Simultaneous progression of oxidative stress and angiogenesis in malignant transformation of Barrett esophagus

BACKGROUND: Oxidative stress and angiogenesis are important elements in the pathogenesis of inflammatory diseases and cancer. Our aim was to evaluate the role of both and of antioxidant capacity in the metaplasia-dysplasia-adenocarcinoma sequence in Barrett epithelium. METHODS: In mucosal specimens from 59 patients grouped as having symptomatic gastroesophageal reflux disease, Barrett epithelium, or adenocarcinoma in the esophagus, plus controls, we measured myeloperoxidase activity, superoxidase dismutase activity, glutathione content, and total aromatic DNA adducts. To evaluate blood vessel densities and angioarchitecture, we used immunohistochemistry and a modified whole-mount technique. Sections were stained with endothelium-specific markers and smooth muscle cell actin. RESULTS: The reflux disease-metaplasia-carcinoma sequence revealed progressively increased oxidative stress (increased myeloperoxidase activity), decreased antioxidant capacity (glutathione content), and simultaneous formation of DNA adducts. Pooled data show a negative correlation between glutathione content and DNA adducts (-0.28; P =.05). This sequence was also characterized by increased intensity in microvessels and an increasing percentage of immature blood vessels. In addition, the whole-mount technique offered 3-dimensional evidence that the rich new vascular bed is highly abnormal, with repeated twists, bends, or turns, even in nonmalignant Barrett esophagus. CONCLUSIONS: Increased oxidative stress, decreased antioxidant capacity, and a negative correlation between glutathione content and DNA adduct formation indicate a link between oxidative stress and malignant transformation of Barrett epithelium. Simultaneously, this transformation acquires angiogenic capacity, strong neovascularization, and abnormal angioarchitecture.     

Aetiology of neonatal conjunctivitis evaluated in a population‐based setting

Aim

Our aim was to study prospectively the aetiology of neonatal conjunctivitis in a population‐based setting.

Methods

Altogether 173 neonates with clinical conjunctivitis aged on average 20 (SD 10) days were recruited from child welfare clinics in Oulu, Finland, in 2010–2015. Conjunctival specimens were collected from 167 neonates for multiplex polymerase chain reaction to detect 16 respiratory viruses, from 163 for polymerase chain reaction to detect Chlamydia trachomatis and Neisseria gonorrhoeae and from 160 for bacterial culture studies. The cases were followed up until the age of 18 months.

Results

Viral conjunctivitis was diagnosed in 8/167 (4.8%; 95% CI 2.1–9.2%), chlamydial or gonococcal conjunctivitis in 0/163 cases (0%; 95% CI 0–2.2%) and other bacterial conjunctivitis in 58/160 (36%; 95% CI 29–44%). Rhinovirus was found at the ocular site in 4/167 (2.4%) neonates, adenovirus in 3/167 (1.8%) and bocavirus in 1/167 (0.6%). The most commonly isolated bacteria included Staphylococcus aureus (16%), Moraxella catarrhalis (9.4%) and Streptococcus pneumoniae (3.1%). None of these pathogens was associated with the 4/173 (2.3%) cases later operated on for persistent nasolacrimal duct obstruction.

Conclusion

Chlamydia trachomatis was a rare pathogen in neonatal conjunctivitis in a population‐based setting, but respiratory viruses were detected more frequently than indicated earlier.

     

Prevalence of adverse drug combinations in a large post-mortem toxicology database

The prevalence of important adverse drug combinations was studied among the 37,367 cases included in the Finnish post-mortem toxicology database during 2000–2006. The new SFINX interaction database (Swedish, Finnish, INteraction X-referencing) was utilised to identify adverse drug combinations. Consequently, the 24 drugs chosen for the study generated 96 two-compound combinations possessing potentially severe interactions. The total number of hits for the combinations found in the post-mortem database was 267, which accounts for approximately 0.71% of all cases. The potential role of adverse drug interaction (ADI) in these cases was evaluated from the background information and death certificate. The possible ADI cases comprised 23% of all hits and 0.17% of all cases analysed. In cases with a pharmacodynamic mechanism, the most prominent combinations were medicines causing serotonin syndrome or a β₁-blocker with verapamil or diltiazem. In cases with a pharmacokinetic mechanism, half of the cases involved digoxin in combination with verapamil. In one third of the possible ADI cases, a forensic pathologist had noted the studied compounds as an underlying or contributing cause of death, although the agents’ specific role in ADIs was rarely recognised. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Prenatal diagnosis of vein of Galen malformation: a multidisciplinary challenge

Vein of Galen aneurysmal malformation (VGAM) is a rare congenital arteriovenous malformation of the choroid plexus situated within the roof of the third ventricle. If large, it leads to an extracardiac left-to-right shunt featuring as a high output heart failure in the neonate. In our case of VGAM, hypoxic-ischemic brain lesions due to the steal phenomenon could be demonstrated prenatally. In a multidisciplinary clinical setting, withdrawal of active care and initiation of good end-of-life care was decided on and carried through.     

