New drug candidates for depression - a nationwide population-based study.

OBJECTIVE: To investigate whether continued use of non-aspirin NSAID, low-dose aspirin, high-dose aspirin, statins, allopurinol and angiotensin agents decreases the rate of incident depression using Danish nationwide population-based registers. METHODS: All persons in Denmark who purchased the exposure medications of interest between 1995 and 2015 and a random sample of 30% of the Danish population was included in the study. Two different outcome measures were included, (i) a diagnosis of depressive disorder at a psychiatric hospital as in-patient or out-patient and (ii) a combined measure of a diagnosis of depression or use of antidepressants. RESULTS: A total of 1 576 253 subjects were exposed to one of the six drugs of interest during the exposure period from 2005 to 2015. Continued use of low-dose aspirin, statins, allopurinol and angiotensin agents was associated with a decreased rate of incident depression according to both outcome measures. Continued uses of non-aspirin NSAIDs as well as high-dose aspirin were associated with an increased rate of incident depression. CONCLUSION: The findings support the potential of agents acting on inflammation and the stress response system in depression as well as the potential of population-based registers to systematically identify drugs with repurposing potential.

Effect of a stent bandage on the likelihood of incisional infection following exploratory coeliotomy for colic in horses: a comparative retrospective study.

REASONS FOR PERFORMING STUDY: Incisional infections are common in horses after colic surgery. There is a clinical impression that the use of a stent bandage reduces the prevalence of such infections. OBJECTIVE: To determine the effect of a stent bandage on the likelihood of incisional infection after ventral midline exploratory coeliotomy. It was hypothesised that the use of a stent bandage would reduce the likelihood of incisional infection. METHODS: Medical records of horses that underwent exploratory coeliotomy for colic between January 2005 and September 2011 were reviewed. Inclusion criteria were animals that had one ventral midline coeliotomy and had survived at least 10 days after surgery. Horses were categorised into 2 groups:no-stent group and stent group. The following data were collected for each case: age, sex, weight, heart rate, packed cell volume, primary lesion, performance of an enterotomy or intestinal resection, surgical classification, use of local antimicrobials, duration of surgery, intra-abdominal administration of sodium carboxymethylcellulose, intravenous administration of lidocaine, surgeon, use of a stent bandage, duration of stent use, and use of a belly band. Factors associated with the outcome measure 'wound infection' vs. 'no wound infection' were analysed using a generalised linear mixed model for logistic regression with surgeon as a random effect. RESULTS: The inclusion criteria were met in 130 horses: 55 were assigned to the no-stent group and 75 to the stent group. In the no-stent group, 12 (21.8%) horses developed incisional infections, whereas only 2 horses (2.7%) in the stent group had incisional infections. In the stent group, no incisional infections were observed during the last 20 months of the study. Statistical analysis showed that only the effect of the use of a stent bandage was significant (P = 0.005). CONCLUSIONS: The prevalence of incisional infections when a stent bandage was used was 2.7%, a finding that compared favourably to information in the literature. Use of a stent bandage significantly reduced the likelihood of incisional infections. POTENTIAL RELEVANCE: A stent bandage would reduce the likelihood of incisional infection in horses undergoing exploratory coeliotomy for colic.

Infection dynamics of digital dermatitis in first-lactation Holstein cows in an infected herd.

Digital dermatitis (DD) refers to painful lesions primarily affecting the skin in the interdigital region of dairy cattle. The purpose of this study was to evaluate the dynamics of DD in 39 cows, observed at approximately 3-d intervals, for the first 6 mo of lactation. Specifically, the study aimed at evaluating different levels of DD susceptibility in cows, identifying the bacterial colonization of the interdigital skin, and exploring the relationship between clinical DD diagnosis and laboratory findings. Three different susceptibility categories were identified for DD: 1=consistently healthy cow; 2=intermittently infected cow; and 3=consistently infected cow. Susceptibility categories were associated with age at calving. The average age at calving was 775 d (SD ±43.4), with the youngest heifer calving at age 669 d and the oldest heifer at 858 d. Advancing age at calving was associated with greater odds of being intermittently or consistently infected. This corresponded with an odds ratio of 2.02 over a period of 30 d. During the study period, 161 DD lesions were identified in 28 of the 39 cows (72%). Of those 28 cows, 13 cows were consistently infected. The remaining 11 of the 39 cows (28%) showed slight thickening of the skin with no pain (5 cows) and no signs of skin changes (6 cows). Histopathology and fluorescence in situ hybridization were possible to perform on 132 biopsy samples. A clinical diagnosis of DD was confirmed in 70% of the lesions by histopathology, and colonization of Treponema spp. Dichelobacter nodosus was found in 35 samples (29%).

