Growth hormone resistance and somatomedins in children with end-stage liver disease awaiting transplantation

Background: The success of orthotopic liver transplantation as treatment for end-stage liver disease has prompted investigation of strategies to maintain or improve nutrition and growth in children awaiting transplantation, because malnutrition is an adverse prognostic factor. The purpose of this study was to evaluate the effect of recombinant human growth hormone therapy on body composition and indices of liver function in patients awaiting transplant. Methods: The study was designed as a placebo- controlled, double-blind, crossover trial. Patients received 0.2 U/kg growth hormone, subcutaneously, or placebo daily for 28 days during two treatment periods, separated by a 2-week washout period. Ten patients (mean age, 3.06 ± 1.15 years; range, 0.51-11.65 years, five men), with extrahepatic biliary atresia (n = 8) or two with Alagille's syndrome (n = 2), with end-stage liver disease, completed the trial while awaiting orthotopic liver transplantation. Height, weight, total body potassium, total body fat, resting energy expenditure, respiratory quotient, hematologic and multiple biochemical profile, number of albumin infusions, insulin-like growth factor-1 and 1, growth hormone binding protein (GHBP), and insulin-like growth factor binding protein-1 (IGFBP-1) and insulin-like growth factor binding protein (IGFBP-3) were measured at the beginning and end of each treatment period. Results: Growth hormone treatment was associated with a significant decline in serum bilirubin (-34.6 ± 16.5 μmol/l vs. 18.2 ± 11.59 μmol/l; p < 0.02) but there was no significant effect on any anthropometric or body composition measurements, or on any biochemical or hematologic parameters. Conclusions: These children with end-stage liver disease displayed growth hormone resistance, particularly in relation to the somatomedin axis. Exogenous growth hormone administration may be of limited value in these patients

Studies of water and electrolyte movement from oral rehydration solutions (rice- and glucose-based) across a normal and secreting gut using a dual isotope tracer technique in a rat perfusion model

Aims: To establish a model to measure bidirectional flow of water from a glucose oral rehydration solution (G-ORS) and a newly developed rice-based oral rehydration solution (R-ORS) using a dual isotope tracer technique in a rat perfusion model. To measure net water, sodium and potassium absorption from the ORS. Methods: In viva steady-state perfusion studies were carried out in normal and secreting (induced by cholera toxin) rat small intestine (n = 11 in each group). To determine bidirectional flow of water from the ORS the animals were initially labelled with tritium, and deuterium was added to the perfusion solution. Sequential perfusate and blood samples were collected after attainment of steady-state conditions and analysed for water and electrolyte content. Results: There was a significant increase in net water absorption from the R-ORS compared to the G-ORS in both the normal (P < 0.02) and secreting intestine (P < 0.05). Water efflux was significantly reduced in the R-ORS group compared to the G-ORS group in both the normal (P < 0.01) and the secreting intestine (P < 0.01). There was an increase in sodium absorption in the R-ORS group compared to the G-ORS. The G-ORS produced a significantly greater blood glucose level at 75 min compared to the R-ORS (P < 0.03) in the secreting intestine. Conclusions: This study demonstrates the improved water absorption from a rice-based ORS in both the normal and secreting intestine. Evidence that the absorption of water may be influenced by the osmolality of the ORS was also demonstrated.

A New Method For The Generation Of 5,6-Quinolinedione 5-Methide .5. Synthesis Of Polycyclic Heteroaromatics

Reaction of 6-acetoxy-5-bromomethylquinoline (1c) and 2-bromomethyl-4-(2'-pyridyl)phenyl acetate (2b) with tetrachlorocatechol in acetone in the presence of anhydrous potassium carbonate resulted in the formation of diastereomeric products 3c, 3d, 4e and 4f.

Ultrasonic Degradation of Poly(acrylic acid)

The ultrasonic degradation of poly(acrylic acid), a water-soluble polymer, was studied in the presence of persulfates at different temperatures in binary solvent Mixtures of methanol and water. The degraded samples were analyzed by gel permeation chromatography for the time evolution of the molecular weight distributions. A continuous distribution kinetics model based on midpoint chain scission was developed, and the degradation rate coefficients were determined. The decline in the rate of degradation of poly(acrylic acid) with increasing temperature and with an increment in the methanol content in the binary solvent mixture of methanol and water was attributed to the increased vapor pressure of the solutions. The experimental data showed an augmentation of the degradation rate of the polymer with increasing oxidizing agent (persulfate) concentrations. Different concentrations of three persulfates-potassium persulfate, ammonium persulfate, and sodium persulfate-were used. It was found that the ratio of the polymer degradation rate coefficient to the dissociation rate constant of the persulfate was constant. This implies that the ultrasonic degradation rate of poly(acrylic acid) can be determined a priori in the presence of any initiator.

