Pediatric SAPHO syndrome with pleural effusion: case report of a unique finding in a rare disease.

Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome is a rare autoinflammatory disease characterized by bone inflammation and skin manifestations including acne, palmoplantar pustulosis, psoriasis, or hidradenitis suppurativa. SAPHO syndrome is considered on the same spectrum as chronic nonbacterial osteomyelitis/chronic recurrent multifocal osteomyelitis (CNO/CRMO), the former often being the nomenclature in adults and the latter in children. The diagnosis is made on patterns of clinical manifestations and is a diagnosis of exclusion. While skin and bone manifestations are commonly described with SAPHO syndrome, pleural involvement is rare, and few cases have been described in the literature, especially in pediatric patients. Herein we present a 14-year-old female with a past medical history of hidradenitis supprtiva, eczema, psoriasis, and a prior episode of culture-negative osteomyelitis who presented to the emergency room with chief complaints of right sided pain with inspiration and back pain. Exam revealed palmoplantar pustulosis, hidradenitis supprativa, psoriasis, and tenderness of vertebrae. Imaging showed a right sided pleural effusion and multiple sites of osteitis. Laboratory evaluation revealed elevated inflammatory markers, an exudative pleural effusion with neutrophilic predominance, and no evidence of malignancy, infection, or immunodeficiency. The patient was diagnosed with SAPHO syndrome and treated with naproxen, methotrexate, and golimumab with significant improvement including resolution of the pleural effusion. Pediatric SAPHO syndrome is a rare disease that classically causes osteitis and skin manifestations. This case highlights that pleural effusion can be a rare manifestation of pediatric SAPHO syndrome. Patients with suspected SAPHO syndrome with respiratory symptoms should be evaluated for pleural effusion.

Is it too complex? A survey of pediatric residency program's educational approach for the care of children with medical complexity.

BACKGROUND: Although Entrustable Professional Activities (EPAs) regarding pediatric training in care for children with medical complexity (CMC) exist, it is unknown what US pediatric training programs provide for education related to care of CMC and whether educators perceive that pediatric residents are prepared to care for CMC upon graduation. METHODS: From June, 2021 through March 2022, we surveyed US pediatric residency program delegates about practice settings, current educational offerings, perception of resident preparedness regarding care of CMC, and likelihood to implement CMC education in the future. RESULTS: Response rate was 29% (56 /195). A third of responding programs (34%, n = 19) provide a specific educational CMC offering including combinations of traditional didactics (84%, n = 16), asynchronous modules/reading (63%, n = 12), experiential learning (58%, n = 11), and simulation-based didactics (26%, n = 5). The majority (93%, n = 52) of respondents agreed residents should be competent in providing primary care for CMC upon graduation and CMC should receive primary care from a resident (84%, n = 47). A total of 49% (n = 27) of respondents reported their residents are very or extremely well prepared to care for CMC after graduation. A total of 33% (n = 18) of programs reported CMC receive primary care from residents. Respondent average perception of resident preparedness was significantly higher in programs with educational offerings in five of eleven EPAs (nutrition and weight, transitions, feeding tubes, advocacy, and care coordination). The majority (78%, n = 29) of programs without educational offerings are at least somewhat likely to implement CMC curricula in the next three years. CONCLUSION: Pediatric residency programs report residents should be competent in care for CMC upon graduation. Pediatric residents are exposed to a wide variety of clinical care models for CMC. The minority of responding programs have intentional CMC educational offerings. Of those programs that provide CMC education, the offerings are variable and are associated with a perception of improved preparedness to care for CMC upon graduation.

BPDE-induced genotoxicity: relationship between DNA adducts, mutagenicity in the in vitro PIG-A assay, and the transcriptional response to DNA damage in TK6 cells.

