Integration of radiation oncology teaching in medical studies by German medical faculties due to the new licensing regulations : An overview and recommendations of the consortium academic radiation oncology of the German Society for Radiation Oncology (DEGRO).

The new Medical Licensing Regulations 2025 (Ärztliche Approbationsordnung, ÄApprO) will soon be passed by the Federal Council (Bundesrat) and will be implemented step by step by the individual faculties in the coming months. The further development of medical studies essentially involves an orientation from fact-based to competence-based learning and focuses on practical, longitudinal and interdisciplinary training. Radiation oncology and radiation therapy are important components of therapeutic oncology and are of great importance for public health, both clinically and epidemiologically, and therefore should be given appropriate attention in medical education. This report is based on a recent survey on the current state of radiation therapy teaching at university hospitals in Germany as well as the contents of the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog Medizin 2.0, NKLM) and the closely related Subject Catalogue (Gegenstandskatalog, GK) of the Institute for Medical and Pharmaceutical Examination Questions (Institut für Medizinische und Pharmazeutische Prüfungsfragen, IMPP). The current recommendations of the German Society for Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO) regarding topics, scope and rationale for the establishment of radiation oncology teaching at the respective faculties are also included.

[Preconditioning of vascularized high-risk eyes using fine-needle diathermy and cross-linking]. / Präkonditionierung von vaskularisierten Hochrisikoaugen mittels Feinnadeldiathermie und Crosslinking.

BACKGROUND: The risk of allograft rejection following high-risk keratoplasty increases with the area of corneal neovascularization. Pharmaceutical and physical regression of corneal neovascularization before keratoplasty may offer the potential to reduce the risk of graft rejection after high-risk keratoplasty. OBJECTIVE: This article provides a review of the literature on the preconditioning of vascularized high-risk eyes using fine-needle diathermy and corneal cross-linking (preoperative preconditioning by lymphangioregression). METHODS: A literature search was carried out in PubMed and a summary of own data is presented. RESULTS: Animal experimental studies showed that both fine-needle diathermy and corneal cross-linking lead to a regression of corneal neovascularization and prolong graft survival after high-risk keratoplasty. Furthermore, studies from our institute provide first evidence that both procedures also lead to a reduction of corneal neovascularization in the clinical practice and thus potentially reduce the risk of allograft rejection after subsequent high-risk keratoplasty. DISCUSSION: Fine-needle diathermy and corneal cross-linking provide effective therapeutic approaches for angioregressive treatment and seem to prolong graft survival following high-risk keratoplasty. Larger prospective and controlled clinical trials are needed to further investigate these promising therapeutic approaches.

[Descemet membrane endothelial keratoplasty (DMEK) for graft failure after penetrating keratoplasty and in vascularized high-risk eyes]. / "Descemet membrane endothelial keratoplasty" (DMEK) bei Transplantatversagen nach perforierender Keratoplastik und in vaskularisierten Hochrisikoaugen.

BACKGROUND: Descemet membrane endothelial keratoplasty (DMEK) is considered the gold standard for the treatment of corneal endothelial dysfunction and generally leads to good postoperative results. Recently, studies have also analyzed the outcome of DMEK in so-called high-risk eyes. MATERIAL AND METHODS: The relevant literature and own data on DMEK for graft failure after penetrating keratoplasty and in vascularized high-risk eyes are presented and discussed. RESULTS: A DMEK for the treatment of transplant failure after penetrating keratoplasty can be considered for eyes without stromal scars and without high astigmatism. A retrospective analysis of 52 patients with failed penetrating grafts showed that DMEK leads to a significant increase in visual acuity, albeit to a lesser extent than after primary DMEK. Rejection and transplant failure rates seem to be similar those seen after penetrating re-keratoplasty and are thus higher than after primary DMEK. A DMEK might also be a feasible option for eyes with corneal neovascularization and stromal edema without stromal scars. A retrospective analysis of 24 eyes with at least 2 vascularized corneal quadrants demonstrated that DMEK leads to a significant improvement in visual acuity and regression of corneal neovascularization. The rejection rate in this cohort was 4.2% and is therefore slightly higher than after low-risk DMEK in eyes without corneal neovascularization but still much better compared to penetrating keratoplasty. CONCLUSION: Indications for DMEK are expanding and it can be a therapeutic option for transplant failure after penetrating keratoplasty with acceptable outcomes. Furthermore, DMEK seems to be a good option for the treatment of endothelial dysfunction in vascularized high-risk eyes without stromal scars.

