INQ‐15 cut‐off scores for suicidal ideation screening of women with chronic,invisible illnesses

In the interpersonal theory of suicide, perceived burdensomeness (PB) and thwarted belongingness (TB) are proximal triggers of suicidal ideation. Using the 15‐item version of the Interpersonal Needs Questionnaire (INQ‐15), suicidal ideation in psychiatric inpatients was predicted by the PB and TB scales, and cut‐off scores were recommended. In this study, women (N = 942) who reported one or more chronic, invisible illnesses completed an online survey including the INQ‐15 and the Suicide Behaviours Questionnaire‐Revised (SBQ‐R). PB and TB correlated significantly with SBQ‐R total scores (r = 0.575 and 0.437, respectively; p < 0.01). In a Receiver Operating Characteristic analysis, scores of 17 for PB and 37 for TB maximized the correct classification of high‐risk and low‐risk participants, with slightly higher classification accuracy for PB than TB (AUCs = 0.781 and 0.701, respectively). These results support the INQ‐15 scales in screening for suicidal ideation among chronically ill women.     

Expression of miR‐100 and miR‐138 as prognostic biomarkers in non‐muscle‐invasive bladder cancer

microRNA alterations are involved in bladder cancer tumorigenesis. The aim of the current study was to evaluate the potential role of miR‐100 and miR‐138 as prognostic biomarkers in Ta/T1 non‐muscle‐invasive bladder cancer (NMIBC). We assessed a quantitative RT‐PCR analysis of miR‐100 and miR‐138 in 50 bladder tumor samples (stage Ta/T1) and four healthy adjacent tissues. Western blot analysis was used to measure protein expression of FGFR3 and cyclin D3 in order to know whether these targets can be regulated by miR‐100 and miR‐138, respectively. The statistical analysis included non‐parametric tests (Mann–Whitney U and Kruskal–Wallis) and univariate survival analysis by Kaplan–Meier method and the log‐rank test. Low expression of miR‐138 characterized recurrent tumors (p = 0.043), and higher expression levels were associated with longer recurrence‐free survival (p = 0.012). However, low miR‐100 expression correlated with longer progression‐free survival (marginal significance; p = 0.053) and cancer‐specific overall survival (p = 0.006). Additionally, higher levels of miR‐100 were associated with negative FGFR3 protein expression (p = 0.032) and higher levels of miR‐138 were associated with positive cyclin D3 protein expression (p = 0.037). Our results support miR‐138 and miR‐100 as prognostic biomarkers in patients with NMIBC.     

Evaluation of the new AmpliSens multiplex real‐time PCR assay for simultaneous detection of Neisseria gonorrhoeae,Chlamydia trachomatis,Mycoplasma genitalium,and Trichomonas vaginalis

In this study, we performed an evaluation of the new CE‐marked multiplex real‐time AmpliSens N.gonorrhoeae/C.trachomatis/M.genitalium/T.vaginalis‐MULTIPRIME‐FRT PCR assay compared to APTIMA tests, i.e., APTIMA COMBO 2 assay, APTIMA Trichomonas vaginalis assay (FDA‐approved), and two different APTIMA Mycoplasma genitalium assays (research use only; one of them only used for discrepancy analysis). Vaginal swabs (n = 209) and first‐void urine (FVU) specimens from females (n = 498) and males (n = 554), consecutive attendees (n = 1261) at a dermatovenerological clinic in Sweden, were examined. The sensitivity of the AmpliSens PCR assay for detection of C. trachomatis (6.3% prevalence), M. genitalium (5.7% prevalence), N. gonorrhoeae (0.3% prevalence), and T. vaginalis (0.08% prevalence) was 97.5% (95% confidence interval (CI): 91.2–99.6%), 81.9% (95% CI: 70.7–89.7%), 100% (95% CI: 40.2–100%) and 100% (95% CI: 16.5–100%), respectively. The specificity of the AmpliSens PCR assay was 100% (95% CI: 99.6–100%) for all agents. The analytical sensitivity and specificity for N. gonorrhoeae detection was excellent, i.e., 55 international gonococcal strains detected and 135 isolates of 13 non‐gonococcal Neisseria species were negative. In conclusion, the multiplex real‐time AmpliSens N.gonorrhoeae/C.trachomatis/M.genitalium/T.vaginalis‐MULTIPRIME‐FRT PCR assay demonstrated high sensitivity and excellent specificity for the detection of C. trachomatis, N. gonorrhoeae, and T. vaginalis, and excellent specificity but suboptimal sensitivity for M. genitalium detection.     