Impressive Gelation in Organic Solvents by Synthetic, Low Molecular Mass, Self-Organizing Urethane Amides of L-Phenylalanine

Synthetic routes leading to 12 L-phenylalanine based mono- and bipolar derivatives (1-12) and an in-depth study of their structure-property relationship with respect to gelation have been presented. These include monopolar systems such as N-[(benzyloxy)carbonyl]-L-phenylalanine-N-alkylamides and the corresponding bipolar derivatives with flexible and rigid spacers such as with 1,12-diaminododecane and 4,4'-diaminodiphenylmethane, respectively. The two ends of the latter have been functionalized with N-[(benzyloxy)carbonyl]-L-phenylalanine units via amide connection. Another bipolar molecule was synthesized in which the middle portion of the hydrocarbon segment contained polymerizable diacetylene unit. To ascertain the role of the presence of urethane linkages in the gelator molecule protected L-phenylalanine derivatives were also synthesized in which the (benzyloxy)carbonyl group has been replaced with (tert-butyloxy)carbonyl, acetyl, and benzoyl groups, respectively. Upon completion of the synthesis and adequate characterization of the newly described molecules, we examined the aggregation and gelation properties of each of them in a number of solvents and their mixtures. Optical microscopy and electron microscopy further characterized the systems that formed gels. Few representative systems, which showed excellent gelation behavior was, further examined by FT-IR, calorimetric, and powder X-ray diffraction studies. To explain the possible reasons for gelation, the results of molecular modeling and energy-minimization studies were also included. Taken together these results demonstrate the importance of the presence of (benzyloxy)carbonyl unit, urethane and secondary amide linkages, chiral purities of the headgroup and the length of the alkyl chain of the hydrophobic segment as critical determinants toward effective gelation.

Nutritional support in children with end-stage liver disease : a randomized crossover trial of a branched-chain amino acid supplement

Malnutrition is common in children with end-stage liver disease (ESLD) awaiting orthotopic liver transplantation (OLT), and nutritional support is assuming an important role in preoperative management. To evaluate preoperative nutritional therapy, 19 children (median age 1.25 y) with ESLD awaiting OLT were prospectively studied. Two high-energy, isoenergetic and isonitrogenous nutritional formulations delivered nasogastrically were compared: a branched-chain amino acid (BCAA)-enriched semielemental formulation and a matched standard semielemental formulation. Twelve of 19 patients completed a randomized controlled study before OLT and 10 of 19 completed a full crossover study. Improvements in weight and height occurred during the BCAA supplements, with no statistical change on the standard formulation. Significant increases in total body potassium, midupper arm circumference, and subscapular skinfold thickness occurred during the BCAA supplements, whereas no significant changes occurred during the standard formulation period. Significantly fewer albumin infusions were required during the BCAA supplement. These findings suggest that BCAA-enriched formulas have advantages over standard semielemental formulas in improving nutritional status in children with ESLD. and are deserving of wider application and study.

Purification and functional characterization of type II DNA topoisomerase from rat testis and comparison with topoisomerase II from liver

A number of studies in yeast have shown that DNA topoisomerase TI is essential for chromosome condensation and disjunction during mitosis at the metaphase/anaphase transition and meiosis I. Accordingly, kinetic and mechanistic studies have implied a role for topoisomerase rr in chromosome disjunction. As a step toward understanding the nature and role of topoisomerase II in a mammalian germline in vivo, we have purified topoisomerase II from rat testis to homogeneity and ascertained several of its catalytic activities in conjunction with that of the purified enzyme from liver. The purified enzymes appeared to be monomers under denaturing conditions; however, they differed in their relative molecular mass. Topoisomerase II from testis and liver have apparent molecular masses of 150 +/- 10 kDa and 160 +/- 10 kDa, respectively. The native molecular mass of testis topoisomerase II as assayed by immunoblot analysis of cell-foe extracts, prepared in the presence of SDS and a number of protease inhibitors, corroborated with the size of the purified enzyme. Both enzymes are able to promote decatenation and relax supercoiled DNA substrates in an ATP and Mg2+-dependent manner. However, quantitative comparison of catalytic properties of topoisomerase II from testis with that of the enzyme from liver displayed significant differences in their efficiencies. Optimal pH values for testis enzyme are 6.5 to 8.5 while they are 6 to 7.5 for the liver enzyme. Intriguingly, the relaxation activity of liver topoisomerase II was inhibited by potassium glutamate at 1 M, whereas testis enzyme required about half its concentration. These findings argue that topoisomerase II from rat testis is structurally distinct from that of its somatic form and the functional differences between the two enzymes parallels with the physiological environment that is unique to these two tissues.