Factors associated with postponed health checkups during the COVID-19 pandemic in Germany.

OBJECTIVES: The COVID-19 pandemic has serious social, economic and health consequences. Particularly in these times, it is important to maintain individual health. Therefore, it is important to take part in routine health checkups. Consequently, our objective was to describe the frequency and to identify the determinants of postponed routine health checkups. STUDY DESIGN: Cross-sectional data from the nationally representative online-survey "COVID-19 Snapshot Monitoring in Germany (COSMO)" was used (wave 17; July 2020). METHODS: In sum, 974 individuals were included in our analytical sample (average age was 45.9 years, SD: 16.5, 18-74 years). Postponed routine health checkups (yes or no) since March 2020 due to the COVID-19 pandemic were assessed. RESULTS: More than 16% of the individuals reported postponed routine health checkups in the past few months due to the COVID-19 pandemic. Particularly, individuals aged 30-49 years had postponed health checkups (21%). The probability of postponed health checkups was positively associated with the presence of chronic diseases (odds ratio [OR]: 1.68, 95% confidence interval [CI]: 1.15-2.47), higher affect regarding COVID-19 (OR: 1.44, 95%-CI: 1.16-1.78), and higher presumed severity of COVID-19 (OR: 1.17, 95%-CI: 1.01-1.35), whereas the outcome measure was not associated with socioeconomic factors. Data showed that a sizeable part (about one of six individuals) of the population reported postponed routine health checkups due to the COVID-19 pandemic between March and July 2020. CONCLUSIONS: Postponed checkups should not be neglected during the COVID-19 pandemic. Individuals at risk for postponed health checkups should be appropriately addressed.

Thrombomodulin-dependent protein C activation is required for mitochondrial function and myelination in the central nervous system.

Essentials The role of protein C (PC) activation in experimental autoimmune encephalitis (EAE) is unknown. PC activation is required for mitochondrial function in the central nervous system. Impaired PC activation aggravates EAE, which can be compensated for by soluble thrombomodulin. Protection of myelin by activated PC or solulin is partially independent of immune-modulation. SUMMARY: Background Studies with human samples and in rodents established a function of coagulation proteases in neuro-inflammatory demyelinating diseases (e.g. in multiple sclerosis [MS] and experimental autoimmune encephalitis [EAE]). Surprisingly, approaches to increase activated protein C (aPC) plasma levels as well as antibody-mediated inhibition of PC/aPC ameliorated EAE in mice. Hence, the role of aPC generation in demyelinating diseases and potential mechanisms involved remain controversial. Furthermore, it is not known whether loss of aPC has pathological consequences at baseline (e.g. in the absence of disease). Objective To explore the role of thrombomodulin (TM)-dependent aPC generation at baseline and in immunological and non-immunological demyelinating disease models. Methods Myelination and reactive oxygen species (ROS) generation were evaluated in mice with genetically reduced TM-mediated protein C activation (TMPro/Pro ) and in wild-type (WT) mice under control conditions or following induction of EAE. Non-immunological demyelination was analyzed in the cuprizone-diet model. Results Impaired TM-dependent aPC generation already disturbs myelination and mitochondrial function at baseline. This basal phenotype is linked with increased mitochondrial ROS and aggravates EAE. Reducing mitochondrial ROS (p66Shc deficiency), restoring aPC plasma levels or injecting soluble TM (solulin) ameliorates EAE in TMPro/Pro mice. Soluble TM additionally conveyed protection in WT-EAE mice. Furthermore, soluble TM dampened demyelination in the cuprizone-diet model, demonstrating that its myelin-protective effect is partially independent of an immune-driven process. Conclusion These results uncover a novel physiological function of TM-dependent aPC generation within the CNS. Loss of TM-dependent aPC generation causes a neurological defect in healthy mice and aggravates EAE, which can be therapeutically corrected.

[Structure of pain management facilities in Germany : Classification of medical and psychological pain treatment services-Consensus of the Joint Commission of the Professional Societies and Organizations for Quality in Pain Medicine]. / Struktur der schmerzmedizinischen Versorgung in Deutschland : Klassifikation schmerzmedizinischer Einrichtungen - Konsens der Gemeinsamen Kommission der Fachgesellschaften und Verbände für Qualität in der Schmerzmedizin.