Cognitive‐Behavioral School‐Based Interventions for Anxious and Depressed Youth: A Meta‐Analysis of Outcomes

A meta‐analysis of school‐based interventions for anxious and depressed youth using QUORUM guidelines was conducted. Studies were located by searching electronic databases, manual effort, and contact with expert researchers. Analyses examined 63 studies with 8,225 participants receiving cognitive‐behavioral therapy (CBT) and 6,986 in comparison conditions. Mean pre–post effect sizes indicate that anxiety‐focused school‐based CBT was moderately effective in reducing anxiety (Hedge's g = 0.501) and depression‐focused school‐based CBT was mildly effective in reducing depression (Hedge's g = 0.298) for youth receiving interventions as compared to those in anxiety intervention control conditions (Hedge's g = 0.193) and depression intervention controls (Hedge's g = 0.091). Predictors of outcome were explored. School‐based CBT interventions for youth anxiety and for youth depression hold considerable promise, although investigation is still needed to identify features that optimize service delivery and outcome.     

Unique sleep‐stage transitions determined by obstructive sleep apnea severity,age and gender

In obstructive sleep apnea, patients’ sleep is fragmented leading to excessive daytime sleepiness and co‐morbidities like arterial hypertension. However, traditional metrics are not always directly correlated with daytime sleepiness, and the association between traditional sleep quality metrics like sleep duration and arterial hypertension is still ambiguous. In a development cohort, we analysed hypnograms from mild (n = 209), moderate (n = 222) and severe (n = 272) obstructive sleep apnea patients as well as healthy controls (n = 105) from the European Sleep Apnea Database. We assessed sleep by the analysis of two‐step transitions depending on obstructive sleep apnea severity and anthropometric factors. Two‐step transition patterns were examined for an association to arterial hypertension or daytime sleepiness. We also tested cumulative distributions of wake as well as sleep‐states for power‐laws (exponent α) and exponential distributions (decay time τ) in dependency on obstructive sleep apnea severity and potential confounders. Independent of obstructive sleep apnea severity and potential confounders, wake‐state durations followed a power‐law distribution, while sleep‐state durations were characterized by an exponential distribution. Sleep‐stage transitions are influenced by obstructive sleep apnea severity, age and gender. N2 → N3 → wake transitions were associated with high diastolic blood pressure. We observed higher frequencies of alternating (symmetric) patterns (e.g. N2 → N1 → N2, N2 → wake → N2) in sleepy patients both in the development cohort and in a validation cohort (n = 425). In conclusion, effects of obstructive sleep apnea severity and potential confounders on sleep architecture are small, but transition patterns still link sleep fragmentation directly to obstructive sleep apnea‐related clinical outcomes like arterial hypertension and daytime sleepiness.     

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.     

Genetic association of interleukin‐2, interleukin‐4, interleukin‐6, transforming growth factor‐β, tumour necrosis factor‐α and blood concentrations of calcineurin inhibitors in Turkish renal transplant patients

