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The dermal route is important in many occupational exposures. Some materials may reduce the barrier function of the skin to enhance absorption and effect on internal organs. We have reported previously that kerosene cleaning following treatment with used engine oil increased DNA adduct levels in the lungs of mice compared with animals treated with used oil alone. To investigate what other physiological parameters might be affected by kerosene, we conducted in vitro and in vivo measurements of skin barrier function. We also topically applied 3H-BAP(100 nM in 25 μL acetone) and washed half the mice with 25 μL kerosene 1 hr after carcinogen application. Groups of four mice were euthanized from 1 to 72 hr after treatment. Skin, lungs, and livers were harvested from each animal and stored separately. Kerosene application reduced the barrier function of the skin in vitro beyond the effect of the acetone vehicle and the vehicle plus BAP. In vivo studies indicated that kerosene treatment reduced the barrier function at 4 and 8 hr post application and that the barrier function recovered at 24 hr after a single treatment. The fraction of the radiolabel remaining in the skin of animals treated with 3H-BAP and washed with kerosene was significantly less than those not washed, beginning at 24 hr (p< 0.05). Fractional distribution to the lungs and livers of these animals became significantly elevated at this time. Kerosene treatment compromises dermal barrier function and the ability of the skin to retain water, enhances carcinogen absorption, and alters organ distribution. This appears to contribute to the increase in BAP DNA adducts we reported earlier. [ABSTRACT FROM PUBLISHER]

Abstract: Commercially obtained aged male CBA/J mice presented a complex pattern of hearing loss and morphological changes. A significant threshold shift in auditory brainstem responses (ABR) occurred at 3 months of age at 4kHz without apparent loss of hair cells, rising slowly at later ages accompanied by loss of apical hair cells. A delayed high-frequency deficit started at 24kHz around the age of 12 months. At 20–26 months, threshold shifts at 12 and 24kHz and the accompanying hair cell loss at the base of the cochlea were highly variable with some animals appearing almost normal and others showing large deficits. Spiral ganglion cells degenerated by 18 months in all regions of the cochlea, with cell density reduced by approximately 25%. There was no degeneration of the stria vascularis and the endocochlear potential remained stable from 3 to 25 months of age regardless of whether the animals had normal or highly elevated ABR thresholds. The slow high-frequency hearing loss combined with a modest reduction of ganglion cell density and an unchanged endocochlear potential suggest sensorineural presbycusis. The superimposed early hearing loss at low frequencies, which is not seen in animals bred in-house, may complicate the use of these animals as a presbycusis model. [Copyright &y& Elsevier]

A novel line immunoassay for the multiparametric detection of 11 antiganglioside autoantibodies (GM1, GM2, GM3, GM4, GD1a, GD1b, GD2, GD3, GT1a, GT1b, and GQ1b) was evaluated by comparing the reactivities in sera of 77 patients with suspected or definite autoimmune peripheral neuropathies (PNP), 60 blood donors, and 30 systemic lupus erythematodes (SLE) patients. At least one antiganglioside autoantibody was detectable in 97.4% of the patients with neuropathies compared to 12.2% in the control group. A broad spectrum of reactivities with more than two antiganglioside autoantibodies including all tested gangliosides except GD2 and GT1b was found in nearly one-third of the patients with neuropathies whereas in the control group autoantibody profiles with more than two reactivities were observed in two SLE patients only. For the first time anti-GM4 IgG and IgM antibodies were shown in PNP including Guillain–Barré syndrome (GBS), Miller–Fisher syndrome (MFS), and multifocal motor neuropathy (MMN). Different autoantibody profiles detectable by this multiparametric assay may help to diagnose different entities within the growing spectrum of autoimmune PNP. [ABSTRACT FROM AUTHOR]

Abstract: Urinary bladder cancer is the fourth most commonly diagnosed malignancy in men and the tenth most commonly diagnosed malignancy in women in the US. Arylamines have long been associated with bladder cancer and several studies documented that men exposed to arylamines (cigarette smokers, hairdressers, and workers of dye and textile industries) have several times increased risk compared to women. N-glucuronidation is an important phase II conjugation reaction that delivers the active metabolites of arylamines from the liver to the urinary bladder. In the current study, we found that male mice are more active in 4-ABP N-glucuronidation than female mice and this difference was statistically significant. In the in vivo experiments, male and female mice (strain C57BL/6) were treated with 4-ABP after modulating their 4-ABP N-glucuronidation using the plant steroid, hecogenin. The distribution of 4-ABP adducts in liver and bladder was then determined. In animals treated with 4-ABP only, males had statistically significant higher levels of DNA adducts in the bladder (p-value 0.0004) while females had statistically significant higher levels in the liver (p-value<0.0001). Hecogenin co-treatment increased levels of DNA adducts in the liver in both males and females but this increase was statistically significant only in males (p-value 0.0024). There was a slight decrease in levels of DNA adducts in the bladder in both males and females co-treated with hecogenin, but this decrease was statistically insignificant. Using two-way ANOVA, we found that gender and hecogenin treatment both had a statistically significant effect on liver DNA adduct levels, whereas only gender had statistically significant effect on bladder adduct levels where males have about 2.2-fold higher DNA adducts than females. The current data suggests that N-glucuronidation of 4-ABP may have an important impact on the organ distribution of DNA damage. The fact that there was only a slight decrease in bladder adduct levels compared to the significant increase in the liver in groups co-treated with hecogenin indicates that besides N-glucuronidation, conjugation and metabolic activation by other enzymes may also contribute to the transport of the proximate metabolites of 4-ABP to the bladder. [Copyright &y& Elsevier]

