Patterns of IgA Autoantibody Generation, Inflammatory Responses and Extracellular Matrix Metabolism in Patients with Alcohol Use Disorder.

Recent data have emphasized the role of inflammation and intestinal immunoglobulin A (IgA) responses in the pathogenesis of alcoholic liver disease (ALD). In order to further explore such associations, we compared IgA titers against antigens targeted to ethanol metabolites and tissue transglutaminase with pro- and anti-inflammatory mediators of inflammation, markers of liver status, transferrin protein desialylation and extracellular matrix metabolism in alcohol-dependent patients with or without liver disease and in healthy controls. Serum IgAs against protein adducts with acetaldehyde (HbAch-IgA), the first metabolite of ethanol, and tissue transglutaminase (tTG-IgA), desialylated transferrin (CDT), pro- and anti-inflammatory cytokines, markers of liver status (GT, ALP) and extracellular matrix metabolism (PIIINP, PINP, hyaluronic acid, ICTP and CTx) were measured in alcohol-dependent patients with (n = 83) or without (n = 105) liver disease and 88 healthy controls representing either moderate drinkers or abstainers. In ALD patients, both tTG-IgA and HbAch-IgA titers were significantly higher than those in the alcoholics without liver disease (p < 0.0005 for tTG-IgA, p = 0.006 for Hb-Ach-IgA) or in healthy controls (p < 0.0005 for both comparisons). The HbAch-IgA levels in the alcoholics without liver disease also exceeded those found in healthy controls (p = 0.0008). In ROC analyses, anti-tTG-antibodies showed an excellent discriminative value in differentiating between ALD patients and healthy controls (AUC = 0.95, p < 0.0005). Significant correlations emerged between tTG-IgAs and HbAch-IgAs (rs = 0.462, p < 0.0005), CDT (rs = 0.413, p < 0.0001), GT (rs = 0.487, p < 0.0001), alkaline phosphatase (rs = 0.466, p < 0.0001), serum markers of fibrogenesis: PIIINP (rs = 0.634, p < 0.0001), hyaluronic acid (rs = 0.575, p < 0.0001), ICTP (rs = 0.482, p < 0.0001), pro-inflammatory cytokines IL-6 (rs = 0.581, p < 0.0001), IL-8 (rs = 0.535, p < 0.0001) and TNF-α (rs = 0.591, p < 0.0001), whereas significant inverse correlations were observed with serum TGF-ß (rs = -0.366, p < 0.0001) and CTx, a marker of collagen degradation (rs = -0.495, p < 0.0001). The data indicate that the induction of IgA immune responses toward ethanol metabolites and tissue transglutaminaseis a characteristic feature of patients with AUD and coincides with the activation of inflammation, extracellular matrix remodeling and the generation of aberrantly glycosylated proteins. These processes appear to work in concert in the sequence of events leading from heavy drinking to ALD.

Blood Cell Responses Following Heavy Alcohol Consumption Coincide with Changes in Acute Phase Reactants of Inflammation, Indices of Hemolysis and Immune Responses to Ethanol Metabolites.

Aberrations in blood cells are common among heavy alcohol drinkers. In order to shed further light on such responses, we compared blood cell status with markers of hemolysis, mediators of inflammation and immune responses to ethanol metabolites in alcohol-dependent patients at the time of admission for detoxification and after abstinence. Blood cell counts, indices of hemolysis (LDH, haptoglobin, bilirubin), calprotectin (a marker of neutrophil activation), suPAR, CD163, pro- and anti-inflammatory cytokines and autoantibodies against protein adducts with acetaldehyde, the first metabolite of ethanol, were measured from alcohol-dependent patients (73 men, 26 women, mean age 43.8 ± 10.4 years) at baseline and after 8 ± 1 days of abstinence. The assessments also included information on the quantities of alcohol drinking and assays for biomarkers of alcohol consumption (CDT), liver function (AST, ALT, ALP, GGT) and acute phase reactants of inflammation. At baseline, the patients showed elevated values of CDT and biomarkers of liver status, which decreased significantly during abstinence. A significant decrease also occurred in LDH, bilirubin, CD163 and IgA and IgM antibodies against acetaldehyde adducts, whereas a significant increase was noted in blood leukocytes, platelets, MCV and suPAR levels. The changes in blood leukocytes correlated with those in serum calprotectin (p < 0.001), haptoglobin (p < 0.001), IL-6 (p < 0.02) and suPAR (p < 0.02). The changes in MCV correlated with those in LDH (p < 0.02), MCH (p < 0.01), bilirubin (p < 0.001) and anti-adduct IgG (p < 0.01). The data indicates that ethanol-induced changes in blood leukocytes are related with acute phase reactants of inflammation and release of neutrophil calprotectin. The studies also highlight the role of hemolysis and immune responses to ethanol metabolites underlying erythrocyte abnormalities in alcohol abusers.