Cytokines are essential for the control of the immune response as most of the immunosuppressive drugs target cytokine production or their action. The calcineurin inhibitors (CNIs) cyclosporine (CsA) and tacrolimus are immunosuppressive drugs widely used after renal transplantation to prevent allograft rejection. They are characterized by large interindividual variability in their pharmacokinetics; therefore, monitoring their blood concentrations is important to predict their optimal dosage following transplantation. Calcineurin inhibitors inhibit the phosphatase activity of calcineurin, thereby suppressing the production of other cytokines such as transforming growth factor (TGF‐β), tumour necrosis factor‐α (TNF‐α), interleukin (IL)‐6, IL‐2, and IL‐4. The aim of this study was to investigate the relationship between polymorphisms of cytokines and blood concentrations of CNIs in renal transplant patients. The study included 53 CsA‐treated renal transplant patients and 37 tacrolimus‐treated renal transplant patients. Cytokine polymorphisms were analysed using polymerase chain reaction (PCR) sequence‐specific primers with the cytokine CTS‐PCR‐sequence‐specific primers Tray Kit; University of Heidelberg. Blood concentrations of CNIs were determined with Cloned Enzyme Donor Immunoassay (CEDIA) method. Patients with TC genotype of TGF‐β at codon 10 had lower CsA blood concentrations than the TT and CC genotypes (P = 0.005) at 1 month in CsA treatment group. The ratio of blood concentration/dose of CsA for patients with TGF‐β1‐codon 10 TC genotype was lower than for patients with TT, CC genotypes, and the dose given to these patients was higher in the first month (P = 0.046). The ratio of blood concentration/dose of CsA for patients with IL‐2‐330 GG genotype was higher than for patients with GT, TT genotypes, and the dose given to these patients was lower at first month and sixth months (P = 0.043, P = 0.035 respectively). The tacrolimus blood concentrations were significantly higher in patients with the genotype GG of IL‐2‐330 (P = 0.012) at the third month. Patients who had the TC genotype TGF‐β codon 10 had lower CsA blood concentrations and this group had higher acute rejection (P = 0.033). These results suggest that the genotyping for TGF‐β‐codon 10, IL‐2‐330 and IL‐6‐174 polymorphisms may help individualized immunosuppressive dosage regiments.     

Emerging psychiatric disorders in Kleine‐Levin syndrome

In Kleine‐Levin syndrome (KLS), episodes of hypersomnia and cognitive, psychiatric and behavioural disturbances alternate with asymptomatic periods in adolescents. We evaluated whether psychiatric disorders would emerge during asymptomatic periods in a naturalistic, uncontrolled clinical cohort. Patients with primary KLS underwent psychiatric interviews at diagnosis and every year for 1–10 years, leading to diagnosis of former and present comorbid psychiatric disorders. Among the 115 patients (65.2% male and aged 16.1 ± 4.8 years at KLS onset), 19 (16.5%) had a history of psychiatric disorder prior to KLS onset, which persisted afterwards in 10. Twenty‐five (21%) patients developed a new, comorbid psychiatric disorder 1–6 years after KLS onset, during ‘asymptomatic’ periods, including mood disorders (n = 14; including major depressive episodes, n = 8; recurrent depressive episodes, n = 2; bipolar I disorder, n = 1; dysthymic disorder, n = 1; adjustment disorder with depressive mood, n = 1; and mood disorder not otherwise specified, n = 1), anxiety disorders (n = 7), eating disorders (n = 2), psychotic disorders not otherwise specified (n = 2), schizoaffective disorder (n = 1) and cannabis dependence (n = 1). Six patients attempted suicide: two before and two after KLS onset, and two during episodes. Female sex, longer disease course, longer time incapacitated (356 ± 223 versus 155 ± 186 days) and more frequent psychiatric symptoms during episodes (but no family or personal history of psychiatric disorders) were associated with emerging psychiatric disorders. Contrary to the alleged benignity of KLS and normality between episodes, one KLS patient in five suffers from emerging psychiatric disorders. These disorders may depend on personal vulnerability and, most probably, on psychiatric symptoms during episodes.     

IL‐1A rs1800587, IL‐1B rs1143634 and IL‐1R1 rs2234650 polymorphisms in Iranian patients with systemic sclerosis