Abstract: Exposure to inorganic arsenic in drinking water is linked to skin, lung and bladder cancer in humans. The mechanism of arsenic-induced cancer is not clear, but exposure to arsenic and polycyclic arylhydrocarbons (PAH) is more carcinogenic than exposure to either type of carcinogen alone. Arsenic can also generate reactive oxygen species, suggesting that oxidation of DNA may play a role in carcinogenesis. Oxidization of guanosines in polyG tracts is known to cause frameshift mutations, and such events can be detected in situ using the G11 placental alkaline phosphatase (PLAP) transgenic mouse model, which reports frameshift mutations in a run of 11 G:C basepairs by generating cells containing heat-resistant alkaline phosphatase activity. PAH can also induce frameshift mutations. In the study described here, FVB/N mice carrying the G11 PLAP transgene were crossed to C57Bl/6 mice. Half of the hybrid mice were given drinking water with sodium arsenite (10mg/L) for 10 weeks. Half of the arsenic treated mice were also exposed to benzo[a]pyrene (BaP) by skin painting (500nmol/week) for 8 weeks. Another group of mice was exposed to BaP but not arsenic. The effect on frameshift mutation was assessed by staining sections of skin tissue to detect cells with PLAP activity. Arsenic alone had no significant effect. On average, mice given BaP alone had approximately three times more PLAP-positive (PLAP+) cells. By contrast, mice exposed to both arsenic and BaP exhibited 10-fold more PLAP+ cells in the skin, and these cells were often arranged in large clusters, suggesting derivation from stem cells. Whereas combined treatment produced more PLAP+ cells, stable BaP adduct levels and arsenic burdens were not higher in mice exposed to both agents compared to mice exposed to either one agent or the other. [Copyright &y& Elsevier]

The article presents a study on farm pesticide exposure and glioma risk in men. The study involved adult men who were nonmetropolitan residents of Michigan, Wisconsin, Minnesota, and Iowa. Multiple logistic regressions, which were used to control for farm residence, education, age, age group, and exposure to other pesticides, revealed no association between glioma and 12 specific pesticides. Farm pesticide exposure was found to have no positive association with glioma. The excess brain cancer risk may be caused by other farm exposures.

The role of Fenton oxidants in DNA damage, aging, and cancer is appreciated, but not well understood. Six potential iron-binding (PIB) DNA motifs were previously identified as sites of preferential strand cleavage. Since DNA–metal binding domains are a known determinant of oxidative DNA damage, and the location of strand breaks explains where oxidant attack occurs, we sought to determine whether the likelihood of base change mutations is a function of neighboring PIB motifs. We developed a sliding window function that computes the density of PIB motifs on both strands, within 4–12 bp, for each location along a target gene. This range of window sizes reflects known diffusion distances of Fenton reaction products. Using mutational databases, odds of mutation at each base were calculated relative to PIB motif density, for all PIB motif types in aggregate, or for individual PIB motifs. Using mutational data from lacI transgenic animals, we observed a non-random distribution of PIB motifs, associated with increased odds of mutation, showing a strand bias. Sensitivity analysis confirmed that the optimum association between PIB motif density and mutations occurs when a 7 bp radius is used for the window size. Randomly simulated mutations showed no association with PIB motif density. When the method was applied to human TP53 mutation data, we saw similar results, but no strand bias. As PIB motif density rises, linear trends are observed for increasing odds of mutation. Sensitivity analysis revealed associations between PIB motifs and GC → AT transitions and GC → TA transversions—the most commonly observed types of mutations arising from oxidative DNA damage. DNA–metal binding motifs are found in a wide variety of biological contexts, including many where conformational sensitivity to redox state is important. These techniques can help elucidate how DNA–iron-binding may affect lesions and subsequent mutations from multiple agents. [Copyright &y& Elsevier]

Presents a summary of the workshop titled Applying Biomarkers to Occupational Health Practice in the U.S. Analysis of biomarker application from toxicology perspective; Biomarker research for risk assessment; Background on the development and use of biomarkers.

