Asylum-Seeking Children with Medical Complexity and Rare Diseases in a Tertiary Hospital in Switzerland.

The aim of this study was to assess the characteristics of asylum-seeking children with medical complexity visiting a tertiary care hospital in Switzerland, detailing their underlying medical conditions and management. Asylum-seeking patients with frequent visits between January 2016 and December 2017 were identified using administrative and electronic health records. Of 462 patients, 19 (4%) fulfilled the inclusion criteria with 811 (45%) visits. The age of the 19 patients ranged from 0 to 16.7 years (median of 7 years) with two main age groups identified: < 2 years and > 12 years. Nine (47%) patients originated from Syria. A total of 34/811(4%) visits were hospital admissions, 66/811 (8%) emergency department visits and 320/811(39%) outpatient department visits. In children < 2 years genetic diseases (5/8; 63%) and nutritional problems (6/8; 75%) were most common; in adolescents, orthopedic diseases (4/8; 50%) and mental health problems (4/8; 50%). Asylum-seeking children with medical complexity represent a small but important group of patients requiring frequent medical consultations. The high proportion of young patients with genetic diseases and severe nutritional problems suggests that new strategies are required in the management of this specific group of asylum-seeking children. This could be achieved by improved co-ordination between hospital and non-hospital care exploring options for integrated care.

Dose dependency of canthaxanthin crystals in monkey retina and spatial distribution of its metabolites.

PURPOSE: To establish the threshold level of canthaxanthin crystals in the retina of cynomolgus monkeys. To correlate the spatial distribution of all-trans canthaxanthin and its metabolites with the grade of crystals. METHODS: Monkeys were orally administered 0, 0.2, 0.6, 1.8, 5.4, 16.2, and 48.6 mg/kg body wt canthaxanthin daily for 2.5 to 3 years. A second group of monkeys were administered 200 and 500 mg/kg body wt/d for 5 years. Ophthalmoscopy, electroretinography (ERG), retina and carotenoid analysis were performed as previously reported. RESULTS: Crystals in the retina periphery were observed by ophthalmoscopy preterminally only in the extreme high doses of 200 to 500 mg/kg body wt/d. There were no adverse effects on visual functions as measured by ERG. Crystals in the peripheral retina, and/or in the macula, were detected microscopically in all canthaxanthin treated groups except at the lowest dose of 0.2 mg/kg body wt/d. The grade of crystals increased up to a dose of 16.2 mg/kg body wt/d. Dose-dependent increases in canthaxanthin content also were noted in the retina, the liver, and in plasma. All-trans canthaxanthin was the major compound in the peripheral and paracentral retina of very highly dosed animals, where its concentration correlated largely with the grade of inclusions. In the macula, 4'-OH-echinenone was the dominant canthaxanthin metabolite. CONCLUSIONS: The grade of crystals in monkey retinas was dose dependent with a threshold level at 0.6 mg canthaxanthin/kg body wt/d. It correlated in the retinal periphery with the concentrations of all-trans-canthaxanthin and in the macula with its metabolites.

Occurrence of birefringent retinal inclusions in cynomolgus monkeys after high doses of canthaxanthin.

PURPOSE: To reproduce and investigate in a primate animal model the phenomenon of the red carotenoid canthaxanthin (beta, beta-carotene-4'4'-dione) to induce crystal-like retinal deposits as they have been observed in the ocular fundus of humans after high canthaxanthin intake (i.e., more than 30 mg/day). METHODS: Groups of four cynomolgus monkeys (Macaca fascicularis) per gender and dose were administered 5.4, 16.2, or 48.6 mg canthaxanthin/kg body weight daily by oral gavage for 2.5 years. Eight control animals received placebo. In vivo ophthalmoscopy was performed at intervals of 3 months along with electroretinography after 12 and 24 months and retinal biomicroscopy just before the monkeys were killed. Retinal wholemounts or frozen sections were investigated postmortem by polarization, bright field, and differential interference contrast microscopy. Retinal and preterminal plasma canthaxanthin concentrations were determined by high-performance liquid chromatography (HPLC). RESULTS: By ophthalmoscopy and retinal biomicroscopy in vivo, no crystals or other light-reflecting particles were observed in the central paramacular retina. However, postmortem polarization microscopy of all 24 canthaxanthin-treated animals showed a circular zone in the peripheral retina containing birefringent, polymorphous red, orange, or white inclusions. The density of these inclusions was diminished within 1 to 8 mm posterior to the ora serrata. These inclusions were located mainly in the inner retinal layers, that is the nerve fiber layer and ganglion cell layer, inner plexiform layer, and inner nuclear layer. Twelve of the 24 canthaxanthin-treated animals showed yellow, golden birefringent inclusions in the macula. Retinas of placebo-treated monkeys were free of birefringent, crystal-like inclusions. The HPLC confirmed the presence of all-trans canthaxanthin, and 4-OH-echinenone and isozeaxanthin as well, in the retinas of all canthaxanthin-treated animals. Neither electroretinography nor histopathology indicated any adverse effects of the canthaxanthin-induced retinal inclusions seen in this study. CONCLUSIONS: A high intake of canthaxanthin for 2.5 years led to the deposition of crystal-like birefringent inclusions in the inner layers of the peripheral retina and, to some extent, the central retina of cynomolgus monkeys. The presence of these deposits did not interfere with morphology nor with retinal function.

