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"Retraction artefacts" in basal cell carcinomas do not result from fixation but likely arise by degradation of extracellular matrix during tumour growth 2), the tumour (MMP1) or equal distribution in the tumour and stroma (MMP14). MMP1 showed a stronger expression in the tumour (f), MMP9 showed a stronger expression in the stroma (g) and MMP14 was equally distributed in the tumour and stroma (h). [Extracted from the article]

The traditional approach is a pattern-based histopathological analysis, in which inflammatory diseases are categorized by major tissue reaction patterns and the distribution of the inflammatory infiltrate.8 The aim of this study was to evaluate CLSM combined with digital staining for identifying the histopathological patterns and features of inflammatory skin diseases. I Ex vivo i confocal laser scanning microscopy (CLSM) is an emerging imaging technology that allows the direct microscopic examination of fresh skin tissue. [Extracted from the article]

(1) Head and neck squamous cell carcinoma (HNSCC) is common, while treatment is difficult, and mortality is high. Kinase inhibitors are promising to enhance the effects of radiotherapy. We compared the effects of the PARP inhibitors talazoparib and niraparib and that of the DNA-PKcs inhibitor AZD7648, combined with ionizing radiation. (2) Seven HNSCC cell lines, including Cal33, CLS-354, Detroit 562, HSC4, RPMI2650 (HPV-negative), UD-SCC-2 and UM-SCC-47 (HPV-positive), and two healthy fibroblast cell lines, SBLF8 and SBLF9, were studied. Flow cytometry was used to analyze apoptosis and necrosis induction (AnnexinV/7AAD) and cell cycle distribution (Hoechst). Cell inactivation was studied by the colony-forming assay. (3) AZD7648 had the strongest effects, radiosensitizing all HNSCC cell lines, almost always in a supra-additive manner. Talazoparib and niraparib were effective in both HPV-positive cell lines but only consistently in one and two HPV-negative cell lines, respectively. Healthy fibroblasts were not affected by any combined treatment in apoptosis and necrosis induction or G2/M-phase arrest. AZD7648 alone was not toxic to healthy fibroblasts, while the combination with ionizing radiation reduced clonogenicity. (4) In conclusion, talazoparib, niraparib and, most potently, AZD7648 could improve radiation therapy in HNSCC. Healthy fibroblasts tolerated AZD7648 alone extremely well, but irradiation-induced effects might occur. Our results justify in vivo studies.

Psoriasis is a chronic inflammatory disease of the skin and joints. More recent data emphasize an association with dysregulated glucose and fatty acid metabolism, obesity, elevated blood pressure and cardiac disease, summarized as metabolic syndrome. TNF-α and IL-17, central players in the pathogenesis of psoriasis, are known to impair bone formation. Therefore, the relation between psoriasis and bone metabolism parameters was investigated. Two serum markers of either bone formation-N-terminal propeptide of type I procollagen (P1NP) or bone resorption-C-terminal telopeptide of type I collagen (CTX-I)-were analyzed in a cohort of patients with psoriasis vulgaris. In patients with psoriasis, P1NP serum levels were reduced compared to gender-, age-, and body mass index-matched healthy controls. CTX-I levels were indistinguishable between patients with psoriasis and controls. Consistently, induction of psoriasis-like skin inflammation in mice decreases bone volume and activity of osteoblasts. Moreover, efficient anti-psoriatic treatment improved psoriasis severity, but did not reverse decreased P1NP level suggesting that independent of efficient skin treatment psoriasis did affect bone metabolism and might favor the development of osteoporosis. Taken together, evidence is provided that bone metabolism might be affected by psoriatic inflammation, which may have consequences for future patient counseling and disease monitoring., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mentzel, Kynast, Kohlmann, Kirsten, Blüher, Simon, Kunz and Saalbach.)

Background and Objectives: Ex vivo confocal laser scanning microscopy (CLSM) allows histologic examination of native tissue based on tissue reflection and nuclear fluorescence staining. The newly introduced digital staining process almost perfectly mimics conventional hematoxylin and eosin (HE) slides. The aim was to evaluate the new method in clinical routine, with regard to quality of findings and time requirements, in the examination of surgical margins of basal cell carcinomas., Patients and Methods: 78 patients with 101 basal cell carcinomas were prospectively enrolled. Surgery was performed either with complete margin control (n = 60) or as elliptical excision (n = 41). Immediately after excision specimens were scanned with CLSM and then routinely processed by conventional histopathology. Blinded evaluation of images and slides was performed by a dermatopathologist., Results: Basal cell carcinomas were excellently recognizable by CLSM directly after excision, and the use of digital staining did not require any adjustment of the examiner's visualization preferences. CLSM images showed a sensitivity of 73.6 % and a specificity of 96.5 % compared to conventional HE stained slides. Erroneous findings were often due to limited assessment potential in cases where the epidermis could not be fully visualized., Conclusions: CLSM with digital HE staining is very well suited to diagnose basal cell carcinomas and their incision margins even under routine conditions and thus represents a tissue-saving alternative to rapid cryostat sectioning., (© 2021 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