On behalf of the Medical/Psychological Pain Associations, Pain Patients Alliance and the Professional Association of Pain Physicians and Psychologists, the Joint Commission of Professional Societies and Organizations for Quality in Pain Medicine, working in close collaboration with the respective presidents, has developed verifiable structural and process-related criteria for the classification of medical and psychological pain treatment facilities in Germany. Based on the established system of graded care in Germany and on existing qualifications, these criteria also argue for the introduction of a basic qualification in pain medicine. In addition to the first-ever comprehensive description of psychological pain facilities, the criteria presented can be used to classify five different levels of pain facilities, from basic pain management facilities, to specialized institutions, to the Centre for Interdisciplinary Pain Medicine. The recommendations offer binding and verifiable criteria for quality assurance in pain medicine and improved pain treatment.

Blockade of CCR7 leads to decreased dendritic cell migration to draining lymph nodes and promotes graft survival in low-risk corneal transplantation.

The chemokine receptor CCR7 is essential for migration of mature dendritic cells (DCs) to the regional lymph nodes, and it has been shown that blocking of CCR7 improves graft survival after high-risk corneal transplantation in vascularized recipient corneas. However, it is so far unknown whether blocking of CCR7 reduces migration of DCs from the avascular cornea to the draining lymph nodes and whether this leads to improved graft survival also in the low-risk setting of corneal transplantation, which accounts for the majority of perforating transplantations performed. Therefore, in this study, pellets containing Freund's adjuvant and bovine serum albumin (BSA) conjugated to Alexa488 fluorescent dye were implanted into the corneal stroma of BALB/c mice to analyze antigen uptake by corneal DCs and their migration to the regional lymph nodes. After pellet implantation, mice were either treated by local administration of a CCR7 blocking fusion protein that consisted of CCL19 fused to the Fc part of human IgG1 or a control-IgG. In vivo fluorescence microscopy showed uptake of Alexa488-conjugated BSA by corneal DCs within 8 h. Furthermore, analysis of single cell suspensions of draining lymph nodes prepared after 48 h revealed that 2.1 ± 0.3% of CD11c(+) cells were also Alexa488(+). Importantly, DC migration was significantly reduced after topical administration of CCL19-IgG (1.2 ± 0.2%; p < 0.05). To test the effect of CCR7 blockade on graft rejection after allogeneic low-risk keratoplasty, corneal transplantations were performed using C57BL/6-mice as donors and BALB/c-mice as recipients. Treatment mice received two intraperitoneal loading doses of CCL19-IgG prior to transplantation, followed by local treatment with CCL19-IgG containing eye drops for the first two weeks after transplantation. Control mice received same amounts of control-IgG. Kaplan-Meier survival analysis showed that in the CCL19-IgG treated group, 76% of the grafts survived through the end of the 8 week observation period, whereas 38% of the grafts survived in the control group (p < 0.05). Taken together, our study shows that blockade of CCR7 reduces the migration of mature corneal DCs to the draining lymph nodes and leads to improved graft survival in low-risk corneal transplantation.

Short-term uvb-irradiation leads to putative limbal stem cell damage and niche cell-mediated upregulation of macrophage recruiting cytokines.

Ultraviolet light B (UVB)-irradiation is linked to various ocular pathologies such as limbal stem cell defects in pterygium. Despite the large circumstantial evidence linking UVB irradiation and limbal epithelial stem cell damage, the precise molecular responses of limbal stem cells to UVB irradiation are unclear. Here the effect of UVB irradiation on the putative stem cell phenotype, limbal niche cells and the subsequent effects on corneal (lymph)angiogenic privilege were investigated. Primary human limbal epithelial stem cells and fibroblasts were irradiated with 0.02 J/cm(2) of UVB, a low dose corresponding to 3 min of solar irradiation. UVB irradiation caused significant reduction of limbal epithelial and limbal fibroblast proliferation for 24 h, but apoptosis of limbal epithelial stem cells only. Moreover, UVB induced stem-like character loss of limbal epithelial cells, as their colony forming efficiency and putative stem cell marker expression significantly decreased. Interestingly, limbal epithelial cells co-cultured with UVB-irradiated limbal fibroblasts also exhibited loss of stem cell character and decrease of colony forming efficiency. Conditioned media from limbal epithelial cells inhibited lymphatic endothelial cell proliferation and tube network complexity; however this effect diminished following UVB irradiation. In contrast, pro-inflammatory and macrophage-recruiting cytokines such as TNFα, IFNγ and MCP1 were significantly upregulated following cell irradiation of limbal fibroblasts. These data demonstrate the key role of the limbal stem cell niche in response to UVB and subsequent (lymph)angiogenic and inflammatory events. These data suggest that the known pro(lymph)angiogenic effect of UVB irradiation in pterygium is not linked to a direct up-regulation of pro-angiogenic cytokines, but rather to indirect macrophage-recruiting cytokines being upregulated after UVB irradiation.