Benzo[a]pyrene is a known human carcinogen. As underlying mechanism, the induction of stable DNA adducts and mutations have been repeatedly demonstrated. Also, the activation of cellular stress response on the transcriptional level has been described. Nevertheless, the interrelationship between these different events is less well understood, especially at low, for human exposure relevant concentrations. Within the present study, we applied the reactive metabolite benzo[a]pyrene diolepoxide (BPDE) in the nanomolar, non-cytotoxic concentration range in human TK6 cells and quantified the induction and repair of stable DNA adducts at the N 2-position of guanine by HPLC with fluorescence detection. Significant levels of DNA lesions were detected even at the lowest concentration of 10 nM BPDE, with a linear increase up to 50 nM. Relative repair was similar at all damage levels, reaching about 30% after 8 h and 60% after 24 h. Mutation frequencies were quantified as GPI-deficient cells by the recently established in vitro PIG-A mutagenicity assay. Again, a linear dose-response-relationship in the before-mentioned concentration range was observed, also when plotting the number of GPI-deficient cells against the number of DNA adducts. Furthermore, we explored the time- and concentration-dependent DNA damage response on the transcriptional level via a high-throughput RT-qPCR technique by quantifying the impact of BPDE on the transcription of 95 genes comprising DNA damage response, DNA repair factors, oxidative stress response, cell cycle arrest, cell proliferation, and apoptosis. As expected, BPDE activated DNA damage signaling, p53 and AP-1 dependent signaling, oxidative stress response, and apoptosis. However, in contrast to DNA adducts and mutations, the onset of the transcriptional DNA damage response was restricted to higher concentrations, indicating that its respective activations require a certain level of DNA lesions. Altogether, the results indicate that in case of BPDE, DNA lesions and mutations were correlated at all concentrations, suggesting that repair is not complete even at low levels of DNA damage. Considering the ongoing discussion on potential thresholds also for genotoxic carcinogens, the results are of major relevance, both with respect to basic research as well as to risk assessment of chemical carcinogens.

The Pig-a Gene Mutation Assay in Mice and Human Cells: A Review.

This MiniReview describes the principle of mutation assays based on the endogenous Pig-a gene and summarizes results for two species of toxicological interest, mice and human beings. The work summarized here largely avoids rat-based studies, as are summarized elsewhere. The Pig-a gene mutation assay has emerged as a valuable tool for quantifying in vivo and in vitro mutational events. The Pig-a locus is located at the X-chromosome, giving the advantage that one inactivated allele can give rise to a mutated phenotype, detectable by multicolour flow cytometry. For in vivo studies, only minute blood volumes are required, making it easily incorporated into ongoing studies or experiments with limited biological materials. Low blood volumes also allow individuals to serve as their own controls, providing temporal information of the mutagenic process, and/or outcome of intervention. These characteristics make it a promising exposure marker. To date, the Pig-a gene mutation assay has been most commonly performed in rats, while reports regarding its usefulness in other species are accumulating. Besides its applicability to in vivo studies, it holds promise for genotoxicity testing using cultured cells, as shown in recent studies. In addition to safety assessment roles, it is becoming a valuable tool in basic research to identify mutagenic effects of different interventions or to understand implications of various gene defects by investigating modified mouse models or cell systems. Human blood-based assays are also being developed that may be able to identify genotoxic environmental exposures, treatment- and lifestyle-related factors or endogenous host factors that contribute to mutagenesis.

The in vitro PIG-A gene mutation assay: glycosylphosphatidylinositol (GPI)-related genotype-to-phenotype relationship in TK6 cells.