Retardation of spermiation following short-term treatment of rats with theobromine.

Groups of 4-6 Fü-albino rats were examined 24 h after 3 daily doses of 500 mg/kg bw of theobromine administered orally by gavage as well as 1, 2, 4, 6, and 10 weeks after 5 daily doses. Controls received the standard solvent vehicle (SSV) only. A variety of parameters were assessed including body and organ weights, serum clinical chemistry, hematological parameters, epididymal sperm motility and LDH-X fraction in seminal plasma, serum gonadotropins and testosterone, and the morphology of various organs. Testes were perfused with 5% glutaraldehyde and semi-thin sections were evaluated. The most striking morphological observation was a retarded release of late spermatids into the tubular lumen mainly 2 weeks post treatment. This partial disruption of the rigid spermatogenic synchronization was not followed by substantial germ cell death. The other parameters investigated remained relatively normal throughout the study. These observations suggest that theobromine at the dose tested rather selectively interferes with germ cell kinetics. Sertoli cell toxicity could account for these early and subtle effects as well as for the late and severe effects of subchronic exposure of rats to theobromine as reported in the literature.

Peptides isolated from human liver with specific inhibitory effects on reassociation/reactivation of in vitro dissociated lactic dehydrogenase (LDH-M4 and -H4) isozymes.

Two different peptides have been purified from human liver, similar to those previously reported (Schoenenberger, G.A., and Wacker, W.E.C. (1966) Biochemistry 5, 1375--1379) to be present in human urine, which may serve as metabolic regulators of lactate dehydrogenase (EC 1.1.1.27) isoenzymes (LDH-M4 = muscle type; LDH-H4 = heart type). By trichloroacetic acid precipitation, ultrafiltration, Sephadex G-25 and Bio-Gel P-2 columns, affinity chromatography on immobilized LDH-isozymes and HPLC two peptides which differed with respect to molecular weight, retention on the affinity columns and amino acid composition were isolated. No effect was observed when native, tetrameric lactate dehydrogenase was incubated with these peptides. However, when lactate dehydrogenase was dissociated to monomers at low pH and allowed to reassociate by adjusting the pH to 7.5 complete inhibition of the reactivation occurred when the inhibitors were incubated together with respective reassociating monomeric isozymes. The two peptides showed no cross-specificity, i.e. each peptide exhibited inhibitory activity only on one of the two isozymes LDH-M4 or LDH-H4. From the amino acid analyses, gel filtrations and PAGE + SDS, molecular weights of 1800 for the M4 and approximately 2700 for the H4 inhibitor were calculated. An apparent Ki of approximately 3 X 10(-5) mM for the H4 and approximately 7 X 10(-5) mM for the H4 inhibitor was estimated. The interaction of the inhibitors with the enzyme system showed strong cooperativity with Hill coefficients of 2.9 (LDH-M4-specific) and 2.4 (LDH-H4-specific). Mathematical modelling of the reassociation and reactivation of lactate dehydrogenase and its specific inhibition by the peptides led to the conclusion that the peptides react with monomers, dimers or a transition state during the tetramerisation process. kappa 1 for the dimerisation step of M4 = 2.0 X 10(5) M-1 . S-1 and of H4 = 8.2 X 10(4) M-1 . S-1; kappa 2 for the tetramerisation step of M4 = 2.8 X 10(5) M-1 . S-1 and of H4 = 1.2 X 10(5) . M-1 S-1, were calculated, the second step still being the faster one (Rudolf, R. and Jaenicke, R. (1976) Eur. J Biochem. 63, 409--417).

