Combined regression score predicts outcome after neoadjuvant treatment of oesophageal cancer.

BACKGROUND: Histopathologic regression following neoadjuvant treatment (NT) of oesophageal cancer is a prognostic factor of survival, but the nodal status is not considered. Here, a score combining both to improve prediction of survival after neoadjuvant therapy is developed. METHODS: Seven hundred and fifteen patients with oesophageal squamous cell (SCC) or adenocarcinoma (AC) undergoing NT and esophagectomy were analysed. Histopathologic response was classified according to percentage of vital residual tumour cells (VRTC): complete response (CR) without VRTC, major response with <10% VRTC, minor response with >10% VRTC. Nodal stage was classified as ypN0 and ypN+. Kaplan-Meier and Cox regression were used for survival analysis. RESULTS: Survival analysis identified three groups with significantly different mortality risks: (1) low-risk group for CR (ypT0N0) with 72% 5-year overall survival (5y-OS), (2) intermediate-risk group for minor/major responders and ypN0 with 59% 5y-OS, and (3) high-risk group for minor/major responders and ypN+ with 20% 5y-OS (p < 0.001). Median survival in AC and SCC cohorts were comparable (3.8 (CI 95%: 3.1, 5.3) vs. 4.6 years (CI 95%: 3.3, not reached), p = 0.3). CONCLUSIONS: Histopathologic regression and nodal status should be combined for estimating AC and SCC prognosis. Poor survival in the high-risk group highlights need for adjuvant therapy.

The dynamics of CO production from the photolysis of acetone across the whole S1 ← S0 absorption spectrum: Roaming and triple fragmentation pathways.

The unimolecular photodissociation dynamics of acetone spanning the entire S1 ← S0 absorption spectrum have been reinvestigated, with a focus on mechanisms that produce CO. At excitation wavelengths of λ > 305.8 nm, all photoproducts are formed on the S0 state after internal conversion. A roaming mechanism forming C2H6 + CO is active in the window λ = 311.2-305.8 nm. From λ = 305.8 to 262 nm, little or no CO is produced with the photochemistry dominated by the Norrish-type I C-C bond cleavage on the lowest excited triplet state, T1. At higher energy (λ < 262 nm), an increasing fraction of CH3CO radicals from the primary reaction have sufficient internal energy to spontaneously decompose to CH3 + CO. A new model is presented to account for the kinetic energy distribution of the secondary CH3 radical, allowing us to determine the height of the energetic barrier to CH3CO decomposition as 68 ± 4 kJ mol-1, which lies midway between previous measurements. The fraction of CO from triple fragmentation rises smoothly from 260 to 248 nm. We see no evidence of the return of roaming, or any other S0 reaction, in this higher energy region of the first electronic absorption band.

Proteoglycan 4 reduces friction more than other synovial fluid components for both cartilage-cartilage and cartilage-metal articulation.

OBJECTIVE: The clinical success of focal metallic resurfacing implants depends largely on the friction between implant and opposing cartilage. Therefore, the present study determines the lubricating ability of the synovial fluid components hyaluronic acid (HA), proteoglycan 4 (PRG4) and a surface-active phospholipid (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, POPC), on the articulation between cartilage and a Cobalt Chromium Molybdenum (CoCrMo) implant surface, compared with two cartilage surfaces. METHODS: A ring-on-disk geometry was used to perform repeated friction measurements at physiologically relevant velocities (6 and 60 mm/s) using lubricants with an increasing number of components present. Shear measurements were performed in order to evaluate the viscosity. To ensure that it is clinically relevant to explore the effect of these components, the presence of PRG4 in synovial fluid obtained from primary and revision knee and hip implant surgeries was examined. RESULTS: PRG4 in the presence of HA was found to significantly reduce the coefficient of friction for both cartilage-cartilage and cartilage-CoCrMo interface. This is relevant, as it was also demonstrated that PRG4 is still present at the time of revision surgeries. The addition of POPC had no effect for either configurations. HA increased the viscosity of the lubricating fluid by one order of magnitude, while PRG4 and POPC had no effect. CONCLUSION: The present study demonstrates the importance of selecting the appropriate lubrication solution to evaluate implant materials with biotribology tests. Because PRG4 is a key component for reducing friction between cartilage and an opposing surface, developing coatings which bind PRG4 is recommended for cartilage resurfacing implants.

Meta-analysis of randomized controlled trials and individual patient data comparing minimally invasive with open oesophagectomy for cancer.