The nature of malnutrition in children with end-stage liver disease awaiting orthotopic liver transplantation

To evaluate malnutrition in chronic liver disease, and its relationship to nutrient deficiencies and hepatic dysfunction. 27 children with end-stage liver disease were studied. Mean protein-energy intakes were 70% of recommended daily intakes. The patients were underweight and stunted with reduced mean triceps and subscapular skinfold thicknesses and midupper arm circumference. Mean total body potassium was only 63 ± 18% of that expected for age and sex. Deficiency of essential fatty acids (32%), and low concentrations of fat-soluble vitamins (A, 92%; E, 32%), iron (32%), zinc (42%), and selenium (13%) were common. Serum ammonia concentrations were raised in all patients, and increased methionine, tyrosine, and glutamic acid, and reduced glutamine concentrations were noted. There was no correlation between the degree of malnutrition and the degree of liver synthetic function, the degree of cholestasis, or the degree of liver injury. We suggest that potentially correctable factors in addition to liver failure (eg, inadequate absorbed intake) were important determinants of malnutrition in these patients.

Malnutrition in children with chronic liver disease accepted for liver transplantation : clinical profile and effect on outcome

The nutritional profiles of 37 children (aged 0.5-14.0 years) with chronic liver disease at the time of acceptance for orthotopic liver transplantation (OLTP) have been evaluated using clinical, biochemical and body composition methods. Nutritional progress while waiting for a donor has been related to outcome, whether transplanted or not. At the time of acceptance, most children were underweight (mean standard deviation (s.d.) weight = -1.4 ± 0.2) and stunted (mean s.d. height = - 2.2 ± 0.4), had low serum albumin (27/35) and had reduced body fat and depleted body cell mass (measured by total body potassium - mean % expected for age = 58 ± 5%, n = 15). Mean ad libitum nutrient intake was 63 ± 5% of recommended daily intake (RDI). Those who died while waiting (n = 8) had significantly lower mean initial s.d. weight compared with those transplanted. The overall actuarial 1 year survival of those who were transplanted (mean waiting time = 75 days) was 81% but those who were initially well nourished (s.d. weight >-1.0) had an actuarial 1 year survival of 100%. There were no significant differences in actuarial survival in relationship to age, type of transplant (whole liver or segmental), liver biochemistry or the presence or absence of ascites. Of the total group accepted for OLTP, whether transplanted or not, the overall 1 year survival for those who were relatively well nourished was 88% and for those undernourished (initial s.d. weight <-1.0) was 38% (P<0.003). Declining nutritional status during the waiting period also adversely affected outcome. We conclude that malnutrition and/or declining nutritional status is a major factor adversely affecting survival in children awaiting OLTP. In transplant units where waiting time is greater than 40 days, earlier referral, prioritization of cases and the use of adult donor livers may reduce this risk and efforts to maintain or improve nutritional status deserve further study.

Structure of nonactin-calcium perchlorate, C40H64O12.Ca(ClO4)2, and a comparative study of metal-nonactin complexes

M r= 975.9, orthorhombic, Pnna, a = 20.262 (3), b= 15.717 (2), c= 15.038 (1)A, V= 4788.97 A 3, z = 4, D x = 1.35 Mg m -3, Cu Kct radiation, 2 = 1.5418 A, /t = 2.79 mm -1, F(000) -= 2072, T = 293 K, R = 0.08, 3335 observed reflections. The molecular structure and the crystal packing are similar to those observed in the nonactin complexes of sodium thiocyanate and potassium thiocyanate. The eight metal-O distances are nearly the same in the potassium complex whereas the four distances involving carbonyl O atoms are shorter than the remaining four involving the tetrahydrofuran-ring O atoms in the Na and the Ca complexes. This observation can be explained in terms of the small ionic radii of Na + and Ca 2+, and leads to a plausible structural rationale for the stronger affinity of nonactin for K + than for the other two metal ions.

Short-lived triplets of aliphatic thioketenes

The photophysical behavior of the triplets of three aliphatic thioketenes, namely di-tert-butylthioketene (1), 2,6-di-tert-butylcyclohexylthioketene (2) and 2,2,6,6-tetramethylcyclohexylthioketene, has been studied in fluid solutions at room temperature by nanosecond laser flash photolysis. Upon 532 nm laser excitation into the S1 state, the thioketenes in concentrated benzene solutions produce very short-lived transient absorptions (τ < 5 ns; λmax ≈ 450 nm) attributable to their triplets. The photogeneration of the latter under S1 excitation has also been established by energy transfer to all-trans-1,6-diphenyl-1,3,5-hexatriene. The factors which render the triplet lifetimes short are shown to be intrinsic in origin (rather than self-quenching). Unlike thiocarbonyl compounds in general, the thioketenes posses low intersystem crossing yields (less than 0.1 in benzene). From the kinetics of the quenching of a series of sensitizer triplets by 1 and 2, the thioketene triplet energies are estimated to be 43 – 44 kcal mol−1.