Differentiating middle-aged long-term and short-term frequent attenders by means of the Northern Finland Birth Cohort 1966 Study.

BACKGROUND: Frequent attendance is largely a temporary phenomenon, but only few previous studies have made a distinction between long-term frequent attenders (FAs) and short-term FAs. AIMS: The aim of this study is to compare the characteristics of middle-aged long-term FAs and short-term FAs. METHODS: Data from a large Northern Finland Birth Cohort 1966 study's (NFBC1966) 46-year follow-up study (performed in 2012, N = 10 321) were used. The participants (n = 4390) had used public primary healthcare (PPHC) services at least once during 2013-2016 according to Finnish national register data on outpatient visits. A FA was considered a patient who had used PPHC services ≥8 times during 1 year. A long-term FA: a patient who was a FA in at least 3 years during 2013-2016. A short-term FA: a patient who was a FA in 1 or 2 years in 2013-2016. Cross-tabulation, Pearson's chi-squared test, Mann-Whitney U test, and univariate and multivariate binary logistic regression analyses were used. RESULTS: Of the 4390 participants, 132 (3.0%) were long-term FAs, 645 (14.7%) were short-term FAs, and 3613 (82.3%) were non-FAs. During 2013-2016, long-term FAs accounted for 34.8% of PPHC visits, while short-term FAs accounted 15.4%. Compared to short-term FAs, depression and high income (preventive attribute) were associated with long-term FAs. Female gender and managing usual activities were associated with short-term FAs. Poor self-reported health was associated with both long-term FAs and short-term FAs but increased the risk of being a long-term FA over three times compared to short-term FAs. CONCLUSIONS: Middle-aged long-term FAs and short-term FAs have distinct characteristics; namely, depression and high income differentiate long-term FAs from short-term FAs. Poor self-reported health was associated with long-term FAs in particular. In order to identify FAs with prolonged service needs and to develop far-reaching interventions, the focus of research should be on long-term FAs.

Thioredoxin-1 as a biological predictive marker for selecting diffuse large B-cell lymphoma patients for etoposide-containing treatment.

OBJECTIVE: In diffuse large B-cell lymphoma (DLBCL), there is an unmet medical need to select patients who would benefit from intensified frontline treatments such as adding etoposide to an R-CHOP regimen. METHODS: The present work included a retrospective clinical analysis of two patient cohorts and an in vitro study. Primary biopsy samples from DLBCL patients treated with an etoposide-containing high-dose regimen (n = 37) and etoposide-containing frontline treatment (n = 69, R-CHOEP) were studied using immunohistochemical thioredoxin-1 (Trx1) staining. Two DLBCL cell lines expressing Trx1 were cultured, and their expression was silenced using the small interfering RNA knockdown technique. Chemoresistance was tested with doxorubicin, etoposide, vincristine, prednisolone and carboplatin. RESULTS: Thioredoxin-1 knockdown sensitised DLBCL cells to doxorubicin (P < .0001) but decreased etoposide-induced cell death (P < .00001). In DLBCL patients who received etoposide-containing frontline treatment, low cytoplasmic Trx1 expression was associated with inferior 5-year overall survival (46% vs 76%, P = .026) and disease-specific survival (68% vs 90%, P = .026). CONCLUSIONS: Strong Trx1 expression appears to increase drug resistance to doxorubicin but sensitises cells to etoposide. This implies that Trx1 expression might be the first predictive biological marker to select the patients who might benefit from adding etoposide to R-CHOP immunochemotherapy.

