[COVID-19: treatment strategies of German-speaking pediatric rheumatologists : Results of an online survey]. / COVID-19: Behandlungsstrategien der deutschsprachigen Kinderrheumatologen : Ergebnisse einer Online-Umfrage.

BACKGROUND: Reliable data on the course and treatment of pediatric COVID-19 ("corona virus disease 2019") in immunosuppressed patients with rheumatic diseases are missing. AIM: Delineation of individual strategies of the members of the Society for Pediatric Rheumatology (GKJR) in cases of COVID-19. METHODS: In May 2020 all GKJR members were invited to take part in an online survey. Opinion data regarding an approach using disease-modifying anti-rheumatic drugs (DMARD) in cases of COVID-19 as well as the readiness to use new therapeutic agents in patients in different stages of the disease were collected. RESULTS: A total of 71 respondents (27.3% of all contacted pediatric rheumatologists) took part in the survey. Of these 28.2% had treated patients with COVID-19. Over 95% of the respondents did not support a preventive adaptation of the anti-rheumatic treatment during the SARS-CoV­2 pandemic. In the case of outpatients under immunosuppression with proven COVID-19 more than 50% of the respondents would refrain from administering intravenous high-dose steroids, cyclophosphamide, anti-CD20 antibodies as well as BAFF, CTLA­4 and TNF-alpha blockades. Conversely, >70% of the respondents would continue the treatment with nonsteroidal anti-inflammatory drugs, hydroxychloroquine (HCQ), oral steroids, mycophenolate, IL­1 blockade and immunoglobulins (Ig). In the case of inpatients 74.6% of respondents would consider targeted COVID-19 treatment. In stable patients with oxygen treatment (stage I) HCQ (18.3%), azithromycin (16.9%) and Ig (9.9%) were most frequently used. In cases of early signs (stage II) or a manifest cytokine storm (stage III) anakinra (40.8% for stage II and 46.5% for stage III), tocilizumab (26.8% and 40.8%, respectively), steroids (25.4% and 33.8%, respectively) and remdesivir (29.6% and 38.0%, respectively) were most frequently used. The need for a personalized approach based on the current clinical situation was emphasized by many respondents. CONCLUSION: The currently low prevalence of COVID-19 in Germany limits the general clinical experience. Therefore, the presented results have to be interpreted with caution and mostly as hypothetical treatment considerations. It is to be expected that there will always be a limited amount of evidence on pediatric COVID-19; therefore, a continuous and critical exchange of expert opinions on the treatment strategies is important.

High-dimensional profiling reveals Tc17 cell enrichment in active Crohn's disease and identifies a potentially targetable signature.

The immune-pathology in Crohn's disease is linked to dysregulated CD4+ T cell responses biased towards pathogenic TH17 cells. However, the role of CD8+ T cells able to produce IL-17 (Tc17 cells) remains unclear. Here we characterize the peripheral blood and intestinal tissue of Crohn's disease patients (n = 61) with flow and mass cytometry and reveal a strong increase of Tc17 cells in active disease, mainly due to induction of conventional T cells. Mass cytometry shows that Tc17 cells express a distinct immune signature (CD6high, CD39, CD69, PD-1, CD27low) which was validated in an independent patient cohort. This signature stratifies patients into groups with distinct flare-free survival associated with differential CD6 expression. Targeting of CD6 in vitro reduces IL-17, IFN-γ and TNF production. These results identify a distinct Tc17 cell population in Crohn's disease with proinflammatory features linked to disease activity. The Tc17 signature informs clinical outcomes and may guide personalized treatment decisions.

Cationic [99mTcIII(DIARS)2(SR)2]+ complexes as potential myocardial perfusion imaging agents (DIARS = o-phenylenebis(dimethylarsine);SR- = thiolate).

Reduction-substitution reactions on [99mTcO4]- with both o-phenylenebis(dimethylarsine) (DIARS) and various thiols produce a series of monocationic [99Tc(DIARS)2(SR)2]+ complexes. Addition of [99gTcO4]- to the above reaction mixtures allows the characterization of the "carrier-added" complexes by means of reverse-phase high-performance liquid chromatography with radiometric and optical detection systems. The identity of the [99mTc(DIARS)2(SR)2]+ complexes is confirmed by fast atom bombardment mass spectroscopy; equivalence of the [99gTc(DIARS)2-(SR)2]+ and [99mTc(DIARS)2(SR)2]+ species is demonstrated by identical HPLC retention times. All the [99mTc(DIARS)2(SR)2]+ complexes tested accumulate in the myocardium of Sprague-Dawley rats with an average uptake of 1.5-2.0% of injected dose/g at 30 min. Thus, as designed, these nonreducible Tc(III) complexes do not exhibit the rapid myocardial washout observed for reducible Tc(III) complexes. These [99mTc(DIARS)2(SR)2]+ complexes also exhibit an initially high liver uptake, but the presence of ether groups within the thiolate ligands causes this liver uptake to decrease over time without affecting the heart uptake, thereby improving the heart/liver ratio.