PDGFRß(+) cells in human and experimental neuro-vascular dysplasia and seizures.

INTRODUCTION: Neuro-vascular rearrangement occurs in brain disorders, including epilepsy. Platelet-derived growth factor receptor beta (PDGFRß) is used as a marker of perivascular pericytes. Whether PDGFRß(+) cell reorganization occurs in regions of neuro-vascular dysplasia associated with seizures is unknown. METHODS: We used brain specimens derived from epileptic subjects affected by intractable seizures associated with focal cortical dysplasia (FCD) or temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). Tissues from cryptogenic epilepsy, non-sclerotic hippocampi or peritumoral were used for comparison. An in vivo rat model of neuro-vascular dysplasia was obtained by pre-natal exposure to methyl-axozy methanoic acid (MAM). Status epilepticus (SE) was induced in adult MAM rats by intraperitoneal pilocarpine. MAM tissues were also used to establish organotypic hippocampal cultures (OHC) to further assess pericytes positioning at the dysplastic microvasculature. PDGFRß and its colocalization with RECA-1 or CD34 were used to segregate perivascular pericytes. PDGFRß and NG2 or IBA1 colocalization were performed. Rat cortices and hippocampi were used for PDGFRß western blot analysis. RESULTS: Human FCD displayed the highest perivascular PDGFRß immunoreactivity, indicating pericytes, and presence of ramified PDGFRß(+) cells in the parenchyma and proximal to microvessels. Tissues deriving from human cryptogenic epilepsy displayed a similar pattern of immunoreactivity, although to a lesser extent compared to FCD. In TLE-HS, CD34 vascular proliferation was paralleled by increased perivascular PDGFRß(+) pericytes, as compared to non-HS. Parenchymal PDGFRß immunoreactivity co-localized with NG2 but was distinct from IBA1(+) microglia. In MAM rats, we found pericyte-vascular changes in regions characterized by neuronal heterotopias. PDGFRß immunoreactivity was differentially distributed in the heterotopic and adjacent normal CA1 region. The use of MAM OHC revealed microvascular-pericyte dysplasia at the capillary tree lining the dentate gyrus (DG) molecular layer as compared to control OHC. Severe SE induced PDGFRß(+) immunoreactivity mostly in the CA1 region of MAM rats. CONCLUSION: Our descriptive study points to microvascular-pericyte changes in the epileptic pathology. The possible link between PDGFRß(+) cells, neuro-vascular dysplasia and remodeling during seizures is discussed.

Meibography and meibomian gland measurements in ocular graft-versus-host disease.

Meibomian gland loss in ocular GvHD was described as a mechanism contributing to dry eye and severe damage to the ocular surface. Infrared images of upper eyelid meibomian glands from 86 ocular GvHD patients, from 10 patients after allogeneic stem cell transplantation (aSCT) without ocular GvHD, from 32 patients prior to aSCT and from 30 healthy controls were analyzed retrospectively and evaluated using two grading schemes. The upper meibomian gland area (uMGA) was calculated and set in relation to the total tarsal area of the lid. Results demonstrate that meibomian gland loss is significantly increased in patients with ocular GvHD as well as in patients prior to aSCT in comparison with controls (P between 0.05 and <0.001). Patients after aSCT without ocular GvHD had no significant difference in uMGA in comparison with controls. This study suggests that meibomian gland loss in GvHD patients is likely to be a multifactorial process that also occurs prior to aSCT, possibly due to underlying diseases and/or secondary to chemotherapy or irradiation. In addition, the question has to be addressed whether meibomian gland loss could serve as a predictor for the development of ocular GvHD. Overall, infrared meibography should be included in routine examination of patients undergoing aSCT and during follow-up.

