Immune checkpoint molecules soluble program death ligand 1 and galectin‐9 are increased in pregnancy

Problem

Pregnancy requires balance between tolerance to the haploidentical fetus and the mother's ability to mount immune responses. There are parallels to this phenomenon that occur in metastatic cancer. We assessed soluble program death ligand‐1 soluble PD‐L1 (sPD‐L1) and galectin‐9 in the blood of pregnant women during gestation as these molecules are highly involved in immune suppression during cancer.

Method of study

Maternal blood was collected from 30 primigravida women at monthly intervals during pregnancy, delivery and 6‐week post‐partum. Blood was analyzed for sPD‐L1 and galectin‐9 concentrations by ELISA. Term placentas were collected in formalin and IHC was completed for PD‐L1 and galectin‐9 expression.

Results

Maternal blood levels of sPD‐L1 (0.438 ng/mL) and galectin‐9 (1976 pg/mL) were elevated early in normal pregnancies compared to non‐pregnant controls (0.242 ng/mL and 773 pg/mL, respectively). sPD‐L1 increased throughout gestation, whereas galectin‐9 remained elevated until parturition; both proteins returned to control levels post‐partum. Women carrying male fetuses had significantly higher galectin‐9 levels, but not sPD‐L1, than those carrying females (2263 pg/mL vs 1874 pg/mL; P = .0005). Trophoblast cells of the term placenta coexpress galectin‐9 and PD‐L1.

Conclusion

Immune‐regulatory molecules galectin‐9 and sPD‐L1 increased during pregnancy and may play a role in immune tolerance that is critical for the fetus.     

Chemokine Patterns in Children with Acute Bacterial Infections

Chemokines are chemotactic cytokines that are mainly involved in the migratory patterns of immune cells. Few studies have evaluated the levels of chemokines in children with acute bacterial infections. The aim of this study was to evaluate the serum levels of chemokines MCP‐1, RANTES, MIG and IP‐10 in children with sepsis, community‐acquired pneumonia (CAP) and skin abscess. Serum levels of MCP‐1, RANTES, MIG and IP‐10 were measured in 37 children with sepsis, 27 children with CAP, 25 children with skin abscess and 20 controls with no signs of infection. Patients with sepsis, CAP and skin abscess had higher concentrations of RANTES compared to controls (P = 0.0057, P = 0.0004 and P = 0.0108, respectively). IP‐10 values were higher in patients with sepsis compared to children with skin abscess (P = 0.0075). However, MCP‐1 levels were lower in septic patients compared to controls (P = 0.0136). There was no difference on MIG concentrations between the groups. Our original findings observed that RANTES was consistently elevated in all types of infections suggesting this chemokine may play an important role in the pathogenesis of bacterial infection. Additionally, patients with sepsis had a unique pattern of response with high levels of IP‐10 but low levels of MCP‐1, which should be further explored as the markers of disease severity.     

The Plasma Level of Proprotein Convertase FURIN in Patients with Suspected Infection in the Emergency Room: A Prospective Cohort Study

There is an increasing need for novel biomarkers that enable better diagnostic and prognostic stratification of patients with suspected infection. A proprotein convertase enzyme FURIN is upregulated upon immune cell activation, and it promotes infectivity by cleaving and activating pathogens. In this study, we determined FURIN levels in plasma using ELISA from 537 patients that were admitted to emergency room with suspected infection. Patients were sorted to high‐ and low‐level FURIN groups with a cut‐off level of 370 pg/ml. The study cohort included five diagnostic groups: Group 1, no systemic inflammatory response syndrome (SIRS, n = 59 patients); Group 2, bacterial infection without SIRS (n = 67); Group 3, SIRS, but no bacterial infection (n = 308); Group 4, sepsis without organ failure (n = 308); and Group 5, severe sepsis (n = 49). Statistically significant associations were not found between the plasma level of FURIN and the prevalence of sepsis (P = 0.957), diagnostic group of a patient (P = 0.737) or the bacteria in blood culture (P = 0.499). Additionally, the concentration of FURIN did not predict the severity or case fatality of the infectious disease. However, statistically significant associations were found between high plasma level of FURIN and diagnosed rheumatic disease (P < 0.001) as well as with the prevalence of non‐smokers (P = 0.034). Thus, albeit the plasma level of FURIN does not predict the severity of infectious disease, it may be of use in the diagnostics of autoimmune diseases.     

