Early Vascular Ageing in adolescents with migraine with aura: a community-based study.

BACKGROUND: Migraine with aura is associated with an increased risk of cardiovascular disease, yet the pathophysiology is unknown. Suggested underlying mechanisms of aura formation point into the direction of an abnormal vasoreactivity that also extends to the extracranial vasculature. METHODS: In the Early Vascular Ageing Tyrol study, a community-based non-randomized controlled trial conducted in 45 schools and companies in Tyrol (Austria) and South-Tyrol (Italy) between May 2015 and September 2018 aiming to increase cardiovascular health in adolescents, headache syndromes were classified according to the International Classification of Headache Disorders in a face-to-face interview. Carotid-femoral pulse-wave-velocity was measured by applanation tonometry and carotid intima-media-thickness by high-resolution ultrasound of the distal common carotid arteries. Differences in pulse-wave-velocity and carotid intima-media-thickness in youngsters with migraine with aura were compared respectively to those without headache and with other headaches by multivariable linear regression analysis. RESULTS: Of the 2102 study participants 1589 were aged 14 to 19 (mean 16.8) years and had complete data. 43 (2.7%) reported migraine with aura and 737 (46.4%) other headaches. Mean pulse-wave-velocity was 6.17 m/s (± 0.85) for migraine with aura, 6.06 m/s (± 0.82) for all other headaches and 6.15 (0.95) m/s for participants without headaches. Carotid intima-media-thickness was 411.3 µm (± 43.5) for migraine with aura, 410.9 µm (± 46.0) for all other headaches and 421.6 µm (± 48.4) for participants without headaches. In multivariable linear regression analysis, we found no differences in carotid-femoral pulse-wave-velocity or carotid intima-media-thickness in young subjects with migraine with aura, all other headaches, or no headaches. CONCLUSIONS: In line with previous large-scale studies in adults, we could not demonstrate relevant associations of migraine with aura with markers of arterial stiffness or subclinical atherosclerosis making early vascular ageing an unlikely pathophysiological link between migraine with aura and cardiovascular diseases. TRIAL REGISTRATION: First registered on ClinicalTrials.gov 29/04/2019 (NCT03929692).

Online Medical Education: Utilization of Google Forms for Remote Active Learning Experiences in a Large Medical School Class During the COVID-19 Pandemic.

Remote delivery of preclinical medical scientific curriculum during the COVID pandemic to a large medical school class (n = 429) provided limited options for active learning. We implemented adjunct Google Forms in a first-year medical school class to provide online, active learning with automated feedback and mastery learning approaches.

Artificial microbial consortia for bioproduction processes.

The application of artificial microbial consortia for biotechnological production processes is an emerging field in research as it offers great potential for the improvement of established as well as the development of novel processes. In this review, we summarize recent highlights in the usage of various microbial consortia for the production of, for example, platform chemicals, biofuels, or pharmaceutical compounds. It aims to demonstrate the great potential of co-cultures by employing different organisms and interaction mechanisms and exploiting their respective advantages. Bacteria and yeasts often offer a broad spectrum of possible products, fungi enable the utilization of complex lignocellulosic substrates via enzyme secretion and hydrolysis, and microalgae can feature their abilities to fixate CO2 through photosynthesis for other organisms as well as to form lipids as potential fuelstocks. However, the complexity of interactions between microbes require methods for observing population dynamics within the process and modern approaches such as modeling or automation for process development. After shortly discussing these interaction mechanisms, we aim to present a broad variety of successfully established co-culture processes to display the potential of artificial microbial consortia for the production of biotechnological products.

Occurrence of inadequate ACL healing after Dynamic Intraligamentary Stabilization and functional outcome-a multicentre case series.