BACKGROUND: Minimally invasive oesophagectomy (MIO) for oesophageal cancer may reduce surgical complications compared with open oesophagectomy. MIO is, however, technically challenging and may impair optimal oncological resection. The aim of the present study was to assess if MIO for cancer is beneficial. METHODS: A systematic literature search in MEDLINE, Web of Science and CENTRAL was performed and randomized controlled trials (RCTs) comparing MIO with open oesophagectomy were included in a meta-analysis. Survival was analysed using individual patient data. Random-effects model was used for pooled estimates of perioperative effects. RESULTS: Among 3219 articles, six RCTs were identified including 822 patients. Three-year overall survival (56 (95 per cent c.i. 49 to 62) per cent for MIO versus 52 (95 per cent c.i. 44 to 60) per cent for open; P = 0.54) and disease-free survival (54 (95 per cent c.i. 47 to 61) per cent versus 50 (95 per cent c.i. 42 to 58) per cent; P = 0.38) were comparable. Overall complication rate was lower for MIO (odds ratio 0.33 (95 per cent c.i. 0.20 to 0.53); P < 0.010) mainly due to fewer pulmonary complications (OR 0.44 (95 per cent c.i. 0.27 to 0.72); P < 0.010), including pneumonia (OR 0.41 (95 per cent c.i. 0.22 to 0.77); P < 0.010). CONCLUSION: MIO for cancer is associated with a lower risk of postoperative complications compared with open resection. Overall and disease-free survival are comparable for the two techniques. LAY SUMMARY: Oesophagectomy for cancer is associated with a high risk of complications. A minimally invasive approach might be less traumatic, leading to fewer complications and may also improve oncological outcome. A meta-analysis of randomized controlled trials comparing minimally invasive to open oesophagectomy was performed. The analysis showed that the minimally invasive approach led to fewer postoperative complications, in particular, fewer pulmonary complications. Survival after surgery was comparable for the two techniques.

Oesophagectomy for cancer is associated with a high risk of complications. A minimally invasive approach might be less traumatic, leading to fewer complications and may also improve oncological outcome. A meta-analysis of randomized controlled trials comparing minimally invasive to open oesophagectomy was performed. The analysis showed that the minimally invasive approach led to fewer postoperative complications, in particular, fewer pulmonary complications. Survival after surgery was comparable for the two techniques.

Salivary gland cancer in Southern Brazil: a prognostic study of 107 cases.

BACKGROUND: Salivary gland cancers (SGC) represent an uncommon group of heterogeneous tumors. We performed a retrospective survey of SGC diagnosed in a reference center for treatment of malignant tumors from the south of Brazil aiming to determine the prognostic value of demographic, clinic and pathologic features. MATERIAL AND METHODS: Cases diagnosed as SGC between 2006 and 2016 were retrospectively collected. Medical records were examined to extract demographic, clinic, pathologic and follow-up information. RESULTS: One-hundred and seven cases of SGC were identified. The most common SGC were mucoepidermoid carcinoma (MEC) (n = 39) followed by adenoid cystic carcinoma (AdCC) (n = 29). Among AdCCs, 55.2% of cases were classified as cribriform, 27.6% as tubular and 17.2% as solid. The tubular subtype had the highest percentage of cases with perineural invasion (p=0.01). Among MEC, 61.5% of cases were classified as low grade, 15.4% as intermediate grade and 19.9% as high grade. Low grade MEC had the lowest percentage of cases with perineural invasion (p=0.04). The 5-year survival for loco-regional control, disease-free survival (DFS) and disease-specific survival were 75%, 70% and 84%, respectively. The following features were associated with poor DFS: advanced age (p=0.03), rural residency (p=0.01), being a smoker or former smoker (p=0.01), pain (p=0.03), nodal metastasis (p<0.001), need for chemotherapy (p=0.02), neck dissection (p=0.04), perineural invasion (p=0.01), and being diagnosed with AdCC compared to MEC (p=0.02). CONCLUSIONS: The clinco-demographic and pathologic features identified as prognostic factors reveal the profile of patients at increased risk of recurrence and who would benefit from closer follow-up.

Skeletal deterioration in COL2A1-related spondyloepiphyseal dysplasia occurs prior to osteoarthritis.