Background: Metabolites of the potent human carcinogen 4-aminobiphenyl (ABP) induce oxidative stress and form DNA adducts that are associated with hepatic and urinary bladder toxicity and bladder tumorigenesis. Results of in vitro and cell culture studies have suggested that cytochrome P450 1A2 (CYP1A2) is the major metabolic activator of ABP. We used Cyp1a2(-/-) knockout mice to examine the role of CYP1A2 in ABP-DNA adduct formation in the liver and the bladder.Methods: Cyp1a2(+/+) wild-type and Cyp1a2(-/-) mice (total of four mice per group) were treated topically with 10 mg/kg ABP for various times, with or without pretreatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an inducer of CYP1A2 activity. We evaluated ABP-induced toxicity by carrying out quantitative histology (of the liver, skin, and bladder), oxidative stress by measuring hepatic thiol levels, and liver and bladder DNA adduct formation by using 32P-postlabeling. Data were analyzed by general linear models and analysis of variance. All statistical tests were two-sided.Results: At the experimental times selected, we observed no histologic evidence of toxicity in the liver, skin, or bladder. Overall, Cyp1a2(+/+) mice had fewer DNA adducts 24 hours after ABP treatment than similarly treated Cyp1a2(-/-) mice. Compared with male mice, female mice had more DNA adducts in the liver but fewer adducts in the bladder, regardless of Cyp1a2 genotype. TCDD pretreatment was associated with a decrease in ABP-DNA adduct levels overall. After 2 hours of ABP treatment, hepatic thiol levels underwent statistically significant declines of severalfold in Cyp1a2(+/+) and Cyp1a2(-/-) males and in Cyp1a2(-/-) females.Conclusions: Contrary to our expectations, CYP1A2 expression was not associated with ABP-induced hepatic oxidative stress or with ABP-DNA adduct formation. Either CYP1A2 is not the major metabolic activator of ABP or other enzymes metabolically activate ABP in mice in the absence of CYP1A2. [ABSTRACT FROM AUTHOR]

We compared two protocols for 7,12-dimethylbenz[ a ]anthracene (DMBA)-induced mammary carcinogenesis. DMBA (20 mg/ml) was prepared at room temperature or at 60°C and administered by gavage to 50-day-old Sprague-Dawley rats. Two days post-DMBA, mammary epithelial DNA was 32 P-postlabeled. At 12 weeks post-DMBA, tumor DNA was screened for H- ras codon 61 mutations using an enriched polymerase chain reaction (EPCR). The number of in situ carcinomas (3.0 ± 2.7 vs. 2.5 ± 2.7), invasive carcinomas (1.1 ± 1.6 vs. 0.6 ± 0.8), and H- ras codon 61 mutations (34 ± 13% vs. 23 ± 13%) were statistically not different ( p = 0.05) between the groups. The relative adduct levels in mammary organoids were significantly ( p ≤ 0.001) greater in the 60°C (568 ± 158) than the room temperature (150 ± 130) group. While DMBA-DNA adduct levels differed significantly between these protocols, this did not correlate with significant differences in tumor pathologies or H- ras codon 61 mutations. [ABSTRACT FROM AUTHOR]

Tamoxifen (TAM), an antiestrogenic compound, has been approved for the treatment of breast cancer in high risk women. TAM has been shown to be an effective agent for prevention of breast cancer in women of varying degrees of risk and has been proposed to be used prophylactically in women whose genetic background suggests a high risk for breast cancer. However, it is not known whether TAM given prophylactically will alter the response of women to carcinogens from common environmental exposures such as tobacco smoke. Therefore, we studied the effects of TAM pretreatment on mammary DNA adducts of the model carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA), in the female rats to assess whether TAM would alter the adduct pattern of DMBA. TAM (0.3 mg/day) was given for 7 days prior to a single 20 mg DMBA gavage treatment that is considered a carcinogenic dose in the rat. At 7 days post-DMBA, there was a reduction in the major DMBA–DNA adduct and a significant reduction in the minor DMBA–DNA adduct in mammary glands (P=0.002) of TAM pretreated rats compared to control rats. These data indicate that TAM may alter either metabolic steps in the formation of DNA binding species and/or enhance adduct removal. These data suggest that TAM given to women prior to the development of breast cancer may modulate the impact of environmental exposures, for example, tobacco smoke. Furthermore, research is needed to determine if modulation will be positive, or negative as in the current study. [Copyright &y& Elsevier]