Combined effects of lifestyle risk factors on fatty liver index.

BACKGROUND: Factors of lifestyle may have a major impact on liver-related morbidity and mortality. We examined independent and joint effects of lifestyle risk factors on fatty liver index (FLI), a biomarker of hepatic steatosis, in a population-based cross-sectional national health survey. METHODS: The study included 12,368 participants (5784 men, 6584 women) aged 25-74 years. Quantitative estimates of alcohol use, smoking, adiposity and physical activity were used to establish a total score of risk factors, with higher scores indicating an unhealthier lifestyle. FLI was calculated based on an algorithm including body mass index, waist circumference, serum gamma-glutamyltransferase and triglycerides. RESULTS: The occurrence of FLI ≥ 60% indicating fatty liver increased from 2.4% in men with zero risk factors to 81.9% in those with a total risk score of 7-8 (p <  0.0005 for linear trend) and in women from 0 to 73.5% (p <  0.0005). The most striking individual impacts on the likelihood for FLI above 60% were observed for physical inactivity (p <  0.0005 for both genders) and alcohol consumption (p <  0.0005 for men). Interestingly, coffee consumption was also found to increase with increasing risk factor scores (p <  0.0005 for linear trend in both genders). CONCLUSIONS: The data indicates that unfavorable combinations of lifestyle risk factors lead to a high likelihood of hepatic steatosis. Use of FLI as a diagnostic tool may benefit the assessment of interventions aimed at maintaining a healthy lifestyle and prevention of liver-related morbidity.

Comparison of optic disc evaluation methods in neurology emergency patients.

BACKGROUND: The optic disc examination is critical for the diagnostics of several acute neurological disorders. However, dilation of the pupil is not recommended for neurological patients, which complicates ophthalmoscopy. AIMS OF THE STUDY: Present pilot study compared a portable fundus camera to an ophthalmoscope in fundus examinations of neurological emergency patients. To our knowledge, this is the first comparative study of the subject. The fundus photographs were later reviewed with an ophthalmologist. METHODS: The study included 60 adults, volunteer neurological emergency patients with either headache, cerebrovascular disorder, or acute confusional state (delirium). Patients' non-mydriatic fundus examination was conducted with an ophthalmoscope and a Smartscope Pro fundus camera. RESULTS: Fundus photography succeeded in 56 (93%), partially succeeded in 2 (3%), and failed in 2 (3%) cases compared with ophthalmoscopy that succeeded in 35 (58%), partially succeeded in 14 (23%), and failed in 11 (18%) cases (P < .0005). The researcher and the ophthalmologist agreed in the findings in 54 out of 58 cases (93%). In six cases (7%), the researcher had failed to detect a non-critical ophthalmic finding. CONCLUSIONS: The neurological fundus examination by fundus camera seems to be superior to regular ophthalmoscopy in defining the critical optic disc findings in emergency patients.

Bronchoalveolar cell differential count and the number of asbestos bodies correlate with survival in patients with asbestosis.

OBJECTIVES: To determine cell differential counts and the number of asbestos bodies (ABs) in bronchoalveolar lavage (BAL) fluid obtained from patients with asbestosis, and to correlate the results with their survival. METHODS: The BAL cell differential counts and ABs from 91 patients with asbestosis were determined. The BAL cell differential counts were analysed in relation to smoking status. BAL cell differential counts and the number of ABs were correlated with the patients' survivals. RESULTS: A neutrophilic cell pattern was observed independently of smoking habits with both Papanicolau (8.4%) and May-Grunwald-Giemsa (6.5%) staining. Smoking and a high number of ABs (>2 AB/mL) were associated with high total cell counts and high macrophage and low lymphocyte differential counts. The median survival of the patients was 131.8 months. Shortened survival was associated with high numbers of ABs (78 vs 165 months; p=0.042) and low lymphocyte (77 vs 179 months; p=0.005), high neutrophil (102 vs 180 months; p=0.016) and high eosinophil (104 vs170 months; p=0.007) differential counts. CONCLUSION: A neutrophilic cell pattern was evident in BAL from patients with asbestosis. Smoking and ABs both affected the total cell count and the macrophage and lymphocyte differential counts. Several BAL parameters associated with patient survival, suggesting that BAL cell count analyses could be used in the estimation of the prognosis of patients with asbestosis.

