Psychiatric illness in patients with end-stage renal disease

The cause of hyperglycemia in extremely-low-birth-weight (ELBW) infants is not well understood. We studied infants weighing <1,000 g to investigate the relationship of hyperglycemia to blood levels of insulin-like growth factor (IGF)-I and IGF-II. We also compared two methods of treatment for hyperglycemia: continuous insulin infusion and reduction of glucose intake. Fifty-six ELBW infants were enrolled on day 2 of life. Intravenous glucose intake was increased incrementally to a maximum of 12 mg/kg/min on day 6. Infants who developed hyperglycemia were randomly assigned to receive reduced glucose intake (n = 11) or insulin infusion (n = 12). Infants whose blood sugar remained normal served as controls (n = 33). Blood was drawn on days 3, 8 and 15 in all infants, and again when they developed hyperglycemia. Nutritional intake and laboratory results for the treatment groups were compared with controls. Hyperglycemic infants had lower birth weights than controls. Hyperglycemic infants treated with glucose reduction remained <60 kcal/kg/day longer than control or insulin infusion groups (8.6 +/- 1.3 days vs. 4.1 +/- 0.2 and 5.5 +/- 0.6 days). No infants became hypoglycemic during insulin infusion. There was no difference in baseline blood levels of IGF-I or IGF-II among the groups, and these growth factors did not change in response to hyperglycemia. Hyperglycemic infants had baseline levels of insulin which were similar to normal controls, and endogenous insulin increased in response to hyperglycemia in 15 of the 23 infants who developed hyperglycemia. IGF-I and IGF-II are not related to hyperglycemia. In our population, hyperglycemic infants did not have baseline insulin deficiency and most had a normal insulin response to hyperglycemia. Insulin infusion appears safe in these infants and helped to maintain normal caloric intake, whereas glucose reduction was associated with a prolonged caloric deprivation.     

Immunologic function and survival in hemodialysis patients

Human immunodeficiency virus type 1 integrase (HIV-1 IN) which catalyzes viral DNA integration into the host genome of infected cells represents an attractive target for AIDS therapy. We have previously demonstrated the ability of the IN-(147-175)-peptide derived from the catalytic core domain of HIV-1 IN to inhibit the enzyme activity in vitro. IN-(147-175)-peptide contains four heptad repeats and displays a high propensity for coiled-coil formation while its [P159]IN-(147-175)-peptide analog (Lys159-->Pro in the protein, Lys13-->Pro in the peptide) is unable to form a stable coiled-coil and is devoid of inhibitory activity [Sourgen, F., Maroun, R. G., Frère, V., Bouziane, M., Auclair, C., Troalen, F. & Fermandjian, S. (1996) Eur. J. Biochem. 240, 765-773]. Now, we report results from an NMR study on IN-(147-175)-peptide and [P159]IN-(147- 175)-peptide as well as on an optimized [E156, A163, A167]IN-(147-175)-peptide that is a better inhibitor of IN than IN-(147-175)-peptide. While in aqueous solution, IN-(147-175)-peptide and [P159]IN-(147-175)-peptide display only nascent helical features, [E156, A163, A167]IN-(147-175)-peptide exhibits 20% of helical content. In 20% trifluoroethanol/80% H2O, the helix content is the highest for [E156, A163, A167]IN-(147-175)-peptide (approximately 70%) and the lowest for [P159]IN-(147-175)-peptide (approximately 40%), due to a local helix break caused by the Pro residue. The NHs of residues in the two central helical heptads (a-g) of IN-(147-175)-peptide and [E156, A163, A167]IN-(147-175)-peptide display a regular periodic variation of their temperature coefficients in 20% trifluoroethanol. The b, c and f residues on the hydrophilic face of the amphipathic helix show high coefficients reflecting hydrogen bonded NHs, while the a and d residues on the hydrophobic face exhibit low coefficients, near random-coil values. The particular arrangement of the hydrophobic side-chains of a and d residues at the coiled-coil interface reduces the access of trifluoroethanol molecules to their amide groups. The inability of trifluoroethanol molecules to create interactions with the amide C=O groups, these being required to strengthen the intrahelical C=O...H-N hydrogen bonds, is the main cause for observation of heptadic a and d residues with low NH temperature coefficients. Such effects concern mostly the two central helical heptads of IN-(147-175)-peptide and [E156, A163, A167]IN-(147-175)-peptide implying that these ones are engaged in stable parallel coiled coils. Our results provide a link between the propensity of peptides for helix formation, their coiled-coil properties and their efficiency to inhibit IN.     