Karsch-Neugebauer syndrome in two sibs with unaffected parents.

We report on 2 sisters with Karsch-Neugebauer syndrome comprising split foot and split hand anomalies in association with congenital nystagmus. These sisters share a nearly identical phenotype with the 8 previously reported instances of this disorder. Although genetic heterogeneity can not be formally excluded, most evidence suggests that Karsch-Neugebauer syndrome is an autosomal dominant disorder. If so, then this report of 2 affected sibs born to healthy parents is the second instance of apparent gonadal mosaicism in this disorder. The apparent high frequency of gonadal mosaicism is important to recognize in counseling families with this disorder.

Skeletal conformations and receptor binding of some 9,11-modified estradiols.

The effect of the modification of the 9-11 positions on the skeletal conformation of estradiol (E2) has been analyzed by X-ray crystallography and MM2 molecular mechanics. The 11 beta-hydroxyl and 11-keto analogs of E2 maintained ring conformations which were similar to the natural hormone (E2). Introduction of a double bond at position 9-11 induced a flattening of the entire steroid molecule. An 11 alpha-hydroxyl group brought about significant changes in the alicyclic rings of E2. 9 beta-Estradiol and 11-keto-9 beta-estradiol formed ring conformations which were significantly bent from E2 (below the plane of the A-ring). Examination of the affinity of these C-ring analogs of E2 for the human estrogen receptor has shown extreme variations. A hydroxyl group placed either alpha or beta at the 11-position yielded ligands with vastly different and reduced affinities for the receptor. The low affinity of 11 alpha-hydroxyestradiol (1/300th of E2) may be due to the drastic structural change induced in the alicyclic portion of the molecule, as well as, to the steric or electrostatic effects of the alpha-hydroxyl group upon the receptor protein. An 11 beta-hydroxyl group diminished the receptor binding to 1/60th that of E2 without alicyclic ring distortions, whereas a 9-11 unsaturation reduced the binding to 1/5th although this steroid displayed a flattening of rings B, C, and D. The 11-keto function, which had little effect on the conformation of the estrogen nucleus, reduced the affinity of this ligand to 1/1000th that of E2. The negative bend at the C-ring of 11-keto-9 beta-estradiol and 9 beta-estradiol prevented these ligands from binding receptor. Some of the observed receptor interactions were related to structural alterations in the estrogen ring system induced by modifications on the 9-11 region.

A novel chromium(0)-promoted four-component cycloaddition reaction.

[formula: see text] Reaction of (eta 6-thiepin-1,1-dioxide)tricarbonylchromium(0) with excess terminal alkynes under photoactivation conditions affords novel pentacyclic adducts formally derived from a sequential [6 pi + 2 pi]/[6 pi + 2 pi]/[2 sigma + 2 pi] cycloaddition process.

Superficial bladder cancer treated with intravesical bacillus Calmette-Guérin or adriamycin: follow-up report.

We evaluated 139 patients with superficial bladder cancer (Stages Ta, Tl, and TIS) and treated them with either intravesical bacillus Calmette-Guérin, Tice strain (BCG), or doxorubicin hydrochloride (Adriamycin [ADR]) in a nonrandomized, multicenter study. Our follow-up study comprises 135 of these patients. Of these patients, 78 tumors were completely resected, and 61 were incompletely resected. When a proportional-hazards model (Cox) was applied, there was a statistically significant difference between the recurrence rates for the two drugs. On the basis of recurrence rates per 100 patient-months, both BCG (1.2) and ADR (0.9) worked well with completely resected tumors. However, for incomplete resections, the recurrence rate for BCG (0.9) was less than half that for ADR (1.9). The overall recurrence rates were 1.1 and 1.3 for BCG and ADR, respectively. There have been 42 failures of treatment with either BCG or ADR. We defined failure as any recurrence of tumor; progression of the cancer in stage, grade, tumor number or size; or any residual tumor after 18 treatments (14 months of therapy). As to the failures in patients whom we followed up, and whose treatment was either switched from ADR to BCG or continued on further BCG treatment, 53 per cent have achieved complete remission. Complete remission for BCG and ADR were 76 per cent and 52 per cent, respectively. Of the various factors considered in the study, only tumor grade and treatment drug were statistically significant. The cystectomy rate was 1 per cent for BCG-treated patients and 0 for ADR-treated patients.