Assessment of alcohol consumption in depression follow-up using self-reports and blood measures including inflammatory biomarkers.

AIMS: Alcohol consumption has been suggested a major role in the pathogenesis and prognosis of depression. However, reliable identification of hazardous drinking continues to be problematic. We compared the accuracy of different biomarkers and self-reports of alcohol consumption in the follow-up study of depression. METHODS: Data from 202 patients with major depressive disorder were obtained through self-reports, AUDIT and AUDIT-C questionnaires and biomarker analyses. The clinical assessments and measurements of biomarkers (GT, CDT, GT-CDT-combination, MCV, ALT, AST, hs-CRP, IL-6) were performed at baseline and after six months of treatment. Based on self-reported alcohol intake at baseline the patients were classified to three subgroups. RESULTS: About 27.2% of patients were categorized to high-risk drinkers, 26.3% low-risk drinkers and 46.5% abstainers. High-risk drinkers showed significantly higher mean values of GT, CDT, GT-CDT-combination and IL-6 than abstainers, diagnostic accuracy being highest with the combined marker of GT-CDT. The accuracy of AUDIT and AUDIT-C to detect high-risk drinking was also significant. During follow-up, the differences observed in the biomarkers at baseline disappeared together with recovery from depression. CONCLUSIONS: Our data suggest the combined use of GT-CDT and AUDIT questionnaires to improve the identification of drinking of patients with depression. This approach could be useful for improving treatment adherence and outcome in depressed patients.

Laboratory test based assessment of WHO alcohol risk drinking levels.

Low-risk thresholds for alcohol use differ across various national guidelines. To assess the novel WHO risk drinking levels in light of alcohol-sensitive common laboratory tests, we analysed biomarkers of liver status, inflammation and lipid profiles from a population-based survey of individuals classified to abstainers and different WHO risk drinking levels defined in terms of mean alcohol consumption per day. The study included 22,327 participants aged 25-74 years from the National FINRISK Study. Data on alcohol use, health status, diet, body weight and lifestyle (smoking, coffee consumption and physical activity) were recorded from structured interviews. Alcohol data from self-reports covering the past 12 months were used to categorize the participants into subgroups of abstainers and WHO risk drinking categories representing low, moderate, high and very high risk drinkers. Serum liver enzymes (GGT, ALT), C-reactive protein (CRP) and lipid profiles were measured using standard laboratory techniques. Alcohol risk category was roughly linearly related with the occurrence of elevated values for GGT, ALT and CRP. Alcohol drinking also significantly influenced the incidence of abnormalities in serum lipids. Significantly higher odds for abnormal GGT, ALT and altered lipid profiles remained in alcohol drinkers even after adjustment for age, waist circumference, physical inactivity, smoking and coffee consumption. A more systematic use of laboratory tests during treatment of individuals classified to WHO risk drinking categories may improve the assessment of alcohol-related health risks. Follow-ups of biomarker responses may also prove to be useful in health interventions aimed at reducing alcohol consumption.

Hormone profiling, including anti-Müllerian hormone (AMH), for the diagnosis of polycystic ovary syndrome (PCOS) and characterization of PCOS phenotypes.

Objective was to evaluate serum anti-Müllerian hormone (AMH) levels in polycystic ovary syndrome (PCOS) and in its different phenotypes in relation to clinical, endocrine and metabolic parameters using a new automated VIDAS® method and to compare it with the Gen II method. Study design was multi-center study including 319 PCOS women and 109 healthy controls. Serum AMH levels measured using VIDAS® were significantly higher in PCOS women than controls (p < .001), and they correlated with those measured using the AMH Gen II method. An AMH cutoff value of 42.1 pmol/L distinguished PCOS women from controls with 67% sensitivity and 83% specificity. The PCOS women with three Rotterdam criteria or hyperandrogenism displayed significantly higher AMH levels compared with those with two Rotterdam criteria or normoandrogenism. In PCOS, AMH levels correlated positively with luteinizing hormone (LH), androgen and sex hormone-binding globulin (SHBG) levels and negatively with BMI, abdominal obesity, follicle-stimulating hormone (FSH), fasting glucose and insulin, and insulin resistance. In conclusion, AMH evaluated using the VIDAS® method distinguished PCOS patients from healthy controls relatively well, especially in those with more severe phenotypes. Further studies are needed to establish whether AMH measurements can distinguish PCOS patients with different metabolic risk factors.