OBJECTIVE: Spondyloepiphyseal dysplasia, a combination of progressive arthropathy with variable signs of skeletal dysplasia, can be a result of mutations in the collagen, type II, alpha 1 (COL2A1) gene. However, the bone involvement (e.g., density, microstructure) in this disorder has hitherto not been studied. DESIGN: A 50-year-old female patient and her 8-year-old son with flattening of vertebral bodies and early-onset osteoarthritis were genetically tested using a custom designed gene bone panel including 386 genes. Bone microstructure and turnover were assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT) and serum bone turnover markers, respectively. Furthermore, the bone and cartilage phenotype of male mice heterozygous for the loss-of-function mutation of Col2a1 (Col2a1+/d) was analyzed compared to wildtype littermates using µ-CT and histomorphometry. RESULTS: We identified a dominant COL2A1 mutation (c.620G > A p.(Gly207Glu)) indicating spondyloepiphyseal dysplasia in the female patient and her son, both being severely affected by skeletal deterioration. Although there was no osteoarthritis detectable at first visit, the son was affected by trabecular osteopenia, which progressed over time. In an iliac crest biopsy obtained from the mother, osteoclast indices were remarkably increased. Col2a1+/d mice developed a moderate skeletal phenotype expressed by reduced cortical and trabecular parameters at 4 weeks. Importantly, no articular defects could be observed in the knee joints at 4 weeks, while osteoarthritis was only detectable in 12-week-old mice. CONCLUSIONS: Our results indicate that collagen type II deficiency in spondyloepiphyseal dysplasia leads to skeletal deterioration with early-onset in humans and mice that occurs prior to the development of osteoarthritis.

YAP/TAZ regulates the expression of proteoglycan 4 and tenascin C in superficial-zone chondrocytes.

The roles of cell division control protein 42 homologue (CDC42) and actin polymerisation in regulating the phenotype of superficial-zone chondrocytes (SZCs) have been demonstrated in vitro; however, the signalling pathway(s) downstream have yet to be fully elucidated. The study hypothesis was that Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) act downstream to regulate proteoglycan 4 (PRG4) and tenascin C (TNC). Bovine SZCs grown in monolayer were treated with ML141 (CDC42 inhibitor) or the actin depolymerising agents, latrunculin B and cytochalasin D, to determine the effect on YAP/TAZ. Verteporfin (YAP/TAZ inhibitor) and YAP/TAZ siRNA-mediated knockdown were used to determine their role in regulating PRG4 and TNC. ML141 treatment reduced total YAP/TAZ protein, nuclear TAZ levels and the YAP/TAZ target gene, connective tissue growth factor (CTGF) mRNA levels. Latrunculin B decreased nuclear TAZ, while cytochalasin D treatment trended towards increased nuclear TAZ (p = 0.06), correlating with decreased and increased CTGF mRNA levels, respectively. Verteporfin treatment decreased PRG4 and TNC expression, with no effect on actin polymerisation. siRNA-mediated knockdown of YAP/TAZ revealed that PRG4 was regulated by YAP/TAZ while TNC was regulated by TAZ only. As cytochalasin D can activate myocardin-related transcription factor-A (MRTF-A), siRNA-mediated knockdown was performed to determine the role of MRTF-A in regulating YAP/TAZ. Although nuclear TAZ decreased, no significant changes in total protein levels were observed. Findings suggested that CDC42 and actin polymerisation regulated SZCs through multiple actin-regulated pathways. Understanding the regulation of these chondroprotective molecules may have important implications for prevention/treatment of osteoarthritis.

Evaluation of the inflammatory markers CCL8, CXCL5, and LIF in patients with anastomotic leakage after colorectal cancer surgery.

PURPOSE: Anastomotic leakage constitutes a dreaded complication after colorectal surgery, leading to increased morbidity and mortality as well as prolonged hospitalization. Most leakages become clinically apparent about 8 days after surgery; however, early detection is quintessential to reduce complications and to improve patients' outcome. We therefore investigated the significance of specific protein expression profiles as putative biomarkers, indicating anastomotic leakage. METHODS: In this single-center prospective cohort study serum and peritoneal fluid samples-from routinely intraoperatively inserted drainages-of colorectal cancer patients were collected 3 days after colorectal resection. Twenty patients without anastomotic leakage and 18 patients with an anastomotic leakage and without other complications were included. Protein expression of seven inflammatory markers in serum and peritoneal fluid was assessed by multiplex ELISA and correlated with patients' clinical data. RESULTS: Monocyte chemoattractant protein 2 (CCL8/MCP-2), leukemia-inhibiting factor (LIF), and epithelial-derived neutrophil-activating protein (CXCL5/ENA-78) were significantly elevated in peritoneal fluid but not in serum samples from patients subsequently developing anastomotic leakage after colorectal surgery. No expressional differences could be found between grade B and grade C anastomotic leakages. CONCLUSION: Measurement 3 days after surgery revealed altered protein expression patterns of the inflammatory markers CCL8/MCP2, LIF, and CXCL5/ENA-78 in peritoneal fluid from patients developing anastomotic leakage after colorectal surgery. Further studies with a larger patient cohort with inclusion of different variables are needed to evaluate their potential as predictive biomarkers for anastomotic leakage.

[Mediation of data literacy in curricular education in otorhinolaryngology: watch and wait or anticipatory obedience?] / Vermittlung digitaler Kompetenzen in der curricularen HNO-Lehre: abwartende Haltung oder vorauseilender Gehorsam?

