Assessment of Nocturnal Blood Pressure: Importance of Determining the Time in Bed-A Pilot Study.

Objectives: Nocturnal blood pressure (BP) monitoring is essential for evaluating cardiovascular risk and guiding treatment decisions. However, the standardized narrow-fixed nighttime period between 10 p.m. and 6 a.m. may not accurately reflect individual sleep schedules. This pilot study aimed to investigate the comparability between the standardized nighttime period and actual time in bed (TIB) regarding BP assessment. Further, our goal was to evaluate the clinical relevance of the observed BP differences. Methods: A total of 30 participants underwent 24 h ambulatory blood pressure monitoring (ABPM). Patient-specific TIB was precisely assessed through an accelerometer and a position sensor from the SOMNOtouch NIBP™ (SOMNOmedics GmbH, Randersacker, Germany). We analysed the effect of considering individual TIB as nighttime instead of the conventional narrow-fixed interval on the resulting nocturnal BP levels and dipping patterns. Results: We observed differences in both systolic and diastolic BP between the standardized nighttime period and the TIB. Furthermore, a notable percentage of patients (27%) changed their dipping pattern classification as a function of the nighttime definition adopted. We found strong correlations between the start (r = 0.75, p < 0.01), as well as the duration (r = -0.42, p = 0.02) of TIB and the changes in dipping pattern classification. Conclusions: Definition of nocturnal period based on the individual TIB leads to clinically relevant changes of nocturnal BP and dipping pattern classifications. TIB is easily detected using a body position sensor and accelerometer. This approach may thus improve the accuracy of cardiovascular risk evaluation and enhance treatment strategies.

Unlocking longevity: the role of telomeres and its targeting interventions.

Average life expectancy has been steadily increasing in developed countries worldwide. These demographic changes are associated with an ever-growing social and economic strain to healthcare systems as well as society. The aging process typically manifests as a decline in physiological and cognitive functions, accompanied by a rise in chronic diseases. Consequently, strategies that both mitigate age-related diseases and promote healthy aging are urgently needed. Telomere attrition, characterized by the shortening of telomeres with each cell division, paradoxically serves as both a protective mechanism and a contributor to tissue degeneration and age-related ailments. Based on the essential role of telomere biology in aging, research efforts aim to develop approaches designed to counteract telomere attrition, aiming to delay or reduce age-related diseases. In this review, telomere biology and its role in aging and age-related diseases is summarized along with recent approaches to interfere with telomere shortening aiming at well- and healthy-aging as well as longevity. As aging research enters a new era, this review emphasizes telomere-targeting therapeutics, including telomerase activators and tankyrase inhibitors, while also exploring the effects of antioxidative and anti-inflammatory agents, along with indirectly related approaches like statins.

Probing real-world Central European population midfacial skeleton symmetry for maxillofacial surgery.

OBJECTIVES: Symmetry is essential for computer-aided surgical (CAS) procedures in oral and maxillofacial surgery (OMFS). A critical step for successful CAS is mirroring the unaffected side to create a template for the virtual reconstruction of the injured anatomical structure. The aim was to identify specific anatomical landmarks of the midfacial skeleton, to evaluate the symmetry in a group of the real-world Central European population, and to use these landmarks to assess midfacial symmetry in CT scans. MATERIAL AND METHODS: The retrospective cross-sectional study defined landmarks of the midface's bony contour using viscerocranial CT data. The distances of the skeletal landmarks (e.g., the frontozygomatic suture and temporozygomatic suture) of the left and right sides from the midline were measured and statistically compared. Midfacial symmetry for reference points was defined as a difference within 0 mm and their mean difference plus one standard deviation. RESULTS: We examined a total of 101 CT scans. 75% of our population shows symmetrical proportions of the midface. The means of the differences for the left and right sides ranged from 0.8 to 1.3 mm, averaging 1.1 ± 0.2 mm for all skeletal landmarks. The standard deviations ranged from 0.6 to 1.4 mm, with a computed mean of 0.9 ± 0.3 mm. CONCLUSION: We established a methodology to assess the symmetry of the bony midface. If the determined differences were equal to or lower than 2.5 mm in the mentioned midfacial skeletal landmarks, then the symmetry of the bony midface was considered present, and symmetry-based methods for CAS procedures are applicable. CLINICAL RELEVANCE: Many CAS procedures require facial symmetry. We provide an easy-to-apply method to probe for symmetry of the midface. The method may be used for population-based research, to check for proper reduction of fractures after reposition or to screen for symmetry prior to CAS planning.

