Clinical manifestations of Pacak‐Zhuang syndrome in a male pediatric patient

We report an index case of a male patient who presented with all clinical manifestations of Pacak‐Zhuang syndrome, including early‐age polycythemia, multiple pheochromocytomas/paragangliomas, duodenal somatostatinoma, and ocular findings. Sequencing analysis detected an EPAS1 mutation in all tumors tested, but not in the germline.     

Research on medication use in the neonatal intensive care unit

Introduction: Research on medication use aims at assessing how much of current pharmacotherapy is rational. In neonates, this is hampered by extensive off-label drug use and limited knowledge.

Areas covered: We report on medication use research and have conducted a systematic review of observational studies on medication use to provide an updated overview on characteristics, objectives, methods, and patterns in hospitalized neonates. Moreover, a review on aspects of medication use for opioids, anti-epileptics, gastric acid-related disorders and respiratory stimulants with emphasis on trends and impact of interventions is presented, illustrating how research on medication use can contribute to improved neonatal pharmacotherapy and more focused research. Medication use reports describe patterns and provide signals on irrational use, benchmarking, or can guide research priorities. Moreover, this may generate information on how neonatal health topics and their pharmacotherapy are handled over time or across regions.

Expert opinion: Research on medicine utilization is relevant, since it will inform us on aspects like trends, variability, or about the impact and pattern of implementation of guidelines in neonates. Further progress necessitates to merge datasets on medication use with clinical characteristics, and perinatal drug use remains an area in need of additional research.     

Emergencies caused by pheochromocytoma, neuroblastoma, or ganglioneuroma.

Pheochromocytoma may lead to important emergency situations, ranging from cardiovascular emergencies to acute abdomen and multiorgan failure. It is vital to think about this disease in any emergency situation when conventional therapy fails to achieve control or symptoms occur that do not fit the initial diagnosis. The importance of keeping this diagnosis in minds is underscored by the fact that, in 50% of pheochromocytoma patients, the diagnosis is initially overlooked. Two other tumors of the sympathetic nervous system, neuroblastoma and ganglioneuroma, are less commonly associated with emergency conditions. If they occur, they are often linked to catecholamine excess, paraneoplastic phenomena, or local tumor mass effect.     

Cytochrome P450 3A4 and P-glycoprotein Activity and Assimilation of Tacrolimus in Transplant Patients with Persistent Diarrhea

Renal transplant recipients suffering from persistent diarrhea have been repeatedly reported to have increased tacrolimus (Tac) trough levels. This study aimed to explore this phenomenon in detail in 15 renal transplant recipients with diarrhea, whose immunosuppression consisted of corticosteroids, mofetil mycophenolate and Tac. Both hepatic and intestinal CYP3A4 and PGP activity, important determinants of Tac bioavailability, were assessed, together with global CYP activity and investigations for gastrointestinal infection, function and morphology. Global CYP, CYP3A4, PGP and trough/dose levels of Tac were compared with diarrhea-free controls. In addition, a pharmacokinetic study of Tac was performed in 11 patients affected by diarrhea versus 9 controls. As expected, diarrhea was associated with increased Tac trough levels. An even stronger, significant increase of dose-normalized Tac levels was observed between 90 and 360 min after Tac intake. Time to peak concentration and drug half-life, however, were not altered. In addition, a concomitant decrease (+/-50%) of intestinal PGP activity was noticed in patients with diarrhea. For global CYP, CYP3A4 and hepatic PGP activity no such differences were noted. This pattern was not influenced by the specific cause of diarrhea. These data strongly suggest that persistent diarrhea is associated with an increased oral bioavailability of Tac.     

The effect of liquid silicone on the corneal endothelium in rabbits

Specular microscopic and histopathologic findings in the corneal endothelium were compared after the injection of liquid silicone into the anterior chamber of both eyes in 15 rabbits. The findings demonstrated serious damage to the endothelium in the area of contact of liquid silicone with the posterior surface of the cornea and disclosed some problems in the interpretation of specular microscopic findings. An abnormal endothelial mosaic can be probably found even in a zone of preserved intercellular borders or in a zone with a relief of the bases of extinct endothelial cells.     

Polymerizable amphiphiles, 2. Micellization of 1-O-3-(4-vinylphenyl)propyl-β-D-glucopyranose

1-O-3-(4-Vinylphenyl)propyl-β-D -glucopyranose ( 1 ) undergoes in water a closed association under formation of N-mers. The unimer/N-mer association is directly visible in the Schlieren pattern of ultracentrifugal synthetic boundary experiments. Association numbers and mass-concentration-based equilibrium constants of association were calculated from the variation of N-mer concentrations with unimer concentrations and from the concentration dependence of inverse apparent average molar masses as measured by both vapor phase osmometry and sedimentation equilibrium. Association numbers were also calculated from the combination of sedimentation coefficients with diffusion coefficients, sedimentation coefficients with intrinsic viscosities, and diffusion coefficients with interinsic viscosities as well as from the dependence of apparent mass-average molar masses on inverse apparent number-average molar masses. All methods gave in general different association numbers and equilibrium constants. The effect, which was not found for other non-ionic amphiphiles, is probably due to the existence of consecutive equilibria between the unimer and a low molar mass P-mer which associates to a higher molar mass R-mer. Viscosity data are in agreement with the picture of a spherical micelle for the dominant P-mers with about 10 water molecules per glucose residue. The micellization of 1 is both enthalpy- and entropy-driven, in contrast to the micellization of 1-O-octyl-β-D -glucopyranose which is a strictly entropy-driven process.     