Systemic Sclerosis (SSc) is a systemic autoimmune disorder, with ambiguous pathogenesis. Genetic and environmental factors were proved to be correlated with SSc aetiology. Single nucleotide polymorphisms (SNPs) in cytokine genes can alter the structure and function of the cytokines and consequently may increase the susceptibility to a specific disease. In this study, we investigated SNPs of the IL‐1 gene cluster in Iranian SSc patients. We obtained blood samples from 170 SSc patients and 213 healthy individuals. Cytokine genotyping results were obtained by polymerase chain reaction with sequence‐specific primers (PCR‐SSP). IL‐1A rs1800587, IL‐1B rs1143634 and IL‐1R1 rs2234650 were evaluated for SNP study. The frequency of the IL‐1B rs1143634 CT genotype was significantly lower in SSc patients compared to the controls (OR = 0.584; 95% CI = 0.385–0.886; P‐value = 0.023), so we propose that CT genotype of this allele might be protective. According to our haplotype analysis, CCC haplotype frequency is higher in the control group compared to SSc patients (OR = 1.575; 95% CI = 1.176–2.111; P‐value = 0.008) and in contrast, CTC haplotype frequency is lower in the control group compared to SSc patients (OR = 0.152; 95% CI = 0.047–0.484; P‐value = 0.002), so they might decrease and increase the susceptibility of having SSc, respectively. In addition, we reported two significant diplotypes frequency differences among SSc patients and healthy individuals. It is highly important that there is not much resemblance between the IL‐1 gene cluster polymorphism in different populations, so we can indicate that SNPs may play critical roles when they are combined with other genetic and environmental factors.     

Schizotypy,neuroticism, and saccadic eye movements: New data and meta‐analysis

Deficits on saccade tasks, particularly antisaccade performance, have been reliably reported in schizophrenia. However, less evidence is available on saccade performance in relation to schizotypy, a personality constellation harboring risk for schizophrenia. Here, we report a large empirical study of the associations of schizotypy and neuroticism with antisaccade and prosaccade performance (Study I). Additionally, we carried out meta‐analyses of the association between schizotypy and antisaccade error rate (Study II). In Study I, N = 526 healthy individuals from the general population aged 18–54 years completed prosaccade and antisaccade tasks as well as the Schizotypal Personality Questionnaire (SPQ). Schizotypy was significantly associated with increased antisaccade error rate, with the disorganized dimension emerging as strongest predictor (β = .118, p = .007). Neuroticism emerged as a significant predictor for prosaccade gain (β = .103, p = .023) and antisaccade latency (β = .101, p = .025). In Study II, random‐effects meta‐analyses were performed on the published data and those from Study I. Meta‐analyses revealed significant associations (all p ≤ .003) of antisaccade error rate with positive (g = 0.37), negative (g = 0.26), disorganized (g = 0.36) and overall schizotypy (g = 0.37). Overall, the present work replicates the association between antisaccade direction errors and schizotypy. Significant findings from meta‐analyses provide further evidence of the antisaccade error rate as a putative schizophrenia spectrum marker.     

Associative role of HLA‐DRB1 SNP genotypes as risk factors for susceptibility and severity of rheumatoid arthritis: A North‐east Indian population‐based study

Rheumatoid arthritis (RA) is a complex, multifactorial, systemic autoimmune disease. Reports are suggestive of the role of HLA especially HLA‐DRB1 alterations in RA pathogenesis. Existing data involving different geographical populations on the role of alterations in specific locus of HLA‐DRB1 in RA susceptibility and severity are equivocal, with no data available from ethnically distinct North‐east Indian population, where RA cases are alarmingly increasing. This study aimed to evaluate the association of HLA‐DRB1 gene SNPs (rs13192471, rs660895 and rs6457617) with susceptibility and severity of RA in an ethnically distinct North‐east Indian population. Whole blood was collected from clinically characterized RA cases (satisfying the American College of Rheumatology 1987 criteria) (n = 123) and community‐based age and sex‐matched healthy controls (n = 156) with informed consent. The HLA‐DRB1 SNP analysis was performed for all the RA and control cases using ARMS‐PCR using case and control genomic DNA as template. Statistical analysis was performed by SPSSv13.0 software. The HLA‐DRB1 rs660895 showed both wild (AA) and heterozygote (AG) genotype but the heterozygote allele was found to be associated with reduced risk of RA compared to controls [OR = 0.531, p = .024]. The difference in distribution of rs6457617 polymorphism between RA and control cases was comparable [OR = 0.525, p = .079]. Significantly higher distribution of variant rs13192471 genotype was observed in RA cases (69.92%) compared to controls (46.75%) (p < .001) and was associated with increased risk of susceptibility to RA [OR = 2.576, p < .001] compared to controls, as well as progression to severity in RA cases [OR = 2.404, p = .048]. Combinatorially also, the presence of rs13192471 variant genotype was associated with increased risk of RA susceptibility [OR = 8.267, p = .026] and RA severity [OR = 3.647, p = .280]. Alterations in HLA‐DRB1 are associated with RA susceptibility. HLA‐DRB1 rs13192471 SNP plays a critical role in RA susceptibility and severity in North‐east Indian cases and has prognostic significance in RA.     

