Insights from a laboratory and naturalistic investigation on stress, rumination and frontal brain functioning in MDD: An fNIRS study.

Recent research has emphasized rumination as an important maintaining factor in various mental disorders. However, operationalization and therefore induction of rumination in experimental settings poses a major challenge in terms of ecological validity. As stress seems to play a key role in everyday situations eliciting rumination, we conducted two stress paradigms while assessing behavioral and neurophysiological measures. Aiming to replicate previous findings on induced rumination by means of the Trier Social Stress Test (TSST) and comparing them to physiological (pain) stress, a clinical sample of patients with Major Depressive Disorder (MDD; n = 22) and healthy controls (HC; n = 23) was recruited. Cortical blood oxygenation was assessed during the stress paradigms using functional near-infrared spectroscopy (fNIRS). Further, we used ecological momentary assessment (EMA) of stress, rumination and mood to be able to correlate ruminative responses during induced stress and everyday rumination. Our results showed that social stress but not physiological stress induced depressive rumination in MDD but not in HC. Further, rumination reactivity in response to social stress but not to physiological stress was significantly associated with rumination reactivity in everyday life as assessed with EMA. With respect to cortical oxygenation, MDD subjects showed hypoactivity in the Cognitive Control Network during the TSST, which mediated the differences between MDD and HC in post-stress rumination. Our findings emphasize the role of negative social triggers in depressive rumination and validate the TSST as an induction method for depressive rumination. The results inform future developments in psychotherapeutic treatment for depressive rumination.

Brain activation in frontotemporal and Alzheimer's dementia: a functional near-infrared spectroscopy study.

BACKGROUND: Frontotemporal dementia is an increasingly studied disease, the underlying functional impairments on a neurobiological level of which have not been fully understood. Patients with the behavioral-subtype frontotemporal dementia (bvFTD) are particularly challenging for clinical measurements such as functional imaging due to their behavioral symptoms. Here, an alternative imaging method, functional near-infrared spectroscopy (fNIRS), is introduced to measure task-related cortical brain activation based on blood oxygenation. The current study investigated differences in cortical activation patterns of patients with bvFTD, Alzheimer's dementia (AD), and healthy elderly subjects measured by fNIRS. METHOD: Eight probable bvFTD patients completed the semantic, phonological, and control conditions of a verbal fluency task. Eight AD patients and eight healthy controls were compared on the same task. Simultaneously, an fNIRS measurement was conducted and analyzed using a correction method based on the expected negative correlation between oxygenated and deoxygenated hemoglobin. RESULTS: Healthy controls show an increase in cortical activation measured in frontoparietal areas such as the dorsolateral prefrontal cortex. The activation pattern of patients with AD is similar, but weaker. In contrast, bvFTD patients show a more frontopolar pattern, with activation of Broca's area, instead of the dorsolateral prefrontal cortex and the superior temporal gyrus. The frontoparietal compensation mechanisms, seen in the healthy elderly, were missing in bvFTD patients. CONCLUSION: Different frontoparietal cortical activation patterns may indicate a correlate of diverse pathophysiological mechanisms of AD and bvFTD during verbal fluency processing. The AD pattern is weaker and more similar to the healthy pattern, whereas the bvFTD pattern is qualitatively different, namely more frontopolar and without frontoparietal compensation activation. It adheres to a change of cortical activation during the course of the disease.

Evaluation of the performance of the novel PapilloCheck HPV genotyping test by comparison with two other genotyping systems and the HC2 test.

The novel PapilloCheck genotyping test was compared with SPF10 PCR LiPav1 and PGMY09/11 on hybrid capture 2 (HC2)-pretested samples. From results of 826 cervical samples detection rates and kappa values for the tests were calculated using a HPV type consensus definition. With PapilloCheck HPV types 53, 56, and 33 were found with a sensitivity of 100%. The lowest detection rate was observed for HPV 35 (72.2%). The SPF10 PCR LiPav1 was found to be 100% positive for HPV 18, 31, 53, 56, and 35 and lowest for HPV 59 (81%). The PGMY09/11 system detected only HPV 59 at 100% detection rate and showed lowest sensitivity for HPV 56 (40.5%). Multiple infection rates ranged from 25.8% (PGMY09/11 PCR-LBA), over 39.5% (PapilloCheck) to 55.9% (SPF10 PCR LiPav1). In samples with higher viral DNA load detection rates and concordance between the genotyping tests increases. The kappa values in comparison to the HPV consensus type ranged from k = 0.21 to k = 0.82 for comparing SPF10 PCR with the HPV consensus type, while values for PGMY09/11 PCR ranged from k = 0 to k = 0.96 and were best for the PapilloCheck (k = 0.49-0.98). Detection rates for the identification of high-grade cervical intraepithelial neoplasia (CIN2+) ranged from 93.7% (PGMY09/11 PCR) to 98.4% (PapilloCheck, SPF10 PCR, HC2). In conclusion, this study shows that the PapilloCheck give comparable results to established PCR methods. However, these results also show a necessity for the standardization of genotype-specific HPV detection assays.