Co-exposures to complex mixtures of arsenic and polycyclic aromatic hydrocarbons such as benzo[a]pyrene (BaP) are common in the environment. These two environmental pollutants are carcinogenic, but the nature of their molecular interactions in the induction of cancer is not well understood. Additive or synergistic interactions have been proposed to explain why arsenic, which is not a potent mutagen itself, is comutagenic with a variety of DNA-damaging agents. We have examined the genotoxicity of BaP-arsenic mixtures. We find that exposure of mouse hepatoma Hepa-1 cells to low concentrations of arsenite increases BaP–DNA adduct levels by as much as 18-fold. This effect requires the activation of BaP by cytochrome p450 1A1 (CYP1A1), although arsenite does not alter BaP-inducible CYP1A1 enzymatic activity, suggesting that arsenite acts downstream of metabolic BaP activation. Glutathione homeostasis was important in modulating the potency of arsenite. In cells depleted of reduced glutathione, arsenite increased BaP–DNA adduct formation by an even greater degree than in cells co-treated with BaP and arsenite in control medium. Although arsenic comutagenicity has been attributed to inhibition of DNA repair, arsenite treatment did not alter adduct removal kinetics in BaP-treated cells, suggesting that mechanisms upstream of DNA repair are responsible for increased adduct levels. Concentrations of arsenite and BaP that had no measurable mutagenic effect alone, increased mutation frequency at the Hprt locus by eight-fold when given in combination, demonstrating a comutagenic response between BaP and arsenite. These results provide strong support for the positive interaction between arsenic and PAH-induced cancer observed in epidemiology studies, and help to identify additional mechanistic steps likely to be involved in arsenic comutagenesis. [Copyright &y& Elsevier]

Solvents such as kerosene or gasoline may be used by workers to clean their skin following contact with oily materials. This practice is not recommended, as it is well known that the solvent will defat the skin. Many also suspect that solvent washing may increase exposure by carrying materials through the skin; however, there is little documentation of this. Auto mechanics may be exposed to used gasoline engine oil (UGEO), an animal carcinogen which forms carcinogen-DNA adducts in skin and lung following topical application. This study was designed to determine if cleaning with kerosene following exposure to UGEO altered absorption of carcinogens from this material. UGEO or new oil (NO) was applied to the shaved skins of groups of HSD-ICR mice for five days. At 1 or 8 hours after application, the treated skins were cleaned with either kerosene or a commercial cleaner, or were not cleaned. Animals were sacrificed 24 hours after the last application, skins and lungs harvested, and DNA analyzed for carcinogen-DNA adducts by [sup 32]P-postlabeling. Five applications of UGEO significantly increased carcinogen-DNA adduct levels in both lungs and skin compared to animals treated with NO. DNA adduct levels in the skin were reduced significantly in groups washed with kerosene or commercial cleaner. Washing at one as opposed to eight hours after UGEO application resulted in lower adduct levels regardless of cleaner. DNA adduct levels in the lung were reduced when the commercial cleaner was used, again in a time-related fashion. However, cleaning with kerosene resulted in mean carcinogen-DNA adduct levels in the lung which were significantly higher than even the positive controls, regardless of cleaning time. This is the first demonstration that kerosene cleaning facilitates passage of carcinogens through the skin, resulting in higher levels of genetic damage in a critical internal organ. [ABSTRACT FROM AUTHOR]

Epidemiological evidence suggests that auto mechanics are at higher risk for lung and urinary bladder cancer. Used gasoline engine oils (UGEO), a common exposure for many mechanics, are carcinogenic and increase carcinogen-DNA adduct levels in the skin and lungs of mice treated topically. The ability of a barrier cream to reduce dermal absorption of carcinogens in UGEO was evaluated. Groups of five animals were treated topically for 5 days with 25 mu l/day UGEO. A barrier cream was applied to two groups prior to exposure. Skin of both groups was washed with a commercial hand cleaner, the first group, one hour after UGEO application, the other, eight hours after application. Two other groups did not receive barrier creams before UGEO application, but were washed at one or eight hours after the oil was applied. Another group was treated with UGEO five times but was never washed; other groups consisted of barrier cream and commercial cleaner controls. Skins and lungs were harvested 24 hours after the final exposure and DNA isolated. Carcinogen-DNA adduct levels were determined by [sup 32]P-postlabelling followed by thin-layer chromatography to separate the adducts and scintillation counting to quantify the adduct level. Pre-application of barrier cream reduced markedly the carcinogen-DNA adduct levels in both skin and lung tissue of mice treated with UGEO and washed at eight hours. In the lung, this reduction was statistically significant. Adduct levels in both tissues were approximately the same in the groups washed at one hour, indicating that if the skin is washed promptly after exposure, barrier cream application is unnecessary. If, however, washing does not take place until several hours after exposure, the pre-application of barrier cream appears to significantly reduce the DNA adduct levels. These data are of practical importance to mechanics who may be working with oily parts for extended periods. [ABSTRACT FROM AUTHOR]