Evaluation of growth and changes in body composition following neonatal diagnosis of cystic fibrosis

Early deficits in nutritional status that might require specific treatment and early response to nutritional therapy were studied longitudinally in 25 infants with cystic fibrosis (CF) diagnosed by neonatal screening, using anthropometric and research body composition methodology, and evaluation of pancreatic function. At the time of confirmed diagnosis (mean 5.4 weeks), body mass, length, total body fat (TBF), and total body potassium (TBK) were all significantly reduced. Following diagnosis and commencement of therapy there was a normalization of weight, length, and TBK by 6-12 months of age, indicating catch-up growth. But in some individuals the response was incomplete, and as a group, mean total body fat remained significantly lower than normal at 1 year of age. Seven of 25 (28%) were pancreatic sufficient at diagnosis, and all but one had evidence of declining pancreatic function requiring the institution of pancreatic enzyme therapy during the next 1-9 months. The median age of commencement of enzyme therapy was 10 weeks (range 5 weeks to 11 months). These longitudinal assessments emphasize the dynamic changes occurring in absorptive function, body composition, and nutritional status following neonatal diagnosis of cystic fibrosis and may reflect previously described abnormalities of energy metabolism in this age group. Abnormal body composition is evident in most CF infants following diagnosis by neonatal screening but pancreatic damage may still be evolving. We suggest that early active nutritional therapy and surveillance for changes in pancreatic function are warranted in CF infants diagnosed by neonatal screening.

Body composition studies in cystic fibrosis and myelomeningocele

One of the major considerations of improving the management of many chronic diseases has been the realisation of the importance of nutrition, and, in children, the maintenance of normal growth. Cystic Fibrosis (CF) and Myelomeningocele (MMC) are two such disease states in which nutritional status has a significant effect on morbidity.

A laser flash photolysis study of pivalothiophenone triplets: steric and electronic effects in thione photoreaction kinetics

Upon laser pulse excitation (Aex = 532 nm) into the lowest-lying '(n,a*) band system, pivalothiophenones in benzene solutions give rise to short-lived triplets (Ama: = 325-335 nm, em: = (1 1-15) X lo3 M-' cm-I) with quantitative intersystem crossing efficiencies. The triplet yields decrease slightly (by 10-30%) upon changing A, to 308 nm (Le., upon excitation into S2). Kinetic data are presented for intrinsic triplet lifetimes, self-quenching, and quenching by oxygen, di-tert-butylnitroxy radical, and various reagents capable of interacting with the triplets via energy, electron, or hydrogen-atom transfer and by biradical formation (possibly leading to cycloaddition). The mechanisms of the quenching processes are discussed. Relative to rigid aromatic thiones, namely, xanthione and thiocoumarin, the interaction of pivalothiophenone triplets with most of the quenchers are kinetically inefficient. This is interpreted primarily as a manifestation of the steric crowding at positions a to the thiocarbonyl group.

The Biosynthesis of Sesquiterpene Isocyanides and Isothiocyanates in the Marine Sponge Acanthella cavernosa (Dendy); Evidence for Dietary Transfer to the Dorid Nudibranch Phyllidiella pustulosa

The tropical marine sponge Acanthella cavernosa (Dendy) converts potassium [14C] cyanide to axisonitrile-3 (1); this precursor is also used for the synthesis of axisothiocyanate-3 (2) suggesting that isocyanides are precursors to isothiocyanates in A. cavernosa. Likewise, potassium [14C] thiocyanate is used for the synthesis of axisothiocyanate-3; unexpectedly this precursor also labelled axisonitrile-3. These results demonstrate either an interconversion between cyanide and thiocyanate prior to secondary metabolite formation or that the secondary metabolites can themselves be interconverted. Specimens of the dorid nudibranch Phyllidiellu pustulosa, preadapted to a diet of A. cavernosa, fed on 14C-labelled sponges and were subsequently found to contain the radioactive terpenes (1) and (2). Specimens of P. pustulosa, which had not expressed a dietary preference for A. cavernosa in the field, did not generally feed in aquarium tests with 14C-labelled sponges and, therefore, provided non-radioactive extracts. Since control experiments demonstrated the inability of P. pustulosa to synthesise the metabolites de novo, we therefore conclude that P. pustulosa acquires secondary metabolites by dietary transfer from A. cavernosa.