SEE CAPPA DOI101093/BRAIN/AWW090 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE  : The phonological structure of speech supports the highly automatic mapping of sound to meaning. While it is uncontroversial that phonotactic knowledge acts upon lexical access, it is unclear at what stage these combinatorial rules, governing phonological well-formedness in a given language, shape speech comprehension. Moreover few studies have investigated the neuronal network affording this important step in speech comprehension. Therefore we asked 70 participants-half of whom suffered from a chronic left hemispheric lesion-to listen to 252 different monosyllabic pseudowords. The material models universal preferences of phonotactic well-formedness by including naturally spoken pseudowords and digitally reversed exemplars. The latter partially violate phonological structure of all human speech and are rich in universally dispreferred phoneme sequences while preserving basic auditory parameters. Language-specific constraints were modelled in that half of the naturally spoken pseudowords complied with the phonotactics of the native language of the monolingual participants (German) while the other half did not. To ensure universal well-formedness and naturalness, the latter stimuli comply with Slovak phonotactics and all stimuli were produced by an early bilingual speaker. To maximally attenuate lexico-semantic influences, transparent pseudowords were avoided and participants had to detect immediate repetitions, a task orthogonal to the contrasts of interest. The results show that phonological 'well-formedness' modulates implicit processing of speech at different levels: universally dispreferred phonological structure elicits early, medium and late latency differences in the evoked potential. On the contrary, the language-specific phonotactic contrast selectively modulates a medium latency component of the event-related potentials around 400 ms. Using a novel event-related potential-lesion approach allowed us to furthermore supply first evidence that implicit processing of these different phonotactic levels relies on partially separable brain areas in the left hemisphere: contrasting forward to reversed speech the approach delineated an area comprising supramarginal and angular gyri. Conversely, the contrast between legal versus illegal phonotactics consistently projected to anterior and middle portions of the middle temporal and superior temporal gyri. Our data support the notion that phonological structure acts on different stages of phonologically and lexically driven steps of speech comprehension. In the context of previous work we propose context-dependent sensitivity to different levels of phonotactic well-formedness., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Caveolin-1 (Cav-1) is a key organizer of membrane specializations and a scaffold protein that regulates signaling in multiple cell types. We found increased Cav-1 expression in human and murine T cells after allogeneic hematopoietic cell transplantation. Indeed, Cav-1(-/-)donor T cells caused less severe acute graft-versus-host disease (GVHD) and yielded higher numbers of regulatory T cells (Tregs) compared with controls. Depletion of Tregs from the graft abrogated this protective effect. Correspondingly, Treg frequencies increased when Cav-1(-/-)T cells were exposed to transforming growth factor-β/T-cell receptor (TCR)/CD28 activation or alloantigen stimulation in vitro compared with wild-type T cells. Mechanistically, we found that the phosphorylation of Cav-1 is dispensable for the control of T-cell fate by using a nonphosphorylatable Cav-1 (Y14F/Y14F) point-mutation variant. Moreover, the close proximity of lymphocyte-specific protein tyrosine kinase (Lck) to the TCR induced by TCR-activation was reduced in Cav-1(-/-)T cells. Therefore, less TCR/Lck clustering results in suboptimal activation of the downstream signaling events, which correlates with the preferential development into a Treg phenotype. Overall, we report a novel role for Cav-1 in TCR/Lck spatial distribution upon TCR triggering, which controls T-cell fate toward a regulatory phenotype. This alteration translated into a significant increase in the frequency of Tregs and reduced GVHD in vivo., (© 2016 by The American Society of Hematology.)