[Recommendations of the updated LONTS guidelines. Long-term opioid therapy for chronic noncancer pain]. / Empfehlungen der aktualisierten Leitlinie LONTS. Langzeitanwendung von Opioiden bei chronischen nicht-tumorbedingten Schmerzen.

BACKGROUND: The regular update of the German S3 guidelines on long-term opioid therapy for chronic noncancer pain (CNCP), the"LONTS" (AWMF registration number 145/003), began in November 2013. METHODS: The guidelines were developed by 26 scientific societies and two patient self-help organisations under the coordination of the Deutsche Schmerzgesellschaft (German Pain Society). A systematic literature search in the Cochrane Central Register of Controlled Trials (CENTRAL), Medline and Scopus databases (up until October 2013) was performed. Levels of evidence were assigned according to the classification system of the Oxford Centre for Evidence-Based Medicine. The strength of the recommendations was established by multistep formal procedures, in order to reach a consensus according to German Association of the Medical Scientific Societies ("Arbeitsgemeinschaft der Wissenschaftlich Medizinischen Fachgesellschaften", AWMF) regulations. The guidelines were reviewed by the Drug Commission of the German Medical Association, the Austrian Pain Society and the Swiss Association for the Study of Pain. RESULTS: Opioids are one drug-based treatment option for short- (4-12 weeks), intermediate- (13-25 weeks) and long-term (≥ 26 weeks) therapy of chronic osteoarthritis, diabetic polyneuropathy, postherpetic neuralgia and low back pain. Contraindications are primary headaches, as well as functional somatic syndromes and mental disorders with the (cardinal) symptom pain. For all other clinical presentations, a short- and long-term therapy with opioid-containing analgesics should be evaluated on an individual basis. Long-term therapy with opioid-containing analgesics is associated with relevant risks (sexual disorders, increased mortality). CONCLUSION: Responsible application of opioid-containing analgesics requires consideration of possible indications and contraindications, as well as regular assessment of efficacy and adverse effects. Neither an uncritical increase in opioid application, nor the global rejection of opioid-containing analgesics is justified in patients with CNCP.

[Caesarean section in german hospitals: validity of hospital quality report data for monitoring C-section rates]. / Kaiserschnitte in deutschen Krankenhäusern: Wie zuverlässig sind Routinedaten aus dem strukturierten Qualitätsbericht für die Bestimmung der Kaiserschnittraten?

OBJECTIVE: It is not known if "hospital quality reports" (HQR) document Caesarean (C-) section rates at the hospital level accurately enough for use as a reliable data source when it comes to explaining regional variations of C-sections in Germany by factors at the hospital level. We aimed to answer this question using HQR from hospitals in Baden-Württemberg as data source. METHOD: Diagnostic and procedure codes from HQR for the year 2008 (HQRdata), were used to calculate numbers of births, numbers of C-sections, and rates of births by C-section (CSR) for 94 of 97 hospitals in Baden-Württemberg. These numbers were compared to internal hospital (IH) data delivered upon request by 80 of 97 hospitals and stemming from vital statistics, birth registry forms, or external quality assurance datasets. RESULTS: There was no difference in the number of births between HQR data and IH data, but the number of C-sections and the CSR differed significantly (p<0.05; Wilcoxon rank sum test). CSR calculated using HQR data was 4.9 ± 17.9% higher than CSR from IH data (absolute difference 1.5 ± 5.8%). The correlation between the 2 data sources was moderate (r=0.73). Only 55% of the variance in IH data-based CSR was explained by HQR data. The proportion between highest and lowest CSR in hospitals in Baden-Württemberg was 4.9 for HQR data and 3.6 for IH data. CONCLUSION: There are significant and relevant differences between C-section rates based on ei-ther HQR or IH data. This questions routine data from HQR for 2008 as a reliable data source for research work.

[Decellularized collagen matrix from tilapia fish scales for corneal reconstruction (BioCornea)]. / Dezellularisierte Kollagenmatrix aus der Schuppe des Tilapia-Fisches als Hornhautersatz ("BioCornea").

