Indoleamine 2,3-dioxygenase activation and depressive symptoms: results from the young Finns study

Objective To examine whether the activation of indoleamine 2,3-dioxygenase (IDO), an enzyme involved in serotonin production, is associated with depressive symptoms. Methods The participants were 544 women and 442 men (aged 24-39 years) from the population-based Young Finns Study who participated in a medical examination in 2001 (including IDO and depression) and 2007 (follow-up assessment for depression). Results At baseline, IDO was associated with depressive symptoms (in the total cohort: B = 0.23, p < .001; women: B = 0.20, p = .007; men: B = 0.29, p = .002; p for interaction = .19). IDO at baseline was also associated with depressive symptoms at follow-up in women (B = 0.17, p = .03), which remained significant when adjusting for any of the biologic and behavioral risk factors. Adjusting for body mass index attenuated the association by 6%. In the final model including all baseline variables, none of the risk factors (except for baseline depressive symptoms) were associated with depressive symptoms at follow-up. Conclusions These data suggest that IDO activity may be a risk factor for future depression especially in women. IDO-induced alterations in serotonergic function may offer one biologic explanation to the well-established associations between inflammation and depression.     

Temperament, health-related behaviors, and autonomic cardiac regulation: the cardiovascular risk in young Finns study

Temperament, as indicated by Cloninger's psychobiological model predicts coronary heart disease risk, but its association with autonomic cardiac regulation, a potential mediating mechanism, is unclear. We examined the associations between temperament traits and autonomic cardiac regulation in a resting situation in 798 women and 580 men derived from a population-based sample. After adjustment for age and sex, harm avoidance was associated with lower level of high-frequency (HF) variation, root mean square successive differences (RMSSDs), the percentage of successive R–R intervals >50 ms (pNN50) and higher heart rate (HR) (all p ≤ 0.005), suggesting that harm avoidance is related to low parasympathetic activity. Additional adjustments for behavioral factors attenuated these associations more than the adjustment for biological risk factors. Novelty seeking was associated with higher RMSSD (p = 0.007) and pNN50 (p = 0.012) and lower heart rate (p < 0.001). With adjustment for behavioral risk factors, the associations with RMSSD (p = 0.136) and pNN50 (p = 0.236) attenuated to the null, but adjustment for biological risk factors had little effect. Reward dependence and persistence were unrelated to indices of cardiac regulation.     

Chlamydia trachomatis: impact on human reproduction

Chlamydia trachomatis infections are the most prevalent bacterial sexually transmitted infections (STI) recognized throughout the world. Worldwide, the magnitude of morbidity associated with sexually transmitted chlamydial infections is enormous. C.trachomatis is a common cause of urethritis and cervicitis, and sequelae include pelvic inflammatory disease (PID), ectopic pregnancy, tubal factor infertility, epididymitis, proctitis and reactive arthritis. The sharp worldwide increase in the incidence of PID during the past two decades has led to the secondary epidemics of tubal factor infertility and ectopic pregnancy. Chlamydial PID is the most important preventable cause of infertility and adverse pregnancy outcome. Chlamydial infections, like STI in general, are primarily a woman's health care issue since the manifestations and consequences are more damaging to the reproductive health in women than in men. Based on the available evidence, approximately 20% of women with chlamydial lower genital tract infection will develop PID, approximately 4% develop chronic pelvic pain, 3% infertility, and 2% adverse pregnancy outcome. However, these estimates are based on relatively weak evidence. Research on the link between C.trachomatis and male aspects of infertility has been much more limited. Currently recommended treatment regimens include azithromycin in a single dose or doxycycline for 7 days. These therapies are highly efficacious. Timely management of sex partners is essential for decreasing the risk for re-infection. Immunopathogenesis of C.trachomatis infection is one of the main focal points of current research into Chlamydia. Chlamydial infection fills the general prerequisites for disease prevention by screening, i.e. chlamydial infections are highly prevalent, usually asymptomatic, are associated with significant morbidity, can be reliably diagnosed, and are treatable. Screening programmes for C.trachomatis will be of paramount importance in the prevention of long-term sequelae. The cost of screening is only a fraction of the health care costs incurred due to complications resulting from undiagnosed and untreated chlamydial infections. Current strategies to control C.trachomatis still largely depend on clinic-based screening of symptomatic patients, and have not been successful. The development of highly sensitive and specific nucleic acid amplification tests for the diagnosis of chlamydial infections has been an important advance in the ability to conduct population-based screening programmes to prevent complications. Thus, the case for screening is clearly made, but much detail remains to be worked out.     

