Outcomes and characteristics of nonmelanoma skin cancers in patients with myeloproliferative neoplasms on ruxolitinib.

ABSTRACT: Nonmelanoma skin cancers (NMSCs) in ruxolitinib-treated patients with myeloproliferative neoplasms behave aggressively, with adverse features and high recurrence. In our cohort, mortality from metastatic NMSC exceeded that from myelofibrosis. Vigilant skin assessment, counseling on NMSC risks, and prospective ruxolitinib-NMSC studies are crucial.

Supplementary orthopaedic screening for children and adolescents to prevent permanent skeletal deformities - protocol for the "OrthoKids" study.

BACKGROUND: Skeletal deformities (SD) in children and adolescents can lead to arthritic conditions, impairment of quality of life, and high treatment costs in the long term. However, comprehensive data on the prevalence of SDs in children and adolescents are limited and it remains therefore unclear whether there is a healthcare gap. "OrthoKids" is a project that addresses this evidence gap by implementing an orthopaedic screening for children and adolescents that supplements existing detection examinations within statutory standard care in Germany. OBJECTIVE: To detect SDs so that they can be treated as needed at an early stage. METHODS: The implementation of the supplementary orthopaedic screening will be evaluated through an exploratory cohort study that is set up in the German state Baden-Wuerttemberg. 20,000 children and adolescents aged 10 to 14 years will be recruited as a prospective cohort. A retrospective control cohort will be formed based on claims data provided by two cooperating statutory health insurances (SHIs). Participating children and adolescents receive a one-time orthopaedic screening. If at least one SD is diagnosed, treatment will be provided as part of the statutory standard care. Within the scope of the project, a follow-up examination will be performed after one year. An IT-platform will complement the study. The primary outcome measure is the point prevalence of scoliosis, genu varum/valgum, hip dysplasia, and flat feet. Secondary outcome measures are (i) the point prevalence of further less common SDs, (ii) health-related quality of life (HRQoL), (iii) sports ability based on activity (physical/athletic), physical constraints, and (sports) injuries, as well as (iv) monetary consequences of the orthopaedic screenings' implementation. Implementation determinants will be evaluated, too. DISCUSSION: If the supplementary orthopaedic screening proves to be viable, it could be considered as a supplementary examination for children and adolescents within the frame of SHI in Germany. This could relieve the burden of disease among children and adolescents with SDs. In addition, it could disburden SHIs in the medium to long term. TRIAL REGISTRATION: The OrthoKids study was registered in the German Clinical Trials Registry (Deutsches Register Klinischer Studien (DRKS)) on 26th July 2022 under the number 00029057.

Effect of apical root resection, orthodontic extrusion, and surgical crown lengthening on load capability.

OBJECTIVES: This study aims to investigate the load-to-fracture of procedures changing crown-to-root ratio (RCRR) aimed to restore severely damaged upper central incisors to avoid tooth extraction compared to implant placement. There is no evidence on load capability after apical root resection (AR), orthodontic extrusion (OE), and surgical crown lengthening (SCL) in respect to RCRR, respectively. MATERIAL AND METHODS: Human maxillary central incisors were endodontically treated, decoronated, and divided into 4 groups (n = 48). The following specimen preparation was performed: (I) adhesive core-and-post build-up (control), (II) as (I) and 2 mm apical root resection (AR), (III) before adhesive core-and-post build-up teeth were shortened 2 mm coronally (OE) (IV) as (I), but specimens were embedded 4 mm instead of 2 mm below the CEJ (SCL), group (V) implant-borne restoration with individual all-ceramic abutments (n = 12; ∅4.1/l = 12 mm) (IBR). All specimens received all-ceramic crowns, thermo-mechanical (TML), and subsequent linear loading (LL) until failure. RCRR were calculated and log-rank, Kruskal-Wallis, Mann-Whitney U, ANOVA, and chi-square tests applied (p = 0.05). RESULTS: Fracture loads after subsequent LL differed significantly (p = 0.001) between groups, while implants showed the highest values. Fmax median (min/max) were as follows: (I) 252 (204/542), (II) 293 (243/443), (III) 253 (183/371), (IV) 195 (140/274), and (V) 446 (370/539). Pair-wise comparison showed significant differences (p = 0.001) between group I/IV and group V, I, and IV (p = 0.045), II and IV (p = 0.001), and III compared to IV (p = 0.033), respectively. RCRR below 1 significantly increased load capability compared to RCRR = 1. CONCLUSIONS: OE appears to preferably ensure biomechanical stability of teeth that are endodontically treated and receive core-and-post and crown placement compared to SCL. AR has no adverse biomechanical impact. RCRR < 1 is biomechanically beneficial. CLINICAL RELEVANCE: For endodontically treated and restored teeth, orthodontic extrusion should be preferred compared to surgical crown lengthening prior single-crown restoration. As orthodontic extrusion, apical root resection has no adverse effect on load capability. Single-crown implant-borne restorations are most load capable.