INTRODUCTION: Dynamic Intraligamentary Stabilization (DIS) is a technique for preservation, anatomical repair and stabilization of a freshly injured anterior cruciate ligament (ACL). The main purpose of this study was to evaluate the short-term re-operation rate when compared to traditional autograft reconstruction. METHODS: Four, from the developer independent, centres enrolled patients that underwent ACL repair by DIS, according to the specific indications given by MRI imaging at a minimum follow-up of 12 months. The re-operation rate was recorded as primary outcome. Secondary outcome measures were the postoperative antero-posterior knee laxity (using a portable Rolimeter®), as well as the Tegner, Lysholm and IKDC Scores. RESULTS: A total of 105 patients were investigated with a median follow-up of 21 months. Thirteen patients were lost to follow-up. Of the remaining 92 patients 15 (16.3%) had insufficient functional stability and required subsequent ACL reconstruction. These patients were excluded from further analysis, leaving 77 consecutive patients for a 12 months follow-up. The median age at time of surgery was 30 years for that group. At time of follow-up a median antero-posterior translation difference of 2 mm was measured. None of these patients reported subjective insufficiency (giving way), but in 14 patients (18.2%), the difference of antero-posterior translation was more than 3 mm. We found a median Tegner Score of 5.5, a median Lysholm Score of 95.0 and a median IKDC Score of 89.4. CONCLUSION: The main finding of this multicentre study is a relevant re-operation rate of 16.3%. Another 18.2% showed objective antero-posterior laxity (≥ 3 mm) during testing raising the suspicion of postoperative non-healing. The failure rate of DIS in this study is higher than for reconstruction with an autologous tendon graft. However, our successfully treated patients had a good clinical and functional outcome based on antero-posterior knee laxity and clinical scores, comparable to patients treated by autograft reconstruction.

Simultaneous photoautotrophic production of DHA and EPA by Tisochrysis lutea and Microchloropsis salina in co-culture.

Marine microalgae have received much attention as a sustainable source of the two health beneficial omega-3-fatty acids docosahexaenoic acid (DHA, C22:6) and eicosapentaenoic acid (EPA, C20:5). However, photoautotrophic monocultures of microalgae can only produce either DHA or EPA enriched biomass. An alternative may be the photoautotrophic co-cultivation of Tisochrysis lutea as DHA-producer with Microchloropsis salina for simultaneous EPA production to obtain EPA- and DHA-rich microalgae biomass in a nutritionally balanced ratio. Photoautotrophic co-cultivation processes of T. lutea and M. salina were studied, applying scalable and fully controlled lab-scale gas-lift flat-plate photobioreactors with LED illumination for dynamic climate simulation of a repeated sunny summer day in Australia [day-night cycles of incident light (PAR) and temperature]. Monocultures of both marine microalgae were used as reference batch processes. Differences in the autofluorescence of both microalgae enabled the individual measurement, of cell distributions in co-culture, by flow cytometry. The co-cultivation of T. lutea and M. salina in artificial sea water with an inoculation ratio of 1:3 resulted in a balanced biomass production of both microalgae simultaneously with a DHA:EPA ratio of almost 1:1 (26 mgDHA gCDW-1, and 23 mgEPA gCDW-1, respectively) at harvest after depletion of the initially added fertilizer. Surprisingly, more microalgae biomass was produced within 8 days in co-cultivation with an increase in the cell dry weight (CDW) concentration by 31%, compared to the monocultures with the same amount of light and fertilizer. What is more, DHA-content of the microalgae biomass was enhanced by 33% in the co-culture, whereas EPA-content remained unchanged compared to the monocultures.

Analysis of Nipple-Areola Complex Localization Using Male Cadavers: Considerations for Gender-Affirming Surgery.

BACKGROUND: Masculinizing chest reconstruction is the most common gender-affirming surgery in transgender males. Despite the current literature's acknowledgment of the vital role that proper placement of the nipple-areola complex (NAC) plays in a masculine chest contour, there is still much debate regarding the best anatomical landmarks to achieve the desired result. OBJECTIVES: The primary aim of this study is to determine which landmarks for NAC placement can be applied across diverse body types and aid surgeons in creating a masculine chest. METHODS: Twenty-five formaldehyde-embalmed male cadavers were analyzed by conducting various measurements of the NAC, nipple, and surrounding bony and muscular landmarks to identify the most consistent landmarks for proper NAC placement. Linear regression analyses were run to determine how the distance between nipple to respective landmarks varied based on antemortem body mass index (BMI), height, weight, and age. RESULTS: The measurements for the inferior and lateral borders of the pectoralis major muscle (PMM) displayed the least amount of variance of all the anatomical landmarks studied. Additionally, there was no significant change in these pectoral measurements with varying BMI, height, weight, or age, indicating that these measurements are reliable landmarks for NAC placement across various body types. The average NAC placement in relation to the inferior and lateral borders of PMM was around 2.5 and 2.0 cm, respectively. CONCLUSIONS: Our cadaveric analysis indicates that aesthetically pleasing masculine chest results can be produced consistently across varying body types when adhering to a simple pectoral approach in NAC placement.