Non-dipping blood pressure pattern and new-onset diabetes in a 21-year follow-up.

Purpose: Non-dipping blood pressure (BP) pattern has been associated with metabolic changes and cardiovascular events. With regard of diabetes, studies are scarce. Our aim was to investigate if there is an association between changes in dipping patterns and incidence of diabetes. Materials and methods: A 24-h ambulatory BP measurement was recorded in addition to other laboratory measurements, and a questionnaire and physical examination were carried out in the baseline study and after 21-year follow-up among a study population (n = 449) consisting of randomly selected middle-aged Finnish females and males without diabetes. Results: 128 (28.5%) developed diabetes during the follow-up. The incidence of new-onset diabetes was the highest, 41.0%, among those subjects who were non-dippers (their systolic BP declined <10% from daytime to nighttime) in the baseline and also in the follow-up study, while the incidence of diabetes was 19.6% in the dipper - dipper (a nighttime decline of systolic BP 10% or more) group (p = 0.003). The difference remained statistically significant after adjustment with age, sex, body mass index, fasting glucose, triglycerides, and insulin levels, smoking status, 24-h mean systolic BP, high-sensitivity C-reactive protein, estimated glomerular filtration and diuretics use. In logistic regression analysis, the non-dipper - non-dippers were at higher risk of diabetes compared with dipper - dipper group (OR = 2.27, 95% CI: 1.13-4.56, p = 0.022). Conclusions: Our prospective study shows that there is an independent association between non-dipping BP pattern and the incidence of diabetes in a 21-year follow-up.

Life style habits, biochemical factors and their interaction in the prediction of incident hypertension during 21-year follow-up.

BACKGROUND: Hypertension is a global health threat and major cardiovascular risk. Various risk-prediction models for incident hypertension have been developed but not many of them have studied the risk-predictive value of life style factors in combination with cardiovascular biomarkers during long-term period of over 10 years. METHODS: We examined differences in several classical variables for 299 subjects in OPERA (Oulu Project Elucidating Risk of Atherosclerosis) cohort in subjects with no or new hypertension during a follow-up period of 21 years. Effect of both various life style habits and biomarkers were investigated. RESULTS: Baseline blood pressure, being overweight and smoking actively were independent predictors of new hypertension in majority of multivariate models during long-term follow-up of 21 years in subjects without previous hypertension. Increased high-sensitive C-reactive protein (hsCRP) level (> 3 mg/L) was the strongest predictor of incident hypertension in univariate model. Subjects with two or all three of main risk factors (being overweight, smoking actively and having high hsCRP) had 4-fold risk for incident hypertension. CONCLUSIONS: Smoking, overweight and increased hsCRP level had risk-predictive value in incident hypertension prediction during long-term follow-up of 21 years. Assessment and measurement of these parameters could be used in help of detecting high risk subjects and primary prevention of hypertension very early on. In addition, the study shows that blood pressure at the middle-age should be followed and treated intensively to prevent hypertension in the older age. KEY MESSAGES: Baseline blood pressure, being overweight and smoking actively are independent predictors of new hypertension during a long-term follow-up of 21 years. Having two or all three risk factors (smoking actively, body mass index over 25 kg/m2, high-sensitive C-reactive protein (hsCRP) level over 3 mg/L) indicates a 4-fold risk for incident hypertension within 21-year follow-up.

Stroke Volume Predicts Nocturnal Hypoxemia in the Acute Ischemic Stroke after Intravenous Thrombolysis.

