Sex-based differences in gene expression in hippocampus following postnatal lead exposure.

The influence of sex as an effect modifier of childhood lead poisoning has received little systematic attention. Considering the paucity of information available concerning the interactive effects of lead and sex on the brain, the current study examined the interactive effects of lead and sex on gene expression patterns in the hippocampus, a structure involved in learning and memory. Male or female rats were fed either 1500 ppm lead-containing chow or control chow for 30 days beginning at weaning.Blood lead levels were 26.7±2.1 µg/dl and 27.1±1.7 µg/dl for females and males, respectively. The expression of 175 unique genes was differentially regulated between control male and female rats. A total of 167 unique genes were differentially expressed in response to lead in either males or females. Lead exposure had a significant effect without a significant difference between male and female responses in 77 of these genes. In another set of 71 genes, there were significant differences in male vs. female response. A third set of 30 genes was differentially expressed in opposite directions in males vs. females, with the majority of genes expressed at a lower level in females than in males. Highly differentially expressed genes in males and females following lead exposure were associated with diverse biological pathways and functions. These results show that a brief exposure to lead produced significant changes in expression of a variety of genes in the hippocampus and that the response of the brain to a given lead exposure may vary depending on sex.

Chlorinated hydrocarbons and eggshell changes in raptorial and fish-eating birds.

Catastrophic declines of three raptorial species in the United States have been accompanied by decreases in eggshell thickness that began in 1947, have amounted to 19 percent or more, and were identical to phenomena reported in Britain. In 1967, shell thickness in herring gull eggs from five states decreased with increases in chlorinated hydrocarbon residues.

Brown pelicans: improved reproduction off the southern California coast.

Although still about 30 percent too low for population stability, productivity of California brown pelicans at their two northern colonies has improved significantly since 1971. Numbers of adults breeding probably reflect food supplies and recruitment from more successful colonies to the south, but improving fledging rates (up to 0.9 young per nest in 1974) reflect better egg survival and improving eggshell condition, with declining DDE contamination in anchovies, their major food source.

Broad neuroprotective profile of nicotinamide in different mouse models of MPTP-induced parkinsonism.

The factors contributing to substantia nigra pars compacta (SNc) dopamine (DA) neuron death and striatal DA depletion in Parkinson's disease (PD) are still poorly understood. However, mitochondrial dysfunction, cellular energy depletion and oxidative stress appear to play important roles in the pathogenesis of PD. In view of this, the current study examined the potential of nicotinamide, a form of the B-complex vitamin niacin, to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced SNc cell loss and striatal DA depletion in two mouse MPTP models that respond differently to putative neuroprotective agents. Adult male C57Bl/6 mice received nicotinamide (125, 250 or 500 mg/kg i.p.) prior to either acute (four injections in 1 day at 2-h intervals) or sub-acute (two injections per day at 4-h intervals for 5 days) MPTP administration. Striatal DA levels, changes in numbers of tyrosine hydroxylase (TH)- and cresyl violet-stained cells in the SNc at 2 and 6 weeks following the last MPTP exposure were analyzed. Nicotinamide administration resulted in a dose-dependent sparing of striatal DA levels and SNc neurons in acute MPTP-treated animals. Only the highest dose of nicotinamide had similar effects in sub-acute MPTP-treated animals. At 6 weeks after MPTP exposure, there was some spontaneous recovery of striatal DA levels in both models: neuroprotective effects were still apparent in acute but not sub-acute MPTP-treated animals. These results show neuroprotective effects of nicotinamide in different mouse Parkinson models associated with different forms of cell death and suggest that nicotinamide may have broad neuroprotective potential in PD.

Postnatal lead exposure alters expression of forebrain p75 and TrkA nerve growth factor receptors.