BACKGROUND: The worldwide need for donor corneal tissue clearly exceeds the availability of transplantable human tissue; therefore, recent efforts aim to identify and characterize alternative tissues, such as decellularized collagen scaffolds. OBJECTIVES: The transparent fish scales of tilapia (Oreochromis mossambicus) were analyzed as a potential alternative for corneal reconstruction ("BioCornea"). MATERIAL AND METHODS: The article gives a review of the literature and own preliminary results. After decellularization the tissue characteristics of the fish scales, the repopulation with corneal epithelium and stromal cells, immunogenicity, the feasibility of corneal transplantation and the angiogenic properties were analyzed in vitro and in various animal models. RESULTS: The fish scales mainly consist of collagen type I and show an architecture that is similar to the human cornea. Corneal epithelium and stromal cells are able to grow over and into the scaffold. It is possible to transplant fish scales in various animal models without severe inflammatory responses. Furthermore, in mice, less blood and lymphatic vessels grow into the xenograft when compared to conventional allogenic transplants. CONCLUSION: Preliminary results with decellularized tilapia fish scales as an alternative for corneal reconstruction ("BioCornea") are promising.

Effect of status epilepticus and antiepileptic drugs on CYP2E1 brain expression.

P450 metabolic enzymes are expressed in the human and rodent brain. Recent data support their involvement in the pathophysiology of epilepsy. However, the determinants of metabolic enzyme expression in the epileptic brain are unclear. We tested the hypothesis that status epilepticus (SE) or exposure to phenytoin or phenobarbital affects brain expression of the metabolic enzyme CYP2E1. SE was induced in C57BL/6J mice by systemic kainic acid. Brain CYP2E1 expression was evaluated 18-24h after severe SE by immunohistochemistry. Co-localization with neuronal nuclei (NEUN), glial fibrillary acidic protein (GFAP) and CD31 was determined by confocal microscopy. The effect of phenytoin, carbamazepine and phenobarbital on CYP2E1 expression was evaluated in vivo or by using organotypic hippocampal cultures in vitro. CYP2E1 expression was investigated in brain resections from a cohort of drug-resistant epileptic brain resections and human endothelial cultures (EPI-EC). Immunohistochemistry showed an increase of CYP2E1 expression limited to hippocampal CA2/3 and hilar neurons after severe SE in mice. CYP2E1 expression was also observed at the astrocyte-vascular interface. Analysis of human brain specimens revealed CYP2E1 expression in neurons and vascular endothelial cells (EC). CYP2E1 was expressed in cultured human EC and over-expressed by EPI-EC. When analyzing the effect of drug exposure on CYP2E1 expression we found that, in vivo or in vitro, ethanol increased CYP2E1 levels in the brain and liver. Treatment with phenytoin induced localized CYP2E1 expression in the brain whereas no significant effects were exerted by carbamazepine or phenobarbital. Our data indicate that the effect of acute SE on brain CYP2E1 expression is localized and cell specific. Exposure to selected anti-epileptic drugs could play a role in determining CYP2E1 brain expression. Additional investigation is required to fully reproduce the culprits of P450 enzyme expression as observed in the human epileptic brain.

Regression of mature lymphatic vessels in the cornea by photodynamic therapy.

BACKGROUND: Corneal (lymph) angiogenesis is a predominant risk-factor for immune rejection after transplantation. Techniques to regress pre-existing pathological corneal lymphatic vessels prior to transplantation are missing so far. Therefore we analysed the possibility to regress corneal lymphatic vessels by photodynamic therapy (PDT), after intrastromal verteporfin injection. METHODS: Combined hemangiogenesis and lymphangiogenesis was induced in female BALB/c mice using the murine model of suture-induced inflammatory neovascularisation. Thereafter, the treatment group received an intrastromal injection of verteporfin (controls: phosphate buffered saline (PBS)) followed by PDT. Corneas were excised at different time points (1 day, 5 days and 10 days) after PDT and corneal whole mounts were stained with CD31 and LYVE-1 to quantify hemangiogenesis and lymphangiogenesis. RESULTS: Whereas blood vessels showed no significant reduction after PDT, lymphatic vessels could significantly be reduced with PDT after intrastromal verteporfin injection: 1 day after PDT, lymphatic vessels were reduced by 62% (p=0.20). After 5 days and 10 days, lymphatic vessels were reduced by 51% and 48% (p<0.001), respectively. CONCLUSIONS: This study for the first time shows that PDT after corneal intrastromal verteporfin injection can selectively regress lymphatic vessels. This may become a new 'preconditioning strategy' to reduce pre-existing corneal lymphatic vessels prior to transplantation and thereby reduce allograft rejection in high-risk patients.