Human In Vitro Skin Models for Wound Healing and Wound Healing Disorders.

Skin wound healing is essential to health and survival. Consequently, high amounts of research effort have been put into investigating the cellular and molecular components involved in the wound healing process. The use of animal experiments has contributed greatly to the knowledge of wound healing, skin diseases, and the exploration of treatment options. However, in addition to ethical concerns, anatomical and physiological inter-species differences often influence the translatability of animal-based studies. Human in vitro skin models, which include essential cellular and structural components for wound healing analyses, would improve the translatability of results and reduce animal experiments during the preclinical evaluation of novel therapy approaches. In this review, we summarize in vitro approaches, which are used to study wound healing as well as wound healing-pathologies such as chronic wounds, keloids, and hypertrophic scars in a human setting.

Modelling the Complexity of Human Skin In Vitro.

The skin serves as an important barrier protecting the body from physical, chemical and pathogenic hazards as well as regulating the bi-directional transport of water, ions and nutrients. In order to improve the knowledge on skin structure and function as well as on skin diseases, animal experiments are often employed, but anatomical as well as physiological interspecies differences may result in poor translatability of animal-based data to the clinical situation. In vitro models, such as human reconstructed epidermis or full skin equivalents, are valuable alternatives to animal experiments. Enormous advances have been achieved in establishing skin models of increasing complexity in the past. In this review, human skin structures are described as well as the fast evolving technologies developed to reconstruct the complexity of human skin structures in vitro.

The Impact of Prolonged Inflammation on Wound Healing.

The treatment of chronic wounds still challenges modern medicine because of these wounds' heterogenic pathophysiology. Processes such as inflammation, ischemia and bacterial infection play major roles in the progression of a chronic wound. In recent years, preclinical wound models have been used to understand the underlying processes of chronic wound formation. However, the wound models used to investigate chronic wounds often lack translatability from preclinical models to patients, and often do not take exaggerated inflammation into consideration. Therefore, we aimed to investigate prolonged inflammation in a porcine wound model by using resiquimod, a TLR7 and TLR8 agonist. Pigs received full thickness excisional wounds, where resiquimod was applied daily for 6 days, and untreated wounds served as controls. Dressing change, visual documentation and wound scoring were performed daily. Biopsies were collected for histological as well as gene expression analysis. Resiquimod application on full thickness wounds induced a visible inflammation of wounds, resulting in delayed wound healing compared to non-treated control wounds. Gene expression analysis revealed high levels of IL6, MMP1 and CD68 expression after resiquimod application, and histological analysis showed increased immune cell infiltration. By using resiquimod, we were able to show that prolonged inflammation delayed wound healing, which is often observed in chronic wounds in patients. The model we used shows the importance of inflammation in wound healing and gives an insight into the progression of chronic wounds.

The impact of resveratrol on skin wound healing, scarring, and aging.