Expression of NK Cell and Monocyte Receptors in Critically Ill Patients – Potential Biomarkers of Sepsis

Sepsis is characterized by activation of both the innate and adaptive immune systems as a response to infection. During sepsis, the expression of surface receptors expressed on immune competent cells, such as NKG2D and NKp30 on NK cells and TLR4 and CD14 on monocytes, is partly regulated by pro‐ and anti‐inflammatory mediators. In this observational study, we aimed to explore whether the expression of these receptors could be used as diagnostic and/or prognostic biomarkers in sepsis. Patients with severe sepsis or septic shock (n = 21) were compared with critically ill non‐septic patients (n = 15). Healthy volunteers (n = 15) served as controls. To elucidate variations over time, all patients were followed for 4 days. Cell surface expression of NKG2D, NKp30, TLR4 and CD14 and serum levels of IL‐1β, IL‐6, IFN‐γ, TNF‐α, IL‐4 and IL‐10 was estimated by flow cytometry. We found that NK cell expression of NKG2D and monocyte expression of CD14 were lower in the septic patients compared with the non‐septic patients, both at ICU admission and during the observation period (P < 0.01 for all comparisons). Both at ICU admission, and during the observation period, levels of IL‐6 and IL‐10 were higher in the septic patients compared with the non‐septic patients (P < 0.001 for all comparisons). Conclusion: As both NKG2D and CD14 levels appear to distinguish between septic and non‐septic patients, both NKG2D and CD14 may be considered potential diagnostic biomarkers of severe sepsis and septic shock.     

sPD‐L1 Expression is Associated with Immunosuppression and Infectious Complications in Patients with Acute Pancreatitis

Acute pancreatitis (AP) with infectious complications has high mortality because of early‐stage immunosuppression. The programmed cell death‐1 (PD‐1)/programmed cell death ligand 1 (PD‐L1) pathway is an important host immunosuppression mechanism. Soluble PD‐L1 (sPD‐L1) expression regulates co‐inhibitory signals in malignancies or autoimmune disorders; however, its effects in AP are unknown. Here, we evaluated whether serum sPD‐L1 is involved in immune dysfunction and assessed its relationship with infectious complications in early AP. Blood samples were obtained from 56 patients with acute pancreatitis and 21 healthy individuals in this prospective study. Serum sPD‐L1 levels within 48 h after AP onset were tested by enzyme‐linked immunosorbent assays. Relevant immune parameters (human leucocyte antigen‐DR, lymphocyte count) and inflammatory markers (C‐reactive protein, white blood cell count) were analysed. sPD‐L1 was significantly upregulated in patients with early AP, especially those with infectious complications, compared to healthy controls. Significant negative correlations were observed among monocyte HLA‐DR expression, lymphocyte count and sPD‐L1 levels in AP. Multivariate regression indicated that sPD‐L1 was an independent risk factor for infectious complications in AP. The findings suggest that increased sPD‐L1 expression appears to be involved in the development of immunosuppression in the early stage of AP and that sPD‐L1 might be an early parameter for prediction of infectious complications in patients with AP.     

