Cumulative Blood Pressure Exposure During Young Adulthood and Mobility and Cognitive Function in Midlife.

BACKGROUND: High blood pressure (BP) is a known risk factor for mobility and cognitive impairment in older adults. This study tested the association of cumulative BP exposure from young adulthood to midlife with gait and cognitive function in midlife. Furthermore, we tested whether these associations were modified by cerebral white matter hyperintensity (WMH) burden. METHODS: We included 191 participants from the CARDIA study (Coronary Artery Risk Development in Young Adults), a community-based cohort of young individuals followed over 30 years. Cumulative BP was calculated as the area under the curve (mm Hg×years) from baseline up to year 30 examination. Gait and cognition were assessed at the year 30 examination. Cerebral WMH was available at year 30 in a subset of participants (n=144) who underwent magnetic resonance imaging. Multiple linear regression models were used to assess the association of cumulative BP exposure with gait and cognition. To test effect modification by WMH burden, participants were stratified at the median of WMH and tested for interaction. RESULTS: Higher cumulative systolic and diastolic BPs were associated with slower walking speed (both P=0.010), smaller step length (P=0.011 and 0.005, respectively), and higher gait variability (P=0.018 and 0.001, respectively). Higher cumulative systolic BP was associated with lower cognitive performance in the executive (P=0.021), memory (P=0.015), and global domains (P=0.010), and higher cumulative diastolic BP was associated with lower cognitive performance in the memory domain (P=0.012). All associations were independent of socio-demographics and vascular risk factors (body mass index, smoking, diabetes mellitus and total cholesterol). The association between cumulative BP and gait was moderated by WMH burden (interaction P<0.05). However, the relation between cumulative BP and cognitive function was not different based on the WMH burden (interaction P>0.05). CONCLUSIONS: Exposure to higher BP levels from young to midlife is associated with worse gait and cognitive performance in midlife. Furthermore, WMH moderates the association of cumulative BP exposure with gait, but not with cognitive function in midlife. The mechanisms underpinning the impact of BP exposure on brain structure and function must be investigated in longitudinal studies using a life course approach.

Root uptake and shoot accumulation of cadmium by lettuce at various Cd:Zn ratios in nutrient solution.

Cadmium (Cd) is toxic to animals and humans after it accumulates over decades in the kidney cortex. Food crops grown in Cd-contaminated soils are the primary sources of excessive Cd entry into humans. Although plant available Zn concentration in soil is an important factor which can greatly reduce Cd uptake by plant roots and its translocation into the edible parts, Cd:Zn ratio is suggested to be a more important factor in comparison with Zn concentration alone in determining Cd uptake by plants. In the present study, the physiological mechanisms of Cd absorption by roots and its translocation to leaves of lettuce (Lactuca sativa L.) at various Cd:Zn ratios in the rooting media were investigated. For this purpose, seedlings of hydroponically-grown lettuce were exposed to combinations of four Zn (0, 12.5, 50 and 100µM) and four Cd (0, 0.5, 1 and 10µM) concentrations providing different ratios of Cd:Zn. At each level of Cd, decreasing the Cd:Zn ratio by increasing Zn concentration in the nutrient solution caused significant reduction of root symplastic Cd and also reduced Cd loading into the xylem and Cd transport to and accumulation in leaves. The highest root symplastic Cd (1087mg/kg-1 Dry Weight [DW]) and shoot Cd concentrations (64mg/kg-1 DW) were observed at the highest Cd:Zn ratio of = 0.8 (Zn = 12.5, Cd = 10). At the Cd:Zn ratios of ≤ 0.01, shoot Cd concentration was less than the Detection Limit (< 0.02mg/kg DW). Decreasing Cd:Zn ratio in nutrient solution was accompanied with significant increase in root apoplastic Cd and decrease in the root symplastic Cd. According to the obtained results, at the Cd:Zn ratio equal to 0.01 and less, Cd concentration in lettuce shoots decreased to < 0.02mg/kg.

Potential Adherence of Flue Gas Desulfurization Gypsum to Forage as a Consideration for Excessive Ingestion by Ruminants.