Resveratrol is a well-known antioxidant that harbours many health beneficial properties. Multiple studies associated the antioxidant, anti-inflammatory, and cell protective effects of resveratrol. These diverse effects of resveratrol are also potentially involved in cutaneous wound healing, scarring, and (photo-)aging of the skin. Hence, this review highlighted the most relevant studies involving resveratrol in wound healing, scarring, and photo-aging of the skin. A systematic review was performed and the database PubMed was searched for suitable publications. Only original articles in English that investigated the effects of resveratrol in wound healing, scarring, and (photo-)aging of the skin were analysed. The literature search yielded a total of 826 studies, but only 41 studies met the inclusion criteria. The included studies showed promising results that resveratrol might be a feasible treatment approach to support wound healing, counteract excessive scarring, and even prevent photo-aging of the skin. Resveratrol represents an interesting and promising novel therapy regime but to confirm resveratrol-associated effects, more evidence based in vitro and in vivo studies are needed.

Administration of a VEGFR­2-specific MRI contrast agent to assess orthodontic tooth movement : A pilot study.

PURPOSE: It is thought that orthodontic forces initially reduce periodontal blood flow during orthodontic tooth movement (OTM) via tissue compression with cells responding to concomitant oxygen deprivation with expression of vascular endothelial growth factor (VEGF) triggering angiogenesis via binding to its receptor VEGFR­2. To test this hypothesis, we performed a pilot study to establish a protocol for molecular magnetic resonance imaging (MRI) of rat jaws administering a VEGFR-2-specific contrast agent. METHODS: Mesial OTM of a first upper left rat molar was initiated in one male Fischer 344 rat 4 days prior to MRI by insertion of an elastic band between the first and second upper molars with the contralateral side left untreated (internal control). T1-weighted MRI sequences including dynamic contrast-enhanced MRI (DCE-MRI) were recorded before and after administration of a molecular VEGFR­2 MRI marker with a 7 T MRI dedicated for small animal use. RESULTS: After injection of anti-VEGFR2-albumin-gadolinium-DTPA, volume enhancement on T1-weighted images was increased at the OTM side distally of the moved first upper molar (M1) compared to the control side, whereas the T1 relaxation time was reduced on the OTM side. DCE-MRI resulted in an increased area under the curve (AUC), whereas time-to-peak (TTP) and washout rate were reduced during OTM distally of the moved M1 compared to the contralateral side. CONCLUSIONS: OTM resulted in uptake of the VEGFR-2-specific MRI contrast agent in tension areas of the periodontal ligament. The imaging protocol presented here is useful for the assessment of VEGFR­2 expression in tension areas of the periodontal ligament in vivo.

miRNAs as Regulators of the Early Local Response to Burn Injuries.

In burn injuries, risk factors and limitations to treatment success are difficult to assess clinically. However, local cellular responses are characterized by specific gene-expression patterns. MicroRNAs (miRNAs) are single-stranded, non-coding RNAs that regulate mRNA expression on a posttranscriptional level. Secreted through exosome-like vesicles (ELV), miRNAs are intracellular signalers and epigenetic regulators. To date, their role in the regulation of the early burn response remains unclear. Here, we identified 43 miRNAs as potential regulators of the early burn response through the bioinformatics analysis of an existing dataset. We used an established human ex vivo skin model of a deep partial-thickness burn to characterize ELVs and miRNAs in dermal interstitial fluid (dISF). Moreover, we identified miR-497-5p as stably downregulated in tissue and dISF in the early phase after a burn injury. MiR-218-5p and miR-212-3p were downregulated in dISF, but not in tissue. Target genes of the miRNAs were mainly upregulated in tissue post-burn. The altered levels of miRNAs in dISF of thermally injured skin mark them as new biomarker candidates for burn injuries. To our knowledge, this is the first study to report miRNAs altered in the dISF in the early phase of deep partial-thickness burns.

A novel human ex vivo skin model to study early local responses to burn injuries.