The Prognostic Significance of Soluble Programmed Death Ligand 1 Expression in Cancers: A Systematic Review and Meta‐analysis

The differential expression of soluble programmed death ligand 1 (sPD‐L1) has been found in some cancers; however, the correlation between sPD‐L1 expression and prognosis value in tumour is still unclear. Here, we conducted a meta‐analysis and systematic review to assess the prognostic value of sPD‐L1 in patients with cancer. Eligible studies were searched for in the databases including PubMed, Web of Science, ScienceDirect and Wiley Online Library database. The pooled hazard ratios (HRs) with a 95% confidence interval (95%CI) were calculated to assess the prognostic significance of sPD‐L1 in human cancer. Eight studies and 1102 patients with cancer were included in the final analysis, and the combined analysis indicated that a higher level of sPD‐L1 was associated with worse overall survival (OS) (HR = 1.60, 95%CI: 1.21–1.99). Furthermore, statistical significance was also observed in subgroup analysis stratified by the cancer type (haematological neoplasms or non‐haematological neoplasms), sample size (more or less than 100), cut‐off value of sPD‐L1 (more or less than 6.51 ng/ml) and ethnicity (Asian or European). The meta‐analysis indicates that circulating sPD‐L1 changes may serve as a useful biomarker for cancer prognosis, and higher level of sPD‐L1 may also be associated with poor outcomes in patients with cancer.     

Low immunoglobulin G level is associated with poor outcomes in patients with sepsis and septic shock

BackgroundDespite studies on low immunoglobulin G (IgG) levels in critically ill patients, their association with clinical outcomes in sepsis patients remains disputed. Herein, we determined the association between low IgG levels and clinical outcomes and investigated the 28-day mortality in patients with low IgG levels.MethodsWe retrospectively identified 238 patients whose serum IgG levels were measured upon intensive care unit admission using medical record data collected between January 2013 and August 2018. We extracted data on patient characteristics, severity scores (APACHE II, SOFA score), neutrophil-lymphocyte ratio (NLR), procalcitonin levels, and serum IgG levels and calculated the cut-off value for the IgG level according to the evaluated clinical outcomes. The primary outcome was 28-day mortality.ResultsThere were no significant differences in NLR and procalcitonin levels between survivors and non-survivors; serum IgG levels were significantly higher in survivors than in non-survivors (P = 0.004). A serum IgG cut-off value of 670 mg/dL was calculated from receiver operating characteristic curve analysis, and serum IgG levels significantly predicted survival with an area under the curve of 0.63 (95% CI, 0.54–0.72) (P = 0.004). Patients with low IgG levels (<670 mg/dL) had significantly higher mortality rates than those with normal IgG levels (≥670 mg/dL) (P < 0.001).ConclusionOur results reveal that low IgG levels (<670 mg/dL) in critically ill patients are associated with poor clinical outcomes related to 28-day mortality. In patients with sepsis, low IgG levels could be a predictor of poor outcome.     

Antibodies to Influenza Virus A/H1N1 Hemagglutinin in Type 1 Diabetes Children Diagnosed Before,During and After the SWEDISH A(H1N1)pdm09 Vaccination Campaign 2009–2010

We determined A/H1N1‐hemagglutinin (HA) antibodies in relation to HLA‐DQ genotypes and islet autoantibodies at clinical diagnosis in 1141 incident 0.7‐to 18‐year‐old type 1 diabetes patients diagnosed April 2009–December 2010. Antibodies to ³⁵S‐methionine‐labelled A/H1N1 hemagglutinin were determined in a radiobinding assay in patients diagnosed before (n = 325), during (n = 355) and after (n = 461) the October 2009–March 2010 Swedish A(H1N1)pdm09 vaccination campaign, along with HLA‐DQ genotypes and autoantibodies against GAD, insulin, IA‐2 and ZnT8 transporter. Before vaccination, 0.6% patients had A/H1N1‐HA antibodies compared with 40% during and 27% after vaccination (P < 0.0001). In children <3 years of age, A/H1N1‐HA antibodies were found only during vaccination. The frequency of A/H1N1‐HA antibodies during vaccination decreased after vaccination among the 3 < 6 (P = 0.006) and 13 < 18 (P = 0.001), but not among the 6 < 13‐year‐olds. HLA‐DQ2/8 positive children <3 years decreased from 54% (15/28) before and 68% (19/28) during, to 30% (9/30) after vaccination (P = 0.014). Regardless of age, DQ2/2; 2/X (n = 177) patients had lower frequency (P = 0.020) and levels (P = 0.042) of A/H1N1‐HA antibodies compared with non‐DQ2/2; 2/X (n = 964) patients. GADA frequency was 50% before, 60% during and 51% after vaccination (P = 0.009). ZnT8QA frequency increased from 30% before to 34% during and 41% after vaccination (P = 0.002). Our findings suggest that young (<3 years) along with DQ2/2; 2/X patients were low responders to Pandemrix^®. As the proportion of DQ2/8 patients <3 years of age decreased after vaccination and the frequencies of GADA and ZnT8QA were enhanced, it cannot be excluded that the vaccine affected clinical onset of type 1 diabetes.     