Haplotype analysis of HLA‐A, ‐B antigens and ‐DRB1 alleles in south Indian HIV‐1‐infected patients with and without pulmonary tuberculosis

We have shown earlier the association of human leucocyte antigen (HLA)‐A11 with resistance and HLA‐B40 and ‐DR2 with susceptibility to HIV and HIV‐TB. In the present study, we have attempted to find out the HLA‐DR2 subtypes and the possible HLA‐A/‐B/‐DRB1 haplotype combinations that are associated with susceptibility or resistance to HIV and HIV with pulmonary tuberculosis (HIV+PTB+). HLA‐DR2 subtyping was carried out by polymerase chain reaction‐based sequence‐specific oligonucleotide probe method. Overrepresentation of HLA‐DRB1*1501 in HIV‐positive PTB‐negative (HIV+PTB–) patients (P = 0.004, P_c = 0.06) and ‐DRB1*1502 in HIV‐positive PTB‐positive (HIV+PTB+) patients (P = 0.019) was observed as compared to healthy controls. Haplotype analysis revealed an increased frequency of HLA‐A2‐DRB1*1501 haplotype in HIV+PTB– patients (P = 0.008) and HLA‐A2‐DRB1*1502 among HIV+PTB+ patients (P = 0.01) compared to healthy controls. The haplotypes B40‐DRB1*1501 and B40‐DRB1*04 were found to be moderately increased in HIV+PTB– and HIV+PTB+ patients (P < 0.05). The study suggests that HLA‐A2‐DRB1*1501 haplotype may be associated with HIV infection while HLA‐A2‐DRB1*1502 haplotype might be associated with susceptibility to PTB in HIV patients. Moreover, HLA‐B40‐DRB1*1501 and HLA‐B40‐DRB1*04 haplotypes may be associated with susceptibility to HIV infection and to PTB in HIV patients.     

Three‐dimensional echo planar spectroscopic imaging for differentiation of true progression from pseudoprogression in patients with glioblastoma

Accurate differentiation of true progression (TP) from pseudoprogression (PsP) in patients with glioblastomas (GBMs) is essential for planning adequate treatment and for estimating clinical outcome measures and future prognosis. The purpose of this study was to investigate the utility of three‐dimensional echo planar spectroscopic imaging (3D‐EPSI) in distinguishing TP from PsP in GBM patients. For this institutional review board approved and HIPAA compliant retrospective study, 27 patients with GBM demonstrating enhancing lesions within six months of completion of concurrent chemo‐radiation therapy were included. Of these, 18 were subsequently classified as TP and 9 as PsP based on histological features or follow‐up MRI studies. Parametric maps of choline/creatine (Cho/Cr) and choline/N‐acetylaspartate (Cho/NAA) were computed and co‐registered with post‐contrast T₁‐weighted and FLAIR images. All lesions were segmented into contrast enhancing (CER), immediate peritumoral (IPR), and distal peritumoral (DPR) regions. For each region, Cho/Cr and Cho/NAA ratios were normalized to corresponding metabolite ratios from contralateral normal parenchyma and compared between TP and PsP groups. Logistic regression analyses were performed to obtain the best model to distinguish TP from PsP. Significantly higher Cho/NAA was observed from CER (2.69 ± 1.00 versus 1.56 ± 0.51, p = 0.003), IPR (2.31 ± 0.92 versus 1.53 ± 0.56, p = 0.030), and DPR (1.80 ± 0.68 versus 1.19 ± 0.28, p = 0.035) regions in TP patients compared with those with PsP. Additionally, significantly elevated Cho/Cr (1.74 ± 0.44 versus 1.34 ± 0.26, p = 0.023) from CER was observed in TP compared with PsP. When these parameters were incorporated in multivariate regression analyses, a discriminatory model with a sensitivity of 94% and a specificity of 87% was observed in distinguishing TP from PsP. These results indicate the utility of 3D‐EPSI in differentiating TP from PsP with high sensitivity and specificity.     