Burn injuries initiate numerous processes such as heat shock response, inflammation and tissue regeneration. Reliable burn models are needed to elucidate the exact sequence of local events to be able to better predict when local inflammation triggers systemic inflammatory processes. In contrast to other ex vivo skin culture approaches, we used fresh abdominal skin explants to introduce contact burn injuries. Histological and ultrastructural analyses confirmed a partial-thickness burn pathology. Gene expression patterns and cytokine production profiles of key mediators of the local inflammation, heat shock response, and tissue regeneration were analyzed for 24 h after burn injury. We found significantly increased expression of factors involved in tissue regeneration and inflammation soon after burn injury. To investigate purely inflammation-mediated reactions we injected lipopolysaccharide into the dermis. In comparison to burn injury, lipopolysaccharide injection initiated an inflammatory response while expression patterns of heat shock and tissue regeneration genes were unaffected for the duration of the experiment. This novel ex vivo human skin model is suitable to study the local, early responses to skin injuries such as burns while maintaining an intact overall tissue structure and it gives valuable insights into local mechanisms at the very beginning of the wound healing process after burn injuries.

Evidence-based therapy in hypertrophic scars: An update of a systematic review.

Hypertrophic scars are still a major burden for numerous patients, especially after burns. Many treatment options are available; however, no evidence-based treatment protocol is available with recommendations mostly emerging from experience or lower quality studies. This review serves to discuss the currently available literature. A systematic review was performed and the databases PubMed and Web of Science were searched for suitable publications. Only original articles in English that dealt with the treatment of hypertrophic scars in living humans were analyzed. Further, studies with a level of evidence lower than 1 as defined by the American Society of Plastic Surgeons were excluded. After duplicate exclusion, 1638 studies were screened. A qualitative assessment yielded 163 articles eligible for evidence grading. Finally nine studies were included. Four of them used intralesional injections, four topical therapeutics and one assessed the efficacy of CO2 -laser. Intralesional triamcinolone + fluorouracil injections, and topical pressure and/or silicone therapy revealed significant improvements in terms of scar height, pliability, and pigmentation. This systematic review showed that still few high-quality studies exist to evaluate therapeutic means and their mechanisms for hypertrophic scars. Among these, most of them assessed the efficacy of intralesional triamcinolone injections with the same treatment protocol. Intralesional injection appears to be the best option for hypertrophic scar treatment. Future studies should focus on a possible optimization of infiltrative therapies, consistent end-point evaluations, adequate follow-up periods, and possibly intraindividual treatments.

Oculoauriculovertebral spectrum and maxillary sinus volumes : CT-based comparative evaluation.

OBJECTIVES: To evaluate, by comparing maxillary sinus volumes, how asymmetries related to oculoauriculovertebral spectrum (OAVS) affect upper-jaw development. METHODS: From pre-existing multislice spiral computed tomography (MSCT) datasets, we selected 20 cases of 11 female and 9 male patients aged 6.1-24 years who were clinically and radiographically symmetrical (group 1) plus 20 cases of 8 female and 12 male patients aged 5.7-23.9 years who had OAVS (group 2). After three-dimensional reconstruction of the datasets, the volumes of the left and right maxillary sinuses were calculated and compared based on patient groups and based on the sides affected or unaffected by OAVS. To this end, the OAVS patients were subdivided into a group in whom both external acoustic pores were radiographically present (group 2a) and a group in whom the pore on the affected side was congenitally missing (group 2b). RESULTS: Intrarater reliability was very high (0.997). Significantly larger volumes of the maxillary sinuses, amounting to a mean of 13.4 ml, were observed in the control group than in the asymmetric OAVS groups where the volumes averaged 9.8 ml or 10.3 ml, respectively (p = 0.03). No statistically significant differences in sinus volumes were found between the two OAVS groups (p = 0.557) and between the sides affected or unaffected by the OAVS (p = 0.8311 in group 2a and 0.4961 in group 2b). CONCLUSIONS: Overall, we found the volumes of both maxillary sinuses to be somewhat smaller in the asymmetric patients than in the symmetric control group. This might indicate that OAVS was associated with a mild generalized hypoplasia of the maxilla, but significantly different sinus volumes were not seen between the affected and unaffected sides.