Cytochrome P4503A activity affects the gender difference in the development of steroid‐induced osteonecrosis in rabbits

The aim of this study was to investigate cytochrome P4503A activity and its correlation with the development of osternecrosis (ON) among male and female steroid‐treated rabbits. Forty adult rabbits (male, n = 20; female, n = 20) were injected once with 20 mg/kg of methylprednisolone intramuscularly. Haematologically, cytochrome P4503A activity was measured by plasma 1′‐hydroxymidazolam‐to‐midazolam (1′‐OH‐MDZ/MDZ) ratio just before and 48 h after the steroid injection. We also measured the levels of oestradiol every week. Both femora and humeri were histopathologically examined for the presence of ON. Fifteen of 20 male rabbits (75%) developed ON, while 6 of 20 female rabbits (30%) did so. There was a significant difference in the rate of incidence of ON between male and female rabbits (P = 0.010). The 1′‐OH‐MDZ/MDZ ratio in female rabbits just before, as well as 48 h after the steroid injection was significantly higher than that in male rabbits (P = 0.039 and P = 0.001 respectively). In addition, 1′‐OH‐MDZ/MDZ ratio in female rabbits significantly increased in 48 h after the steroid injection (P = 0.044), while that in male rabbits did not so (P = 0.978). The levels of oestradiol in female rabbits were significantly higher than those in male rabbits during the experimental period (P = 0.008). In conclusion, this study indicates that the gender difference in cytochrome P4503A activity may be one of the important factors for the development of steroid‐induced ON, possibly due to the effects of oestradiol.     

Partial sleep restriction modulates secretory activity of thyrotropic axis in healthy men

Sleep and endocrine function are known to be closely related, but studies on the effect of moderate sleep loss on endocrine axes are still sparse. We examined the influence of partial sleep restriction for 2 days on the secretory activity of the thyrotropic axis. Fifteen healthy, normal‐weight men were tested in a balanced, cross‐over study. Serum concentrations of thyrotrophin (TSH), free triiodothyronine (fT3) and free thyroxine (fT4) were monitored at 1‐h intervals during a 15‐h daytime period (08:00–23:00 h) following two nights of restricted sleep (bedtime 02:45–07:00 h) and two nights of regular sleep (bedtime 22:45–07:00 h), respectively. Serum concentrations of fT3 (P < 0.026) and fT4 (P = 0.089) were higher after sleep restriction than regular sleep, with a subsequent blunting of TSH concentrations in the evening hours of the sleep restriction condition (P = 0.008). These results indicate profound alterations in the secretory activity of the thyrotropic axis after 2 days of sleep restriction to ~4 h, suggesting that acute partial sleep loss impacts endocrine homeostasis, with potential consequences for health and wellbeing.     