Gelsolin Is Associated with Longer Metastasis-free Survival and Reduced Cell Migration in Estrogen Receptor-positive Breast Cancer.

BACKGROUND: Tumor cell migration is a prerequisite for metastasis formation. The role of the actin-modulating protein, gelsolin, in metastasis is controversial, as previous studies have reported associations with both worse and better prognosis. MATERIALS AND METHODS: We analysed the association of gelsolin mRNA levels with metastasis-free survival in three cohorts (n=766) of patients with node-negative breast cancer. To determine its effect on migration, gelsolin expression was down-regulated as well as overexpressed in breast cancer cell lines. RESULTS: Higher gelsolin expression correlated with lower tumor stage and grade, and slower cell proliferation, and was associated with longer metastasis-free survival (hazard ratio (HR)=0.60, p<0.001) in patients with estrogen receptor-positive (ER(+)) erb-b2 receptor tyrosine kinase 2-negative (HER2(-)) tumors. Conversely, the opposite association was observed in those with ER(-)HER(-) tumors (HR=1.95, p=0.014). Down-regulation of gelsolin using siRNA in MCF-7 and MDA-MB-468 cells increased cell migration, whereas overexpression had the opposite effect. CONCLUSION: High gelsolin levels are associated with better prognosis in ER(+)HER2(-) breast cancer and a reduction in tumor cell migration.

Dynamic intraligamentary stabilization and primary repair: a new concept for the treatment of knee dislocation.

BACKGROUND: Traumatic knee dislocation represents a rare but devastating injury. Several controversies persist regarding type of treatment, surgical timing, graft selection, repair versus reconstruction of the medial and lateral structures, surgical techniques and postoperative rehabilitation. A new technique for primary ACL stabilization, dynamic intaligamentary stabilization (DIS) was developed at the authors' institution. The purpose of this study was to analyze the clinical and radiological outcomes of surgically treated traumatic knee dislocations by means of the DIS technique for the ACL, primary suturing for PCL, MCL and LCL. METHODS: Between 2009 and 2012, 35 patients treated surgically for traumatic knee dislocation with primary anterior cruciate ligament (ACL) reconstruction with DIS, suturing of the posterior cruciate ligament (PCL) and primary complete repair of collaterals, were evaluated clinically (IKDC score, SF12 health survey, Lysholm score, Tegner score) and radiologically with a mean follow up of 2.2 years (range 1.00-3.50 years) years. Instrumented anterior-posterior translation was measured (KT-2000). RESULTS: Anterior/posterior translation (KT-2000) for the healthy and injured limb was 4.8mm (range 3-8mm) and 7.3mm (range 5-10) (89N) respectively. Valgus and varus stress testing in 30° flexion was normal in 26 (75%) and 29 (83%) patients, respectively. The IKDC score was B in 29 (83%) and C in 6 (17%) patients, while the mean Tegner score was 6 (range 4-8). The mean Lysholm score was 90.83 (range 81-95) and mean SF-12 physical and mental scores were 54.1 (range 45-60) and 51.0 (range 39-62) respectively. In 2 patients, a secondary operation was performed. CONCLUSIONS: Early, one stage reconstruction with DIS can achieve good functional results and patient satisfaction with overall restoration of sports and working capacity without graft requirements.

Induction of pancreatic cancer cell migration by an autocrine epidermal growth factor receptor activation.