Lead is a potent developmental neurotoxicant that affects many aspects of cognition and behavior. The hippocampus and striatum are among the areas particularly sensitive to the effects of lead and cholinergic neurons in both regions depend upon nerve growth factor (NGF) for their survival and maturation. The present study examined the extent to which postnatal lead exposure may affect the survival and expression of neuroptrophin receptors of septo-hippocampal cholinergic projection neurons in the medial septum/vertical limb of the diagonal band of Broca (MS/VDB) and cholinergic neurons of the striatum. Weanling rats were fed chow containing lead acetate for 30 days and effects on cholinergic cell number and the number of cells expressing neurotrophin receptors p75(NGFR) and trkA were assessed. A decrease in the number of cells expressing p75(NGFR) and an increase in the number of cells expressing trkA receptor was observed in the MS/VDB of lead-exposed rats, without a loss of cholinergic cell number or alteration in cell size. Lead-exposure resulted in a significant decrease in trkA-expressing cells in the striatum but no change in the number or size of cholinergic neurons. These results suggest that a brief postnatal lead exposure does not result in loss of MS/VDB or striatal cholinergic neurons but does modify the expression of neurotrophin receptors in these regions. The significance of these effects on the septo-hippocampal and striatal functioning remains to be studied.

Effects of developmental lead exposure on the hippocampal methylome: Influences of sex and timing and level of exposure.

Developmental lead (Pb) exposure results in persistent cognitive/behavioral impairments as well as an elevated risk for developing a variety of diseases in later life. Environmental exposures during development can result in a variety of epigenetic changes, including alterations in DNA methylation, that can influence gene expression patterns and affect the function and development of the nervous system. The present promoter-based methylation microarray profiling study explored the extent to which developmental Pb exposure may modify the methylome of a brain region, hippocampus, known to be sensitive to the effects of Pb exposure. Male and female Long Evans rats were exposed to 0 ppm, 150 ppm, 375 ppm, or 750 ppm Pb through perinatal exposures (gestation through lactation), early postnatal exposures (birth through weaning), or long-term postnatal exposures (birth through postnatal day 55). Results showed a significant contribution of sex to the hippocampal methylome and effects of Pb exposure level, with non-linear dose response effects on methylation. Surprisingly, the developmental period of exposure contributed only a small amount of variance to the overall data and gene ontology (GO) analysis revealed the largest number of overrepresented GO terms in the groups with the lowest level of exposure. The highest number of significant differentially methylated regions was found in females exposed to Pb at the lowest exposure level. Our data reinforce the significant effect that low level Pb exposure may have on gene-specific DNA methylation patterns in brain and that this occurs in a sex-dependent manner.

Transport of apolipoproteins A-I and A-II by human thoracic duct lymph.

The daily transport of human plasma apolipoproteins A-I and A-II, triglyceride, and total cholesterol from the thoracic duct lymph into plasma was measured in two subjects before and three subjects after renal transplantation. Lymph triglyceride transport was approximately 83% of the daily ingested fat loads, whereas lymph cholesterol transport was consistently greater than the amount of daily ingested cholesterol. Lymph apolipoprotein transport significantly (P < 0.05) exceeded the predicted apolipoprotein synthesis rate by an average of 659+/-578 mg/d for apolipoprotein A-I and 109+/-59 mg/d for apolipoprotein A-II among the five subjects. It is estimated that 22-77% (apolipoprotein A-I) and 28-82% (apolipoprotein A-II) of daily total body apolipoprotein synthesis takes place in the intestine. Lymph high density lipoprotein particles are mostly high density lipoprotein(2b) and high density lipoprotein(2a) and have a greater overall relative triglyceride content and a smaller relative cholesteryl ester content when compared with homologous plasma high density lipoproteins. The major quantity of both lymph apolipoprotein A-I (81+/-8%) and apolipoprotein A-II (90+/-11%) was found within high density lipoproteins with almost all of the remainder found in chylomicrons and very low density lipoproteins. The combined results are consistent with a major contribution of the intestine to total body synthesis of apolipoprotein A-I and apolipoprotein A-II. An important role of lymph in returning filtered apolipoprotein to plasma in association with high density lipoproteins is proposed. Accompanying the return of filtered apolipoprotein to the plasma is a probable transformation, both in size and composition, of at least some of the lymph high density lipoprotein(2b) and high density lipoprotein(2a) particles into high density lipoprotein(3).

The self-pith.

We describe a middle-aged woman who inserted a sewing needle into her spinal cord in an attempt at performing her own acupuncture. Reports of neurologic injury are rare in the literature, despite the widespread use of acupuncture. This is the first case we have identified involving spinal cord injury from self-performed acupuncture.