The clustering and morphology of chondrocytes in normal and mildly degenerate human femoral head cartilage studied by confocal laser scanning microscopy

Chondrocytes are the major cell type present in hyaline cartilage and they play a crucial role in maintaining the mechanical resilience of the tissue through a balance of the synthesis and breakdown of extracellular matrix macromolecules. Histological assessment of cartilage suggests that articular chondrocytes in situ typically occur singly and demonstrate a rounded/elliptical morphology. However, there are suggestions that their grouping and fine shape is more complex and that these change with cartilage degeneration as occurs in osteoarthritis. In the present study we have used confocal laser scanning microscopy and fluorescently labelled in situ human chondrocytes and advanced imaging software to visualise chondrocyte clustering and detailed morphology within grade‐0 (non‐degenerate) and grade‐1 (mildly degenerate) cartilage from human femoral heads. Graded human cartilage explants were incubated with 5‐chloromethylfluorescein diacetate and propidium iodide to identify the morphology and viability, respectively, of in situ chondrocytes within superficial, mid‐ and deep zones. In grade‐0 cartilage, the analysis of confocal microscope images showed that although the majority of chondrocytes were single and morphologically normal, clusters (i.e. three or more chondrocytes within the enclosed lacunar space) were occasionally observed in the superficial zone, and 15–25% of the cell population exhibited at least one cytoplasmic process of ~ 5 μm in length. With degeneration, cluster number increased (~ 50%) but not significantly; however, the number of cells/cluster (P < 0.001) and the percentage of cells forming clusters increased (P = 0.0013). In the superficial zone but not the mid‐ or deep zones, the volume of clusters and average volume of chondrocytes in clusters increased (P < 0.001 and P < 0.05, respectively). The percentage of chondrocytes with processes, the number of processes/cell and the length of processes/cell increased in the superficial zone of grade‐1 cartilage (P = 0.0098, P = 0.02 and P < 0.001, respectively). Processes were categorised based on length (L0 – no cytoplasmic processes; L1 < 5 μm; 5 < L2 ≤ 10 μm; 10 < L3 ≤ 15 μm; L4 > 15 μm). With cartilage degeneration, for chondrocytes in all zones, there was a significant decrease (P = 0.015) in the percentage of chondrocytes with ‘normal’ morphology (i.e. L0), with no change in the percentage of cells with L1 processes; however, there were significant increases in the other categories. In grade‐0 cartilage, chondrocyte clustering and morphological abnormalities occurred and with degeneration these were exacerbated, particularly in the superficial zone. Chondrocyte clustering and abnormal morphology are associated with aberrant matrix metabolism, suggesting that these early changes to chondrocyte properties may be associated with cartilage degeneration.     

Immunometabolic biomarkers of inflammation in Behçet's disease: relationship with epidemiological profile,disease activity and therapeutic regimens

Behcet's disease (BD) is a systemic inflammatory disease with a still unclear pathogenesis. Although several inflammatory molecules have been studied, current biomarkers are largely insensitive in BD and unable to predict disease progression and response to treatment. Our primary aim was to explore serum levels of soluble CD40 L (sCD40L), soluble intracellular adhesion molecule (sICAM‐1), monocyte chemoattractant protein‐1 (MCP‐1), myeloperoxidase (MPO), leptin, resistin, osteoprotegerin (OPG), soluble type 1 tumour necrosis factor receptor (sTNFR), interleukin (IL)?6 and serum amyloid A (SAA) serum concentration in a cohort of 27 BD patients. The secondary aim was to evaluate potential correlations between the putative circulating biomarkers, demographic profile of patients, the status of disease activity, the specific organ involvement at the time of sample collection and different therapeutic regimens. Serum concentrations of sTNFR (P = 0·008), leptin (P = 0·0011), sCD40L (P < 0·0001) and IL‐6 (P = 0·0154) were significantly higher in BD patients than in HC, while no difference was found in MCP‐1, MPO and resistin serum levels. Moreover, we observed significantly higher sTNFR serum concentrations in BD patients presenting inactive disease than HC (P = 0·0108). A correlation between sTNFR and age was also found, with higher levels in patients over 40 years than HC (P = 0·0329). Although further research is warranted to elucidate the role of circulating biomarkers, some of that may contribute to the understanding of the physiopathology processes underlying BD activity and damage as well as to provide useful tools for prognostic purposes and a personalized treatment approach.     