Gypsum (calcium sulfate dihydrate, CaSO⋅2HO) has long been used to improve soils and crop production, and its use has recently been encouraged by the USDA-NRCS for soil conservation through a new Conservation Practice Standard: Code 333. However, there is concern regarding the adverse effects of excessive direct ingestion of sulfate in gypsum by ruminants. The standard requires ruminants to be removed from grazing after application until after a rainfall, but there has been no research documenting gypsum adherence to forage or the potential for rainfall to reduce gypsum adherence. A study was established to examine the adherence and persistence of gypsum on different forage species. Two forages (bermudagrass [ L.] and tall fescue [ Schreb.]) were examined after gypsum applications at rates of 0, 1, and 5 Mg ha. The forage was sampled immediately after application, 1 wk after application, after a 1.5-cm rain, and after a 3.3-cm rain. Immediately after gypsum application, more gypsum adhered to the tall fescue (27.9 g gypsum kg) compared with bermudagrass (8.6 g gypsum kg), likely due to differences in the leaf structure. This represents S concentrations of 0.16 and 0.52% for any grazing ruminants feeding exclusively on the bermudagrass and tall fescue pastures. On succeeding sampling dates, substantial amounts of gypsum persisted only on the wider-leaved tall fescue. With tall fescue, a difference in gypsum adherence could be observed after a 1.5-cm rain, but no significant difference was observed between the gypsum application and the control after an additional 3.3-cm rain. Results indicate that care should be observed with grazing after gypsum application, especially on wide-leaved forages. However, using application rates within normal agronomic beneficial use guidelines (NRCS standard 333), negative results from direct ingestion of gypsum are not likely if grazing is discontinued several weeks and until a rainfall event occurs.

Ovine ruminal microbes are capable of biotransforming hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX).

Bioremediation is of great interest in the detoxification of soil contaminated with residues from explosives such as hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX). Although there are numerous forms of in situ and ex situ bioremediation, ruminants would provide the option of an in situ bioreactor that could be transported to the site of contamination. Bovine rumen fluid has been previously shown to transform 2,4,6-trinitrotoluene (TNT), a similar compound, in 4 h. In this study, RDX incubated in whole ovine rumen fluid was nearly eliminated within 4 h. Whole ovine rumen fluid was then inoculated into five different types of media to select for archaeal and bacterial organisms capable of RDX biotransformation. Cultures containing 30 µg mL(-1) RDX were transferred each time the RDX concentration decreased to 5 µg mL(-1) or less. Time point samples were analyzed for RDX biotransformation by HPLC. The two fastest transforming enrichments were in methanogenic and low nitrogen basal media. After 21 days, DNA was extracted from all enrichments able to partially or completely transform RDX in 7 days or less. To understand microbial diversity, 16S rRNA-gene-targeted denaturing gradient gel electrophoresis (DGGE) fingerprinting was conducted. Cloning and sequencing of partial 16S rRNA fragments were performed on both low nitrogen basal and methanogenic media enrichments. Phylogenetic analysis revealed similar homologies to eight different bacterial and one archaeal genera classified under the phyla Firmicutes, Actinobacteria, and Euryarchaeota. After continuing enrichment for RDX degraders for 1 year, two consortia remained: one that transformed RDX in 4 days and one which had slowed after 2 months of transfers without RDX. DGGE comparison of the slower transforming consortium to the faster one showed identical banding patterns except one band. Homology matches to clones from the two consortia identified the same uncultured Clostridia genus in both; Sporanaerobacter acetigenes was identified only in the consortia able to completely transform RDX. This is the first study to examine the rumen as a potential bioremediation tool for soils contaminated with RDX, as well as to discover S. acetigenes in the rumen and its potential ability to metabolize this energetic compound.

N-Terminal Pro Brain, N-Terminal Pro Atrial Natriuretic Peptides, and Dynamic Cerebral Autoregulation.