In our previous work, we established an in vitro variant of the currently developed in vivo PIG-A assay as promising mutagenicity test system. We applied the human B-lymphoblastoid cell line TK6 for the in vitro assay development, which is based on the cellular glycosylphosphatidylinositol (GPI) status. At least 22 genes are involved in GPI biosynthesis, leading to the complex situation that, in principle, multiple genes could induce a GPI-deficient phenotype by acquiring inactivating mutations. However, only the PIG-A gene is located on the X-chromosome, rendering PIG-A more sensitive compared to autosomal linked, GPI-relevant genes. In this work, we investigated the GPI-related genotype-to-phenotype relationship in TK6 cells. By a next-generation sequencing approach, we identified a heterozygous chromosomal deletion on chromosome 17, where the PIG-L gene is located. In the analyzed TK6 cell clones, the GPI-deficient phenotype was induced either by mutations in PIG-A, by the complete absence of PIG-A mRNA, or by deletions in the remaining functional PIG-L gene, causing loss of heterozygosity. The identified PIG-L heterozygosity could also be responsible for the increased sensitivity toward mutagenic ethyl methanesulfonate or UV-C treatments of p53-proficient TK6 compared to the TK6-related, but p53-deficient WI-L2-NS cell line. Moreover, the WI-L2-NS cell line was found to exhibit a much lower number of GPI-deficient mutant cells in the purchased cell batch, and WI-L2-NS exerted a lower spontaneous rate of GPI deficiency compared to TK6 cells.

Effects of exposure to direct-to-consumer television advertising for statin drugs on food and exercise guilt.

OBJECTIVE: Pharmaceutical direct-to-consumer advertising (DTCA) is widely prevalent on US television. This study tests the relationship between estimated exposure to DTCA for statin drugs, which often feature mixed messages about the efficacy of diet and exercise in reducing risk of cholesterol and heart disease, and guilty feelings regarding food and exercise. METHODS: A series of repeated cross-sectional surveys of the US population between 2001 and 2007 (N=106,859 adults aged 18 and older) were combined with data on the frequency of DTCA appearances on national, cable, and local television during the same time period. RESULTS: Adjusting for potential confounders with ordinary least squares (OLS) regression, increased potential exposure to statin DTCA was associated with increased food guilt (in a dose-response pattern) and exercise guilt (in a threshold pattern). CONCLUSION: This study provides new evidence that DTCA has potential to influence emotional well-being as well as direct behavioral responses emphasized in previous academic research. PRACTICE IMPLICATIONS: Health practitioners should be prepared to encounter and counsel patients who are prompted by DTCA to feel guilty about their food and exercise behaviors, feelings which may impact the likelihood of adherence to prescribed behavioral modification for weight management.

The in vitro PIG-A gene mutation assay: mutagenicity testing via flow cytometry based on the glycosylphosphatidylinositol (GPI) status of TK6 cells.

The X-linked PIG-A gene is involved in the biosynthesis of the cell surface anchor GPI, and its inactivation may serve as a new marker for mutagenicity. The in vivo PIG-A gene mutation assay is currently being validated by several groups. In this study, we established a corresponding in vitro variant of the PIG-A assay applying B-lymphoblastoid TK6 cells. PE-conjugated antibodies against the GPI-anchored proteins CD55 and CD59 were used to determine the GPI status via multicolor flow cytometry. Mutant spiked TK6 cell samples were analyzed, and mutants were quantified with even small numbers being quantitatively recovered. To validate our approach, mutant spiked cell samples were analyzed by flow cytometry and proaerolysin selection in parallel, yielding a high correlation. Further, we developed a procedure to reduce the background level of preexisting mutant cells to lower than 20 in 10(6) cells to increase the sensitivity of the assay. Spontaneous rate of GPI deficiency was investigated being 0.76 × 10(-6)/cell/generation for TK6 cells. The optimal phenotype expression time after ethyl methanesulfonate treatment was found to be 10 days. We applied the in vitro PIG-A assay to demonstrate the mutagenicity of ethyl methanesulfonate, 4-nitroquinoline 1-oxide and UV-C irradiation in a dose-dependent and statistically significant manner. Pyridine and cycloheximide were included as negative controls providing negative test results up to 10 mM. These data suggest that the in vitro PIG-A assay could complement the in vivo PIG-A assay with some distinct advantages compared to other in vitro mammalian mutagenicity tests.

Autotransplantation for the treatment of severe renal artery stenosis in a solitary kidney after repeated percutaneous transluminal angioplasty: a case report.