Objectifying the conjunctival provocation test: photography-based rating and digital analysis.

BACKGROUND: Patients with allergic rhinoconjunctivitis are susceptible to both nasal and ocular symptoms. The conjunctival provocation test (CPT) is an established diagnostic procedure used in allergic rhinoconjunctivitis, particularly to document a patient's current reactivity to allergens. To date, there are no international guidelines defining the CPT. No approved evaluation method exists for interpreting CPT results. This paper aims to establish the digital analysis of macroimages as an objective, validated and standardized method for interpreting CPT results. METHODS: In a clinical immunotherapy trial with 155 patients, treatment progress was documented based on the CPT. Local investigators used a symptom score to grade tearing, reddening and the patients' subjective perception of symptoms (mucosal irritation). A central observer rated conjunctival hyperemia via digital photography. Digital image analysis software was utilized to determine conjunctival hyperemia. RESULTS: Spearman's correlation between the local investigators' and the central observer's ratings was r = 0.729 (p < 0.001); the percentage of total agreement was 48% (based on 739 photos). Digital image analysis (based on 48 photos) had a high percentage of total agreement with the central observer's ratings (69%) but a low percentage of total agreement with the investigators' ratings (38%). The corresponding correlations were r = 0.264 and 0.064, respectively. CONCLUSION: Photography-based rating by a central observer may represent a valuable supplement to the local investigator's assessment for making an objective evaluation of CPT results. Digital image analysis possesses the potential of being an objective evaluation method compared to the wide-spread subjective evaluation by the investigators.

[From heparin to apixaban: anticoagulants cut both ways?]. / Vom Heparin zum Apixaban: Was bringen die "neuen Antikoagulanzien"?

BACKGROUND: Regarding anticoagulant therapies there has been a remarkable shift in recent years. The objective of this brief overview is to provide relevant information and guidelines on the advantages and disadvantages of novel anticoagulants addressing specifically the surgical disciplines. Hitherto, conventional anticoagulant therapy in patients with a high thrombosis risk was largely limited to heparins and vitamin-K antagonists (VKA). Their modes of action, the difficulties in managing VKAs (e.g., bridging therapy) and the risk of HIT (heparin-induced thrombocytopenia) associated with heparins are briefly discussed. Novel anticoagulants supposedly eliminate these obstacles. Fondaparinux (Arixtra®) is a fully synthetic pentasaccharide which acts like a heparin but has an increased half life. Fondaparinux has a diminished risk of HIT. However, no specific antidote is currently available for Fondaparinux. The novel oral anticoagulants (NOAC) dabigatran etexilat (Pradaxa®), rivaroxaban (Xarelto®) and apixaban (Eliquis®), also known as "direct" anticoagulants, act independently from antithrombin by inhibiting thrombin, as in the case of dabigatran, or by inhibiting factor Xa, as in the case of rivaroxaban and apixaban. It is assumed that they are suitable for long-term use and do not require laboratory monitoring. Nevertheless, clinical experience is very limited and caution rather than quick conclusions is necessary. Two major drawbacks are on the one hand the risk of drug accumulation in kidney and/or liver disease and, on the other hand, the lack of specific antidotes. In addition, interactions with other medication may have unexpected effects on serum drug levels. Therefore, the analysis of drug levels in the plasma may become necessary in subgroups of patients. DISCUSSION AND CONCLUSION: Studies establishing clear recommendations for the desirable and measurable reference range are needed. Similarly, evidence-based recommendations regarding perioperative prevention of thrombosis are required ("bridging": yes or no?). Irrespective of these issues, the authors predict a further expansion of the use of NOACs.

Death of p53-defective cells triggered by forced mitotic entry in the presence of DNA damage is not uniquely dependent on Caspase-2 or the PIDDosome.