The Goal: The aim of the study was to investigate whether stroke volume or the presence of ischemic stroke lesion on follow-up computed tomography 1 day after admission had association with sleep apnea among ischemic stroke patients undergoing thrombolysis. MATERIALS AND METHODS: We prospectively recruited 110 consecutive ischemic stroke patients and performed computed tomography on admission and after 24 hours after intravenous thrombolysis. Stroke volume was measured from post-thrombolysis computed tomography scans. Unattended cardiorespiratory polygraphy with a 3-channel device was performed during 48 hours after admission. FINDINGS: Of 110 ischemic stroke patients treated with thrombolysis 65.5% were men. Mean age was 65.8 years and body mass index 27.5 kg/m2. The mean Epworth sleepiness scale score was 4.7. Eight patients (12.7%) with visible acute stroke after thrombolysis and none in the other group had hemorrhage as complication (P ˂ .001). Sleep apnea, determined as a respiratory event index greater than or equal to 5/hour, was diagnosed in 96.4% patients. Respiratory event index greater than 15/h was found in 72.8% of patients. Both mean baseline oxygen desaturation index (23.9 versus 16.5, P = .028) and obstructive apneas/hour (6.2 versus 2.7, P = .007) were higher in visible stroke group. Stroke volume (mean 15.9 mL) correlated with proportion of time spent below saturation less than 90%, P = .025. CONCLUSIONS: Acute ischemic stroke patients treated with thrombolysis with visible stroke were more likely to have nocturnal hypoxemia than patients with not visible strokes. Stroke volume correlated with time spent below saturation of 90%.

Tenascin-C and fibronectin expression divide early stage tongue cancer into low- and high-risk groups.

BACKGROUND: Oral tongue squamous cell carcinoma (OTSCC) metastasises early, especially to regional lymph nodes. There is an ongoing debate on which early stage (T1-T2N0) patients should be treated with elective neck dissection. We need prognosticators for early stage tongue cancer. METHODS: Mice immunisation with human mesenchymal stromal cells resulted in production of antibodies against tenascin-C (TNC) and fibronectin (FN), which were used to stain 178 (98 early stage), oral tongue squamous cell carcinoma samples. Tenascin-C and FN expression in the stroma (negative, moderate or abundant) and tumour cells (negative or positive) were assessed. Similar staining was obtained using corresponding commercial antibodies. RESULTS: Expression of TNC and FN in the stroma, but not in the tumour cells, proved to be excellent prognosticators both in all stages and in early stage cases. Among early stages, when stromal TNC was negative, the 5-year survival rate was 88%. Correspondingly, when FN was negative, no cancer deaths were observed. Five-year survival rates for abundant expression of TNC and FN were 43% and 25%, respectively. CONCLUSIONS: Stromal TNC and, especially, FN expressions differentiate patients into low- and high-risk groups. Surgery alone of early stage primary tumours might be adequate when stromal FN is negative. Aggressive treatments should be considered when both TNC and FN are abundant.

Bone markers in polycystic ovary syndrome: A multicentre study.

OBJECTIVE: Hyperandrogenism, hyperinsulinaemia and obesity, known characteristics of polycystic ovary syndrome (PCOS), may influence bone mineral density and biochemical markers of bone turnover (BTMs) can provide a noninvasive assessment of bone turnover. To this end, the serum concentrations of BTMs and 25-hydroxyvitamin D (25OHD) were analysed in women with PCOS, and their possible associations with metabolic parameters of PCOS were determined. SUBJECTS AND METHODS: Bone formation markers procollagen type I amino-terminal propeptide (PINP) and osteocalcin (OC), and bone resorption marker carboxy-terminal cross-linking telopeptide of type I collagen (CTX), along with 25OHD, were measured in 298 women with PCOS and 194 healthy controls. RESULTS: Serum levels of PINP (47.0 ± 20.2 vs 58.1 ± 28.6 µg/L, P < .001) and OC (18.2 ± 7.5 vs 20.6 ± 9.8 µg/L, P < .001) were decreased in women with PCOS compared with controls, whereas no significant differences were found in CTX and 25OHD levels. Age-stratified analyses suggested that PINP (50.5 ± 21.7 vs 68.2 ± 26.6 µg/L, P < .001) and OC levels (20.4 ± 7.6 vs 25.5 ± 9.6 µg/L, P < .001) were decreased only in the younger age group (≤30 years) women with PCOS compared with controls. The formation markers and resorption marker decreased with age in both study groups. CONCLUSIONS: Bone formation markers were decreased in younger women with PCOS when compared with healthy women, which may affect bone mass in these women.

