Objective To evaluate the difference in 10-year neurocognitive outcomes among extremely low gestational age newborns without bacteremia or with suspected or confirmed late-onset bacteremia. Study design Neurocognitive function was evaluated at 10 years of age in 889 children born at <28 weeks of gestation and followed from birth. Definite (culture positive) late-onset bacteremia during postnatal weeks 2–4 was identified in 223 children and 129 had suspected bacteremia. Results Infants with the lowest gestational age and birth weight Z-score had the highest prevalence of definite and suspected late-onset bacteremia. When compared with peers with no or suspected bacteremia, infants with definite bacteremia performed worse on tests of general cognitive ability, language, academic achievement, and executive function, even when adjusting for potential confounders. Adjustment for low IQ attenuated associations between bacteremia and all dysfunctions at 10 years. Children who had suspected bacteremia did not differ appreciably from children who did not have any evidence of bacteremia. The motor domain was unaffected. Conclusions Extremely low gestational age newborns who had definite late bacteremia during postnatal weeks 2–4 are at heightened risk of neurocognitive limitations at 10 years of age.

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Deficiency of liver arginase (AI) is characterized clinically by hyperargininemia, progressive mental impairment, growth retardation, spasticity, and periodic episodes of hyperammonemia. The rarest of the inborn errors of urea cycle enzymes, it has been considered the least life-threatening, by virtue of the typical absence of catastrophic neonatal hyperammonemia and its compatibility with a longer life span. This has been attributed to the persistence of some ureagenesis in these patients through the activity of a second isozyme of arginase (AII) located predominantly in the kidney. We have treated a number of arginase-deficient patients into young adulthood. While they are severely retarded and wheelchair-bound, their general medical care has been quite tractable. Recently, however, two of the oldest (M.U., age 20, and M.O., age 22) underwent rapid deterioration, ending in hyperammonemic coma and death, precipitated by relatively minor viral respiratory illnesses inducing a catabolic state with increased endogenous nitrogen load. In both cases, postmortem examination revealed severe global cerebral edema and aspiration pneumonia. Enzyme assays confirmed the absence of AI activity in the livers of both patients. In contrast, AII activity (identified by its different cation cofactor requirements and lack of precipitation with anti-AI antibody) was markedly elevated in kidney tissues, 20-fold in M.O. and 34-fold in M.U. Terminal plasma arginine (1500 mumols/l) and ammonia (1693 mmol/l) levels of M.U. were substantially higher than those of M.O. (348 mumols/l and 259 mumols/l, respectively). By Northern blot analysis, AI mRNA was detected in M.O.'s liver but not in M.U.'s; similarly, anti-AI crossreacting material was observed by Western blot in M.O. only. These findings indicate that, despite their more long-lived course, patients with arginase deficiency remain vulnerable to the same catastrophic events of hyperammonemia that patients with other urea cycle disorders typically suffer in infancy. Further, unlike those other disorders, an attempt is made to compensate for the primary enzyme deficiency by induction of another isozyme in a different tissue. Such substrate-stimulated induction of an enzyme may be unique in a medical genetics setting and raises novel options for eventual gene therapy of this disorder.

The gene for LSPI is a lymphocyte-specific gene previously isolated by us using a subtractive hybridization technique. LSPI mRNA is found in normal and transformed B lymphocytes and in normal T lymphocytes but not in transformed T lynrp}iocytes. To study the expression of the mouse LSPI protein, we prepared a polyclonal antiserum spetific for the LSPI protein. Here we report that the gene for LSP1 was expressed in transformed B-lymphoma cell lines and in normal mouse thymocytes as a protein doublet with apparent molecular masses of 52 and 50.5 kilodaltons when analyzed on a sodium dodecyl sulfate-10% polyacrylamide gel. BW5147 cells transfected with an LSP1 cDNA clone expressed only the 52-kilodalton protein. No LSP1 protein was expressed in nine T-lymphoma cell lines tested. Immunofluorescence studies of intact and permeabilized cells and subcellular fractionation experiments showed that the LSPI protein was associated with the cytoplasmic side of the plasma membrane in transformed B-lymphoma cell lines and in normal thymocytes. Using a simple filter-binding assay, we showed that recombinant LSP1 protein was Ca2+ binding, as predicted on the basis of its deduced amino acid sequence. On the basis of the particular expression pattern, the subcellular localization, and the Ca2+-binding property of the LSPI protein, we hypothesize that the LSP1 protein is a lymphocyte-specific component of a signal transduction pathway involved in the regulation of lymphocyte growth.The lymphocyte-specific gene for LSP1 has been isolated by us in the course of a systematic search for cDNA clones which are expressed specifically in all or certain lymphocyte populations but not in nonlymphoid cells (10,12). Such cell type-specific genes are presumably involved in cell typespecific effector functions or, alternatively, they are involved in the regulation of growth or differentiation of the specific cell types in which they are expressed. Northern (RNA) blot analysis has shown that mouse LSP1 mRNA is present in normal B lymphocytes and transformed B-lymphoma cell lines. LSP1 is also expressed in normal thymocytes and in normal functional helper and cytotoxic T-cell lines. However, no LSP1 RNA is present in nine transformed T-lymphoma cell lines tested. The gene for LSP1 is also not expressed in a variety of myeloid cell lines or in nonlymphoid tissues, such as liver, kidney, and heart tissues. A gene with a similar expression pattern can be detected in a series of human cell lines by using the mouse LSP1 cDNA clone as a hybridization probe (12). This lymphocyte-specific expression pattern and the absence of any detectable LSP1 mRNA in transformed T-lymphoma cell lines suggest a role for the LSP1 protein in the regulation of normal lymphocyte growth. Sequence analysis of an LSP1 cDNA clone predicts that the LSP1 protein consists of 330 amino acids with an acidic amino-terminal domain which contains two putative Ca2'-binding sites (12). Given the well-established role of Ca2' as an intracellular mediator of signal transduction (14, 18), ...

Lead is a male reproductive toxicant. Lead exposure results in a general suppression of the hypothalamic-pituitary-testicular (HPT) axis in male rats. The mechanism(s) for this disruption by lead is unknown. Toxic lead levels seem to disrupt central nervous system (CNS) control of the HPT system, resulting in a decrease in serum testosterone levels and sperm concentrations. A study designed to elucidate the mechanisms accounting for the disruption of the normal function of the male axis by toxic lead levels at the molecular level demonstrated a 2-3-fold enhancement of mRNA levels of GnRH and the tropic hormone LH. A 3-fold increase of intracellular stores of LH was also found. Because mRNA levels of LH and GnRH and pituitary levels of stored LH are proportional to blood levels of lead, we hypothesize that lead interferes with the normal release of tropic hormones and disrupts hormonal feedback mechanisms. The observed pleiotropic effects of lead upon the male axis and other systems may be explained by simple and unique competition by lead with normal metal ion binding sites that govern genetic control of specific genes.