Do Headache and Abdominal Pain in Childhood Predict Suicides and Severe Suicide Attempts? Finnish Nationwide 1981 Birth Cohort Study

This study investigated associations between pain symptoms in mid-childhood and severe suicidality in adolescence and early adulthood. Severe suicidality was defined as completed suicide or suicidal attempt requiring hospital admission. In a nationwide prospective population-based study (n = 6,017), parents and children were asked about the child’s headache and abdominal pain at age eight. The outcome was register-based data on suicide or suicidal attempt requiring hospital treatment by age 24. Family composition, parental educational level, and the child’s psychiatric symptoms reported by the child, parents and teacher at baseline were included as covariates in statistical analyses. Boys’ abdominal pain reported by the parents was associated with later severe suicidality after adjusting for family composition, parental educational level, and childhood psychiatric symptoms at baseline. In addition, the association between boys’ own report of headache and later severe suicidality reached borderline significance in unadjusted analysis. Girls’ pain symptoms did not predict later severe suicidality.     

Tamoxifen Impairs Both Longitudinal and Cortical Bone Growth in Young Male Rats

Tamoxifen (Tam) has been used experimentally to treat boys with gynecomastia and girls with McCune‐Albright syndrome. This drug was recently shown to inhibit the growth of cultured fetal rat metatarsal bones and thus might also affect bone growth in vivo. Four‐week‐old Sprague‐Dawley rats were gavaged daily with vehicle alone (peanut oil), Tam (40 mg/kg/d; 1 or 4 wk), or estradiol (40 μg/kg/d; 4 wk). Five of the 10 rats in each group were killed after 4 wk and the other five after 14 wk of recovery. Bone growth was followed by repeat DXA scans, whereas other bone parameters and spine length were evaluated by pQCT and X‐ray at the time of death. Four‐week Tam treatment significantly decreased body weight, nose‐anus distance, spinal and tibial bone lengths, trabecular BMD, cortical periosteal circumference, and bone strength and also reduced serum IGF‐I levels (424 ± 54 versus 606 ± 53 ng/ml in control; p < 0.05). Analysis of the tibial growth plate of treated rats showed elevated chondrocyte proliferation (BrdU) and apoptosis (TUNEL), as well as decreases in the number of hypertrophic chondrocytes and in the size of terminal hypertrophic chondrocytes. Despite a complete catch‐up of body weight after 14 wk of recovery, the tibia was still shorter (p < 0.001) and its cortical region was smaller. We conclude that, when administered at a clinically relevant dose, Tam causes persistent retardation of longitudinal and cortical radial bone growth in young male rats. Our findings suggest that this inhibition results from local effects on the growth plate cartilage and systemic suppression of IGF‐I production. Based on these rat data, we believe that Tam, if given to growing individuals, might compromise cortical bone growth, bone strength, and adult height.     

Renal markers cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) in postmortem samples

Purpose

Renal markers may provide valuable information for cause of death (CoD) investigation when assessing the influence of impaired kidney function. A commonly used marker, creatinine (Cr), increases due to kidney injury and is known to be reasonably stable in postmortem (PM) samples. More sensitive markers are needed, as the increase of serum Cr level only occurs after relatively severe renal damage. We evaluated two markers, cystatin C and neutrophil gelatinase-associated lipocalin (NGAL), in addition to Cr. To the best of our knowledge this was the first study to investigate cystatin C and NGAL in a postmortem (PM) context.

Methods

Cr, cystatin C, and NGAL were measured from PM blood in 39 autopsy cases. NGAL was also measured from urine in 16 cases. Cystatin C and NGAL were analyzed using ELISA, Cr measurements were performed with Jaffe method. Correlations of these markers were evaluated.

Results and conclusions

Both, blood cystatin C and NGAL, levels showed significant correlation with Cr (p = 0.05 and p = 0.01, respectively). Cystatin C and NGAL in blood are promising markers for further studies with PM samples.