An association between reduced interhemispheric EEG coherence in the temporal lobe and genetic risk for schizophrenia

Previous studies have suggested that schizophrenic patients show resting changes such as frequency-slowing and decreased coherence in the frontal and temporal area. We sought to determine whether these findings are also found in clinically unaffected siblings of schizophrenics and estimate heritability by calculating relative risk. We investigated two independent data sets: (1) from the NIMH St. Elisabeth's campus (59 schizophrenics, 76 unaffected siblings and 32 unrelated normal controls) and (2) from the NIH-campus (Bethesda) (59 schizophrenics, 90 unaffected siblings and 26 unrelated normal controls). We computed power spectra and coherence on the first data set and then tried to replicate the results on the second data set. Power spectrum analysis suggested that schizophrenics are cortically hypoactivated, whereas in unaffected siblings, a tendency for hyperactivation was found. In contrast, spectral coherences (0.5-5Hz) were reduced in both data sets in the temporal lobe areas in schizophrenics and in their unaffected siblings. Changes were most pronounced for the interhemispheric coherence linking both posterior temporal lobe areas. Relative risk calculations (lambda(S)) ranged between 3.7 and 9.8, depending on phenotype definition. Thus, while power spectrum EEG abnormalities may be state-dependent, reduced coherence as a possible measure of neuronal synchronization is familial and potentially a heritable trait related to genetic risk for schizophrenia.     

Repeated episodes of C5a-induced neutrophil influx do not result in pulmonary fibrosis

Multiple reactive oxygen species-induced epithelial injury by glucose, glucose oxidase, and lactoperoxidase instillation in the lung results in a progressive interstitial fibrosis. To test the hypothesis that multiple pulmonary inflammatory responses alone would not result in fibrosis, three sequential inflammatory reactions were produced at weekly intervals in hamster lungs via intratracheal instillation of human recombinant C5a. Numbers of neutrophils and total inflammatory cells in bronchoalveolar lavage (BALF) increased significantly at 24 h after each C5a treatment compared with saline controls. Neutrophils increased by 3-, 33-, and 34-fold compared with the corresponding controls at 24 h after the first, second, and third doses, respectively, but returned to control levels by six days postinstillation. LTB₄ levels increased by 24% and 20% compared with the corresponding controls at 24 h after the first and second doses but were not different from controls at other times. Hydroxyproline levels in treated animals did not differ significantly from control levels throughout the study. Protein levels were significantly increased at 24 h after the second and third doses and six days after the third dose compared with the corresponding controls. Occasional foci of neutrophils in alveolar spaces were observed at 24 h after each dose, but they decreased in frequency after six days. No foci of neutrophils were observed six days after the final dose, although some epithelial degeneration was observed by transmission electron microscopy. Our results indicate that pulmonary inflammation resulting from repeated influx of neutrophils in response to multiple instillations of C5a in the lung does not cause sufficient injury to result in pulmonary fibrosis.     

Functional expression of the dihydrofolate reductase and thymidylate synthetase activities of the human malaria parasite Plasmodium falciparum in Escherichia coli

We have developed a recombinant system that directs the functional expression from Escherichia coli of both dihydrofolate reductase-thymidylate synthetase (DHFR-TS) and the isolated DHFR domain from Plasmodium falciparum. Both products are inhibitory to a number of E. coli cell lines to the extent that cell growth ceases immediately upon induction. This dramatic inhibition is not seen in strain AB1899, in which amounts of plasmodial protein of up to 100 times the basal E. coli TS level can be accumulated. However, as well as the full-length DHFR-TS molecule, smaller proteins carrying an intact TS substrate-binding site are produced. These represent ca. 60-75% of the total plasmodial protein expressed and are observed in every E. coli strain examined. We show that they are not derived by degradation of the parent DHFR-TS molecule, but can be correlated with the sizes of proteins expected to be produced if erroneous initiation of translation were occurring at 3 internal methionine residues.     

Unique roles for E2F1 in the mouse lens in the absence of functional pRB proteins

PURPOSE: Normal lens fiber cell differentiation requires functional retinoblastoma protein (pRB), because inactivation of this protein results in proliferation and apoptosis in normally postmitotic, differentiating fiber cells. Loss of either E2F1 or -3 can partially rescue the lens phenotype in Rb-deficient mice, implying that these E2Fs may have specific targets in this system. The purpose of this study was to determine what unique role E2F1 may play. METHODS: Expression of E2F family members and target genes was analyzed in the lenses of nontransgenic, E2F1-null, alphaAE7;E2F1-sufficient; and alphaAE7;E2F1-null mice by in situ hybridization, Northern blot analysis, and RT-PCR. RESULTS: In lenses of E2F1-null mice, there was no change in the expression of E2F-2 to -5 or their target genes, compared with E2F1-sufficient mice. However, in the lens of alphaAE7 mice where pRB proteins are inactivated, expression of E2F2 and -3a was increased. The E2F3a increase, but not that of E2F2, was dependent on E2F1. Expression of E2F target genes was increased with expression of E7 and expression of one of these, p19ARF, was E2F1 dependent. CONCLUSIONS: Although in the normal lens there do not appear to be unique roles for E2F1 that cannot be fulfilled by other E2F family members, in the absence of functional pRB proteins, E2F1 is specifically responsible for the increased expression of E2F3a and p19ARF. These findings suggest that E2F1 may be the preferred E2F regulating these target genes in the normal lens.     

Zebrafish mutagenesis yields eye morphological mutants with retinal and lens defects

A chemical mutagenesis to identify zebrafish eye morphological mutants was performed by screening F(3) larvae at 5 and 7 days post-fertilization (dpf) for changes in eye or pupil size. Based on histological analysis, four different phenotypic classes were obtained. The two Class I and three Class II mutants are all characterized by small eyes and exhibit defects in early retinal development or unregulated cell death, respectively. The single Class III mutant has reduced ocular pigmentation. The three Class IV mutants display defects in the ocular lens, including one mutant line with normal sized eyes and pupils that develops lens opacity at 7 dpf.     

Familial incidence of bifid and double ureters

The incidence of a duplex urinary tract was determined in the parents and sibs of 30 index patients with either unilateral or bilateral bifid or double ureters. Our results support the hypothesis that a duplex urinary tract is inherited by an autosomal dominant gene of variable penetrance. Routine screening by limited intravenous pyelography of sibs of index patients is recommended in order to detect a duplex urinary tract before the onset of complications.