Objectives: Interventional procedures around the knee are widely adopted for treating different musculoskeletal conditions. A panel of experts from the Ultrasound and Interventional Subcommittees of the European Society of Musculoskeletal Radiology (ESSR) reviewed the existing literature to assess the evidence on image-guided musculoskeletal interventional procedures around the knee, with the goal of highlighting some controversies associated with these procedures, specifically the role of imaging guidance, as well as the efficacy of the medications routinely injected., Methods: We report the results of a Delphi-based consensus of 53 experts in musculoskeletal radiology, who reviewed the published literature for evidence on image-guided interventional procedures around the knee to derive a list of pertinent clinical indications., Results: A list of 10 statements about clinical indications of image-guided procedures around the knee was created by a Delphi-based consensus. Only two of them had the highest level of evidence; all of them received 100% consensus., Conclusions: Ultrasonography guidance is strongly recommended for intra-articular and patellar tendinopathy procedures to ensure the precision and efficacy of these treatments. Prospective randomized studies remain warranted to better understand the role of imaging guidance and assess some of the medications used for interventional procedures around the knee., Key Points: • A list of 10 evidence-based statements on clinical indications of image-guided interventional procedures around the knee was produced by an expert panel of the ESSR. • Strong consensus with 100% agreement was obtained for all statements. • Two statements reached the highest level of evidence, allowing us to strongly recommend the use of ultrasonography to guide intra-articular and patellar tendon procedures to ensure higher accuracy and efficacy of these treatments., (© 2021. The Author(s).)

Objectives: To perform a Delphi-based consensus on published evidence on image-guided interventional procedures for peripheral nerves of the lower limb (excluding Morton's neuroma) and provide clinical indications., Methods: We report the results of a Delphi-based consensus of 53 experts from the European Society of Musculoskeletal Radiology who reviewed the published literature for evidence on image-guided interventional procedures offered around peripheral nerves in the lower limb (excluding Morton's neuroma) to derive their clinical indications. Experts drafted a list of statements and graded them according to the Oxford Centre for evidence-based medicine levels of evidence. Consensus was considered strong when > 95% of experts agreed with the statement or broad when > 80% but < 95% agreed. The results of the Delphi-based consensus were used to write the paper., Results: Nine statements on image-guided interventional procedures for peripheral nerves of the lower limb have been drafted. All of them received strong consensus. Image-guided pudendal nerve block is safe, effective, and well tolerated with few complications. US-guided perisciatic injection of anesthetic provides good symptom relief in patients with piriformis syndrome; however, the addition of corticosteroids to local anesthetics still has an unclear role. US-guided lateral femoral cutaneous nerve block can be used to provide effective post-operative regional analgesia., Conclusion: Despite the promising results reported by published papers on image-guided interventional procedures for peripheral nerves of the lower limb, there is still a lack of evidence on the efficacy of most procedures., Key Points: • Image-guided pudendal nerve block is safe, effective, and well tolerated with few complications. • US-guided perisciatic injection of anesthetic provides good symptom relief in patients with piriformis syndrome; however, the addition of corticosteroids to local anesthetics still has an unclear role. • US-guided lateral femoral cutaneous nerve block can be used to provide effective post-operative regional analgesia. The volume of local anesthetic affects the size of the blocked sensory area., (© 2021. The Author(s).)

Objectives: Clarity regarding accuracy and effectiveness for interventional procedures around the foot and ankle is lacking. Consequently, a board of 53 members of the Ultrasound and Interventional Subcommittees of the European Society of Musculoskeletal Radiology (ESSR) reviewed the published literature to evaluate the evidence on image-guided musculoskeletal interventional procedures around this anatomical region., Methods: We report the results of a Delphi-based consensus of 53 experts from the European Society of Musculoskeletal Radiology who reviewed the published literature for evidence on image-guided interventional procedures offered around foot and ankle in order to derive their clinical indications. Experts drafted a list of statements and graded them according to the Oxford Centre for evidence-based medicine levels of evidence. Consensus was considered strong when > 95% of experts agreed with the statement or broad when > 80% but < 95% agreed. The results of the Delphi-based consensus were used to write the paper that was shared with all panel members for final approval., Results: A list of 16 evidence-based statements on clinical indications for image-guided musculoskeletal interventional procedures in the foot and ankle were drafted after a literature review. The highest level of evidence was reported for four statements, all receiving 100% agreement., Conclusion: According to this consensus, image-guided interventions should not be considered a first-level approach for treating Achilles tendinopathy, while ultrasonography guidance is strongly recommended to improve the efficacy of interventional procedures for plantar fasciitis and Morton's neuroma, particularly using platelet-rich plasma and corticosteroids, respectively., Key Points: • The expert panel of the ESSR listed 16 evidence-based statements on clinical indications of image-guided musculoskeletal interventional procedures in the foot and ankle. • Strong consensus was obtained for all statements. • The highest level of evidence was reached by four statements concerning the effectiveness of US-guided injections of corticosteroid for Morton's neuroma and PRP for plantar fasciitis., (© 2021. The Author(s).)