The effect of hysterectomy or levonorgestrel-releasing intrauterine system on cardiovascular disease risk factors in menorrhagia patients: a 10-year follow-up of a randomised trial

Objective

To compare, whether women with menorrhagia, treated with either hysterectomy or LNG-IUS, differ in their cardiovascular risk profile during 10-year follow-up.

Study design

A total of 236 women were randomized to treatment by hysterectomy (n = 117) or LNG-IUS (n = 119). Their cardiovascular risk factors were analyzed at baseline, at 5 years, and at 10 years. As 55 originally randomized to the LNG-IUS group had hysterectomy during the follow-up, all analyzes were performed by actual treatment modality.

Main outcome measures

Waist circumference, body-mass index (BMI), blood pressure, and the levels of blood lipids, serum high-sensitivity CRP (hsCRP) and tumor necrosis factor alpha (TNF-α) were measured, and the use of medication for hypertension, diabetes, hypercholesterolemia, and ischemic heart disease was analyzed.

Results

After 5 years, an increase in the use of diabetes medication during the follow-up was only detected in the hysterectomy group (from 1.7% to 6.7%, P = 0.008 vs from 5.1% to 8.4%, P = 0.08), as well as they had significantly higher serum levels of TNF-α (108.59 pg/ml vs 49.02 pg/ml, P = 0.001) and hsCRP (1.55 μg/ml vs 0.78 μg/ml, P = 0.038) at 5- and 10-years. There was no difference between the groups in the use of cardiovascular medication, neither was there difference in blood pressure, waist circumference, BMI, or concentrations of blood lipids.

Conclusions

Hysterectomy seems to be associated with increased levels of serum inflammatory markers and increased diabetes medication, which in turn, may predispose individual to future cardiovascular events.     

NK cell function and antibodies mediating ADCC in HIV-1-infected viremic and controller patients

Natural killer (NK) cells have been suggested to play a protective role in HIV disease progression. One potent effector mechanism of NK cells is antibody-dependent cellular cytotoxicity (ADCC) mediated by antiviral antibodies binding to the FcγRIIIa receptor (CD16) on NK cells. We investigated NK cell-mediated ADCC function and the presence of ADCC antibodies in plasma from 20 HIV-1-infected patients and 10 healthy donors. The HIV-positive patients were divided into two groups: six who controlled viremia for at least 8 y without treatment (controllers), and 14 who were persistently viremic and not currently on treatment. Plasma from both patient groups induced NK cell IFN-γ expression and degranulation in response to HIV-1 envelope (Env) gp140-protein-coated cells. Patient antibodies mediating ADCC were largely directed towards the Env V3 loop, as identified by a gp140 protein lacking the V3 loop. Interestingly, in two controllers ADCC-mediating antibodies were more broadly directed to other parts of Env. A high viral load in patients correlated with decreased ADCC-mediated cytolysis of gp140-protein-coated target cells. NK cells from both infected patients and healthy donors degranulated efficiently in the presence of antibody-coated HIV-1-infected Jurkat cells. In conclusion, the character of ADCC-mediating antibodies differed in some controllers compared to viremic patients. NK cell ADCC activity is not compromised in HIV-infected patients.     

A similar high level of immunoglobulin A and immunoglobulin G class milk antibodies and increment of local lymphoid tissue on the duodenal mucosa in subjects with cow's milk allergy and recurrent abdominal pains