A comprehensive societal change is currently taking place, which also includes the medical field. The often heard "digital transformation" is also fundamentally transforming the health care system familiar to us, including the medical schools. While the Masterplan 2020 includes changes in the medical school structure and in the curricular content, it unfortunately focuses on special competencies, e.g., communication or scientific work, but not on digitization. However, precisely these skills are becoming increasingly indispensable in daily routine work. The seminar "Digitization in otorhinolaryngology (ORL)" was incorporated as a pilot project in the students' curriculum of the Department of ORL, at the University of Freiburg/Germany: the 141 medical students completed and evaluated this seminar as part of their 2 week rotation in otorhinolaryngology during the fall semester 2017/2018. The content of the seminar mediated digital competencies on the basis of practical examples. The evaluation showed high interest of the students in the topic in general, but also in more detailed subitems of the digitization topic. The students were generally open-minded concerning digitization but also critical of the topic. The acceptance of this newly implemented seminar was clearly positive. Another positive side effect is that this teaching concept can be transferred to other disciplines. Hence, we suggest to consider the training of digital competencies when implementing the Masterplan 2020.

Wetting properties of porous high temperature polymer electrolyte fuel cells materials with phosphoric acid.

Wetting properties of phosphoric acid in porous materials of high temperature fuel cells (HT-PEFC), operating at around 160 °C, are important for cell performance and durability, but the underlying wetting parameters have been unknown so far. Therefore, the influence of phosphoric acid temperature and concentration on the wetting behavior of porous HT-PEFC materials is investigated. The acid filling of gas diffusion and catalyst layers as function of capillary pressure is monitored with X-ray tomographic microscopy under the well defined conditions of an ex situ set-up at temperatures up to 160 °C. For the wetting of gas diffusion layers, with pore sizes in the order of few 10 µm, two opposing trends are shown. With increasing phosphoric acid concentration, less capillary pressure is required, while with increasing temperatures, higher capillary pressures are needed for filling up to a given saturation. The same trends are also found for the contact angle of phosphoric acid on PTFE. A higher contact angle is observed with increasing temperature while increasing the phosphoric acid concentration decreases the contact angle. As both trends are of a similar order of magnitude, the wetting behavior of concentrated (113 wt%) phosphoric acid at 160 °C is astonishingly similar to the wetting behavior of water at room temperature. Another important property for HT-PEFC operation is the filling of cracks in the catalyst layer, which have widths up to 100 µm. For large cracks (>60 µm), a capillary pressure of only 15 mbar was deduced from the measurement, increasing to 30 mbar for cracks between 20 and 60 µm. This, for the first time, allows for assessing the membrane phosphoric acid pressure during fuel cell operation. This can guide the development of improved porous materials for HT-PEFC.

Other Antidepressants.