Objectives: Image-guided musculoskeletal interventional procedures around the hip are widely used in daily clinical practice. The need for clarity concerning the actual added value of imaging guidance and types of medications to be offered led the Ultrasound and the Interventional Subcommittees of the European Society of Musculoskeletal Radiology (ESSR) to promote, with the support of its Research Committee, a collaborative project to review the published literature on image-guided musculoskeletal interventional procedures in the lower limb in order to derive a list of clinical indications., Methods: In this article, we report the results of a Delphi-based consensus of 53 experts who reviewed the published literature for evidence on image-guided interventional procedures offered in the joint and soft tissues around the hip in order of their clinical indications., Results: Ten statements concerning image-guided treatment procedures around the hip have been collected by the panel of ESSR experts., Conclusions: This work highlighted that there is still low evidence in the existing literature on some of these interventional procedures. Further large prospective randomized trials are essential to better confirm the benefits and objectively clarify the role of imaging to guide musculoskeletal interventional procedures around the hip., Key Points: • Expert consensus produced a list of 10 evidence-based statements on clinical indications of image-guided interventional procedures around the hip. • The highest level of evidence was only reached for one statement. • Strong consensus was obtained for all statements., (© 2021. The Author(s).)

In the rare co-occurrence of childhood cancer and severe hemophilia, hemostatic management is of paramount therapeutic importance. We present the case of an 11-month-old boy with severe congenital hemophilia B, who was diagnosed with metastatic high-risk neuroblastoma. He consequently developed paraneoplastic coagulopathy with life-threatening tumor hemorrhage and intracranial hemorrhage, showing central nervous system relapse. Management consisted of factor IX replacement with extended half-life factor IX fusion protein, adjusted to bleeding risk. Additional interventions included factor XIII, fibrinogen, fresh frozen plasma, tranexamic acid, and platelet transfusions. The half-life of factor IX products was markedly reduced requiring close factor IX monitoring and adequate replacement. This intensified treatment allowed chemotherapy, autologous stem cell transplantation, and GD2 antibody immune therapy without bleeding or thrombosis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Although image-guided interventional procedures of the elbow and wrist are routinely performed, there is poor evidence in the literature concerning such treatments. Our aim was to perform a Delphi-based consensus on published evidence on image-guided interventional procedures around the elbow and wrist and provide clinical indications on this topic., Methods: A board of 45 experts in image-guided interventional musculoskeletal procedures from the European Society of Musculoskeletal Radiology were involved in this Delphi-based consensus study. All panelists reviewed and scored published papers on image-guided interventional procedures around the elbow and wrist updated to September 2018 according to the Oxford Centre for Evidence-based Medicine levels of evidence. Consensus on statements drafted by the panelists about clinical indications was considered as "strong" when more than 95% of panelists agreed and as "broad" if more than 80% agreed., Results: Eighteen statements were drafted, 12 about tendon procedures and 6 about intra-articular procedures. Only statement #15 reached the highest level of evidence (ultrasound-guided steroid wrist injections result in greater pain reduction and greater likelihood of attaining clinically important improvement). Seventeen statements received strong consensus (94%), while one received broad consensus (6%)., Conclusions: There is still poor evidence in published papers on image-guided interventional procedures around the elbow and wrist. A strong consensus has been achieved in 17/18 (94%) statements provided by the panel on clinical indications. Large prospective randomized trials are needed to better define the role of these procedures in clinical practice., Key Points: • The panel provided 18 evidence-based statements on clinical indications of image-guided interventional procedures around the elbow and wrist. • Only statement #15 reached the highest level of evidence: ultrasound-guided steroid wrist injections result in greater pain reduction and greater likelihood of attaining clinically important improvement. • Seventeen statements received strong consensus (94%), while broad consensus was obtained by 1 statement (6%).

Background: Image-guided interventional procedures of the nerves are commonly performed by physicians from different medical specialties, although there is a lack of clinical indications for these types of procedures. This Delphi-based consensus provided a list of indications on image-guided interventional procedures for nerves of the upper limb based on updated published evidence., Methods: An expert panel of 45 members of the Ultrasound and Interventional Subcommittees of the ESSR participated in this Delphi-based consensus study. After revision of the published papers on image-guided interventional procedures for nerves of the upper limb updated to September 2018, the experts drafted a list of statements according to the Oxford Centre for evidence-based medicine levels of evidence. Consensus on statements regarding clinical indications was considered as strong when more than 95% of experts agreed, and broad if more than 80% agreed., Results: Ten statements were drafted on procedures for nerves of the upper limb. Only two statements reached the highest level of evidence (ultrasound guidance is a safe and effective method for brachial plexus block; ultrasound-guided non-surgical approaches are safe and effective methods to treat carpal tunnel syndrome in the short term, but there is sparse evidence on the mid- and long-term effectiveness of these interventions). Strong consensus was obtained on 6/10 statements (60%), while 4/10 statements reached broad consensus (40%)., Conclusions: This Delphi-based consensus study reported poor evidence on image-guided interventional procedures for nerves of the upper limb. Sixty percent of statements on clinical indications provided by the expert board reached a strong consensus., Key Points: • An expert panel of the ESSR provided 10 evidence-based statements on clinical indications for image-guided interventional procedures for nerves of the upper limb • Two statements reached the highest level of evidence • Strong consensus was obtained on 6/10 statements (60%), while 4/10 statements reached broad consensus (40%).