In previous studies, we have reported endoscopic and histological alterations locally on the gastrointestinal (GI) tract associated with a gastrointestinal type of cow's milk allergy. In this study, we sought to further characterize endoscopic, and immunological findings in these children. We also hypothesized that the same type of immune responses might also be found in children with unexplained and recurrent abdominal pains. We did a gastroduodenoscopy for persistent GI symptoms, examined the mucosal histology of the small intestine and measured the antibodies to whole cow's milk and its fractions with an enzyme‐linked immunosorbent assay (ELISA) in a consecutive series of 22 subjects with untreated and 14 with treated cow's milk allergy (CMA) and 44 with recurrent abdominal pains (RAP). The immunological findings of the study subjects were compared with 54 controls. Lymphonodular hyperplasia (LNH) of the duodenum was the main endoscopic finding in 11 subjects (50%) with untreated and 5 (36%) with treated CMA. It was also found in 6 of 44 subjects with RAP. Compared with the controls, the patients with CMA showed significantly higher levels of IgA class antibodies to whole milk (p = 0.003) and βLG (p < 0.0001). Of the IgG class antibodies to βLG (p = 0.032), BSA (p < 0.0001) and αCAS (p < 0.0001) were significantly higher. The patients with LNH of the duodenal bulb as the main endoscopic finding showed significantly higher values of IgG class antibodies to βLG (p = 0.01) and αCAS (p = 0.005). Interestingly, the patients examined for RAP showed a similar increment in the pattern of whole milk and specific milk protein antibodies as the CMA children. In conclusion this study showed that gastrointestinal CMA beyond infancy is significantly associated with high levels of IgG and IgA class antibodies to milk and its fractions. As high levels of these antibodies and LNH of the duodenal bulb were also found in subjects with RAP, the study further suggests that gastrointestinal CMA might be one major reason for RAP.     

Aurora-A overexpression and aneuploidy predict poor outcome in serous ovarian carcinoma

Objective

Aurora-A is a potential oncogene and therapeutic target in ovarian carcinoma. It is involved in mitotic events and overexpression leads to centrosome amplification and chromosomal instability. The objective of this study was to evaluate the clinical significance of Aurora-A and DNA ploidy in serous ovarian carcinoma.

Methods

Serous ovarian carcinomas were analysed for Aurora-A protein by immunohistochemistry (n = 592), Aurora-A copy number by CISH (n = 169), Aurora-A mRNA by real-time PCR (n = 158) and DNA ploidy by flowcytometry (n = 440).

Results

Overexpression of Aurora-A was found in 27% of the tumors, cytoplasmic overexpression in 11% and nuclear in 17%. The cytoplasmic and nuclear overexpression were nearly mutually exclusive. Both cytoplasmic and nuclear overexpression were associated with shorter survival, high grade, high proliferation index and aberrant p53. Interestingly, only cytoplasmic expression was associated with aneuploidy and expression of phosphorylated Aurora-A. DNA ploidy was associated with poor patient outcome as well as aggressive clinicopathological parameters. In multivariate analysis, Aurora-A overexpression appeared as an independent prognostic factor for disease-free survival, together with grade, stage and ploidy.

Conclusions

Aurora-A protein expression is strongly linked with poor patient outcome and aggressive disease characteristics, which makes Aurora-A a promising biomarker and a potential therapeutic target in ovarian carcinoma. Cytoplasmic and nuclear Aurora-A protein may have different functions. DNA aneuploidy is a strong predictor of poor prognosis in serous ovarian carcinoma.     

Estimation of genetic risk for type 1 diabetes

The most important gene loci defining risk of type 1 diabetes mellitus (T1DM) are located within the HLA gene region. HLA-DQ molecules are of primary importance but HLA-DR gene products modify the risk conferred by HLA-DQ. The risk associated with an HLA genotype is defined by the particular combination of susceptible and protective alleles. The highest risk is associated with a combination of two different risk haplotypes (7% risk to develop T1DM in Finland) whereas protective genotypes covering 69% of population have a risk of less than 0.2%). The complicated analysis of HLA genotypes is simplified by strong linkage disequilibrium between HLA-DRB1, -DQA1 and -DQB1 loci. In many cases one can deduce the alleles of other loci based on determination of the alleles in one locus. Differences between various populations in the frequency of marker alleles and in the linkages between them has to be taken into account. We have developed PCR based typing methods that utilize blood spot samples, microtiter plate format and lanthanide labeled oligonucleotide probes to define HLA-DQ and -DR alleles relevant for T1DM risk. Typing is run stepwise so that after initial HLA-DQB1 typing only those samples will be further analyzed in which -DQA1 or -DRB1 typing is informative and expected to contribute to the risk estimation. This method has been used to screen more than 50,000 newborn infants in Finland over a time period of 6 years, and it has been able to identify most children who have developed T1D during the follow-up period. The efficiency of the procedure has also been tested in Finnish and Greek populations.