Histological features of malignancy correlate with growth patterns and patient outcome in lung adenocarcinoma.

AIMS: Until the launch of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society adenocarcinoma classification in 2011, there were no uniform histological grading criteria for pulmonary adenocarcinomas. The current classification highlights the prognostic importance of the various histological growth patterns observed in these morphologically heterogeneous neoplasias. In this study, we aimed to evaluate the classic histological parameters of malignancy in correlation with the growth patterns and patient outcomes in a series of 112 surgically operated stage I-IV lung adenocarcinomas. METHODS AND RESULTS: Architectural growth pattern analysis was performed according to the current adenocarcinoma classification. Histological features including, for example, nuclear atypia, mitotic activity, tumour necrosis, and different patterns of invasion were assessed and correlated statistically with the architecture and the clinical data. A solid predominant histology was associated with increased levels of atypia (P = 0.027), mitotic activity (P < 0.001), necrosis (P < 0.001), and lymphovascular invasion (P = 0.001), and a non-predominant solid pattern was associated with intra-alveolar tumour spread (P = 0.004). The presence of a non-predominant lepidic tumour component showed inverse correlations with atypia (P = 0.002), mitotic rate (P = 0.009), and tumour necrosis (P < 0.001). Tumour size (P < 0.001), mitotic activity (P = 0.019), tumour necrosis (P = 0.002), lymphovascular invasion (P = 0.001) and visceral pleural involvement (P = 0.001) were all associated with reduced disease-specific survival. CONCLUSIONS: The classic histological features of malignancy correlate with tumour architecture and patient outcome, confirming the prognostic value of the growth pattern analysis and questioning the need for a parallel grading system in pulmonary adenocarcinoma.

Posterior Transvaginal Mesh without Concurrent Surgery: How Does It have an Effect on the Untreated Vaginal Compartment?

BACKGROUND/AIMS: To report objective and subjective outcomes and adverse events after placement of Elevate® Posterior transvaginal mesh without concurrent surgery. Changes in non-affected anterior compartment were under special interest. METHODS: A prospective study of Elevate® Posterior procedure in patients with symptomatic posterior compartment prolapse. Pelvic organ prolapse (POP) quantification (POP-Q) measurements and Pelvic Floor Dysfunction Inventory-20 (PFDI-20) and POP/urinary Incontinence Sexual Questionnaire (PISQ-12) questionnaires were used. Primary outcome was the incidence of de novo anterior prolapse. Secondary outcomes were complication rate and posterior compartment objective and subjective cure. RESULTS: A total of 111 women underwent an Elevate® Posterior mesh procedure and 109 attended a control visit at 3 months. De novo anterior prolapse emerged in 3.2-15% of the women, depending on the definition. Posterior POP-Q stage ≤I was obtained in 92 (84%) women and leading edge at or above the hymen in 107 (98%) women. Bulge symptoms disappeared in 86% of the cases. One (0.9%) mesh exposure was detected. Reoperation rate was 2.8, and 3.7% patients experienced postoperative pain. PFDI-20 and PISQ-12 scores improved significantly. CONCLUSIONS: A trend of de novo prolapse formation in the non-affected vaginal compartment is observed. The Elevate® Posterior method is effective in terms of both objective and subjective outcomes. According to our results, the mesh exposure rate is low.

Do child healthcare professionals and parents recognize social-emotional and behavioral problems in 1-year-old infants?