Background: Image-guided interventional procedures around the shoulder are commonly performed in clinical practice, although evidence regarding their effectiveness is scarce. We report the results of a Delphi method review of evidence on literature published on image-guided interventional procedures around the shoulder with a list of clinical indications., Methods: Forty-five experts in image-guided musculoskeletal procedures from the ESSR participated in a consensus study using the Delphic method. Peer-reviewed papers regarding interventional procedures around the shoulder up to September 2018 were scored according to the Oxford Centre for Evidence-based Medicine levels of evidence. Statements on clinical indications were constructed. Consensus was considered as strong if more than 95% of experts agreed and as broad if more than 80% agreed., Results: A total of 20 statements were drafted, and 5 reached the highest level of evidence. There were 10 statements about tendon procedures, 6 about intra-articular procedures, and 4 about intrabursal injections. Strong consensus was obtained in 16 of them (80%), while 4 received broad consensus (20%)., Conclusions: Literature evidence on image-guided interventional procedures around the shoulder is limited. A strong consensus has been reached for 80% of statements. The ESSR recommends further research to potentially influence treatment options, patient outcomes, and social impact., Key Points: • Expert consensus produced a list of 20 evidence-based statements on clinical indications of image-guided interventional procedures around the shoulder. • The highest level of evidence was reached for five statements. • Strong consensus was obtained for 16 statements (80%), while 4 received broad consensus (20%).

This report describes the technical features and potential advantages of the application of electronic haemophilia treatment diary smart medication and an evaluation of real-life electronic treatment data collected from haemophilia patients. Since 2012, a total of 663 patients from 30 German haemophilia treatment centres (HTCs) have used the device. Data of nine HTCs were merged for real-life data analysis. Patients were divided into four subgroups according to above versus below mean values for annual factor consumption (AFC) and annual joint bleeds (AJB), respectively. The largest subgroup comprised patients with low mean AFC and AJB less than 2.25 (group A: 42%). Second largest was the group with low mean AJB but high AFC (group B: 32%), suggesting that resources could be saved in some patients. The group with low AFC but high AJB may need increased factor dosing (group D: 13%). Patients who showed a high mean AJB despite high AFC (group C: 13%) may require special medical attention, such as pharmacokinetic-adapted treatment modification or orthopaedic measures. ™ and an evaluation of real-life electronic treatment data collected from haemophilia patients. Since 2012, a total of 663 patients from 30 German haemophilia treatment centres (HTCs) have used the device. Data of nine HTCs were merged for real-life data analysis. Patients were divided into four subgroups according to above versus below mean values for annual factor consumption (AFC) and annual joint bleeds (AJB), respectively. The largest subgroup comprised patients with low mean AFC and AJB less than 2.25 (group A: 42%). Second largest was the group with low mean AJB but high AFC (group B: 32%), suggesting that resources could be saved in some patients. The group with low AFC but high AJB may need increased factor dosing (group D: 13%). Patients who showed a high mean AJB despite high AFC (group C: 13%) may require special medical attention, such as pharmacokinetic-adapted treatment modification or orthopaedic measures. Smart medication ™ enables the HTC to quickly identify patients in need of treatment changes and, thus, to plan individualized therapy modifications prior to patient visits. The growing pool of real-life data facilitates data analysis and may play an important role in the optimization of resource distribution., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Georg Thieme Verlag KG Stuttgart · New York.)