The synthetic ceramide analog L-PDMP partially protects striatal dopamine levels but does not promote dopamine neuron survival in murine models of parkinsonism.

A number of previous studies have demonstrated a positive effect of exogenously administered monosialoganglioside GM1 on striatal dopamine (DA) levels and DA neuron survival in animal models of parkinsonism. However, due to low bioavailability of peripherally administered GM1, the present study investigated the neuroprotective/neurorestorative potential of enhancing endogenous GM1 biosynthesis by administration of the synthetic ceramide analog L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (L-PDMP) in two mouse models of Parkinsonism produced by acute or subacute 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. L-PDMP treatment caused an increase in brain GM1 levels in both Parkinson models and resulted in a partial sparing of striatal DA levels in the subacute MPTP model but not in the acute MPTP model. L-PDMP treatment had no effect on DA neuron survival in either model. These data suggest that the administration of L-PDMP as a means to enhance endogenous brain GM1 levels may hold limited promise as a potential neuroprotective or neurorestorative therapeutic strategy for Parkinson's disease.

Hemithyroidectomy: the preferred initial surgical approach for management of Hurthle cell neoplasm.

BACKGROUND: The objective of this study was to evaluate the cancer risk of patient clinicopathologic characteristics to determine the optimal approach for the surgical management of individuals with Hurthle cell neoplasm (HN) diagnosed by cytology. METHODS: Patient clinicopathologic characteristics evaluated included age, sex, tumor size, and ipsilateral thyroid lobe nodularity. The association of these characteristics with a pathologic cancer diagnosis was evaluated using Fisher's exact test and Student t test. RESULTS: Of the 422 patients undergoing thyroidectomy, 27 presented with a fine-needle aspiration biopsy diagnosis of HN, and by pathologic assessment 7 HN patients (25.9%) had a cancer diagnosis. Although none of the clinicopathologic characteristics evaluated were able to reliably differentiate benign from malignant tumors, large tumor size and male sex were significantly associated with a pathologic diagnosis of Hurthle cell carcinoma (P < .05). CONCLUSIONS: Hemithyroidectomy represents the preferred initial surgical approach for the management of individuals presenting with nodular thyroid disease and a cytologic diagnosis of HN.

Introduction of grids to mobile ICU radiography in a teaching hospital.

The purpose of this study was to review the change in image quality before and after introducing grid use routinely to our mobile X-ray service. This was studied in the intensive care unit (ICU) setting, comparing images obtained over a 2 week period prior to and after the introduction of the change in technique. We introduced a 6:1 grid with appropriate changes in exposure factors. No other alterations were made. There were 133 patients in the preliminary group and 196 patients in the post-grid group. We found a reduction in the proportion of images that were of non-diagnostic or barely diagnostic quality. Non-diagnostic examinations were reduced from 18% to 1%. Introducing grids to our mobile service resulted in improvement in image diagnostic quality, largely by reducing the proportion of poor and unacceptable quality images. This effect does not appear to have been documented in the literature.

Effects of low level lead exposure on associative learning and memory in the rat: Influences of sex and developmental timing of exposure.

Lead (Pb) exposure during development impairs a variety of cognitive, behavioral and neurochemical processes resulting in deficits in learning, memory, attention, impulsivity and executive function. Numerous studies have attempted to model this effect of Pb in rodents, with the majority of studies focusing on hippocampus-associated spatial learning and memory processes. Using a different paradigm, trace fear conditioning, a process requiring coordinated integration of both the medial prefrontal cortex and the hippocampus, we have assessed the effects of Pb exposure on associative learning and memory. The present study examined both female and male long evans rats exposed to three environmentally relevant levels of Pb (150 ppm, 375 ppm and 750 ppm) during different developmental periods: perinatal (PERI; gestation-postnatal day 21), early postnatal (EPN; postnatal days 1-21) and late postnatal (LPN; postnatal days 1-55). Testing began at postnatal day 55 and consisted of a single day of acquisition training, and three post training time points (1, 2 and 10 days) to assess memory consolidation and recall. All animals, regardless of sex, developmental window or level of Pb-exposure, successfully acquired conditioned-unconditioned stimulus association during training. However, there were significant effects of Pb-exposure on consolidation and memory recall at days 1-10 post training. In females, EPN and LPN exposure to 150 ppm Pb (but not PERI exposure) significantly impaired recall. In contrast, only PERI 150 ppm and 750 ppm-exposed males had significant recall deficits. These data suggest a complex interaction between sex, developmental window of exposure and Pb-exposure level on consolidation and recall of associative memories.