This chapter addresses the following FDA-approved medications for the treatment of major depressive disorder available for use in the United States including bupropion, mirtazapine, trazodone, vortioxetine, and vilazodone. These medications do not belong to one of the previously featured classes of antidepressants discussed in the preceding chapters. Each medication featured in this chapter has a unique structure and properties that target diverse receptors in the central nervous system. These diverse targets are distinct from other classes of medications used to treat major depressive disorder. This chapter will provide an overview of each medication's indication for use, history of development, pharmacology, metabolism, dosing recommendations, onset of action, use in special populations, safety and tolerability, adverse effects, potential interactions with additional medications, and data regarding possible overdose with available treatments.Bupropion was initially developed for its combined effects on the norepinephrine and dopamine neurotransmitters. Currently, bupropion is the only antidepressant on the market in the United States with no appreciable activity on serotonin concentrations in the central nervous system. Bupropion is extensively metabolized in humans into three active metabolites including hydroxybupropion, threohydrobupropion, and erythrohydrobuproprion each with substantial antidepressant activity. The most serious side effect of bupropion is the development of seizures, so the dose must be gradually titrated to a maximum dose of 450 mg per day of the immediate-release formulation and 400 mg per day of the sustained-release formulation. Additional adverse effects include agitation, dry mouth, insomnia, headaches, migraines, nausea, vomiting, constipation, and tremor. The onset of action of bupropion is 2 weeks with full efficacy attained at 4 weeks of treatment. Bupropion produced similar depression remission rates when compared to SSRIs with a median time to relapse of 44 weeks. Bupropion has additionally been approved for smoking cessation and may have a combined role in treating nicotine cravings and depression.Mirtazapine has a unique method of action by enhancing norepinephrine and serotonin neurotransmission by blocking the alpha-2 presynaptic adrenoceptors resulting in increased release of serotonin at the nerve terminals. Mirtazapine additionally binds to the 5-HT2, 5-HT3, and H1 receptors resulting in increased sedation, which is the most common side effect. Additional side effects include increased appetite and weight gain, dizziness, and transient elevations in cholesterol levels and liver function tests. Mirtazapine is unlike any other antidepressant in that it also has a hormonal effect that reduces cortisol levels within the body. Patients on mirtazapine showed significant improvement in symptoms of major depressive disorder within the first 1-2 weeks of treatment with long-term studies at 40 weeks showing continued improvements in response rates in addition to lower relapse rates. Mirtazapine has an antagonistic effect at the central presynaptic 5-HT2 receptors and alpha-2 adrenergic inhibitory autoreceptors and heteroreceptors resulting in increased norepinephrine release with an indirect release of serotonin due to increased noradrenergic input to the raphe nucleus. Mirtazapine has an effective dose range from 15 to 45 mg once daily with a long half-life preventing dose adjustments more often than every 1-2 weeks.Trazadone is a 5-HT2A and 5-HT2C receptor antagonist and selective serotonin reuptake inhibitor. While trazodone has only been FDA approved for use in the treatment of major depressive disorder, it has been used off label for numerous conditions including insomnia, anxiety, dementia, Alzheimer's disease, substance abuse, schizophrenia, bulimia, and fibromyalgia. The most common adverse reaction is drowsiness, followed by dizziness, dry mouth, and nervousness. In the United States, trazadone is the second most commonly prescribed agent used to treat insomnia. The hypnotic action of this medication at lower doses is attributed primarily to the antagonism of the 5-HT2A receptors, H1 receptors, and alpha-1 adrenergic receptors. The most active metabolite is m-chlorophenylpiperazine produced by the CYP3A4 enzyme, which is a more profound inhibitor of serotonin reuptake as compared to the parent molecule of trazadone. The maximum outpatient dose should not exceed 400 mg per day in divided doses, but in hospitalized patients, the dose may be increased to a maximum dose of 600 mg daily in divided doses while the patient is being actively monitored for side effects. One third of inpatients and one half of outpatients had a significant therapeutic response to trazadone by the end of the first week with the remainder of patients responding in 2-4 weeks of therapy.Vortioxetine is a novel antidepressant classified by the World Health Organization as a N06AX antidepressant that was derived from studies targeting the combination of direct serotonin transporter inhibition and 5-HT1A receptor modulation leading to rapid desensitization of the somatodendritic 5-HT1A autoreceptors and activation of the postsynaptic 5-HT1A receptors. This medication is an antagonist at 5-HT3, 5-HT1D, and 5-HT7 receptors, an agonist at 5-HT1A receptors, and a partial agonist at 5-HT1B receptors. Blockade of the 5-HT3 receptor was noted to produce increased levels of serotonin, dopamine, norepinephrine, acetylcholine, and histamine in the prefrontal cortex and hippocampus, which are known to be associated with the development of depression. The most common adverse effect is nausea followed by sexual dysfunction, constipation, and vomiting. The maximum dose of vortioxetine is 20 mg daily with improvement in symptoms of depression noted at 2 weeks with a full therapeutic effect observed at 4-6 weeks.Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist. This medication works by enhancing serotonergic activity in the central nervous system through selective inhibition of serotonin reuptake with no significant effects noted on norepinephrine or dopamine uptake. Vilazodone additionally binds with high affinity to the 5-HT1A receptors as a partial agonist resulting in faster onset of action, greater efficacy, and better tolerability with reduced sexual side effects when compared to other SSRIs. The most common adverse effects were diarrhea, nausea, vomiting, and insomnia. Additional reported adverse effects included dizziness, dry mouth, fatigue, abnormal dreams, decreased libido, arthralgias, and palpitations which were self-limited with resolution in 4-5 days after starting the medication. The recommended therapeutic dose of vilazodone is 40 mg daily with improvement noted in depressive symptoms within 1 week of initiating therapy with increased remission rates noted at 6 weeks of therapy.The medications featured in this chapter do not fall within the major categories of antidepressant classes but add additional unique mechanisms for the treatment of major depressive disorder. Each medication targets different receptors in the central nervous system involved in the development of depression. Resolution of depressive symptoms and response rates of these medications are similar to SSRIs with reduced side effects that can often lead to discontinuation of therapy. Use of these unique medications allows clinicians to target specific symptoms and comorbidities often associated with depression resulting in improved symptom resolution and long-term maintenance of remission.

Diagnosis of anti-laminin γ-1 pemphigoid by immunoblot analysis.