A 66-year-old female suffering from massive atherosclerosis with a long history of renal artery stenosis in the left solitary kidney was admitted to reevaluate an in-stent restenosis. Advanced peripheral arterial disease had formerly been treated by aortobifemoral bypass surgery and a highly eccentric infrarenal abdominal aortic stenosis of 70 - 80% had been treated by patch angioplasty. In this patient several percutaneous transluminal renal angioplasties after a former stent deployment had resulted in recurrent in-stent restenoses. The renal artery stenosis was reevaluated and a re-angioplasty attempt was unsuccessful due to technical failure. Blood pressure remained difficult to manage. Renal function decreased as a result of presumed acute renal failure. A further progression of the renal artery stenosis was found. Autotransplantation to the left iliac fossa was done, because aortorenal bypass was considered impossible. Renal function normalized and follow-up Doppler ultrasonography examinations revealed a newly developed ostial anastomotic stenosis of 60 - 70%. While medical therapy and percutaneous transluminal angioplasty with stent deployment are common treatment options, surgical interventions are reserved for cases of complex stenoses. Autotransplantation as a complex option in the treatment of renal artery stenosis seems to be an adequate alternative in patients with severe, generalized atherosclerosis after failure of interventional procedures and the impossibility of standard surgical techniques.

[A 58-year-old hypertensive patient with primary hyperaldosteronism and renal artery stenosis]. / 58-jähriger Patient mit primärem Hyperaldosteronismus und Nierenarterienstenose bei arterieller Hypertonie.

BACKGROUND: Secondary hypertension can rarely be caused by different disorders as shown in the present case with simultaneous occurrence of two possible causes. CASE REPORT: Magnetic resonance imaging findings of a 58-year-old patient showed an eccentric left renal artery stenosis of 60-70% and an inhomogeneous tumor of the left adrenal gland. After percutaneous transluminal angioplasty, elevated plasma aldosterone concentrations persisted. Adrenal vein sampling in the authors' hospital confirmed a primary hyperaldosteronism due to unilateral adenoma. Subsequently, unilateral laparoscopic adrenalectomy was performed. CONCLUSION: Atherosclerotic renal artery stenosis stimulates the renin-angiotensin system and thereby causes secondary hypertension. Furthermore, adrenal disorders that lead to abnormal aldosterone secretion, i.e., primary hyperaldosteronism, often result in secondary hypertension. Though the simultaneous occurrence of two potential causes of secondary hypertension is rare, it has to be considered for differential diagnosis and therapy. The presumed pathophysiological relevance should guide the order of therapeutic measures.

[Surface modification of metal implant materials by low-pressure plasma treatment]. / Oberflächenmodifikation metallischer Implantatmaterialien durch Niederdruckplasmabehandlung / Surface modification of metal implant materials by low-pressure plasma treatment.

BACKGROUND: Plasma treatment leads to a significant change of surface free energy of medical implant materials. These changes strongly influence protein and cell adhesion on the material surface. The aim of the study was to quantify the plasma-induced surface changes and to analyse whether the change of treatment parameters, such as pressure, gas mixture, energy and treatment time, influences the surface free energy of the implant materials. To improve the biocompatibility of the surfaces, polyamino acid coating experiments were performed. MATERIALS AND METHODS: Three different metal implant materials (X2CrNiMo18-15-3, Ti6Al4V, Ti6Al7Nb) were treated with a double-inductively coupled low-pressure plasma. The influence of treatment parameter variation on the surface free energy was evaluated by drop shape analysis. The plasma treated and non-treated materials were incubated in collagen I solution. Afterwards, the coatings were analysed by electron microscopy in terms of structure and adhesion. RESULTS: Drop shape analysis revealed that plasma treatment leads to a significant increase of surface free energy in all groups. Long plasma treatment times and low treatment pressures lead to a significant (p<0.05) extension of the detectable surface free energy increase. Coating experiments showed that only on plasma-treated samples solid and adherent collagen layers could be achieved.