Monogenic diabetes syndromes: Locus‐specific databases for Alström,Wolfram, and Thiamine‐responsive megaloblastic anemia

We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease‐associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine‐responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype–phenotype relations for the WFS1 gene. The presence of biallelic loss‐of‐function variants predicted Wolfram syndrome defined by insulin‐dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%–83%) and specificity of 92% (83%–97%). The presence of minor loss‐of‐function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%–100%]; specificity 78% [73%–82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next‐generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org .     

Co‐expression of TLR‐9 and MMP‐13 is associated with the degree of tumour differentiation in prostate cancer

In vitro experiments demonstrated that stimulation of Toll‐like receptor 9 (TLR‐9) by synthetic TLR‐9 ligands induces the invasion of TLR‐9‐expressing prostate cancer cells through matrix metalloproteinase 13 (MMP‐13). However, the clinical value of TLR‐9 and MMP‐13 co‐expression in the pathophysiology of the prostate is unknown. In the study, we evaluated the expression levels and clinical significance of the TLR‐9 and MMP‐13 in a series of prostate tissues. One hundred and eighty prostate tissues including prostate cancer (PCa) (n = 137), high‐grade prostatic intraepithelial neoplasia (HPIN) (n = 18) and benign prostatic hyperplasia (BPH) (n = 25) were immunostained for the TLR‐9 and MMP‐13 markers. Subsequently, the correlation between the TLR‐9 and MMP‐13 staining scores and clinicopathological parameters was obtained. Higher expressions of TLR‐9 and MMP‐13 were found in PCa and high‐grade prostatic intraepithelial neoplasia compared to benign prostatic hyperplasia tissues. Among PCa samples, a positive relationship was revealed between the MMP‐13 expression and Gleason score (P < 0.001). There was a significant correlation between TLR‐9 expression and regional lymph node involvement (P = 0.04). The expression patterns of TLR‐9 and MMP‐13 markers demonstrated a reciprocal significant correlation between the two markers in the same series of prostate samples (P < 0.001). Furthermore, the Gleason score of TLR‐9^high/MMP‐13^high and TLR‐9^low/MMP‐13^low phenotypes showed a significant difference (P = 0.002). Higher expressions of TLR‐9 and MMP‐13 can confer aggressive behaviour to PCa. Therefore, these markers may be used as a valuable target for tailored therapy of PCa.     

Putative risk alleles for LATE‐NC with hippocampal sclerosis in population‐representative autopsy cohorts

Limbic‐predominant age‐related TAR‐DNA‐binding protein‐43 (TDP‐43) encephalopathy with hippocampal sclerosis pathology (LATE‐NC + HS) is a neurodegenerative disorder characterized by severe hippocampal CA1 neuron loss and TDP‐43‐pathology, leading to cognitive dysfunction and dementia. Polymorphisms in GRN, TMEM106B and ABCC9 are proposed as LATE‐NC + HS risk factors in brain bank collections. To replicate these results in independent population‐representative cohorts, hippocampal sections from brains donated to three such studies (Cambridge City over 75‐Cohort [CC75C], Cognitive Function and Ageing Study [CFAS], and Vantaa 85+ Study) were stained with hematoxylin–eosin (n = 744) and anti‐pTDP‐43 (n = 713), and evaluated for LATE‐NC + HS and TDP‐43 pathology. Single nucleotide polymorphism genotypes in GRN rs5848, TMEM106B rs1990622 and ABCC9 rs704178 were determined. LATE‐NC + HS (n = 58) was significantly associated with the GRN rs5848 genotype (χ²(2) = 20.61, P < 0.001) and T‐allele (χ²(1) = 21.04, P < 0.001), and TMEM106B rs1990622 genotype (Fisher's exact test, P < 0.001) and A‐allele (χ²(1) = 25.75, P < 0.001). No differences in ABCC9 rs704178 genotype or allele frequency were found between LATE‐NC + HS and non‐LATE‐NC + HS neuropathology cases. Dentate gyrus TDP‐43 pathology associated with GRN and TMEM106B variations, but the association with TMEM106B nullified when LATE‐NC + HS cases were excluded. Our results indicate that GRN and TMEM106B are associated with severe loss of CA1 neurons in the aging brain, while ABCC9 was not confirmed as a genetic risk factor for LATE‐NC + HS. The association between TMEM106B and LATE‐NC + HS may be independent of dentate TDP‐43 pathology.     