[Long-term observations on different methods of nephropexy]. / Langzeitergebnisse bei unterschiedlicher Nephropexietechnik.

In 29 patients with nephroptosis two different methods of nephropexy were compared; nephropexy using sutures passing through the parenchyma (n = 16) and nephropexy using tissue adhesives (n = 13). The first group was mobilized 3.5 days after operation, whereas the second group was mobilized one day after operation. On later follow-up 79% of the patients had no or minor complaints. Those patients who had the same disturbances as preoperatively had all been treated by nephropexy using sutures passing through the parenchyma. In 56% of this group radiological recurrence was seen, whereas in the group using tissue adhesives there was only 8% radiological recurrence. We think therefore that the nephroxepy using tissue adhesive is the simplest and least traumatic method.

Experimental approach to the correlation of hemodynamic changes with increases in urinary lactate dehydrogenase as a new parameter reflecting serious renal tissue damages.

From previous investigations with nephroptotic patients increased urinary LDH was assumed to be a reliable marker indicating a renal tissue defect due to the organs descent in erect position. Animal experiments now allowed correlation of this enzymatic activity with controlled changes of anatomical and physiological parameters. Changes of the renal hemodynamics or urinary flow induced in acute experiments in dogs simulated kidney displacement in nephroptotic patients. Both ureters were cannulated for separate urine collection and one kidney was manipulated. The renal arterial or venous flow was reduced or the ureter was occluded under electromagnetic blood-flow control. Arterial constriction alone (30%/15 min) selectively caused a drastic decrease (approximately 80%) of Xenon wash-out (= nutrient-flow) in the renal cortex. Under the same conditions radio-labeled microspheres injected intracardially showed a centralization of the renal capillary blood flow from the outer cortex to the juxtamedullary zone. Urinary LDH activities increased up to 800% immediately after arterial constriction. In accordance with total LDH activity the percentage distribution of isoenzymes changed: LDH-I increased and the LDH-V decreased. Neither constriction of the renal vein nor ureteral occlusion had similar effects. In long-term experiments backward fixation of one kidney in rats would reflect the effects of kidney displacement over years in nephroptotic patients: animals were unilaterally nephrectomized and the remaining kidney was dislocated backwards (approximately 2,5 vertebrae) and fixed to the lateral pelvic wall. "Ptotic" rats showed during the following examinations a constant increase of urinary LDH up to 50% by 26 weeks postoperatively. In accordance with increased LDH the isotope nephrogram was pathological and arteriographies showed a stretched and narrowed renal artery. In a number of rats "ptotic" fixation was not effective enough. All these animals showed normal LDH, isotope nephrograms and arteriographies. Both animal experiments documented that reduced flow/hypoxia is essentially responsible for the tissue damage in the kidney manifested by increased release of urinary LDH.

Diagnostic relevance of urinary lactate dehydrogenase determination in nephroptosis and for the indication to nephropexy.

Previously reported experiments with animals suggested that reduced renal arterial flow might be the actual cause for the pathogenicity of nephroptosis. Clinical studies now give evidence that measurements of urinary LDH may be a criterion equal to the isotope nephrogram (ING) in considering this disease. Patients with a "mobile" kidney verified by i.v. pyelography were examined by an ING and a 1-day test for urinary LDH. In accordance with periodic kidney displacement total urinary LDH activities were measured in a 8-h urine volume in the supine position and a 8-h urine volume in the erect position of the patients. Evaluations were all expressed as percentage increase of LDH activity of the patient in the erect versus supine position and correlated with his ING-pattern. Among 45 nephroptotic individuals 34 showed, in accordance with a pathological ING, a mean LDH increase of more than a 100%. Eleven individuals had normal INGs and less than 20% increase equal to a group of 16 normal controls. We postulated a 30% increase as the upper limit between normal and pathological urinary LDH. The percentage distribution of isoenzymes was also altered within the pathological LDH range: LDH-I, which increases in normal controls, now decreased in nephroptotic patients. LDH-IV and V, which decrease in controls, now increased. Homomeric isoenzymes obviously show reciprocal behavior. The degree of kidney descent in cm does not correlate with percentage increase of urinary LDH, i.e. it is not a criterion for pathogenicity. Biopsies taken during nephropexy revealed that from an anamnestic duration of 50 weeks onwards the kidney is significantly affected and tissue damages become evident. If patients were re-investigated after nephropexy they showed normal i.v. pyelograms and normal LDH and no longer had clinical symptoms.