Growing evidence supports the existence of clinically significant social-emotional/behavioral (SEB) problems among as young as 1-year-old infants. However, a substantial proportion of early SEB problems remain unidentified during contacts with child healthcare professionals. In this study, child healthcare nurse (CHCN; N = 1008) and parental (N = 518) reports about SEB worries were gathered, along with the maternal and paternal Brief Infant-Toddler Social and Emotional Assessment (BITSEA) ratings, for 12-month-old infants randomly recruited through Finnish child health centers. Only 1.4-1.8 % of CHCNs, 3.9 % of mothers, and 3.2 % of fathers reported of being worried about the assessed child's SEB development. When the CHCNs' and parental reports were combined, 7.7 % (33/428) of the infants assessed each by all three adults had one (7.0 %), two (0.7 %) or three (0 %) worry reports. Even the combination of the CHCN's and parental worry reports identified only 7.0-13.8 % of the infants with the maternal and/or paternal BITSEA Problem or Competence rating in the of-concern range. Identified associations across the three informants' worry reports, parental BITSEA ratings and sociodemographic factors are discussed in the paper. Routine and frequent use of developmentally appropriate screening measures, such as the BITSEA, might enhance identification and intervening of early SEB problems in preventive child healthcare by guiding both professionals and parents to pay more attention to substantial aspects of young children's SEB development and encouraging them to discuss possible problems and worries.

PARENTAL REPORTS OF EARLY SOCIOEMOTIONAL AND BEHAVIORAL PROBLEMS: DOES THE FATHER'S VIEW MAKE A DIFFERENCE?

Although both mothers and fathers are essential sources of information to address early socioemotional/behavioral (SEB) problems, there continues to be a dearth of studies considering both parental views. A sample of 208 toddlers (Mage = 19.3 months) was recruited through public child health centers. Both parents of 172 toddlers (76 boys, 96 girls) completed the Child Behavior Checklist (CBCL) 1-5 (T.M. Achenbach & L.A. Rescorla, 2000; Finnish translation by F. Almqvist, ). Correspondence (intraclass correlation coefficients; ICCs) between the maternal and paternal CBCL ratings was good (.64) for the Internalizing and excellent (.76) for the Externalizing and Total Problems scores whereas ICCs varied from .45 for the Withdrawn to .76 for the Sleep Problems and Aggressive Behavior syndrome scores. Regarding discrepancies, mothers consistently reported higher CBCL scale scores than did fathers. Most significant differences between the parental ratings were found on the Aggressive Behavior syndrome, Externalizing, and Total Problems scales. Interparental rating discrepancies increased with elevations in the corresponding CBCL scale scores. Positive correlations were found between maternal, but not paternal, parenting stress and interparental rating discrepancies on the CBCL. The observed differences between maternal and paternal ratings highlight the importance of gathering reports from both parents when assessing early SEB problems. The findings are more profoundly discussed in the article.

The relationships between serum cytokine levels and tumor infiltrating immune cells and their clinical significance in colorectal cancer.

Increased inflammatory cell infiltration correlates to improved survival in colorectal cancer (CRC). Development and progression of CRC is associated with alterations in serum cytokine levels but their significance is not well defined. In this study, we investigated the relationships between the serum levels of 13 cytokines and the densities of eight types of tumor infiltrating inflammatory cells and their impact on disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS) in a prospectively recruited group of 147 CRC patients. There were strong positive correlations between the serum concentrations of different cytokines, as well as between the different types of tumor infiltrating immune cells, whereas the associations between serum cytokines and tumor infiltrating immune cells were generally weak. High serum IL-12 levels associated with increased densities of peritumoral CD8(+) T cells, intraepithelial CD3(+) T cells and intratumoral neutrophils, while high serum CCL4 levels associated with increased densities of peritumoral CD68(+) cells. In multivariate survival models, increased infiltration of intraepithelial CD3(+) T cells and increased serum CCL4 associated with improved DFS, whereas higher intratumoral CD83(+) dendritic cell density and increased serum interferon gamma levels associated with improved CSS and OS. Also high density of peritumoral CD3(+) T cells associated with improved CSS. In conclusion, serum cytokines and tumor infiltrating immune cells in CRC represent entities with high intragroup correlations but relatively weak intergroup correlations. The results suggest that tumor infiltrating CD3(+) T cells, CD83(+) dendritic cells, serum CCL4 and serum interferon gamma represent relevant markers of disease outcome.