Recent advances in genetic research on schizophrenia

Evidence for genetic factors in schizophrenia is reviewed with regard to family, twin and adoption studies, and recent advances in molecular genetic technology are applied to explore possible gene loci susceptible to schizophrenia. Application of neuropsychological and neuroimaging methodologies are also reviewed with an aim to develop criteria for defining phenotypes for genetic studies.Plenary Session, Twelfth Joint Annual Conference of Biomedical Sciences, April 20, 1997, Taipei, Taiwan.     

Enzymatic determinants of the substrate specificity of CYP2C9: role of B'-C loop residues in providing the pi-stacking anchor site for warfarin binding

Previous modeling efforts have suggested that coumarin ligand binding to CYP2C9 is dictated by electrostatic and pi-stacking interactions with complementary amino acids of the protein. In this study, analysis of a combined CoMFA-homology model for the enzyme identified F110 and F114 as potential hydrophobic, aromatic active-site residues which could pi-stack with the nonmetabolized C-9 phenyl ring of the warfarin enantiomers. To test this hypothesis, we introduced mutations at key residues located in the putative loop region between the B' and C helices of CYP2C9. The F110L, F110Y, V113L, and F114L mutants, but not the F114Y mutant, expressed readily, and the purified proteins were each active in the metabolism of lauric acid. The V113L mutant metabolized neither (R)- nor (S)-warfarin, and the F114L mutant alone displayed altered metabolite profiles for the warfarin enantiomers. Therefore, the effect of the F110L and F114L mutants on the interaction of CYP2C9 with several of its substrates as well as the potent inhibitor sulfaphenazole was chosen for examination in further detail. For each substrate examined, the F110L mutant exhibited modest changes in its kinetic parameters and product profiles. However, the F114L mutant altered the metabolite ratios for the warfarin enantiomers such that significant metabolism occurred for the first time on the putative C-9 phenyl anchor, at the 4'-position of (R)- and (S)-warfarin. In addition, the Vmax for (S)-warfarin 7-hydroxylation decreased 4-fold and the Km was increased 13-fold by the F114L mutation, whereas kinetic parameters for lauric acid metabolism, a substrate which cannot interact with the enzyme by a pi-stacking mechanism, were not markedly affected by this mutation. Finally, the F114L mutant effected a greater than 100-fold increase in the Ki for inhibition of CYP2C9 activity by sulfaphenazole. These data support a role for B'-C helix loop residues F114 and V113 in the hydrophobic binding of warfarin to CYP2C9, and are consistent with pi-stacking to F114 for certain aromatic ligands.     

An experimental model of ascending pyelonephritis due toCandida albicans in rats

We developed a new experimental model of ascendingCandida pyelonephritis in female rats with leukopenia and vesicoureteral reflux. Rats were treated transperitoneally with cyclophosphamide (200 mg/kg) to induce leukopenia 3 days before and transurethrally with diluted acetic acid solution to induce vesicoureteral reflux 1 day before inoculation ofCandida albicans strain, ATCC 10259 (containing 10⁷ cells). Microscopy revealed acute pyelonephritis in whichCandida cells invaded from the fornix and/or papilla into the medulla within 3 days after inoculation. Between 7 and 28 days after inoculation, chronic pyelonephritis reached the cortex. The incidence of pyelonephritis increased gradually and was approximately 80% after 7 days.Candida colony counts of bladder urine specimens obtained by direct puncture were significantly greater in rats with pyelonephritis extending into the parenchyma than in those with pyelonephritis located along the pelvis (p<0.01). These results suggest that this rat model shows the characteristic feature of ascending pyelonephritis due toC. albicans and that the severity ofCandida pyelonephritis can be estimated fromCandida counts of bladder urine.     

Demonstration by lectin cytochemistry of rod and cone photoreceptors in the lamprey retina

Summary Lectin cytochemical analysis was undertaken to examine the distribution of glycoconjugates associated with the short and long photoreceptor cells in the lamprey retina. Concanavalin A bound preferentially to the outer segment region of the short cells. Wheat germ agglutinin bound weakly to both long and short cells. The outer segment regions of the long cells were stained intensely with peanut agglutinin. Pretreatment with neuraminidase to remove sialic acid resulted in decreased binding of wheat germ agglutinin throughout the retina and increased binding of peanut agglutinin to the outer segment region of the short cells and the region of myoid process of the long cells. These results suggest that there is a difference in the distribution of glycoconjugate residues between the long and short cells. A rod-like character of the short cell and a cone-like character of the long are tentatively discussed. Lectin-binding patterns in other retinal regions is also examined.     