Comparison of the performance of different HPV genotyping methods for detecting genital HPV types.

Classification of high-risk HPV types for cervical cancer screening depends on epidemiological studies defining HPV type-specific risk. The genotyping tests that are used, are however, not uniform with regard to type-specific detection rates making comparisons between different studies difficult. To overcome the lack of a "gold standard" four tests were evaluated crosswise using 824 cervical smears pretested by HC2. The tests evaluated were the L1-PCR-based assays PGMY09/11 LBA, HPV DNA Chip and SPF LiPA and an E1 consensus PCR followed by cycle sequencing (E1-PCR). A subset of 265 samples was tested in addition with the GP5+/6+ reverse line blot assay. Differences were noted in the sensitivity and range for specific HPV types, e.g. with detection rates for HPV53 ranging from 2.3% to 11.6%. HPV16 was the most prevalent type detected by all tests except for the SPF-10 LiPa, which detected HPV31 more often. Kappa values calculated ranged from poor (k=0.20) to intermediate (k=0.54) for HPV positivity, but were higher for high-risk type positivity (k=0.31-0.61) and best for recognition of HPV16 (k=0.53-0.72). The analytical sensitivity of the tests ranged between 15% and 97% for individual types and specificity was highly dependent on which test system was used as "gold standard" for the analysis. The results of histology were used for calculation of clinical sensitivity and specificity. E1-PCR, PGMY09/11 LBA and SPF-10 LiPA had a high clinical sensitivity (>95%) for the detection of cervical intraepithelial neoplasia 2 or higher, whereas the HPV DNA Chip reached only 84.1%.

Prevalence of human papillomavirus types in women screened by cytology in Germany.

Incidence and mortality rates of cervical cancer are higher in Germany than in other Western European countries. Type-specific human papillomavirus (HPV) distribution was investigated for the first time in Germany in an epidemiological study including 8,101 women. Women above the age of 30 years, self-referring for cervical cancer screening, were enrolled in two study centers in Hannover (Northern Germany) and Tübingen (Southern Germany). Participants were screened by the Pap smear and the hybrid capture 2 (HC2) test using the high-risk probe. All samples that were positive by the HC2 test were genotyped using the prototype PGMY09/11 PCR line blot assay. Most women in the study population had a negative Pap smear (96.7%). Prevalence of high-risk type HPV detected by HC2 was 6.4% and prevalence of carcinogenic types detected by PGMY09/11 was 4.3%. Of the PGMY09/11 PCR-positive women, 70.2% had a single infection, 28.1% had multiple infections and 1.7% remained uncharacterized. 32 different HPV types were detected using PGMY09/11 PCR. HPV 16, 31, 52, 51, 18, and 45 were the most common carcinogenic types in the study population. Among women with histologically confirmed high-grade lesions HPV 16, 45, 58, 18, 31, 33, and 52 were the predominant types. These results provide valuable information for the management of HPV infections in Germany, both in terms of future strategies of screening and vaccination.

Interference of papillomavirus E6 protein with single-strand break repair by interaction with XRCC1.

XRCC1 protein is required for the repair of DNA single-strand breaks and genetic stability, and is essential for viability in mammals. XRCC1 functions as a scaffold protein by interacting and modulating polypeptide components of the single-strand break repair machinery, including AP endonuclease-1, DNA ligase IIIalpha, poly (ADP-ribose) polymerase, DNA polymerase beta and human polynucleotide kinase. We show here that the E6 protein of human papillomavirus type 1, 8 and 16 directly binds XRCC1. When tested in CHO derived XRCC1 'knock out' EM9 cells, co-expression of human papillomavirus 16 E6 with human XRCC1 reduced the ability of the latter protein to correct the methyl methane sulfate sensitivity of XRCC1 mutant CHO cell line EM9. These data identify a novel link between small DNA tumour viruses and DNA repair pathways, and suggest a novel explanation for the development of genomic instability in tissue cells persistently infected with papillomaviruses.