Does bacillus Calmette-Guérin immunotherapy accelerate growth and cause metastatic spread of second primary malignancy?

In our study, 29 of 150 patients with bladder cancer also had other associated primary malignancies, 10 of which were manifested after intravesical treatment with bacillus Calmette-Guérin (BCG). Second primary malignancies developed in 5 of these patients within three months of the start of BCG therapy. All 5 showed acceleration of the second primary tumor, and distant metastatic lesions developed in 4. In the other 5 patients nonbladder primary malignancies developed eight months or more after intravesical BCG therapy started, but did not show acceleration or spread. Twenty patients with other primary malignancies that had developed months to years before intravesical therapy did not show acceleration or spread of those tumors. We have seen enough cases of patients who received intravesical BCG at the time of growth and spread of second primary malignancies to warrant concern. Animal and human studies of BCG use for treatment of malignancy indicate that the temporal relationship between the starting point of tumor development and the starting point of BCG treatment is crucial in determining whether BCG will eradicate or exacerbate the tumor. We have therefore instituted a change in our treatment until the question of whether or not BCG causes the appearance and spread of these second malignancies is answered.

Superficial bladder cancer treated by intravesical bacillus Calmette-Guerin or adriamycin: multicenter study interim report.

One hundred sixteen patients with superficial bladder cancers (Stages Ta, T1, and TIS) were evaluated and treated with either intravesical bacillus Calmette-Guerin [Tice strain] (BCG) or doxorubicin hydrochloride (Adriamycin [ADR]), in a multicenter study. One hundred nine of these patients currently have follow-up. Of these, 54 were completely resected and 55 incompletely resected. For complete resections, based on recurrence rates per 100 patient months, both BCG (0.22) and ADR (0.91) worked well, although BCG had a slightly lower recurrence rate. However, for incomplete resections, BCG (0.20) had a markedly lower recurrence rate than ADR (2.52). Eighteen patients failed initial treatment, with either BCG or ADR. All have been placed on long-term therapy schedules. Of the 12 failures who currently have follow-up, 11 (92%) have either partially or completely responded with additional intravesical therapy. No patients in this study have yet required cystectomies.

Multicenter study of superficial bladder cancer treated with intravesical bacillus Calmette-Guérin or adriamycin.

We evaluated 155 patients with superficial bladder cancers (Stages Ta, T1, and TIS) and treated them with either intravesical bacillus Calmette-Guérin (Tice strain) (BCG) or doxorubicin hydrochloride (Adriamycin), in a multicenter nonrandomized study. At present 140 of these patients in treatment Groups I and II are being followed up. With additional follow-up, BCG continued to produce a higher percentage of complete remissions (71%) than doxorubicin (54%). The percentage of incomplete remission with BCG (7%) was half that with doxorubicin (14%). Half of the patients whose initial therapy failed had complete remission after additional therapy. However, for patients with recurrence, additional follow-up shows a recurrence rate per 100 patient-months for BCG (1.0) only slightly lower than that for doxorubicin (1.1). The percentage of progressions continued to be higher with BCG (8.5%) than with doxorubicin (5%), but the difference between these results for the two drugs proved slightly less than we reported previously. Of the patients in this study, 2.5 percent (all treated with BCG) required cystectomy. A comparison of the results of our study with those of 13 other studies using BCG to treat bladder cancer indicates that therapy beyond an initial course of 6 weekly treatments increases the percentage of complete response. All of the studies showed that the greatest improvement in percentage of complete response occurred with the second course of treatment. The value of maintenance therapy cannot yet be determined, since few studies have used that protocol. The percentage of patients requiring cystectomy in studies with fewer than 20 treatments was 2.2 times higher than in studies with more than 20 treatments.

Multicenter study of superficial bladder cancer treated with intravesical bacillus Calmette-Guerin or adriamycin. Results of long-term follow-up.

We evaluated 158 cases of patients with superficial bladder cancers (Stages Ta, T1, and Tis). These cases were treated with either intravesical bacillus Calmette-Guerin (BCG) (Tice strain) or Adriamycin (ADR), in a multicenter, nonrandomized study. One hundred thirty-one of these patients were followed up; the results continue to show a higher percentage of initial complete remissions with BCG (68%) than with ADR (57%). With additional therapy, both BCG and ADR achieved complete remission in 83 percent of the patients. When 7 failures with patients taking ADR were switched to BCG and the disease cleared, the rate of complete remission for BCG rose to 85 percent. The recurrence rate per 100 patient-months was only slightly different for BCG (0.9) and ADR (0.8). The percentage of progressions continued to be higher for BCG (8%) than for ADR (5%). Cystectomies were performed in 2.5 percent of the BCG patients. Using the Cox regression model with covariates, we found drug treatment, tumor grade, and sex to be statistically significant in determining failures throughout the protocol. Although both BCG and ADR were effective over the course of the study, BCG is the drug of choice for residual tumor (Stages T1 and Tis).