Anti-PF4 VITT antibodies are oligoclonal and variably inhibited by heparin.

BACKGROUND: COVID-19 vaccines have been associated with a rare thrombotic and thrombocytopenic reaction, Vaccine-induced immune thrombotic thrombocytopenia (VITT) characterized by platelet-activating anti-PF4 antibodies. This study sought to assess clonality of VITT antibodies and evaluate their characteristics in antigen-based and functional platelet studies. METHODS: Anti-PF4 antibodies were isolated from five patients with VITT secondary to ChAdOx1 nCoV-19 (n=1) or Ad26.COV2.S (n=4) vaccination. For comparative studies with heparin-induced thrombocytopenia (HIT), anti-PF4 antibodies were isolated from one patient with spontaneous HIT, another with "classical" HIT, and two patients with non-pathogenic (non-platelet activating) anti-PF4 antibodies. Isolated antibodies were subject to ELISA and functional testing, and mass spectrometric evaluation for clonality determination. RESULTS: All five VITT patients had oligoclonal anti-PF4 antibodies (3 monoclonal, one bi- and one tri-clonal antibodies), while HIT anti-PF4 antibodies were polyclonal. Notably, like VITT antibodies, anti-PF4 antibodies from a spontaneous HIT patient were monoclonal. The techniques employed did not detect non-pathogenic anti-PF4 antibodies. The ChAdOx1 nCoV-19-associated VITT patient made an excellent recovery with heparin treatment. In vitro studies demonstrated strong inhibition of VITT antibody-induced platelet activation with therapeutic concentrations of heparin in this and one Ad26.COV2.S-associated VITT patient. Oligoclonal VITT antibodies with persistent platelet-activating potential were detected at 6 and 10 weeks after acute presentation in two patients tested. Two of the 5 VITT patients had recurrence of thrombocytopenia and one patient had focal seizures several weeks after acute presentation. CONCLUSION: Oligoclonal anti-PF4 antibodies mediate VITT. Heparin use in VITT needs to be further studied.

Direct restoration of endodontically treated maxillary central incisors: post or no post at all?

OBJECTIVES: The aim of this ex-vivo study was to evaluate the impact of cavity size and glass-fiber post (GFP) placement on the load capability of endodontically treated maxillary incisors directly restored with resin composite. MATERIALS AND METHODS: Ninety-six extracted human maxillary central incisors were endodontically treated and distributed to four groups (n = 24): access cavity (A), access cavity and uni-proximal class III cavity (U), access cavity and bi-proximal class III cavity (B), and decoronated tooth (D). Specimens were restored with resin composite, and 12 specimen of each group received an adhesively placed glass-fiber post (P). Prior to linear loading, specimens were exposed to thermo-mechanical loading (TCML). Statistical analysis was performed using log-rank test after TCML, Kruskall-Wallis and Mann-Whitney U test to compare load capabilities (Fmax). RESULTS: Significantly more failures occurred in group D for specimens without GFP during TCML (p = 0.001). Fmax (mean (SD) in N was (A) 513 (124), (AP) 554 (201), (U) 438 (171), (UP) 537 (232) (B) 483 (219), (BP) 536 (281), D 143 (181), and DP 500 (331), and differed significantly among groups (p = 0.003). Pair-wise comparison revealed lower Fmax values for group D compared to all other groups (p < 0.034) except group DP. CONCLUSIONS: Endodontically treated maxillary central incisors with cavity sizes up to bi-proximal class III may be successfully directly restored with resin composite. Post placement shows no additional effect except for decoronated endodontically treated incisors. CLINICAL RELEVANCE: Endodontically treated incisors with access cavities to class III cavities can be successfully restored with resin composite. Post placement for decoronated ETT is recommended.