Background Defining of gray scale ultrasound standard reference values of the shoulder joint in childhood and adolescence during maturation., Patients: We examined 445 healthy girls and boys between 1 year and 18 years of age. Method A cross-sectional multicentre grey-scale ultrasound study was performed to examine the shoulder joint on both sides. The children were divided according to their gender and were further classified into six age groups, which constituted three-year age ranges, to record anatomical development changes. We measured the capsule-bone distance (BCD) as a representation of the intracapsular cavity, as well as the thickness of the joint capsule and joint cartilage. Values were expressed in mean±standard deviation (SD) and minimum-maximum (min-max). The shape of the joint capsule and capsule-bone junction zone was qualitatively analysed. Results The joint cartilage thickness decreased with increasing age in all joints independently from sex and body side. However, the BCD and the capsule thickness increased with age. There was no intraarticular fluid visible. The joint capsule had a predominantly concave form, whereas the capsule-bone junction was mostly sharp. Discussion This study is the first describing age-related normal values of the intracapsular cavity, joint capsule and cartilage thickness as well as their respective shape in a large cohort of healthy children. Conclusion The findings could be helpful to differentiate between physiological and pathological joint conditions and thereby distinguishing age-related variations from alterations caused by inflammation., Competing Interests: Conflict of interest: All authors have no conflicts of interest regarding this study., (© Georg Thieme Verlag KG Stuttgart · New York.)

Inherited disorders of platelet function are a heterogeneous group. For optimal prevention and management of bleeding, classification and diagnosis of the underlying defect are highly recommended. An interdisciplinary guideline for a diagnostic approach has been published (AWMF # 086-003 S2K; Hämostaseologie 2014; 34: 201-212). Underlying platelet disorder, platelet count, age and clinical situation modify treatment. Exclusive transfusion of platelet concentrates may be inappropriate as potentially adverse effects can outweigh its benefit. A stepwise and individually adjusted approach for restitution and maintenance of haemostasis is recommended. Administration of antifibrinolytics is generally endorsed, but is of particular use in Quebec disease. Restricted to older children, desmopressin is favourable in storage pool disease and unclassified platelet disorders. Although licensed only for patients with Glanzmann thrombasthenia and alloantibodies, in clinical practice rFVIIa is widely used in inherited platelet disorders with severe bleeding tendency. This guideline aims at presenting the best available advice for the management of patients with inherited platelet function disorders.

Unlabelled: The development of inhibitors in haemophilia B is one of the most important complications of replacement therapy, affecting mortality and morbidity. Inhibitor development is based on complex immunological factors, and to date, only little is known about its underlying mechanisms. Here, we present first results of the haemophilia B group of our Inhibitor-Immunology study., Patients, Methods: So far we have analysed 15 patients with haemophilia B. Four of them developed a high titre inhibitor; the remaining 11 had no inhibitor. We evaluated 9 SNPs in 8 genes (CD40, CTLA-4 , IL-1β, IL-10, TLR2 , TLR4, TLR9, TNF-α). We compared the distribution of these alleles between inhibitor and non-inhibitor haemophilia B patients and between haemophilia B patients and a normal male control population. HLA typing was performed in all patients. Results, discussion: There appears to be a trend towards a skewed distribution of TLR 9, IL-10 and CTLA4 alleles in haemophilia B patients. Due to the limited number these differences are, however, not statistically significant. The t-test of all patients with inhibitor versus without inhibitor was significant for HLA-A*03 and DPB1*0401 and borderline for DRB1*0201.

Unlabelled: The development of inhibitors is one of the most important complications of replacement therapy in haemophilia, affecting mortality and morbidity. Inhibitor development is based on complex immunological factors. Cytokines and their receptors, T-cell receptors, and the Major Histocompatibility Complex may play important roles in the development of inhibitors. Earlier studies showed non significant associations between HLA class and inhibitor development. Later studies found an increased risk of inhibitor development if there was a combination between certain factor VIII mutations and HLA antigens. We performed HLA typing in 50 patients with haemophilia A in an effort to find associations with inhibitor development., Results: 25 patients had developed an inhibitor (11 low titre, 14 high titre), and 25 never had. In logistic regression analysis, HLA-A 34, DRB1 0405, DRB1 1301 seemed to be involved in inhibitor development and HLA-A 30, B 13, B15, B 57, Cw 12, DQB1 0303, DPB1 0201 protection against inhibitor development. In our patients, the HLA-associations with inhibitor development were different from those in previous publications.

We analyzed the records of 3 patients transplanted for end-stage renal failure due to primary hyperoxaluria and evaluated on repeat biopsies the role played by oxalate deposits in the constitution of renal failure after isolated kidney graft, or combined liver and kidney transplantation. Early failure of the renal graft is frequent and often interpreted as the consequence of recurrence because of the presence of oxalate deposits on the graft biopsy. In fact, the decrease in oxalate deposits observed in our 2 cases of combined liver and kidney transplantation despite the progressive renal failure, indicates that crystal deposition is not responsible for the renal lesions. However, we cannot exclude that the oxalate molecule toxicity plays a role in the constitution of the diffuse sclerosis which occurred in these two cases after a primary renal non function, aggravating a hemodynamic process by using cyclosporin. On the other hand, as observed in our isolated kidney graft, renal crystal deposition occurring before the onset of renal failure suggests the true mechanism explaining the slow recurrence of renal oxalosis.