BACKGROUND: Anti-laminin-γ1 (lam-γ1) pemphigoid, a recently described immunobullous disorder sharing immune serological features of bullous pemphigoid and epidermolysis bullosa acquisita (EBA), is characterized by the detection of serum IgG autoantibodies against the lam-γ1 chain, a 200 kDa heterotrimeric component of the dermal-epidermal junction (DEJ). OBJECTIVE: The aim of the study was to develop an easy-to-perform and reliable assay for the serological detection of anti-lam-γ1 IgG autoantibodies. The clinical appearance alone is not sufficient to establish diagnosis of anti-lam-γ1 pemphigoid and rather requires immune serological evidence of (i) IgG reactivity against the dermal portion of salt-split human skin; (ii) exclusion of IgG against other components of the DEJ; and (iii) IgG reactivity with a 200 kDa protein of dermal extracts by immunoblot analysis (IB). METHODS: The sera of 55 patients with anti-lam-γ1 pemphigoid were tested by IB with two recombinant heterotrimers, laminin 111 (lam-111) and laminin 421 (lam-421), as well as with a recombinant lam-γ1 chain monomer. Additionally, a total of 41 control sera from patients with EBA (n = 15), psoriasis vulgaris (PV; n = 14), and healthy controls (HC; n = 12) were tested. RESULTS: Immunoblot analysis revealed a positive reactivity with lam-111 and/or lam-421 in 46/55 (84%) of anti-lam-γ1 pemphigoid sera. Moreover, 8/9 of the initially non-reactive sera were positive with the lam-γ1 monomer, leading to an overall sensitivity of 98.2%. Analyses of 41 control sera with the three lam-γ1 recombinants led to a specificity of 88%. Specifically, 3/15 EBA sera, 1/14 PV serum and 1/12 HC serum reacted with the lam-γ1 monomer while only the 3 EBA sera reacted with lam-421. CONCLUSIONS: Here we show a novel two-step IB assay using the two recombinant laminin trimers and lam-γ1 chain monomer for the detection of anti-lam-γ1 serum IgG with high sensitivity and specificity. This assay will facilitate the diagnosis and further characterization of this disease.

[Cardioband®: Where do we stand, who are suitable patients?] / Cardioband®: Wo stehen wir, was sind geeignete Patienten?

Functional mitral regurgitation (FMR) is characterized by a dilatation of the mitral valve annulus resulting in an insufficient adaptation of the anterior and posterior mitral valve leaflets and/or severe tethering of the leaflets due to dilatation of the left ventricle. The Cardioband® system was introduced in 2015 and is a catheter-based direct mitral valve annuloplasty procedure for treatment of FMR. In the European CE approval study 60 patients with moderate or severe FMR were analyzed per protocol. There were no device or procedure-related deaths. The technical success rate of the procedure, defined as successful implantation and tightening was 97%. At 1 year, the overall survival and survival free of hospital readmission for heart failure were 87% and 66%, respectively. Currently, various interventional treatment procedures are available, such as the edge-to-edge technique as well as direct and indirect annuloplasty. In summary, patients with FMR as a result of a dilatation of the mitral valve annulus appear to be suitable for direct annuloplasty with the Cardioband® system.

Pulmonary hypertension and valvular heart disease.

Pulmonary hypertension (PH) is an important contributor to morbidity and mortality in patients with left-sided heart disease, including valvular heart disease. In this context, elevated left atrial pressure primarily leads to the development of post-capillary PH. Despite the fact that repair of left-sided valvular heart disease by surgical or interventional approaches will improve PH, recent studies have highlighted that PH (pre- or post-interventional) remains an important predictor of long-term outcome. Here, we review the current knowledge on PH in valvular heart disease taking into account new hemodynamic PH definitions, and the distinction between post- and pre-capillary components of PH. A specific focus is on the precise characterization of hemodynamics and cardiopulmonary interaction, and on potential strategies for the management of residual PH after mitral or aortic valve interventions. In addition, we highlight the clinical significance of tricuspid regurgitation, which may occur as a primary condition or as a consequence of PH and right heart dilatation (functional). In this context, proper patient selection for potential tricuspid valve interventions is crucial. Finally, the article highlights gaps in evidence, and points toward future perspectives.

The monogenean Paradiplozoon ichthyoxanthon behaves like a micropredator on two of its hosts, as indicated by stable isotopes.