Success and survival of post-restorations: six-year results of a prospective observational practice-based clinical study.

AIM: This prospective, noninterventional, multi-centre, practice-based study aimed to evaluate the longevity of endodontically treated teeth (ETT) restored with posts and to analyse factors influencing the success and survival of endodontic posts. METHODOLOGY: Eight general dental practitioners each placed up to 27 endodontic posts without any restriction to size and material. Teeth were restricted to incisors, canines and premolars. Multi-level Cox proportional hazards models were used to evaluate the association between clinical factors and time until failure. RESULTS: A total of 195 endodontic posts were followed-up for up to 6.5 years in 195 patients. Of these, 140 posts were judged as successful [mean success time: 59 (55-63) months]; the mean annual failure rate was 8.6%. This decreased to 4.4% when excluding recementations. 152 posts survived [mean survival time: 64 (60-67) months]. Recemented restorations had an eight times higher failure rate compared with new restorations. Furthermore, restorations with glass fibre post had a significantly lower success rate compared with titanium posts. CONCLUSION: Relatively low success and survival rates occurred for restorations with posts after root canal treatment in a private practice setting after a follow-up of up to 6.5 years. Recemented crowns had a high risk of failure.

Longevity of composite build-ups without posts-10-year results of a practice-based study.

AIM: The aim of this prospective, non-interventional, multi-center, practice-based study was, firstly, to evaluate the longevity of composite build-ups in endodontically treated teeth (ETT) without post placement and, secondly, to analyze factors influencing the success of these composite build-ups. METHODOLOGY: Each of seven general dental practitioners placed up to 50 composite build-ups without additional posts in ETT. Teeth were restricted to incisors, canines, and premolars. Several clinical data were recorded for 192 coronal restorations on ETT in 192 patients. Cox proportional hazard models were applied to analyze associations between clinical factors and time until failure. RESULTS: Within a follow-up period of 10 years, 167 restorations were judged as successful [mean success time, 110 (105-115) months] and 180 teeth survived [mean survival time, 114 (110-119) months]. The main failure type was fracture of the restoration (n = 15). The annual failure rate was 2.4%. In bivariate Cox regression, both factors such as number of restored tooth surfaces and adhesive were significantly associated with the failure rate. In multivariate Cox proportional hazards regression, none of the investigated factors were significantly associated with the failure rate. CONCLUSION: For composite build-ups in ETT without post placement, high success rates could be found after up to 10 years of observation time. Within the limitations of the present study, none of the analyzed factors such as "tooth type" or "number of restored tooth surfaces" was a significant predictor for the failure rate. CLINICAL RELEVANCE: Endodontically treated teeth can be successfully directly restored with composite build-ups even when no additional post is inserted. TRIAL REGISTRATION: The study was registered in the German Clinical Trials Register (DRKS-ID: DRKS00012882).

Application of SQUIDs to low temperature and high magnetic field measurements-Ultra low noise torque magnetometry.

Torque magnetometry is a key method to measure the magnetic anisotropy and quantum oscillations in metals. In order to resolve quantum oscillations in sub-millimeter sized samples, piezo-electric micro-cantilevers were introduced. In the case of strongly correlated metals with large Fermi surfaces and high cyclotron masses, magnetic torque resolving powers in excess of 104 are required at temperatures well below 1 K and magnetic fields beyond 10 T. Here, we present a new broadband read-out scheme for piezo-electric micro-cantilevers via Wheatstone-type resistance measurements in magnetic fields up to 15 T and temperatures down to 200 mK. By using a two-stage superconducting-quantum interference device as a null detector of a cold Wheatstone bridge, we were able to achieve a magnetic moment resolution of Δm = 4 × 10-15 J/T at maximal field and 700 mK, outperforming conventional magnetometers by at least one order of magnitude in this temperature and magnetic field range. Exemplary de Haas-van Alphen measurement of a newly grown delafossite, PdRhO2, was used to show the superior performance of our setup.