Fasting and oral glucose-stimulated levels of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are highly familial traits.

AIMS/HYPOTHESIS: Heritability estimates have shown a varying degree of genetic contribution to traits related to type 2 diabetes. Therefore, the objective of this study was to investigate the familiality of fasting and stimulated measures of plasma glucose, serum insulin, serum C-peptide, plasma glucose-dependent insulinotropic polypeptide (GIP) and plasma glucagon-like peptide-1 (GLP-1) among non-diabetic relatives of Danish type 2 diabetic patients. METHODS: Sixty-one families comprising 193 non-diabetic offspring, 29 non-diabetic spouses, 72 non-diabetic relatives (parent, sibling, etc.) and two non-related relatives underwent a 4 h 75 g OGTT with measurements of plasma glucose, serum insulin, serum C-peptide, plasma GIP and plasma GLP-1 levels at 18 time points. Insulin secretion rates (ISR) and beta cell responses to glucose, GIP and GLP-1 were calculated. Familiality was estimated based on OGTT-derived measures. RESULTS: A high level of familiality was observed during the OGTT for plasma levels of GIP and GLP-1, with peak familiality values of 74 ± 16% and 65 ± 15%, respectively (h (2) ± SE). Familiality values were lower for plasma glucose, serum insulin and serum C-peptide during the OGTT (range 8-48%, 14-44% and 15-61%, respectively). ISR presented the highest familiality value at fasting reaching 59 ± 16%. Beta cell responsiveness to glucose, GLP-1 and GIP also revealed a strong genetic influence, with peak familiality estimates of 62 ± 13%, 76 ± 15% and 70 ± 14%, respectively. CONCLUSIONS/INTERPRETATION: Our results suggest that circulating levels of GIP and GLP-1 as well as beta cell response to these incretins are highly familial compared with more commonly investigated measures of glucose homeostasis such as fasting and stimulated plasma glucose, serum insulin and serum C-peptide.

Sporting activity following colic surgery in horses: a retrospective study.

REASONS FOR PERFORMING STUDY: There is a paucity of studies addressing sporting activity and horse owners' satisfaction after horses have undergone colic surgery. OBJECTIVES: To determine 1) survival rate after colic surgery, 2) prevalence of horses returning to, or starting, sporting activities and 3) assess the owners' satisfaction regarding colic surgery. METHODS: Cases that underwent exploratory celiotomy for colic between January 2005 and August 2010 were reviewed. All horses that had one or more celiotomies and were discharged after colic surgery were included in a telephone questionnaire survey. Only horses that survived at least 6 months after colic surgery were included in the sporting activity analysis. Data extracted from the records included case details, intra-operative diagnosis and surgical treatment. Information from a telephone questionnaire included the horses' post surgical details (horse alive or subjected to euthanasia, post operative complications, pre- and post surgical use, return to sporting activity, sporting performance, behavioural changes, management changes and recommendation by owner for colic surgery). A logistic regression model was used for the statistical analysis of post hospitalisation performance and an ordinal regression model used for analysis of post colic complications and of owner's recommendation of surgery. A Kaplan-Meier survival curve was computed to show survival of horses discharged after colic surgery. RESULTS: The survival rates (%) at 6, 12, 24, 36, 48 and 60 months were 95.3, 86.6, 80.9, 76.9, 62.1 and 57.6, respectively. A large majority of horses (86.1%) resumed or started sporting activities after colic surgery. The proportion of horses that the owners believed to achieve the same or better performance after surgery was 83.5%. In 89.9% of the cases, owners stated that they would recommend colic surgery. CONCLUSIONS: Horses discharged after colic surgery had a high long-term survival rate. A high prevalence of horses resumed or started sporting activities with a high proportion of horses at their presurgical performance level. The large majority of owners of discharged horses were satisfied with colic surgery performed on their horses.