SYSTEMATICS AND POPULATION GENETICS OF FIRE ANTS (SOLENOPSIS SAEVISSIMA COMPLEX) FROM ARGENTINA

Specimens of seven fire ant species collected from their native ranges in Argentina were studied by protein electrophoresis and morphological analysis. Concordance between the genetic and morphological character sets is strong (96% agreement on identifications), suggesting that recognition of reproductively isolated populations and partitioning of intra- and interspecific variation can in most cases be achieved using appropriate characters of either type in this taxonomically difficult group. Genetic differentiation between native (Argentina) and introduced (USA) conspecific populations of two species, Solenopsis invicta and S. richteri, is rather typical of the differentiation existing between conspecific populations found within either country. Furthermore, there appears to have been little reduction of variability (heterozygosity) at enzyme loci following colonization by either species of the United States, although some rare alleles have been lost in the introduced populations. Hybridization is rare between S. invicta and S. richteri where their native ranges overlap in central Argentina, in contrast to the extensive hybridization of these species in the United States, suggesting that prezygotic barriers to gene flow have been compromised in introduced populations. Phylogenetic analysis of the seven species indicates that S. invicta and S. richteri are relatively distantly related within the S. saevissima complex. Given that hybrids between these species in the United States suffer little apparent loss of fitness, genomic incompatibilities generally may be insufficient to create effective postzygotic barriers to interspecific gene flow in this group of ants.     

Plasma levels of catechols during reflexive changes in sympathetic nerve activity

Relationships between changes in levels of catechols and directly recorded sympathetic nerve activity were examined using simultaneous measurements of renal sympathetic nerve activity and arterial and renal venous concentrations of norepinephrine (NE), dihydroxyphenylalanine (dopa), and dihydroxyphenylglycol (DHPG) during reflexive alterations in renal sympathetic nerve activity in anesthetized, adrenal-demedullated rats. Nitroprusside infusion increased renal sympathetic nerve activity by 90%, arterial levels of dopa by 96%, NE by 326%, and DHPG by 141%. Phenylephrine infusion increased arterial DHPG levels by 81% and decreased renal sympathetic nerve activity by 37% and NE levels by 26%; arterial dopa levels were unchanged. Ganglionic blockade by chlorisondamine (with concomitant phenylephrine infusion to maintain MAP) decreased renal sympathetic nerve activity by 65% and NE concentrations by 37%; arterial dopa concentrations were unchanged, and DHPG concentrations increased by 60%. Proportionate responses of arterial levels of NE were strongly related to proportionate changes in renal sympathetic nerve activity. Clearance of DHPG from arterial plasma was prolonged by phenylephrine-induced hypertension and by nitroprusside-induced hypotension. The results suggest that changes in arterial NE levels reflect changes in sympathetic activity; changes in dopa levels reflect changes in catecholamine biosynthesis; and changes in DHPG levels depend on reuptake of released NE and on hemodynamic factors affecting DHPG clearance.     

Effects of IL-1 on hematopoietic progenitors after myelosuppressive chemoradiotherapy

Recently it has been recognized that IL-1 plays an important role in hematopoietic regulation. Administration of 5-fluorouracil (5-FU) to mice causes prolonged neutropenia. rHIL-1 injected to mice after 5-FU, accelerated the recovery of hematopoietic progenitors and blood neutrophils. The combination of rhIL-1 and rhG-CSF reduced the neutropenic period significantly. Sublethal irradiation of mice induced profound neutropenia for 3 weeks which was associated with 80% mortality. Administration of rhIL-1 20 hours prior to or 2 hours post irradiation resulted in a significantly improved survival and rapid recovery of the neutrophil count. IL-1 administered alone or in combination with other colony stimulating factors to spontaneous breast tumor bearing mice following 5-FU therapy resulted in a rapid recovery of neutrophils, improved survival, and markedly reduced the tumor mass. Experiments in primates demonstrated that rhIL-1 administered to 5-FU treated animals shortened the neutropenic period from 30 to 17 days and increased the number of marrow progenitors responsive to other CSFs. Prolonged administration of IL-1 (14 days) to these animals resulted in a delayed neutrophil recovery as compared to animals receiving short courses of IL-1. rhIL-1 administered to primates receiving marrow grafts after lethal irradiation, did not result in rapid hematopoietic recovery. In humans, studies with CD-34 positive marrow cells showed that IL-1 had a radioprotective effect on a committed and early marrow progenitors. These data show the therapeutic potential of IL-1 in the treatment of chemoradiotherapy induced myelosuppression.     

Microbiological quality of tomato (<i>Solanum lycopersicum</i> L.) produced under greenhouse conditions in five Municipalities of the State of Mexico

The aim of the current research was to determine tomato (Solanum lycopersicum L.) microbiological quality produced under greenhouse conditions in 5 municipalities of the State of Mexico. Studies were conducted during the 2013 production cycle to know the risks and apply prevention strategies prior to its consumption. A microbiological analysis of samples of irrigation water, soil and 100 tomato fruits variety cid was performed to determine Aerobic Mesophiles, Total Coliforms and Fecal Coliforms. The methodology used were those according to the Official Mexican Standards NOM- 109-SSA1-1994, NOM-110-SSA1-1994, NOM-092-SSA1-1994, NOM-113-SSA1-1994, and the Regulations of the National French Organization for Standardization (AFNOR) NF V08-60, and NOM-093-SSA1-1994, which establish the allowable limits for the study microorganisms. The results showed a zero level of pollution in water and soil samples. For fruits, levels of Aerobic Mesophilic were within the maximum limits permitted by the standards. The municipality of Texcaltitlan showed the highest average for these microorganisms (10083.80 CFU/mL). Huixquilucan showed 2266.84 CFU/mL for Total Coliforms. For Fecal Coliforms, municipalities of Coatepec and Texcaltitlan exceeded the allowed limit.