Impact of simulated reduced alveolar bone support, increased tooth mobility, and distal post-supported, root-treated abutment tooth on load capability of all-ceramic zirconia-supported cantilever FDP.

OBJECTIVES: The aim of this in vitro study was an analysis of the impact of simulated reduced alveolar bone support and post-restored, endodontically treated distal abutment tooth on load capability of all-ceramic zirconia-based cantilever-fixed dental prosthesis (CFDP). MATERIAL AND METHODS: The roots of human lower sound premolars (n = 80) were divided into five experimental groups to be restored with all-ceramic zirconia-supported three-unit CFDP regarding bone loss (BL) relative to the cement-enamel junction (CEJ): 2 mm below CEJ = 0% BL (control group), group 25% distal BL, group 50% distal BL, group 50% mesial and distal BL, and group 50% distal BL and adhesive post-supported restoration. Specimens were exposed to simulated clinical function by thermo-mechanical loading (6.000 cycles 5°-55°; 1.2 × 106 cycles 0-50 N) and subsequent linear loading until failure. RESULTS: Tooth mobility increased significantly for groups with simulated bone loss (p < 0.001). Four specimens failed during thermal cycling and mechanical loading (TCML). The maximum load capability ranged from 350 to 569 N, and did not differ significantly between experimental groups (p = 0.095). Groups with simulated bone loss revealed more tooth fractures at distal abutment teeth, whereas technical failures were more frequent in the control group (p = 0.024). CONCLUSIONS: Differences of alveolar bone support and respectively increased tooth mobility between mesial and distal abutments did not influence load capability. A distal adhesively post-and-core-supported, root-treated abutment tooth did not increase risk of three-unit CFDP failure. CLINICAL RELEVANCE: CFDPs are a treatment option used with caution when reduced alveolar bone support, increased tooth mobility, and distal post-supported, root-treated abutment teeth are involved.

The association of body mass index with complications and functional outcomes after surgery for closed ankle fractures.

AIMS: This study assessed the association of classes of body mass index in kg/m2 (classified as normal weight 18.5 kg/m2 to 24.9 kg/m2, overweight 25.0 kg/m2 to 29.9 kg/m2, and obese ≥ 30.0 kg/m2) with short-term complications and functional outcomes three to six years post-operatively for closed ankle fractures. PATIENTS AND METHODS: We performed a historical cohort study with chart review of 1011 patients who were treated for ankle fractures by open reduction and internal fixation in two hospitals, with a follow-up postal survey of 959 of the patients using three functional outcome scores. RESULTS: Obese patients had more severe overall complications and higher odds of any complication than the normal weight group, with adjusted odds ratio 1.67 (95% confidence interval (CI) 1.08 to 2.59; p = 0.021) and 1.71 (95% CI 1.10 to 2.65; p = 0.016), respectively. In total 479 patients (54.6%) responded to the questionnaire. Obese patients had worse scores on the Olerud and Molander Ankle Score (p < 0.001), Self-Reported Foot and Ankle Questionnaire (p = 0.003) and Lower Extremity Functional Scale (p = 0.01) than those with normal weight. In contrast, overweight patients did not have worse functional scores than those with normal weight. CONCLUSION: Obese patients had more complications, more severe complications, and worse functional outcomes three to six years after ankle surgery compared with those with normal weight. Cite this article: Bone Joint J 2017;99-B:1389-98.

Associations of timing of surgery with postoperative length of stay, complications, and functional outcomes 3-6 years after operative fixation of closed ankle fractures.