Pancreatic cancer is characterized by aggressive local invasion and early metastasis formation. Active migration of the pancreatic cancer cells is essential for these processes. We have shown previously that the pancreatic cancer cells lines CFPAC1 and IMIM-PC2 show high migratory activity, and we have investigated herein the reason for this observation. Cell migration was assessed using a three-dimensional, collagen-based assay and computer-assisted cell tracking. The expression of receptor tyrosine kinases was determined by flow-cytometry and cytokine release was measured by an enzyme-linked immunoassay. Receptor function was blocked by antibodies or pharmacological enzyme inhibitors. Both cells lines express the epidermal growth factor receptor (EGFR) as well as its family-member ErbB2 and the platelet-derived growth factor receptor (PDGFR)α, whereas only weak expression was detected for ErbB3 and no expression of PDGFRß. Pharmacological inhibition of the EGFR or ErbB2 significantly reduced the migratory activity in both cell lines, as did an anti-EGFR antibody. Interestingly, combination of the latter with an anti-PDGFR antibody led to an even more pronounced reduction. Both cell lines release detectable amounts of EGF. Thus, the high migratory activity of the investigated pancreatic cancer cell lines is due to autocrine EGFR activation and possibly of other receptor tyrosine kinases.

Norepinephrine inhibits the migratory activity of pancreatic cancer cells.

We have shown previously that norepinephrine induces migratory activity of tumour cells from breast, colon and prostate tissue via activation of beta-2 adrenergic receptors. Consequently, this effect can be inhibited pharmacologically by clinically established beta-blockers. Tumour cell migration is a prerequisite for metastasis formation, and accordingly we and others have shown that breast cancer patients, which take beta-blockers due to hypertension, have reduced metastasis formation and increased survival probability as compared to patients without hypertension or using other anti-hypertensive medication. Unlike the aforementioned tumour cells, pancreatic cancer cells show a reduced migratory activity upon norepinephrine treatment. By means of our three-dimensional, collagen-based cell migration assay, we have investigated the signal transduction pathways involved in this phenomenon. We have found that this conflicting effect of norepinephrine on pancreatic cancer cells is due to an imbalanced activation of the two pathways that usually mediate a pro-migratory effect of norepinephrine in other tumour cell types. Firstly, the inhibitory effect results from activation of a pathway which causes a strong increase of the secondary cell signalling molecule, cAMP. In addition, activation of phospholipase C gamma and the downstream protein kinase C alpha were shown to be already activated in pancreatic cancer cells and cannot be further activated by norepinephrine. We hypothesize that this constitutive activation of the phospholipase C gamma pathway is due to a cross-talk with receptor tyrosine kinase signalling, and this might also deliver an explanation for the unusual high spontaneous migratory activity of pancreatic cancer cells.

Targets for anti-metastatic drug development.

With a constant focus on the primary tumor, the current approaches in drug development in oncology yield dismal results. However over 90 percent of cancer deaths today are due to metastasis formation and yet there is no anti-metastatic drug on the market. Tumor cell migration is the essential prerequisite for invasion and metastasis formation. It is regulated by signal substances in terms of the grade of activity and in terms of direction (chemotaxis). The latter is important for the organotropism, the localization of metastasis in certain organs. Ligands to G protein-coupled receptors, mainly chemokines and neurotransmitters, as well as ligands to receptor kinases, mainly cytokines and growth factors, form the most important group of such regulators. We provide an overview of currently available agonists and antagonists to these receptors, which have a potential as anti-metastatic targets. Moreover we provide with the example of beta-blockers, how established drugs in other indications are possibly effective and can be co-opted as such anti-metastatics. The increasing knowledge of such regulators opens new opportunities to target cancer spreading and may put forth the development of antimetastatic drugs for oncological therapy.

Hfq influences multiple transport systems and virulence in the plant pathogen Agrobacterium tumefaciens.

The Hfq protein mediates gene regulation by small RNAs (sRNAs) in about 50% of all bacteria. Depending on the species, phenotypic defects of an hfq mutant range from mild to severe. Here, we document that the purified Hfq protein of the plant pathogen and natural genetic engineer Agrobacterium tumefaciens binds to the previously described sRNA AbcR1 and its target mRNA atu2422, which codes for the substrate binding protein of an ABC transporter taking up proline and γ-aminobutyric acid (GABA). Several other ABC transporter components were overproduced in an hfq mutant compared to their levels in the parental strain, suggesting that Hfq plays a major role in controlling the uptake systems and metabolic versatility of A. tumefaciens. The hfq mutant showed delayed growth, altered cell morphology, and reduced motility. Although the DNA-transferring type IV secretion system was produced, tumor formation by the mutant strain was attenuated, demonstrating an important contribution of Hfq to plant transformation by A. tumefaciens.