Recombinant respiratory syncytial virus (RSV) bearing a set of mutations from cold-passaged RSV is attenuated in chimpanzees

A set of five missense mutations previously identified by nucleotide sequence analysis of subgroup A cold-passaged (cp) respiratory syncytial virus (RSV) has been introduced into a recombinant wild-type strain of RSV. This recombinant virus, designated rA2cp, appears to replicate less efficiently in the upper and lower respiratory tracts of seronegative chimpanzees than either biologically derived or recombinant wild-type RSV. Infection with rA2cp also resulted in significantly less rhinorrhea and cough than infection with wild-type RSV. These findings confirm the role of the cp mutations in attenuation of RSV and identify their usefulness for inclusion in future live attenuated recombinant RSV vaccine candidates.     

Enzyme replacement therapy for murine mucopolysaccharidosis type VII leads to improvements in behavior and auditory function

Mucopolysaccharidosis type VII (MPS VII; Sly syndrome) is one of a group of lysosomal storage diseases that share many clinical features, including mental retardation and hearing loss. Lysosomal storage in neurons of the brain and the associated behavioral abnormalities characteristic of a murine model of MPS VII have not been shown to be corrected by either bone marrow transplantation or gene therapy. However, intravenous injections of recombinant beta-glucuronidase initiated at birth reduce the pathological evidence of disease in MPS VII mice. In this study we present evidence that enzyme replacement initiated at birth improved the behavioral performance and reduced hearing loss in MPS VII mice. Enzyme-treated MPS VII mice performed similarly to normal mice and significantly better than mock- treated MPS VII mice in every phase of the Morris Water Maze test. In addition, the auditory function of treated MPS VII mice was dramatically improved, and was indistinguishable from normal mice. These data indicate that some of the learning, memory, and hearing deficits can be prevented in MPS VII mice if enzyme replacement therapy is initiated early in life. These data also provide functional correlates to the biochemical and histopathological improvements observed after enzyme replacement therapy.     

Comparison of the levels of intra-specific genetic variation within Giardia muris and Giardia intestinalis

The extent of intra-specific genetic variation between isolates of Giardia muris was assessed by allozyme electrophoresis. Additionally, the levels of allozymic variation detected within G. muris were compared with those observed between members of the two major assemblages of the morphologically distinct species Giardia intestinalis. Four isolates of G. muris were analysed. Three (Ad-120, -150, -151) were isolated from mice in Australia, while the fourth (R-T) was isolated from a golden hamster in North America. The 11 isolates of G. intestinalis (Ad-1, -12, -2, -62, representing genetic Groups I and II of Assemblage A and BAH-12, BRIS/87/HEPU/694, Ad-19, -22, -28, -45, -52, representing genetic Groups III and IV of Assemblage B) were from humans in Australia. Intra-specific genetic variation was detected between G. muris isolates at four of the 23 enzyme loci examined. Similar levels of variation were found within the genetic groups that comprise Assemblages A and B of G. intestinalis. These levels of intra-specific variation are similar to those observed within other morphologically-distinct species of protozoan parasites. We suggest that the magnitude of the genetic differences detected within G. muris provides an indication of the range of genetic variation within other species of Giardia and that this can be used as a model to delineate morphologically similar but genetically distinct (cryptic) species within this genus.     

Elevation of extracellular cortical noradrenaline may contribute to the antidepressant activity of zotepine: an in vivo microdialysis study in freely moving rats