Soluble CD163, a Specific Macrophage Activation Marker,is Decreased by Anti‐TNF‐α Antibody Treatment in Active Inflammatory Bowel Disease

Activated macrophages shed the haemoglobin–haptoglobin scavenger receptor CD163 into the circulation as soluble(s)‐CD163. We measured sCD163 as an in vivo macrophage activation marker in patients with Crohn's disease (CD) or ulcerative colitis (UC) receiving antitumour necrosis factor (TNF)‐α antibody or prednisolone treatment. We also investigated the CD163 expression on circulating monocytes. 58 patients with CD, 40 patients with UC and 90 healthy controls (HC) were included. All patients had active disease at inclusion and were followed for 6 weeks of anti‐TNF‐α antibody or prednisolone treatment. We measured plasma sCD163 levels at baseline, 1 day, 1 week and 6 weeks after initiating treatment. CD163 expression on circulating CD14⁺ monocytes was measured in 21 patients with CD receiving anti‐TNF‐α antibody treatment. Baseline sCD163 levels were elevated in patients with CD [1.99 (1.80–2.18) mg/l] and in patients with UC [2.07 (1.82–2.32) mg/l] compared with HC [1.51 (1.38–1.63) mg/l] (P < 0.001). Anti‐TNF‐α antibody treatment induced a rapid decrease in sCD163 levels in patients with CD and in patients with UC 1 day after treatment initiation (P < 0.05). One week of prednisolone treatment did not induce a reduction in sCD163 levels. Anti‐TNF‐α treatment normalized sCD163 levels in patients with UC, whereas patients with CD exhibited sustained increased sCD163 levels. In patients with CD, CD163 expression on CD14⁺ monocytes was increased compared with HC. This study highlights that active CD and UC are associated with increased macrophage activation, as indicated by elevated sCD163 levels and monocytic CD163 expression. Anti‐TNF‐α antibody treatment induced a rapid decrease in sCD163 levels, suggesting a specific effect on macrophage activation in inflammatory bowel diseases.     

Tumour‐Infiltrating FoxP3+ and IL‐17‐Producing T Cells Affect the Progression and Prognosis of Gallbladder Carcinoma after Surgery

Tumour‐infiltrating lymphocytes (TILs) have been found to play crucial roles in a series of cancers. However, the impact of these cells on gallbladder carcinoma (GBC) remains poorly understood. In this study, we examined infiltrating FoxP3+, IL‐17+, CD4+ and CD8+ cells by immunohistochemistry in specimens of 104 patients with GBC and evaluated the association of these cells with clinicopathological features and prognosis. The number of FoxP3+ cells was increased in a stepwise manner from CC to GA and GBC (GA versus CC, P = 0.036; early GBC versus GA, P = 0.032; advanced versus early GBC, P = 0.025). Both intratumoral FoxP3+ and IL‐17+ cells correlated with nodal metastasis and TNM stage. Additionally, there were more infiltrating FoxP3+ cells in specimens with distant metastasis (P = 0.014). The group with high FoxP3+ cells showed poor overall survival (OS, P < 0.001) and disease‐free survival (DFS, P < 0.001), and high infiltration of IL‐17‐producing cells was also a predictor of poor OS (P = 0.024). Multivariate analysis revealed that the presence of intratumoral FoxP3+ cells was an independent prognostic indicator for poor DFS (P < 0.01). In summary, these findings indicate that FoxP3+ and IL‐17+ cells cooperatively facilitate pathogenesis and progression of GBC and show prognostic significance for OS or DFS.     