99mTc(L-L)3+ complexes containing ether analogs of DMPE.

Novel 99mTc(L-L)3+ complexes have been investigated for potential use in myocardial perfusion imaging. Bidentate chelators have been prepared that are based on substituent analogs of 1,2-bis(dimethylphosphino)ethane, onto which alkyl ether groups have been incorporated. The new ligands are: (1) MMPE, 1,2-bis(methyl methoxyethyl phosphino)ethane, (2) MIBPE, 1,2-bis(methyl methoxyisobutyl phosphino)ethane, (3) FURPE, 1,2-bis(methyl tetrahydrofuran phosphino)ethane, and (4) PYRPE, 1,2-bis(methyl tetrahydropyran phosphino)ethane. These ligands have been reacted with 99mTc and the resulting complexes evaluated for myocardial imaging properties. 99mTc(MMPE)3+ exhibited the most favorable myocardial imaging characteristics in animal models. Results indicate that pendent ether moieties can improve the myocardial imaging properties of cationic technetium complexes.

Crystal structure, receptor binding, and gene regulation of 2- and 4-nitroestradiols.

Crystal structures of 2-nitroestradiol and 4-nitroestradiol showed two different molecular conformations for each compound. The crystal structure of 4-nitroestradiol, as well as that of 4-nitroestrone-3-methyl ether, displayed a nitro group in which the oxygens were perpendicular to the aromatic ring and were this nonconjugating. On the other hand, the nitro-oxygens in 2-nitroestradiol were periplanar, with the aromatic ring permitting conjugating. This latter structure bound to estrogen receptor with 1/1000th the affinity of estradiol and was inefficient in gene stimulation. 4-Nitroestradiol possessed a relative binding affinity 40-fold greater than that of the 2-nitro derivative and actively induced responsive genes at a concentration of 10(-8) M. Whereas binding affinity can be explained primarily by polar groups and skeletal structure, gene induction may be linked to electronic induction in ring A that causes a requisite electronegative isopotential around the molecule. This electronegative characteristic also produces conformational changes in the alicyclic backbone of the estrogen, specially ring B, which could interfere with the molecular fit of the nitroestradiols with estrogen receptor.

Cortical fibroblast culture from human biopsies.

BACKGROUND: Tubulointerstitial fibrosis is an integral part of progressive renal disease. Human cortical fibroblasts are believed to be key effector cells in fibrogenesis. Thus, a reliable culture of these cells is necessary for studies of their pathophysiology. METHODS: Cortical fibroblast culture from routine kidney biopsies were analyzed and the cells were characterized. Indirect immunofluorescence staining was done after the first passage for cytokeratin, vimentin, alpha-smooth muscle actin, CD 44, CD 54, CD 68, collagen types I, III, and HLA-DR. We then assessed the utility of the putative fibroblast markers CD 90, prolyl-4-hydroxylase (P4H) and F1b in simultaneous stainings of tubular epithelial cells. RESULTS: During the study period, 49 biopsy cores were cultured and cortical fibroblasts could be successfully established in 21 cases (42.9%). There was no relation between the success rate of culture and the degree of interstitial fibrosis, but an association was seen with the time of completion of the first passage. There was a negative correlation between the extent of scarring and the percentage of cytokeratin positive cells (r = -0.66, p < 0.001). All primary fibroblasts were negative for factor VIII, HLA-DR, CD 68, and cytokeratin. They expressed alpha-smooth muscle actin and collagen types I and III to variable degrees. There was a robust correlation between the percentage of alpha-smooth muscle actin positive cells and interstitial scarring but no such association with collagen type I or type III positive cells. The three putative fibroblast markers did not prove useful in differentiating between tubular epithelial cells and fibroblasts. However, since only fibroblasts stained positive for CD 90 and negative for cytokeratin, these two markers may suffice to distinguish fibroblasts from other renal cellular elements. CONCLUSIONS: Cortical renal fibroblasts can be easily cultured from kidney biopsy cores, though the success rate of pure cultures is below 50%. Staining for CD 90 and cytokeratin may suffice for initial characterization of these cells.