Nephrosplenic entrapment of the large colon in 142 horses (2000-2009): analysis of factors associated with decision of treatment and short-term survival.

REASONS FOR PERFORMING STUDY: Previous studies indicate similar overall survival of horses with nephrosplenic entrapment of the large colon (NSE), regardless of treatment strategy. Short-term survival of a primarily conservative treatment strategy without rolling under general anaesthesia (GA) and a low proportion of surgical intervention as well as indicators of short-term nonsurvival has not been documented. OBJECTIVES: To document short-term survival of horses with NSE treated in a university referral hospital with a low rate of surgical interventions and to determine factors associated with the decision of treatment and short-term nonsurvival. METHODS: A retrospective review of medical records of 142 horses diagnosed with NSE between January 2000 and October 2009 was undertaken. Case details and clinical parameters from the initial examination, treatment and outcome were recorded. Factors associated with decision of treatment and short-term survival were identified by multiple logistic regression analysis. RESULTS: Warmblood breeds were over-represented in comparison to the general colic population. Overall short-term survival was 91.5% (130/142) which is similar to previous studies. Three horses considered to be in need of surgery were subjected to euthanasia for economical reasons before treatment. Of 114 conservatively treated horses, 110 (96.5%) survived, as did 20/25 (80%) of surgically treated horses. Nine conservatively managed horses were treated with phenylephrine. Gastric reflux (P = 0.0077), pain (P = 0.024) and abdominal distension (P = 0.05) were associated with the decision to treat surgically. Increased heart rate (P<0.001), and surgery (P = 0.032) were associated with reduced likelihood of short-term survival. CONCLUSIONS AND POTENTIAL RELEVANCE: Overall short-term survival was similar to that reported in previous studies with higher proportions of surgically managed cases. Consequently, horses with NSE should be managed by a primarily conservative treatment strategy, with the decision to treat surgically based on specific evidence based criteria.

GH is a regulator of IGF2 promoter-specific transcription in human liver.

The regulation of the insulin-like growth factor-II gene (IGF2) is complex and involves the usage of four promoters resulting in different 5' untranslated regions, but with a common translated product. The IGF2 gene product is a mitogenic and survival factor that has been suggested to be important for a normal fetal development and cancer. In this paper we present evidence suggesting that the human IGF2 gene is regulated by GH, and that this regulation occurs in a promoter-specific way. Three lines of evidence support this finding. First, in vivo data from patients treated with GH (one injection or daily injections for 5 consecutive days) showed an increase in the IGF2 P2 promoter derived transcript after acute treatment, and of the P4 promoter transcript after short-term treatment while the P1 promoter derived transcript did not show any significant change. Secondly, isolated human liver cells treated with GH for 2 h displayed an upregulation of the P2 promoter derived transcript. Thirdly, employing transfection experiments in GH-receptor positive CHO cells with P2 and P4 promoter-luciferase constructs, an upregulation by GH was evident, while a P1 promoter construct was unresponsive. We suggest that GH may be a physiological regulator of IGF2 in humans.

Studies of variability in the PTEN gene among Danish caucasian patients with Type II diabetes mellitus.