Insulin‐like growth factor‐1 receptor is associated with better prognosis in classical Hodgkin's lymphoma: Correlation with MET expression

The purpose of this study was to examine the prognostic significance of insulin‐like growth factor‐1 receptor (IGF‐1R) expression alone and in relation to the expression of the MET‐ receptor and the MET‐homologous receptor RON, in classical Hodgkin's lymphoma (cHL). Tumour samples from patients with cHL (n = 202; median age 37.5 years) were analysed retrospectively for IGF‐R1, MET or RON expression by immunohistochemistry using tissue microarrays. The median follow‐up time was 3.7 years (range, 0.1–20 years). Twenty‐nine patients (14.3%) expressed IGF‐1R protein in Hodgkin/Reed–Sternberg (HRS) cells, which was associated with a better overall survival (OS) (P = 0.036). IGF‐1R expression was closely associated with MET receptor expression and low level of lactate dehydrogenase. In patients with cHL receiving doxorubicin, bleomycin, vinblastine and dacarbazine, those expressing IGF‐1R showed a trend towards better OS and event‐free survival than IGF‐1R‐negative patients (P = 0.129 and P = 0.115 respectively), but statistical significance was not reached. This study suggests that IGF‐1R expression could be associated with better clinical outcome in cHL but is significantly associated with the expression of MET receptor.     

Perinatal factors associate with vertebral size and shape but not lumbar lordosis in 10‐year‐old children

The intrauterine environment is known to influence foetal development and future health. Low birthweight has been linked to smaller vertebral canals in children and decreased adulthood spine bone mineral content. Perinatal factors affecting lumbar spine curvature have not yet been considered but could be important for adult spinal health, as lumbar movement during lifting, a risk factor for backpain, is associated with lordosis. To investigate this, lumbar spine magnetic resonance images at age 10 years and perinatal and maternal data (birthweight, placental weight, gestation length, crown‐heel length, maternal age, height, weight and smoking status) from 161 children born in Aberdeen in 1988–1989 were acquired. Statistical shape modelling, using principal component analysis, quantified variations in lumbar spine shape and resulting modes of variation were assessed in combination with perinatal data using correlations and analyses of covariance, adjusted for potential confounders. Spine modes 1–3 (SM1–SM3) captured 75% of the variation in lumbar spine shape. The first and third modes described the total amount (SM1) and evenness of curvature distribution (SM3). SM2 accounted for variations in antero‐posterior vertebral diameter relative to vertebral height, increasing positive scores representing a larger relative diameter. Adjusting for gestation length and sex, SM2 positively correlated with birthweight (r = 0.25, P < 0.01), placental weight (r = 0.20, P = 0.04), crown‐heel length (r = 0.36, P < 0.001) and maternal weight (r = 0.19, P = 0.04), and negatively with maternal age (r = ?0.22, P = 0.02). SM2 scores were lower in girls (P < 0.001) and in the low birthweight group (P = 0.02). There were no significant differences in SM1 and SM3 scores between birthweight groups, boys and girls or children of smokers (31%) and non‐smokers (69%). In conclusion, s ome perinatal factors were associated with vertebral body morphology but had little effect on lumbar curvature.     

Altered levels of soluble CD18 may associate immune mechanisms with outcome in sepsis

The pathogenesis of sepsis involves a dual inflammatory response, with a hyperinflammatory phase followed by, or in combination with, a hypoinflammatory phase. The adhesion molecules lymphocyte function‐associated antigen (LFA‐1) (CD11a/CD18) and macrophage‐1 (Mac‐1) (CD11b/CD18) support leucocyte adhesion to intercellular adhesion molecules and phagocytosis through complement opsonization, both processes relevant to the immune response during sepsis. Here, we investigate the role of soluble (s)CD18 in sepsis with emphasis on sCD18 as a mechanistic biomarker of immune reactions and outcome of sepsis. sCD18 levels were measured in 15 septic and 15 critically ill non‐septic patients. Fifteen healthy volunteers served as controls. CD18 shedding from human mononuclear cells was increased in vitro by several proinflammatory mediators relevant in sepsis. sCD18 inhibited cell adhesion to the complement fragment iC3b, which is a ligand for CD11b/CD18, also known as Mac‐1 or complement receptor 3. Serum sCD18 levels in sepsis non‐survivors displayed two distinct peaks permitting a partitioning into two groups, namely sCD18 ‘high’ and sCD18 ‘low’, with median levels of sCD18 at 2158 mU/ml [interquartile range (IQR) 2093–2811 mU/ml] and 488 mU/ml (IQR 360–617 mU/ml), respectively, at the day of intensive care unit admission. Serum sCD18 levels partitioned sepsis non‐survivors into one group of ‘high’ sCD18 and low CRP and another group with ‘low’ sCD18 and high C‐reactive protein. Together with the mechanistic data generated in vitro, we suggest the partitioning in sCD18 to reflect a compensatory anti‐inflammatory response syndrome and hyperinflammation, respectively, manifested as part of sepsis.     