Particle distribution of human serum high density lipoproteins.

Density gradient ultracentrifugation of human serum high density lipoproteins (HDL) from both normolipemic males and females results in a distribution of HDL concentration versus subfraction hydrated density which has three maxima. Gradient gel electrophoresis of total HDL is characterized by three banding maxima, the positions of which suggest the presence of three particle size ranges: I. 10.8-12.0 nm, II. 9.7-10.7 nm, and III. 8.5-9.6 nm. Gradient gel electrophoresis of density gradient subfractions established an inverse relationship between particle size and particle hydrated density which was corroborated by electron microscopy and analytic ultracentrifugation. Comparison of male HDL from size ranges I, II, and III with female HDL from the same size ranges showed only small differences in the mean value of the peak F degrees 1.20 rate, size, molecular weight, protein weight percent, and weight protein/weight phospholipid. Major differences between males and females were seen in the relative amounts of HDL in density gradient subfractions 1-3 (size range I material) and 11-12 (size range III material); the percent total HDL in the group of subfractions 1-3 was greatly increased in female HDL while that of the group of subfractions 11-12 was increased in the male HDL. These studies indicate the presence of at least three major components in HDL instead of two (HDL2 and HDL3) and that peak F degrees 1.20 rate differences in HDL schlieren patterns between males and females are a function of the relative levels of these three components.

Effects of guanidine hydrochloride on human plasma high density lipoproteins.

Denaturation of human plasma high density lipoproteins during ultracentrifugation in guanidine-HCl is characterized by: dissociation of apoA-I, in the range of 2-3 M guanidine-HCl, and dissociation of apoA-I and apoA-II in 5-6 M guanidine-HCl. Denaturation of high density lipoprotein species, during a sequence of timed exposure to guanidine-HCl followed first by removal of the denaturant by dialysis and then by ultracentrifugation, is characterized by:dissociation of lipid-poor apoA-I, which follows a time course similar to denaturation-related changes in reported spectroscopic parameters; and apparent formation of lipoprotein aggregation products depleted in apoA-I and relatively enriched in apoA-II. These studies indicate differential properties of the major apoproteins in stabilizing high density lipoprotein structure and characterize a mode of lipoprotein transformation and degradation which apparently results from apoprotein dissociation coupled with aggregation of denatured lipoprote species.

Prevalent myocarditis at necropsy in the acquired immunodeficiency syndrome.

The prevalence of myocarditis was retrospectively evaluated in 71 consecutive necropsy patients who died from acquired immunodeficiency syndrome (AIDS) between 1982 and 1986. Myocarditis was found in 37 cases (52%). Biventricular dilation at necropsy was present in seven cases (10%) and was accompanied by myocarditis in each case; fatal congestive heart failure occurred in four of these seven cases. Although viral, protozoan, bacterial, fungal and mycobacterial opportunistic pathogens were present in myocardial sections of 7 of 37 myocarditis cases, the etiology of myocarditis in the majority of these patients with AIDS remained idiopathic. Thus, myocarditis is a frequent finding at necropsy in patients with AIDS and may contribute to the development of biventricular dilation.

Inhibition of progenitor cell proliferation in the dentate gyrus of rats following post-weaning lead exposure.

Although lead is a potent developmental neurotoxin, the effects of postnatal lead exposure on progenitor cell proliferation in the hippocampus has not been examined. Postnatal day 25 rats were fed a lead containing diet (1500 ppm lead acetate) for 30-35 days and administered bromodeoxyuridine (BrdU, 50 mg/kg, i.p.) during the last 5 days of lead exposure. Animals were killed 24 h after the last BrdU injection. Proliferation of new cells in the subgranular zone and dentate gyrus was significantly decreased in lead-exposed rats compared to control animals that ate a similar diet devoid of lead. These results suggest that postnatal lead exposure can have significant deleterious effects on progenitor cell proliferation and thus the structure and function of the hippocampus.