AIMS: To evaluate the associations of timing of surgery with postoperative length of stay (LOS), complications, and functional outcomes 3-6 years after open reduction and internal fixation (ORIF) in closed ankle fractures. PATIENTS AND METHODS: Historical cohort study by chart review of 1011 patients for postoperative LOS and complications; 959 individuals were invited to participate in a postal survey with functional outcomes questionnaires. Complications were classified as perioperative, early, or late. The associations with time from trauma to surgery (<8h, 8h to 6days, >6days) were assessed with (1) postoperative LOS using multivariable random-effects negative binomial regression, (2) complications using multivariable binary and multinomial logistic regression, and (3) three different functional outcomes using multivariable linear regression. RESULTS: The mean patient age was 51.4 (range 18-94) years, 556 (55%) were female, and 567 individuals (59%) responded to the questionnaire. There were no statistically significant associations between time to surgery and either postoperative LOS or complications after adjusting for several patient and fracture characteristics. Patients operated on >6days after the trauma had significantly worse scores on the Olerud and Molander Ankle Score (OMAS) (p=0.039) and somewhat worse, but non-significant, scores on the Lower Extremity Functional Scale (LEFS; p=0.573) and the Self-Reported Foot and Ankle Score (SEFAS) scale (p=0.161) than those operated on <8h after trauma. CONCLUSION: In ankle-fracture surgery, there was no apparent association between timing of surgery and postoperative LOS or complications. A delay of surgery for 8h to 6days resulted in similar functional outcomes after 3-6 years suggesting there may be a safe window of time for surgery of up to 6days after trauma that can be used to plan and perform the final ORIF.

Anti-contactin-associated protein-2 encephalitis: relevance of antibody titres, presentation and outcome.

BACKGROUND AND PURPOSE: To clarify the relevance of titres of IgG antibodies against contactin-associated protein-2 (CASPR2) in diagnosing anti-CASPR2 encephalitis and to describe features and outcomes. METHODS: This was a retrospective analysis of 64 patients with CASPR2 antibodies, categorized independently as 'autoimmune encephalitis' or 'other disease'. Logistic regression methods were performed to identify potential predictors of 'autoimmune encephalitis' in addition to CASPR2 antibodies. RESULTS: An upfront CASPR2 antibody serum titre cut-off at ≥1:200 had a diagnostic sensitivity of 85% and a specificity of 81%. Logistic regression analyses indicated that, in addition to titre, encephalitic magnetic resonance imaging (MRI) was a significant predictor of 'autoimmune encephalitis' (Nagelkerke's R2 = 0.81, P < 0.001) with high sensitivity (84%) and very high specificity (100%). Patients with CASPR2 antibodies and an estimated probability of >70% of having anti-CASPR2 encephalitis (n = 22) had limbic encephalitis (n = 18, one patient plus ataxia), Morvan syndrome (n = 2) or a hyperkinetic movement disorder (n = 2). Median modified Rankin score (mRS) at diagnosis was 3 (range 1-4). Twenty patients were male; median age was 64 (range 54-75) years; 5/15 patients with cerebrospinal fluid data had intrathecal CASPR2 antibody synthesis, and 12/19 with follow-ups >3 months (median 12 months, range 4-43 months) improved by ≥1 mRS point resulting in a median mRS of 2 (range 0-6; one death; all but one having received immunotherapy); and 2/15 patients with follow-up MRI developed hippocampal atrophy. CONCLUSIONS: Only higher CASPR2 serum antibody titres indicate anti-CASPR2 encephalitis, and diagnostic accuracy increases if MRI findings are considered. Anti-CASPR2 encephalitis has characteristic features and a favourable outcome with immunotherapy.

Measuring changes in the optic nerve sheath diameter in patients with idiopathic normal-pressure hydrocephalus: a useful diagnostic supplement to spinal tap tests.