The antipsychotic, zotepine, as well as possessing affinity for dopamine D1- and D2-1ike receptors, has high affinity for the noradrenaline (NA) transporter and inhibits [3H]NA uptake by rat frontal cortex synaptosomes, in vitro. The present studies investigated the effects of zotepine on extracellular NA in the frontal cortex of freely moving rats using in vivo microdialysis. Removal of calcium from the perfusate reduced extracellular NA by 70.5% and prevented the 50 mM KCl-stimulated increase in NA levels. Zotepine (0.5-1.5 mg kg(-1) i.p.), evoked biphasic, dose-dependent rises in extracellular NA with maximal increases observed at 60 min (+ 171.0%) and 240 min (+ 211.5%) post-treatment. The increases in NA levels were sustained for up to 100 min post-dosing. Clozapine (10.0 mg kg(-1) i.p.), resulted in a smaller, transient increase in NA levels (+ 72.0%) which lasted for 20 min post-treatment. Neither ziprasidone (3.0 mg kg(-1) i.p.) nor olanzapine (1.0 mg kg(-1) i.p.) influenced extracellular NA. Systemic treatment with the antidepressant desipramine (0.3 mg kg(-1) i.p.) resulted in a prolonged elevation of NA levels over 240 min (maximal increase of + 354.3%), whilst local infusion of nisoxetine (1-100 microM) through the dialysis probe increased NA levels in a concentration-dependent manner (up to 587.8% of control values). These data suggest that the inhibition of NA uptake by zotepine and its subsequent prolonged elevation of extracellular cortical NA may underlie the reported antidepressant properties of zotepine in schizophrenic patients.     

Deep venous thrombosis in a patient with superficial thrombophlebitis. Apropos of 2 cases]

Many schools refer children who have sustained an injury, directly to the local Accident & Emergency (A&E) department. This prospective study monitored these referrals for one school term (08.01.96-31.03.96). During this time 200 children under the age of 14 years presented from school to the A&E department of the Royal Aberdeen Childrens Hospital (RACH). The majority presented with trivial or mild injuries and 45% of parents felt that attending A&E was inappropriate. Half the accidents happened to unsupervised children. Rural children and children of working parents were less likely to attend A&E. In Grampian Region school referrals to A&E generate a significant workload for the A&E department with resultant cost implications. It would appear that a large number of these attendances are medically unnecessary and result from a desire by the school to avoid any complaint or litigation.     

Identification and molecular cloning of a unique hyaluronan synthase from Pasteurella multocida

Type A Pasteurella multocida, a prevalent animal pathogen, employs a hyaluronan [HA] polysaccharide capsule to avoid host defenses. We utilized transposon insertional mutagenesis to identify the P. multocida HA synthase, the enzyme that polymerizes HA. A DNA fragment from a wild-type genomic library could direct HA production in vivo in Escherichia coli, a bacterium that normally does not produce HA. Analysis of truncated plasmids derived from the original clone indicated that an open reading frame encoding a 972-residue protein was responsible for HA polymerization. This identification was confirmed by expression cloning in E. coli; we observed HA capsule formation in vivo and detected activity in membrane preparations in vitro. The polypeptide size was verified by photoaffinity labeling of the native P. multocida HA synthase with azido-UDP sugar analogs. Overall, the P. multocida sequence is not very similar to the other known HA synthases from streptococci, PBCV-1 virus, or vertebrates. Instead, a portion of the central region of the new enzyme is more homologous to the amino termini of other bacterial glycosyltransferases that produce different capsular polysaccharides or lipopolysaccharides. In summary, we have discovered a unique HA synthase that differs in sequence and predicted topology from the other known enzymes.     

Boron neutron capture therapy: re-irradiation response of the rat spinal cord

PURPOSE: To examine factors that influenced, positively or negatively, the specialty career choices of physicians trained at Yale-New Haven Hospital (YNHH) from 1929 to 1994. METHOD: The authors sent questionnaires to 4,888 physicians who had trained or were training in YNHH-sponsored residency programs. The physicians rated 36 factors posited to be influenced in career choice on a seven-point Likert scale from very negative to very positive. The authors compared the means of each factor's ratings by decade of medical school graduation. RESULTS: The most positively rated influences were similar in each decade from the 1920s to the 1990s. These influences shared characteristics of intellectual curiosity ("intellectual content of the specialty" and "challenging diagnostic problems"), altruism ("interest in helping people" and "opportunity to make differences in people's lives"), and personal identity ("consistent with personality" and "possess the required skill or ability"). Negative factors, such as "demands on time and effort," "stress in the field," and "malpractice costs," were also consistently rated throughout the decades. CONCLUSION: The reasons that physicians choose certain specialty careers have not changed significantly over the past 65 years despite all the changes that have occurred in medicine. Physicians continue to seek professional opportunities that are viewed as intellectually challenging and of benefit to others.