Association analysis of polymorphisms in OAS1 with susceptibility and severity of hand,foot and mouth disease

Hand, foot and mouth disease (HFMD) is a common childhood illness that mainly affects Asian children under the age of 5 years. Human enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the most common pathogens of HFMD. It is imperative that the susceptible population is screened early and that the severe illness population can be identified via genetic variation detection in children. Four single‐nucleotide polymorphisms (SNP) [2′‐5′‐oligoadenylate synthetase1 (OAS1) rs10774671, selectin P ligand (SELPLG) rs2228315, scavenger receptor class B member 2 (SCARB2) rs41284767 and interleukin 28B (IL28B) rs12979860] were determined by Taqman assays in 333 HFMD samples and 163 control samples. The rs2228315, rs41284767 and rs12979860 polymorphisms did not differ significantly between HFMD patients and the controls, but the prevalence of the rs10774671 polymorphism was significantly different between the control children and children infected with CA16 (GG genotype vs. AA + AG genotype, P < 0.05). Children with the GG genotype were more susceptible to CA16‐type HFMD. Furthermore, the rs10774671 genotype distribution was clearly different between children with severe HFMD and those with mild HFMD [P < 0.05, OR 0.240, 95% CI (0.071–0.809)]. HFMD children with the AA+AG genotype were more likely to progress to encephalitis than were those with the GG genotype. Plasma γ‐interferon (IFN) expression levels among control children and the mild and severe HFMD children were detected by ELISA. Those with mild HFMD had higher γ‐IFN expression levels compared with those with severe HFMD (P < 0.05). In addition, there is a significant correlation between γ‐IFN levels and OAS1 rs10774671 SNP, as analysed by linear correlation assay. The GG genotype correlated with higher γ‐IFN levels (P < 0.05). In short, the OAS1 rs10774671 SNP GG genotype contributed to CA16 susceptibility and was associated with the development of mild HFMD.     

Association of Disease Severity with IL‐1 levels in Methotrexate‐treated Psoriasis Patients

Interleukin‐1 plays a key role in inflammation and keratinocyte activation. It is an important mediator in the initiation and maintenance of psoriatic plaques and may represent an attractive therapeutic target. The aim of this study is to evaluate the effect of Methotrexate (MTX) on IL‐1 α and IL‐1 β levels in both plasma and skin biopsy of patients with psoriasis and to investigate their association with clinical disease activity. Forty‐five control subjects and 58 patients with psoriasis were recruited for this study. The patients were treated with 7.5 mg of MTX per week for 12 weeks. Folic acid was given at 5 mg once daily except on the day of MTX for 12 weeks. Blood samples and lesional skin biopsy were taken. Disease severity was assessed by Psoriasis Area Severity Index (PASI) score. IL‐1 levels in plasma and skin biopsy were analysed using ELISA. PASI score declined significantly (P < 0.001) from day 0 to 12 weeks of MTX treatment. IL‐1 α level in plasma and skin biopsy was reduced at day 0 sample and elevated significantly (P < 0.001) after MTX treatment. IL‐1β level in plasma and skin biopsy was higher at day 0 sample and reduced significantly (P < 0.001) after MTX treatment. IL‐1α levels and PASI score showed inverse correlation score before and after treatment with MTX. Whereas IL‐1β levels showed positive correlation before and after treatment with MTX. Decreasing IL‐1β levels by MTXs in psoriasis may block the Th17 differentiation. This shows the therapeutic effect of MTX in controlling the immunopathogenesis of psoriasis.