BACKGROUND AND PURPOSE: Cerebrospinal fluid (CSF) removal improves clinical symptoms of many patients with idiopathic normal-pressure hydrocephalus (iNPH). The aim of this study was to investigate the correlation of changes in the optic nerve sheath diameter (ONSD) with patient responses to CSF removal. METHODS: Transorbital ultrasonography was performed to obtain ONSD measurements in 31 patients with iNPH before and after lumbar puncture. Measurements were obtained while patients were supine and upright. Changes in the ONSD between supine and upright positions [ONSD variability (ONSD-V)] were assessed and compared with those in 60 healthy volunteers. ONSD-V was correlated with relative changes in a validated iNPH severity (Boon) score. RESULTS: Mean pre-puncture ONSD-V was significantly lower in healthy volunteers and patients with no response to CSF removal (Fisher test) [0.05 ± 0.14 mm (SD)] than in responsive patients [0.37 ± 0.20 mm (SD), P < 0.001]. ONSD-V predicted response to the spinal tap test (odds ratio, 0.30; 95% confidence interval, 0.12-0.75 mm, P = 0.011). The higher the ONSD-V, the better the therapeutic effect (χ2 = 14.980, P < 0.001). The post-spinal tap test ONSD-V correlated significantly with clinical severity in the motor portion of the Boon score [0.16 ± 0.23 mm (SD), P = 0.003]. CONCLUSIONS: The ONSD-V before and after spinal tap test correlated well with the clinical effects of CSF removal. Transorbital ultrasonography seems to be a reliable, safe add-on to the Fisher test and may support selection of patients for shunt intervention.

Melt growth and properties of bulk BaSnO3 single crystals.

We present the first-time growth of bulk BaSnO3 single crystals from the melt by direct solidification, their basic electrical and optical properties as well as their structural quality. Our measurement of the melting point (MP) of BaSnO3 amounts to 1855 °C ± 25 K. At this temperature an intensive decomposition and non-stoichiometric evaporation takes place as the partial pressure of SnO(g) is about 90 times higher than that of BaO(g). X ray powder diffraction identified only the BaSnO3 perovskite phase, while narrow rocking curves having a full width at half maximum of 26 arcsec and etch pit densities below 106 cm-2 confirm a high degree of structural perfection of the single crystals. In this respect they surpass the structural properties of those single crystals that were reported in the literature. The electrical conductivity of nominally undoped crystals depends on the growth conditions and ranges from insulating to medium n-type conductivity. After post-growth annealing in an oxidizing atmosphere undoped crystals are generally insulating. Doping the crystals with lanthanum during growth results in a high n-type conductivity. For a La doping concentration of 0.123 wt.% we measured an electron concentration of 3.3 × 1019 cm-3 and an electron mobility of 219 cm2 V-1 s-1. Based on optical absorption measurements we determined an energy of 3.17 ± 0.04 eV at 5 K and of 2.99 ± 0.04 eV at 297 K for the indirect band gap of BaSnO3.

Chiral Weyl Pockets and Fermi Surface Topology of the Weyl Semimetal TaAs.

Tantalum arsenide is a member of the noncentrosymmetric monopnictides, which are putative Weyl semimetals. In these materials, three-dimensional chiral massless quasiparticles, the so-called Weyl fermions, are predicted to induce novel quantum mechanical phenomena, such as the chiral anomaly and topological surface states. However, their chirality is only well defined if the Fermi level is close enough to the Weyl points that separate Fermi surface pockets of opposite chirality exist. In this Letter, we present the bulk Fermi surface topology of high quality single crystals of TaAs, as determined by angle-dependent Shubnikov-de Haas and de Haas-van Alphen measurements combined with ab initio band-structure calculations. Quantum oscillations originating from three different types of Fermi surface pockets were found in magnetization, magnetic torque, and magnetoresistance measurements performed in magnetic fields up to 14 T and temperatures down to 1.8 K. Of these Fermi pockets, two are pairs of topologically nontrivial electron pockets around the Weyl points and one is a trivial hole pocket. Unlike the other members of the noncentrosymmetric monopnictides, TaAs is the first Weyl semimetal candidate with the Fermi energy sufficiently close to both types of Weyl points to generate chiral quasiparticles at the Fermi surface.

Incidence and risk factors for removal of an internal fixation following surgery for ankle fracture: A retrospective cohort study of 997 patients.