In the present study, the sequential affective priming paradigm developed by Fazio et al. [Fazio, R.H., Sanbonmatsu, D.M., Powell, M.C., Kardes, F.R., 1986. On the automatic activation of attitudes. Journal of Personality and Social Psychology 50, 229-238.] was applied for the first time to investigate automatic cognitive bias in depressed patients. Unipolar depressed patients (n=22) were tested on admission and after about 7 weeks of inpatient psychotherapy. Half of the patients (n=11) were suffering from a comorbid anxiety disorder. Twenty-two healthy subjects served as controls. Affectively polarized prime words were presented subliminally followed by positive or negative target words, which had to be evaluated. Subjects' affective state was assessed by self-report measures. In the course of psychotherapy, patients recovered significantly. Study groups exhibited qualitatively different affective priming effects: In non-comorbid depressed patients, no affective priming was found. Instead, a highly significant main effect of prime valence emerged, indicating a Stroop-like interference of negative prime words at time 1. This negative bias was associated with depression level at time 1 and could not be found after recovery. Affective priming was observed in controls and comorbid patients, but in opposite directions. Direction and strength of affective priming was directly associated with anxiety level at both times. The affective priming paradigm provides evidence for differential group effects regarding unconscious emotional information processing.

In this study automatic processing of verbal information was investigated in 22 clinically depressed inpatients and 22 healthy controls in a longitudinal design. A semantic priming task with word pronunciation was administered twice, about 7 weeks apart. Following brief presentations of prime words, subjects had to read target words aloud as quickly as possible. Prime words were directly related, indirectly related, or unrelated to the target words. Stimulus onset asynchrony (SOA) of prime and target was 250 ms. In the course of inpatient treatment, patients recovered significantly. Semantic priming occurred in both study groups for the directly and indirectly related conditions across both testing times. As expected, directly related primes resulted in stronger priming than indirectly related primes. Patients and controls did not differ in semantic priming at either time or relatedness condition. Size of priming was not associated with depression severity, anxiety level, intelligence, medication, or clinical features. We conclude that depression is not characterized by dysfunctional automatic processing of verbal information.

Background: In this study, a face-in-the-crowd task was applied to examine the spatial detection of facial emotion as a function of depression and comorbid anxiety in the course of a psychotherapeutic inpatient treatment., Methods: Patients with unipolar depression (n=22) and normal controls (n=22) were tested twice, about 7 weeks apart, on a face-in-the-crowd task using displays of schematic faces. Half the patients were suffering from a comorbid anxiety disorder., Results: From test 1 to test 2, depressivity, frequency of negative thoughts, and worrying of patients improved significantly. At both sessions, depressed patients, irrespective of the presence of comorbid anxiety disorders, showed no performance differences in the detection of negative faces compared to controls. However, depressed patients with but not those without comorbid anxiety disorders were slower in responding to positive faces than controls. Both patient groups were slower in responding to the neutral faces' condition than controls., Conclusions: Our data indicate a spatial processing deficit for positive facial expression in depressives with a comorbid anxiety disorder. This impairment, which appears to persist during remission, might be due to deficits in effortful visual search processes.

The aim of this study was to investigate the relationship between cognitive impairment and cerebral metabolites in patients with anorexia nervosa (AN). N-acetylaspartate (NAA), creatine/phosphocreatine (Cr), choline-containing compounds, glutamate/glutamine (Glx) and myoinositol were measured by proton magnetic resonance spectroscopy (H-MRS) of the left prefrontal cortex. Compared with healthy controls, AN patients displayed a significantly poorer performance in verbal learning and in attentional and executive tasks. Performance in the divided attention task was correlated with NAA and Cr in the dorsolateral prefrontal cortex, while executive functioning and depressive symptomatology were associated with Glx levels in the anterior cingulate. Our results provide evidence for cognitive impairment in AN patients which is associated with cerebral metabolism in the prefrontal cortex., (Copyright 2004 Lippincott Williams & Wilkins)

Based on the data of a questionnaire this study was designed to follow the obstetrical and gynecological history of 269 women who were delivered at our hospital by Caesarean section during 1960-1969. The Caesarean section group was compared with a control group of 229 women who were delivered spontaneously during the same period. Patients with cesarean sections had less children and more often they had been afraid of further deliveries. In patients with vaginal deliveries there was a significant higher incidence of descensus and prolapse uteri and more often a therapy because of premalignant or malignant diseases of the cervix had to be performed. However, there was no significant difference in the frequency of hysterectomies in both groups. The main indication for hysterectomy in the vaginal delivery group was prolapse and descensus, and in the Caesarean section group fibromyoma of the uterus. Except one case of uterine rupture the rate of complications in subsequent pregnancies was similar for both groups. Compared to the control group a higher rate of maternal morbidity due to Caesarean section could not be proved.