SPINK5 is associated with early‐onset and CHI3L1 with late‐onset atopic dermatitis

We have recently showed that filaggrin (FLG) mutations are associated only with early‐onset of AD, but not with late‐onset of AD. Consequently, other susceptibility genes should receive attention, especially in patients with late‐onset of AD. Our aim was to assess the associations between development of AD and the polymorphisms rs2303067 in SPINK5 and rs490928 in CHI3L1. A study population of 241 AD patients and 164 healthy controls was genotyped for two polymorphisms (rs2303067 in SPINK5 and rs490928 in CHI3L1). Rs2303067 in SPINK5 was significantly associated with early‐onset AD (≤8 years: p = .003; OR = 2.57) and was characterized by the need for hospitalization (p = .006; OR = 2.76), prolonged duration (≥10 years; p = .008; OR = 2.32) and more body parts affected (p = .015; OR = 2.01). In contrast, rs490928 in CHI3L1 was associated with late‐onset AD (>8 years: p = .048; OR = 1.65) and was characterized by no need for hospitalization (p = .049; OR = 1.59), shorter duration (<10 years; p = .017; OR = 1.94) and fewer body parts affected (p = .049; OR = 1.75). Our results confirmed that different AD phenotypes, specifically early‐ and late‐onset AD, have different genetic backgrounds. Early‐onset AD was associated with rs2303067 in SPINK5, which is involved in skin barrier functioning, and late‐onset was associated with rs4950928 in CHI3L1, which is involved in the immune response. Future studies should examine the early‐ versus late‐onset subgrouping more closely.     

The Responses of Multiple Cytokines Following Incubation of Whole Blood from TB Patients,Latently Infected Individuals and Controls with the TB Antigens ESAT‐6, CFP‐10 and TB7.7

The development of clinically relevant biomarkers is important for diagnosing latent tuberculosis infection (LTBI) and active tuberculosis (TB) and predicting their prognoses. This study examined whether the responses of multiple cytokines can be used as a biomarker to distinguish the TB infection status and mycobacterial load. We analysed the responses of multiple cytokines (IFN‐γ, IL‐2, IL‐10, IL‐13, IL‐17 and TNF‐α) in the supernatant from the QuantiFERON‐TB Gold In‐Tube assay following stimulation of whole blood from the TB group (n = 32), LTBI group (n = 19) and healthy controls (n = 30) with TB antigens (ESAT‐6, CFP‐10 and TB7.7). The median responses of IFN‐γ, IL‐2, IL‐10 and IL‐13 were higher in the LTBI and active TB groups than in the non‐TB control group (IFN‐γ, P < 0.001; IL‐2, P < 0.001; IL‐10, P = 0.012; IL‐13, P < 0.001). The median IL‐2/IFN‐γ ratio of the LTBI group was higher than that of the active TB group (P = 0.014) and differed significantly between patients with LTBI, patients with smear‐negative TB and patients with smear‐positive TB (P = 0.027). This difference was especially evident between the patients with LTBI and patients with smear‐positive TB (P = 0.047). In conclusion, IFN‐γ, IL‐2, IL‐10 and IL‐13 can serve as biomarkers for distinguishing TB infection. In addition, the IL‐2/IFN‐γ ratio appears to be a biomarker for diagnosing LTBI and may be useful as a prognostic factor and for evaluating treatment responses.