Treatment of diabetic polyneuropathy with the neurotrophic peptide ORG 2766

The efficacy of the neurotrophic peptide ORG 2766 in diabetic patients with polyneuropathy was evaluated in a double-blind, placebo-controlled, multicentre trial. One hundred and twenty four patients were randomised in five groups to receive 0.1, 0.4, 2 or 5 mg ORG 2766 or placebo, once daily, administered subcutaneously 52 weeks. Thermal discrimination thresholds (TDT) and vibration perception thresholds (VPT), motor and sensory nerve conduction velocity, Hoffmann reflex, heart rate variation during deep breathing and heart rate response after standing up, neurological examination score and neuropathic symptom score were determined at baseline and after 17, 34 and 52 weeks of treatment. Of the nerve function indices studied, at week 52 the TDT_warmth of the hand in the ORG 2766 0.1, 0.4 and 5 mg groups and the TDT_cold of the foot in the ORG 2766 0.1 and 0.4 mg groups significantly improved compared with placebo. Further significant improvement as compared with placebo was observed in the paraesthesia score at week 34 and week 52 in the ORG 2766 2 mg group. Only at week 34 had both the heartbeat variation during deep breathing and the VPT of the foot in the ORG 2766 0.1 mg group improved significantly, compared with placebo. No further statistically significant differences were observed at time for the other measures. No adverse reactions were observed. The only recorded drug-induced side effect was pain at the injection site. Taking all measures of efficacy into account, the statistically significant results observed did not show consistency within each measure. Therefore, it is concluded that ORG 2766, in contrast to earlier reports, is not effective in treating diabetic polyneuropathy.     

Effect of silymarin and its polyphenolic fraction on cholesterol absorption in rats.

This study evaluated the influence of silymarin (SM) and polyphenolic fraction (PF) of silymarin on cholesterol absorption in rats fed on high cholesterol diet (HCD). HCD induced a remarkable increase in hepatic, plasma, VLDL and LDL cholesterol, a decrease in HDL cholesterol and an elevation in triacylglycerol (TAG) levels in plasma, VLDL and in the liver. SM and PF were administered as dietary supplements (1.0%) in HCD for 18 days. Intestinal cholesterol absorption was measured by dual-isotope plasma ratio method, which calculates percent of cholesterol absorption from the ratio of two labelled cholesterol doses, one given intragastrically (14C) and one intravenously (3H). Silymarin and PF significantly reduced cholesterol absorption in rats fed on HCD and caused significant decreases in plasma and VLDL cholesterol and content of cholesterol and TAG in the liver. The level of HDL cholesterol was significantly increased after silymarin, but not after administration of PF. The levels of TAG in plasma and VLDL were not affected by either silymarin or PF. These results suggest that the inhibition of cholesterol absorption caused by silymarin and its polyphenolic fraction could be a mechanism contributing to the positive changes in plasma cholesterol lipoprotein profile and in lipid content in liver.     

Cytostatic and immunomobilizing activities of polymer-bound drugs: experimental and first clinical data.

An N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carrier containing doxorubicin and human immunoglobulin as an actively/passively targeting moiety was used in four patients with generalized breast cancer resistant to standard cytotoxic chemotherapy. The dose and time schedule were deduced from a Phase I clinical trial in which doxorubicin bound to HPMA copolymer carrier (PK1) was tested. It was confirmed that the Dox-HPMA-HuIg conjugate is stable and doxorubicin remains in the peripheral blood with a small amount also in the urine, mostly in its polymer-bound form. More than 116 biochemical, immunological and hematological parameters were determined for blood samples taken from patients 24 h, 48 h, 72 h and 1 to 11 weeks after treatment. Depending on the patient, some parameters decreased permanently or temporarily to the normal level (CRP, C3, CA 72-4, beta(2)-microglobulin, ferritin, CEA, CA 125, CD4, CD8, CE19, CD16(+)56(+), leu, ery) and some moved markedly towards physiological values (AST, ALT, ALP, GMT, CA 15-3, NSE, AFP). While the number of peripheral blood reticulocytes was significantly decreased after treatment with the classical free drug, their number was not affected or was even elevated after treatment with Dox-HPMA-HuIg. Increased absolute numbers of CD16(+)56(+) and CD4(+) cells in the peripheral blood and activation of NK and LAK cells in all patients support data obtained in experimental animals, pointing to a dual, i.e. cytostatic and immunomobilizing character of Dox-HPMA conjugates containing a targeting immunoglobulin moiety.