The analysis of stable isotopes of carbon and nitrogen has been used as a fingerprint for understanding the trophic interactions of organisms. Most of these studies have been applied to free-living organisms, while parasites have largely been neglected. Studies dealing with parasites so far have assessed the carbon and nitrogen signatures in endoparasites or ectoparasites of different hosts, without showing general trends concerning the nutritional relationships within host-parasite associations. Moreover, in most cases such systems involved a single host and parasite species. The present study is therefore the first to detail the trophic interactions of a freshwater monogenean-host model using δ13C and δ15N, where a single monogenean species infects two distinctly different hosts. Host fishes, Labeobarbus aeneus and Labeobarbus kimberleyensis from the Vaal Dam, South Africa, were assessed for the monogenean parasite Paradiplozoon ichthyoxanthon, individuals of which were removed from the gills of the hosts. The parasites and host muscle samples were analysed for signatures of δ13C and δ15N using an elemental analyser connected to an isotope ratio mass spectrometer. Host fish appear to use partly different food sources, with L. aeneus having slightly elevated δ13C signatures compared to L. kimberleyensis, and showed only small differences with regard to their nitrogen signatures, suggesting that both species range on the same trophic level. Carbon and nitrogen signatures in P. ichthyoxanthon showed that the parasites mirrored the small differences in dietary carbon sources of the host but, according to δ15N signatures, the parasite ranged on a higher trophic level than the hosts. This relationship resembles predator-prey relationships and therefore suggests that P. ichthyoxanthon might act as a micropredator, similar to blood-sucking arthropods such as mites and fleas.

[Social reimbursement-the Spanish-German ENT Society's (SDGHNO) Latin America project]. / Soziale Rückvergütung ­ das Projekt "Lateinamerika" der Spanisch-Deutschen HNO-Gesellschaft (SDGHNO).

Nowadays, social projects are usually oriented in such a way that after a given period of time, they can either support themselves independently or even allow a pecuniary reimbursement. In the latter case, experts speak of a profit-oriented reimbursement. On the other hand, there is so-called social reimbursement, which in contrast to the abovementioned form is not profit oriented, but, for example, considers its task fulfilled by the fact of successful knowledge transfer. The Spanish-German Society for ENT Medicine and Head and Neck Surgery (SDGHNO) launched the Latin America project in 2001 under the patronage of the then President Prof. Dr. Wolfgang Draf (Fulda). The goal of the SDGHNO was and is to create a professional as well as cultural platform for Spanish- and German-speaking ENT doctors. This platform can and should be used for professional purposes, e.g., for knowledge transfer. Since the beginning of its existence, the Latin America project has thus brought numerous scientific events into being and created specific contacts which have lasted until today or have even been continued and further developed. Particularly successful examples are Chile, Colombia, and Peru. This is a vivid example of social reimbursement, because the participating German-speaking members/speakers carried out their tasks on an entirely voluntary basis. Thus, the SDGHNO did not bear any travel, catering, or accommodation costs. The activities of the SDGHNO within the framework of the Latin America project are explained.

A novel pretherapeutic gene expression-based risk score for treatment guidance in gastric cancer.

Background: Perioperative chemotherapy is an established treatment of advanced gastric cancer patients. Treatment selection is based on clinical staging (cT). We aimed to establish and validate a prognostic score including clinical and molecular factors, to optimize treatment decisions for these patients. Patients and methods: We analyzed 626 carcinomas of the stomach and of the gastro-esophageal junction from two academic centers including primarily resected and pre-/perioperatively treated patients. Patients were divided into a training (N = 269) and validation (N = 357) set. Expression of 11 target genes was measured by quantitative PCR in resected tumors. A risk score to predict overall survival (OS) was generated and validated. Intra-tumoral heterogeneity was assessed by analyzing 50 tumor areas from 10 patients. Results: A risk score including the expression of CCL5, CTNNB1, EXOSC3 and LZTR1 and the clinical parameters cT, tumor localization and histopathologic type suggested two groups with a significant difference in OS [hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.17-0.52]. The risk score was successfully validated in an independent cohort (HR 0.32; 95% CI 0.21-0.51; P < 0.001) as well as in subgroups of primarily resected (HR 0.30; 95% CI 0.17-0.54; P < 0.001) and pre-/perioperatively treated patients (HR 0.37; 95% CI 0.17-0.81; P = 0.009). A significant difference in OS of high- and low-risk patients was also found in primarily resected patients with intestinal (HR 0.45; 95% CI 0.23-0.90; P = 0.020) and nonintestinal-type carcinomas (HR 0.1; 95% CI 0.02-0.42; P < 0.001). Intra-tumor heterogeneity analysis indicated a classification reliability of 95% for a supposed analysis of three biopsies. Conclusion: The identified risk score could substantially contribute to an improved management of gastric cancer patients in the context of perioperative chemotherapy.

Cellular electrophysiological principles that modulate secretion from synovial fibroblasts.

