mitigate ischaemia–reperfusion injury (IRI) in various organ systems in animals, but data in humans are scarce. The aim of this double-blinded, placebo-controlled pilot study was to evaluate the safety and efficacy of reparixin to suppress IRI and inflammation in patients undergoing on-pump coronary artery bypass grafting (CABG). Patients received either reparixin or placebo (n = 16 in each group) after induction of anaesthesia until 8 h after cardiopulmonary bypass (CPB). We compared markers of systemic and pulmonary inflammation, surrogates of myocardial IRI and clinical outcomes using Mann–Whitney U- and Fisher''s exact tests. Thirty- and 90-day mortality was 0% in both groups. No side effects were observed in the treatment group. Surgical revision, pleural and pericardial effusion, infection and atrial fibrillation rates were not different between groups. Reparixin significantly reduced the proportion of neutrophil granulocytes in blood at the beginning [49%, interquartile range (IQR) = 45–57 versus 58%, IQR = 53–66, P = 0·035], end (71%, IQR = 67–76 versus 79%, IQR = 71–83, P = 0·023) and 1 h after CPB (73%, IQR = 71–75 versus 77%, IQR = 72–80, P = 0·035). Reparixin patients required a lesser positive fluid balance during surgery (2575 ml, IQR = 2027–3080 versus 3200 ml, IQR = 2928–3778, P = 0·029) and during ICU stay (2603 ml, IQR = 1023–4288 versus 4200 ml, IQR = 2313–8160, P = 0·021). Numerically, more control patients required noradrenaline ≥ 0·11 μg/kg/min (50 versus 19%, P = 0·063) and dobutamine (50 versus 25%, P = 0·14). Therefore, administration of reparixin in CABG patients appears to be feasible and safe. It concurrently attenuated postoperative granulocytosis in peripheral blood.     

Variable histopathology features of neuronal dyslamination in the cerebral neocortex adjacent to epilepsy‐associated vascular malformations suggest complex pathogenesis of focal cortical dysplasia ILAE type IIIc

Focal cortical dysplasia type IIIc (FCD‐IIIc) is histopathologically defined by the International League Against Epilepsy''s classification scheme as abnormal cortical organization adjacent to epilepsy‐associated vascular malformations (VM). However, the incidence of FCD‐IIIc, its pathogenesis, or association with the epileptogenic condition remains to be clarified. We reviewed a retrospective series of surgical brain specimens from 14 epilepsy patients with leptomeningeal angiomatosis of Sturge‐Weber syndrome (LMA‐SWS; n = 6), cerebral cavernous malformations (CCM; n = 7), and an arteriovenous malformation (AVM; n = 1) to assess the histopathological spectrum of FCD‐IIIc patterns in VM. FCD‐IIIc was observed in all cases of LMA‐SWS and was designated as cortical pseudolaminar sclerosis (CPLS). CPLS showed a common pattern of horizontally organized layer abnormalities, including neuronal cell loss and astrogliosis, either manifesting predominantly in cortical layer (L) 3 extending variably to deeper areas with or without further extension to L2 and/or L4. Another pattern was more localized, targeting mainly L4 with extension to L3 and/or L5. Abnormal cortical layering characterized by a fusion of L2 and L3 or L4–L6 was also noted in two LMA‐SWS cases and the AVM case. No horizontal or vertical lamination abnormalities were observed in the specimens adjacent to the CCM, despite the presence of vascular congestion and dilated parenchymal veins in all VM. These findings suggest that FCD‐IIIc depends on the type of the VM and developmental timing. We further conclude that FCD‐IIIc represents a secondary lesion acquired during pre‐ and/or perinatal development rather than following a pathomechanism independent of LMA‐SWS. Further studies will be necessary to address the selective vulnerability of the developing cerebral neocortex in LMA‐SWS, including genetic, encephaloclastic, hemodynamic, or metabolic events.     

Assessment of bacterial exposure on phagocytic capability and surface marker expression of sputum macrophages and neutrophils in COPD patients

Defective phagocytosis has been shown in chronic obstructive pulmonary disease (COPD) bronchoalveolar lavage and blood monocyte‐derived macrophages. Phagocytic capabilities of sputum macrophages and neutrophils in COPD are unknown. We investigated phagocytosis in these cells from COPD patients and controls. Phagocytosis of Streptococcus pneumoniae or fluorescently labelled non‐typeable Haemophilus influenzae (NTHi) by sputum macrophages and neutrophils was determined by gentamycin protection assay (COPD; n = 5) or flow cytometry in 14 COPD patients, 8 healthy smokers (HS) and 9 healthy never‐smokers (HNS). Sputum macrophages and neutrophils were differentiated by adherence for the gentamycin protection assay or receptor expression (CD206 and CD66b, respectively), by flow cytometry. The effects of NTHi on macrophage expression of CD206 and CD14 and neutrophil expression of CD16 were determined by flow cytometry. There was greater uptake of S. pneumoniae [~10‐fold more colony‐forming units (CFU)/ml] by sputum neutrophils compared to macrophages in COPD patients. Flow cytometry showed greater NTHi uptake by neutrophils compared to macrophages in COPD (67 versus 38%, respectively) and HS (61 versus 31%, respectively). NTHi uptake by macrophages was lower in HS (31%, p = 0.019) and COPD patients (38%, p = 0.069) compared to HNS (57%). NTHi uptake by neutrophils was similar between groups. NTHi exposure reduced CD206 and CD14 expression on macrophages and CD16 expression on neutrophils. Sputum neutrophils showed more phagocytic activity than macrophages. There was some evidence that bacterial phagocytosis was impaired in HS sputum macrophages, but no impairment of neutrophils was observed in HS or COPD patients. These results highlight the relative contributions of neutrophils and macrophages to bacterial clearance in COPD.