A randomized trial of the long-term effects of digital ocular compression in the late postoperative period.

PURPOSE: To determine whether digital ocular compression is a viable technique to lower intraocular pressure in patients at least 3 months after trabeculectomy. PATIENTS AND METHODS: A 6-month prospective, randomized, controlled, single-masked trial of 29 patients who underwent a trabeculectomy at the Glaucoma Service of Wills Eye Hospital. Patients were assigned to two groups: ocular compression or cheekbone compression (control group). The ocular compression group performed compression to the operated eye three times a day in the pattern of 10 seconds of pressure, 5 seconds of rest, and 10 seconds of pressure. Pressure was applied with the index finger through the closed lid to the center of the cornea. Pressure was steady and firm, but not painful. No massaging was performed. The cheekbone compression group applied pressure to the zygomatic arch with an identical style and frequency. RESULTS: At 6 months, the change in mean intraocular pressure for the ocular compression group was 0.25 mm Hg compared with -0.44 mm Hg for the control group (P = 0.7). A few patients in both groups experienced large swings in intraocular pressure and mild to moderate discomfort. CONCLUSION: Ocular compression had little to no success in the long-term management of increased intraocular pressure in the late postoperative period in this study.

Neonatal infectious spondylitis of the cervical spine presenting with quadriplegia: a case report.

STUDY DESIGN: A case report.- OBJECTIVE: To highlight the evaluation and treatment of neonatal infectious spondylitis of the cervical spine. SUMMARY OF BACKGROUND DATA: Most authors advise intravenous antibiotics as first-choice treatment. The place of aspiration or operative drainage is debated, as is the position and duration of immobilization. METHODS: A 3-week-old neonate was presented with intermittent quadriplegia. RESULTS: Additional investigation demonstrated an osteolytic process in the body of C3 with a large epidural abscess compressing the spinal cord. Because an infectious spondylitis of C3 was suspected, aspiration of the abscess was performed, and antibiotic therapy was started. The patient improved to neurologically normal within 3 weeks and remains asymptomatic throughout a follow-up period of 7 years. CONCLUSIONS: Neonatal infectious spondylitis should be diagnosed early and treated promptly; otherwise, it may have devastating consequences.

Injuries of the acetabular triradiate cartilage and sacroiliac joint.

Four patients with injuries of the acetabular triradiate cartilage are presented. In three of them premature fusion of the cartilage occurred; two of these developed acetabular deformity and subluxation of the hip. In all patients the sacroiliac joint also was injured; in two, the joint was completely disrupted, leading to fusion and growth disturbance of the ilium. As injury of the triradiate cartilage is easily missed on the initial radiograph, it is advised that all patients with pelvic trauma should be followed clinically and radiographically for at least one year.

Acetabular fractures in children and adolescents.

A retrospective study of 23 acetabular fractures in patients up to 17 years of age is presented, with an average follow-up of eight years. Good or excellent functional results were achieved in 21 patients; radiographic results were good or excellent in 16. Conservative treatment gave consistently good results in fractures with minimal initial displacement, stable posterior fracture-dislocations and Salter-Harris type 1 and 2 triradiate cartilage fractures. Less favourable results were seen in type 5 triradiate cartilage fractures and in comminuted fractures, but operation was no better. Unstable posterior fracture-dislocations and irreducible central fracture-dislocations need operative treatment but the results may still be unsatisfactory.

Operative treatment for acetabular fractures.

We report a retrospective study of 54 acetabular fractures treated by open reduction and internal fixation, with an average follow-up of 9.6 years (3 to 17). Reduction leaving displacement of less than or equal to 2 mm was achieved in 36 hips (67%); good or excellent functional results were obtained in 33 patients (61%). Early complications requiring re-operation included postoperative loss of reduction in one case and an intra-articular screw in another. Arthrodesis or total hip arthroplasty had been performed in 10 patients (19%) who had late symptomatic degenerative changes. Failure to obtain accurate reduction was the most important factor leading to a poor result, but heterotopic calcification caused poor results in seven patients, five of whom had had an anatomical reduction.

Anterior column fractures of the acetabulum.

We retrospectively reviewed 20 patients at three to 19 years after displaced anterior fracture-dislocations of the hip. Eighteen of them were treated by traction, after ensuring that the femoral head was adequately reduced beneath the undisrupted part of the weight-bearing dome. Two required operation. Although none of the 18 conservatively treated fractures was reduced anatomically, the results were good in ten patients and excellent in the seven in whom the fracture did not involve the weight-bearing dome. We conclude that anterior column fractures have a favourable prognosis after conservative treatment.