AIM/HYPOTHESIS: Phosphatase and tensin homologue deleted from chromosome ten (PTEN) has recently been characterized as a novel member in the expanding network of proteins regulating the intracellular effects of insulin. By dephosphorylation of phosphatidyl-inositol-(3, 4, 5)-trisphosphate (PIP3) the PTEN protein regulates the insulin-dependent phosphoinositide 3-kinase (PI3K) signalling cassette and accordingly might function as a regulator of insulin sensitivity in skeletal muscle and adipose tissue. In this study we tested PTEN as a candidate gene for insulin resistance and late-onset Type II (non-insulin-dependent) diabetes mellitus in a Danish Caucasian population. METHODS: The nine exons of the PTEN, including intronic flanking regions were analysed by PCR-SSCP and heteroduplex analysis in 62 patients with insulin-resistant Type II diabetes. RESULTS: No mutations predicted to influence the expression or biological function of the PTEN protein but four intronic polymorphisms were identified: IVS1-96 A-->G (allelic frequency 0.22, 95 % CI: 0.12-0.32), IVS3 + 99 C-->T (0.01, CI: 0-0.03), IVS7-3 TT-->T (0.10, CI: 0.03-0.18) and IVS8 + 32 G-->T (0.35, CI: 0.23-0.47). The IVS8 + 32 G-->T polymorphism was used as a bi-allelic marker for the PTEN locus and examined in 379 patients with Type II diabetes and in 224 control subjects with normal glucose tolerance. The IVS8 + 32 G-->T polymorphism in the PTEN was not associated with Type II diabetes and it did not have any effect on body-mass index, blood pressure, HOMA insulin resistance index, or concentrations of plasma glucose, serum insulin or serum C peptide obtained during an oral glucose tolerance test (OGTT). CONCLUSION/INTERPRETATION: Variability in the PTEN is not a common cause of Type II diabetes in the Danish Caucasian population.

Expression of genes involved with cell cycle control, cell growth and chromatin modification are altered in hepatoblastomas.

Hepatoblastoma is a rare pediatric liver tumor. While much progress has been made in the treatment of the disease, very little is known about the moleculer events underlying the pathogenesis of this disease. We sought to investigate a series of hepatoblastomas for alterations in gene expression patterns with emphasis on important cell regulatory genes, including chromatin modifying enzymes, cyclin dependent kinase inhibitors, growth factors, oncogenes and cell cycle regulators. Total RNA was extracted from a series of sporadic hepatoblastomas with matched normal liver, some unmatched tumors and fetal livers, and gene expression was measured for various genes using RNase Protection Analysis (RPA). The results of this analysis show that the expression of many important regulatory genes are distinctly altered in these tumors, and a subset of tumors can be distinguished on the basis of these gene expression differences and histopathological features. Because the molecular events underlying the pathogenesis of this rare tumor are so poorly understood, this study represents a first step in determining some of the possible mechanisms involved which may provide future avenues of research.

Altered expression of members of the IGF-axis in hepatoblastomas.

Previous reports have demonstrated that expression of insulin-like growth factor 2 (IGF2) is altered in hepatoblastoma. Using RNAase protection analysis (RPA), we examined the gene expression for IGF1, IGF2, IGF1R, M6P/IGF2R, IGFBP-1 and IGFBP-2 in a series of hepatoblastomas with corresponding normal liver from the same individuals. The results show that the expression of the IGF-axis members included in the present study are altered between tumour and normal, and indicate that the IGF-axis may be involved in hepatoblastoma development.

Disrupted IGF2 promoter control by silencing of promoter P1 in human hepatocellular carcinoma.

Previous investigations have supported or indicated a stimulatory role of the insulin-like growth factor II gene (IGF2) in hepatocarcinogenesis. We have studied the transcript levels, promoter usage, and imprinting status of the ICF2 gene and its relationship to H19 in human hepatocellular carcinomas (HCCs) and liver tumor cell lines. The activity of the IGF2 promoter P1 was lost in about 70% of the cases (18 of 25). This is the most prominent abnormality regarding the IGF2 regulation in this study. Total IGF2 as well as promoter P3 transcription were up-regulated in a small group of the tumors. Twenty genetically informative cases were obtained from 26 cases, thus excluding the probability of loss of heterozygosity of the IGF2 gene. Among these, nine showed abnormal monoallelic expression of IGF2. One HCC and one HCC cell line proved loss of functional imprinting of IGF2. H19 and IGF2 were regulated in parallel, and expression levels were variable. Taken together, the disruption of the IGF2 promoter regulation, particularly the loss of P1 activity, is a common feature of human HCCs. The loss of P1 activity explains the frequent loss of biallelic IGF2 expression and may potentially be used as a diagnostic or monitoring marker for human HCC.