Much effort has been put in the discovery of ways to selectively kill p53-deficient tumor cells and targeting cell cycle checkpoint pathways has revealed promising candidates. Studies in zebrafish and human cell lines suggested that the DNA damage response kinase, checkpoint kinase 1 (Chk1), not only regulates onset of mitosis but also cell death in response to DNA damage in the absence of p53. This effect reportedly relies on ataxia telangiectasia mutated (ATM)-dependent and PIDDosome-mediated activation of Caspase-2. However, we show that genetic ablation of PIDDosome components in mice does not affect cell death in response to γ-irradiation. Furthermore, Chk1 inhibition largely failed to sensitize normal and malignant cells from p53(-/-) mice toward DNA damaging agents, and p53 status did not affect the death-inducing activity of DNA damage after Chk1 inhibition in human cancer cells. These observations argue against cross-species conservation of a Chk1-controlled cell survival pathway demanding further investigation of the molecular machinery responsible for cell death elicited by forced mitotic entry in the presence of DNA damage in different cell types and model organisms.

Two-step retrograde closed stenting: a novel method for treating canalicular lacerations in Chinese patients.

PURPOSE: To evaluate the efficacy of two-step retrograde closed stenting for treating canalicular laceration. methods: Forty-eight consecutive canalicular laceration cases (48 eyes) were randomised and divided into two groups: a one-step group and a two-step group. In the two-step group (23 cases), the first step was performed in the outpatient department and included identifying the medial cut end of the canaliculus and probing under a slit-lamp microscope, followed by a retrograde canalicular stenting assisted by a memory titanium stylet. The second step was canalicular anastomosis, which was performed in the operating room. In the one-step group (25 cases), all of the surgical procedures were performed when preoperative preparations were simultaneously available. RESULTS: The time elapsed from the doctor visit to the treatment was 4.3 ± 2.4 h in the two-step group and 18.8 ± 6.3 h in the one-step group (P<0.01). The canalicular medial cut ends were found in all cases, but 8.6 ± 3.5 min was needed in the two-step group, and 51.4 ± 24.2 min was needed in the one-step group (P<0.01). The numerical rating scale for pain during surgery was 1.8 ± 1.2 in the two-step group and 5.4 ± 2.2 in the one-step group (P<0.01). One case (2.63%) in the two-step group and nine cases (36%) in the one-step group required other assisted methods to locate the medial cut end (P=0.007). Twenty-one cases (91.3%) in the two-step group and 20 cases (80%) in the one-step group achieved patent lacrimal drainage systems during a 12-month follow-up (P=0.528). CONCLUSIONS: The two-step canalicular anastomosis method allows an early search for the medial cut end of the canaliculus and improves the chances of finding it; it is also a quicker, less invasive method for treating canalicular lacerations.

Effects of concurrent low back conditions on depression outcomes.

CONTEXT: Depression and low back problems are common issues in primary care. OBJECTIVE: To compare 6-month depression outcomes (specifically, clinical results and number of outpatient visits) in patients with or without comorbid low back conditions (LBCs). The authors hypothesized that the presence of an LBC within 3 months of the diagnosis of depression would negatively affect clinical outcomes of depression treatment after 6 months. DESIGN: Retrospective record review. SETTING: Collaborative care management program in a large primary care practice. PARTICIPANTS: Patients with a diagnosis of depression enrolled in collaborative care management (N=1326), including 172 with and 1154 without evidence of an LBC within 3 months of enrollment. MAIN OUTCOME MEASURES: Clinical depression outcomes (remission and persistent depressive symptoms) and number of outpatient visits at 6 months. RESULTS: Regression modeling for clinical remission and persistent depressive symptoms at 6 months demonstrated that LBCs were not an independent factor affecting clinical remission (P=.24) but were associated with persistent depressive symptoms (odds ratio, 1.559; 95% confidence interval, 1.065-2.282; P=.02); LBCs remained an independent predictor of outlier status for outpatient visits (≥8 clinical visits after 6 months of enrollment), with an odds ratio of 1.581 (95% confidence interval, 1.086-2.30; P=.02). CONCLUSION: Increased odds of persistent depressive symptoms and increased number of outpatient visits were found in patients with depression and concomitant LBCs 6 months after enrollment into collaborative care management, compared with those in patients with depression and without LBCs. The data suggest that temporally related LBCs could lead to worse outcomes in primary care patients being treated for depression, encouraging closer observation and possible therapeutic changes in this cohort.