BACKGROUND: Implant removal in ankle fractures treated by open reduction and fixation is often based on diffuse complaints. This study determined the incidence of implant removal and identified risk factors for two principal causes for removal: complaints and surgical site infection (SSI). METHODS: Retrospective cohort study involving 997 patients operated on 2009-2011 with follow-up through to 2013. The incidence of implant removal was analysed using competing risk analysis. Risk factors for implant removal were assessed using cause-specific hazard ratios (HRs) from a Cox regression analysis. RESULTS: The mean age at surgery was 51.6 years, 550 (55%) of the patients were female, and 170 patients (17%) had implant removal: 144 due to complaints and 26 due to infection. Multivariable HRs for implant removal due to complaints were 0.70 for male sex (p=0.047), 0.79 for each 10-year increase in age (p<0.001), 0.70 for treatment with a syndesmosis screw (p=0.038), and 1.09 for each 15-min increase in operation duration (p=0.007). HRs for hardware removal due to infection were 1.42 for each 10-year increase in age (p=0.006) and 3.15 for current smoking (p=0.005). CONCLUSION: In total 17% of patients had implant removal after open reduction and fixation; the majority because of subjective complaints. The risk factors for implant removal were different for removal due to complaints than for those removed due to infection. This information may be used to inform patients about the risk and risk factors for future implant removal.

Impacts of a high-discharge submarine sewage outfall on water quality in the coastal zone of Salvador (Bahia, Brazil).

Carbon and nitrogen stable isotopic signatures of suspended particulate organic matter and seawater biological oxygen demand (BOD) were measured along a coastal transect during summer 2015 to investigate pollution impacts of a high-discharge submarine sewage outfall close to Salvador, Brazil. Impacts of untreated sewage discharge were evident at the outfall site by depleted δ(13)Corg and δ(15)N signatures and 4-fold increased BOD rates. Pollution effects of a sewage plume were detectable for more than 6km downstream from the outfall site, as seasonal wind- and tide-driven shelf hydrodynamics facilitated its advective transport into near-shore waters. There, sewage pollution was detectable at recreational beaches by depleted stable isotope signatures and elevated BOD rates at high tides, suggesting high bacterial activity and increased infection risk by human pathogens. These findings indicate the urgent necessity for appropriate wastewater treatment in Salvador to achieve acceptable standards for released effluents and coastal zone water quality.

Molecular architecture of the DED chains at the DISC: regulation of procaspase-8 activation by short DED proteins c-FLIP and procaspase-8 prodomain.

The CD95/Fas/APO-1 death-inducing signaling complex (DISC), comprising CD95, FADD, procaspase-8, procaspase-10, and c-FLIP, has a key role in apoptosis induction. Recently, it was demonstrated that procaspase-8 activation is driven by death effector domain (DED) chains at the DISC. Here, we analyzed the molecular architecture of the chains and the role of the short DED proteins in regulating procaspase-8 activation in the chain model. We demonstrate that the DED chains are largely composed of procaspase-8 cleavage products and, in particular, of its prodomain. The DED chain also comprises c-FLIP and procaspase-10 that are present in 10 times lower amounts compared with procaspase-8. We show that short c-FLIP isoforms can inhibit CD95-induced cell death upon overexpression, likely by forming inactive heterodimers with procaspase-8. Furthermore, we have addressed mechanisms of the termination of chain elongation using experimental and mathematical modeling approaches. We show that neither c-FLIP nor procaspase-8 prodomain terminates the DED chain, but rather the dissociation/association rates of procaspase-8 define the stability of the chain and thereby its length. In addition, we provide evidence that procaspase-8 prodomain generated at the DISC constitutes a negative feedback loop in procaspase-8 activation. Overall, these findings provide new insights into caspase-8 activation in DED chains and apoptosis initiation.

Clinical comparison of botulinum toxin in motor and autonomic disorders: Similarities and differences.

Botulinum toxin is a well established, highly effective and safe treatment option for movement disorders and autonomic diseases with excellent long term results. There is increasing evidence that the beneficial effect in both motor and autonomic indication is based on a complex mode of botulinum toxin action modulating efferent as well as afferent nerve fiber activity. In particular, this has been shown for the treatment of dystonia, spasticity and overactive bladder. A unique observation is that botulinum toxin has a markedly longer duration of action in autonomic than in motor disorders for which the reason remains unclear. Although botulinum toxin type B seems to have an initially higher affinity to autonomic nerve endings there is currently no clear evidence that type B is superior to type A in autonomic disorders. The risk of antibody formation probably does not depend on the target tissue injected and seems to be similar for movement disorders and autonomic indications. More research is needed to better understand similarities and differences of treatment outcome in motor and autonomic disorders.