Bilateral absence of the internal carotid artery: MR angiography and ultrasound findings.

Presented is a case of congenital absence of the internal carotid arteries (ICAs) in a 13-year-old boy. This condition has been rarely reported in the literature and presented are our imaging findings, including descriptions of findings with MRI, MR angiography and ultrasound.

Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders.

We investigated the validity and reliability of diagnoses made by eight neuropathologists who used the preliminary NINDS neuropathologic diagnostic criteria for progressive supranuclear palsy (PSP) and related disorders. The specific disorders were typical, atypical, and combined PSP, postencephalitic parkinsonism, corticobasal ganglionic degeneration, and Pick's disease. These disorders were chosen because of the difficulties in their neuropathologic differentiation. We assessed validity by measuring sensitivity and positive predictive value. Reliability was evaluated by measuring pairwise and group agreement. From a total of 62 histologic cases, each neuropathologist independently classified 16 to 19 cases for the pairwise analysis and 5 to 6 cases for the group analysis. The neuropathologists were unaware of the study design, unfamiliar with the assigned cases, and initially had no clinical information about the cases. Our results showed that with routine sampling and staining methods, neuropathologic examination alone was not fully adequate for differentiating the disorders. The main difficulties were discriminating the subtypes of PSP and separating postencephalitic parkinsonism from PSP. Corticobasal ganglionic degeneration and Pick's disease were less difficult to distinguish from PSP. The addition of minimal clinical information contributed to the accuracy of the diagnosis. On the basis of results obtained, we propose clinicopathologic diagnostic criteria to improve on the NINDS criteria.

Oncogenic osteomalacia: evidence for a humoral phosphaturic factor.

Oncogenic osteomalacia is a syndrome characterized by phosphaturia, hypophosphatemia, reduced vitamin D levels, and osteomalacia. The cause is not known, but all patients have had a tumor; usually of mesenchymal origin. Removal of the tumor reverses the metabolic abnormalities. We report a patient with osteomalacia, severe hypophosphatemia, elevated alkaline phosphatase, low 1,25-dihydroxyvitamin D3, and phosphaturia. A tumor was identified in the infratemporal fossa. The tumor was removed, and all of the biochemical abnormalities resolved over the subsequent 8 months. The bone density returned to normal values. The tumor had the appearance of a paraganglioma and was used to establish a cell culture line called JH-55. Electron microscopy of the original tumor and the JH-55 cells demonstrated the presence of neurosecretory granules. A bioassay using opossum kidney cells was used to evaluate phosphate transport. Conditioned medium from the JH-55 cells inhibited phosphate reabsorption by the kidney tubular cells. Maximal inhibition required a 24-h incubation period and was not altered by the presence of an inhibitor of protein synthesis (10 micrograms/mL cycloheximide). Immunoassays revealed no detectable PTH-related peptide or intact PTH in the JH-55 medium. The cause of this paraneoplastic syndrome is not known, but all of the evidence is consistent with the action of a hormone that produces phosphaturia. This putative factor is distinct from other hormones that cause phosphaturia.

Geographic patterns of parkinsonism-dementia complex on Guam. 1956 through 1985.

Average annual age-adjusted incidence rates of parkinsonism-dementia complex were obtained for the 19 election districts of Guam from 1956 through 1985. The highest rates were found in the southern and central districts, and the lowest rates were found in the northern and western districts. Geographic and temporal patterns of incidence were associated with socioeconomic status but not with geochemical factors. The risk of parkinsonism-dementia complex in susceptible sibships was much higher than that in the general population--even in districts with the highest incidence rates, but especially in districts with the lowest incidence rates. Our evidence tends to support the hypothesis that multiple factors linked to cycad use play an important role in the cause of PDC. Hypotheses related to metal exposure and simple genetic factors were unsatisfactory explanations for the epidemiologic patterns observed.