Prevalence of temporomandibular disorders in patients with Hashimoto thyroiditis.

OBJECTIVES: Autoimmune thyroid disease (AITD), also known as Hashimoto thyroiditis (HT), is a degenerative inflammatory disease with high prevalence among women and has been associated with fibromyalgia and widespread chronic pain. The goal was to determine the frequency of temporomandibular disorders (TMD) in patients with HT. METHODS: In all, 119 women (age 19-60 years) were divided into a study (52 women diagnosed with HT) and a control (67 healthy individuals, of which 15 were excluded) group. Serum concentrations of thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), anti-thyroglobulin (Tg) and anti-thyroid peroxidase (TPO) antibody levels were measured. The temporomandibular jaw and muscles were examined using the German Society of Functional Diagnostics and Therapy guidelines. The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) was used to assess TMD. Standardized questionnaires, incorporating epidemiological criteria, state and treatment of the thyroid disease, Helkimo Index (HI), and Fonseca Anamnestic Index (FAI), were filled out by all patients. RESULTS: The two groups did not differ in terms of demographic parameters or mandibular jaw mobility. Significantly higher levels of anti-TPO and anti-Tg were attested in all subjects of the HT group. Markedly elevated prevalence of TMD was found in the HT group. Muscle pain and stiffness were found in 45 (86.5%) subjects of the HT group (p < 0.001), of whom 33 (63.4%) also had disc displacement with reposition (p < 0.001). Whereas 50% of the control group showed no TMD symptoms, all subjects in the HT group had symptoms. CONCLUSIONS: A significantly elevated prevalence of TMD was found in patients with HT. Thus, patients with TMD who do not respond to therapy should be referred for thyroid diagnostic workup.

ErbB Family Signalling: A Paradigm for Oncogene Addiction and Personalized Oncology.

ErbB family members represent important biomarkers and drug targets for modern precision therapy. They have gained considerable importance as paradigms for oncoprotein addiction and personalized medicine. This review summarizes the current understanding of ErbB proteins in cell signalling and cancer and describes the molecular rationale of prominent cases of ErbB oncoprotein addiction in different cancer types. In addition, we have highlighted experimental technologies for the development of innovative cancer cell models that accurately predicted clinical ErbB drug efficacies. In the future, such cancer models might facilitate the identification and validation of physiologically relevant novel forms of oncoprotein and non-oncoprotein addiction or synthetic lethality. The identification of genotype-drug response relationships will further advance personalized oncology and improve drug efficacy in the clinic. Finally, we review the most important drugs targeting ErbB family members that are under investigation in clinical trials or that made their way already into clinical routine. Taken together, the functional characterization of ErbB oncoproteins have significantly increased our knowledge on predictive biomarkers, oncoprotein addiction and patient stratification and treatment.

A Screening Approach for Identifying Gliadin Neutralizing Antibodies on Epithelial Intestinal Caco-2 Cells.

Celiac disease (CD) is a chronic inflammatory condition caused by the ingestion of gliadin-containing food in genetically susceptible individuals. Undigested peptides of gliadin exert various effects, including increased intestinal permeability and inflammation in the small intestine. Although many therapeutic approaches are in development, a gluten-free diet is the only effective treatment for CD. Affecting at least 1% of the population in industrialized countries, it is important to generate therapeutic options against CD. Here, we describe the establishment of a high-throughput screening (HTS) platform based on AlphaLISA and electrical cell-substrate impedance sensing (ECIS) technology for the identification of anti-inflammatory and barrier-protective compounds in human enterocytes after pepsin-trypsin-digested gliadin (PT-gliadin) treatment. Our results show that the combination of these HTS technologies enables fast, reliable, simple, and label-free screening of IgY antibodies against PT-gliadin. Using this platform, we have identified a new chicken anti-PT-gliadin IgY antibody as a potential anti-CD agent.