Rheumatoid arthritis (RA) is a progressive disease that affects both pediatric and adult populations. The cellular basis for RA has been investigated extensively using animal models, human tissues and isolated cells in culture. However, many aspects of its aetiology and molecular mechanisms remain unknown. Some of the electrophysiological principles that regulate secretion of essential lubricants (hyaluronan and lubricin) and cytokines from synovial fibroblasts have been identified. Data sets describing the main types of ion channels that are expressed in human synovial fibroblast preparations have begun to provide important new insights into the interplay among: (i) ion fluxes, (ii) Ca2+ release from the endoplasmic reticulum, (iii) intercellular coupling, and (iv) both transient and longer duration changes in synovial fibroblast membrane potential. A combination of this information, knowledge of similar patterns of responses in cells that regulate the immune system, and the availability of adult human synovial fibroblasts are likely to provide new pathophysiological insights.

Clinical, radiographic and biochemical characteristics of adult hypophosphatasia.

In this study, we report on clinical, radiographic and biochemical characteristics of 38 patients with adult hypophosphatasia. High-resolution peripheral quantitative computed tomography showed alterations of bone microstructure in a subgroup of 14 patients. Pyridoxal-5-phosphate levels correlated with the occurrence of fractures and the number of symptoms. INTRODUCTION: Hypophosphatasia (HPP) is a rare disorder with a wide range of clinical manifestations. A reduced enzymatic activity of alkaline phosphatase (ALP) is the key marker of the disease, causing an accumulation of ALP substrates such as pyridoxal-5-phosphate (PLP). The purpose of this retrospective study was to further characterize adult onset HPP. METHODS: We assessed clinical, radiographic and laboratory characteristics of 38 adult patients with HPP. Diagnosis of HPP was established by the combination of low-serum ALP, raised PLP levels and typical symptoms and was genetically confirmed in 32 patients. Dual-energy X-ray absorptiometry (DXA) and laboratory data were available in most patients. High-resolution peripheral quantitative computed tomography (HR-pQCT) was performed in 14 patients. RESULTS: Clinical characteristics included a wide spectrum of symptoms. A history of fracture was present in 15 patients (39%). Twenty-one patients (55%) complained about recurring headaches, 23 patients (61%) had recurring muscle pain, 4 patients (11%) suffered from severe muscle weakness and 18 patients (47%) showed dental abnormalities. Z-scores assessed by DXA were only slightly reduced in most adult HPP patients. HR-pQCT of 14 patients showed microstructural changes of trabecular and cortical bone compared to reference values of healthy subjects. The occurrence of fractures and multiple symptoms (>2 typical HPP symptoms) were associated with significantly elevated levels of PLP. CONCLUSION: Adult HPP presents with a wide range of clinical symptoms and is not associated with low bone mass in general. PLP seems to be a good marker for disease severity in adult patients as its level is correlated with the occurrence of fractures and number of symptoms.

Serological diagnostics in the detection of IgG autoantibodies against human collagen VII in epidermolysis bullosa acquisita: a multicentre analysis.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a rare, potentially devastating autoimmune disease of the skin. IgG autoantibodies directed against type VII collagen (Col7), the major component of anchoring fibrils, induce skin fragility leading to cutaneous and mucocutaneous blister formation, which is mostly of a scarring phenotype. Thus, powerful and reproducible diagnostic assays are critical to establish the diagnosis of EBA early to avoid irreversible sequelae. OBJECTIVES: The present international, retrospective multicentre study included a large cohort of patients with EBA and evaluated the diagnostic power of four different diagnostic assays for the detection of anti-Col7 IgG autoantibodies. METHODS: Overall, 95 EBA sera and 200 control sera consisting of 100 bullous pemphigoid sera, 50 pemphigus vulgaris sera and 50 sera of healthy controls were tested for anti-Col7 IgG autoantibodies using indirect immunofluorescence (IIF), two commercial enzyme-linked immunosorbent assay (ELISA) systems and Western blot (WB) analysis. EBA sera were taken from patients with positive direct immunofluorescence and IgG reactivity in at least one of the immunoserological assays (IIF, ELISA, WB). RESULTS: A Col7-NC1/NC2 ELISA (MBL, Nagoya, Japan) showed the highest sensitivity (97·9%), followed by a Col7-NC1 ELISA (Euroimmun, Lübeck, Germany) (89·5%), WB with Col7-NC1 (85·3%), and IIF on saline-split human skin (74·7%). The specificities of both ELISA systems were comparable (NC1 98·7%, NC1/NC2 99·3%). Furthermore, WB was more sensitive than IIF, which was more specific. CONCLUSIONS: The two commercially available ELISA systems allow for a highly sensitive and specific diagnosis of EBA. The sensitivity of the Col7-NC1/NC2 ELISA is significantly higher compared with the ELISA based on the Col7-NC1 domain only.