Background Elevated natriuretic peptides (NP) are associated with adverse cerebrovascular conditions including stroke, cerebral small vessel disease, and dementia. However, the mechanisms underlying these associations remain unclear. In this study, we examined the relationship of NT-proBNP (N-terminal pro brain NP) and NT-proANP (N-terminal pro atrial NP) with cerebrovascular function, measured by cerebral autoregulation. Methods and Results We included 154 participants (mean age 56±4 years old) from the CARDIA (Coronary Artery Risk Development in Young Adults) cohort. NT-proBNP and NT-proANP were measured in blood samples from the year 25 examination using electrochemiluminescence Immunoassay and enzyme-linked immunoassay, respectively. Dynamic cerebral autoregulation (dCA) was assessed at the year 30 examination by transcranial Doppler ultrasound, using transfer function analysis (phase and gain) of spontaneous blood pressure and flow velocity oscillations, where lower phase and higher gain reflect less efficient cerebral autoregulation. We used multivariable linear regression models adjusted for demographics, vascular risk factors, and history of kidney and cardiac diseases. Higher NT-proBNP levels at year 25 were associated with lower phase (ß [95% CI]=-5.30 lower degrees of phase [-10.05 to -0.54]) and higher gain (ß [95% CI]=0.06 higher cm/s per mm Hg of gain [0.004-0.12]) at year 30. Similarly, higher NT-proANP levels were associated with lower phase (ß [95% CI]=-9.08 lower degrees of phase [-16.46 to -1.70]). Conclusions Higher circulating levels of NT-proBNP and NT-proANP are associated with less efficient dCA 5 years later. These findings link circulating NP to cerebral autoregulation and may be one mechanism tying NP to adverse cerebrovascular outcomes.

Cumulative Blood Pressure Exposure, Basal Ganglia, and Thalamic Morphology in Midlife.

High blood pressure (BP) negatively affects brain structure and function. Hypertension is associated with white matter hyperintensities, cognitive and mobility impairment in late-life. However, the impact of BP exposure from young adulthood on brain structure and function in mid-life is unclear. Identifying early brain structural changes associated with BP exposure, before clinical onset of cognitive dysfunction and mobility impairment, is essential for understanding mechanisms and developing interventions. We examined the effect of cumulative BP exposure from young adulthood on brain structure in a substudy of 144 (61 female) individuals from the CARDIA (Coronary Artery Risk Development in Young Adults) study. At year 30 (Y30, ninth visit), participants (56±4 years old) completed brain magnetic resonance imaging and gait measures (pace, rhythm, and postural control). Cumulative systolic and diastolic BP (cumulative systolic blood pressure, cDBP) over 9 visits were calculated, multiplying mean values between 2 consecutive visits by years between visits. Surface-based analysis of basal ganglia and thalamus was achieved using FreeSurfer-initiated Large Deformation Diffeomorphic Metric Mapping. Morphometric changes were regressed onto cumulative BP to localize regions of shape variation. Y30 white matter hyperintensity volumes were small and positively correlated with cumulative BP but not gait. Negative morphometric associations with cumulative systolic blood pressure were seen in the caudate, putamen, nucleus accumbens, pallidum, and thalamus. A concave right medial putamen shape mediated the relationship between cumulative systolic blood pressure and stride width. Basal ganglia and thalamic morphometric changes, rather than volumes, may be earlier manifestation of gray matter structural signatures of BP exposure that impact midlife gait.

Selection and breeding of plant cultivars to minimize cadmium accumulation.

Natural variation occurs in the uptake and distribution of essential and nonessential trace elements among crop species and among cultivars within species. Such variation can be responsible for trace element deficiencies and toxicities, which in turn can affect the quality of food. Plant breeding can be an important tool to both increase the concentration of desirable trace elements and reduce that of potentially harmful trace elements such as cadmium (Cd). Selection programs for a low-Cd content of various crops, including durum wheat, sunflower, rice and soybean have been established and low-Cd durum wheat cultivars and sunflower hybrids have been developed. In durum wheat (Triticum turgidum L. var durum), low-Cd concentration is controlled by a single dominant gene. The trait is highly heritable, and incorporation of the low-Cd allele can help to reduce the average grain Cd to levels below proposed international limits. The allele for low-Cd concentration does not appear to affect major economic traits and should not cause problems when incorporated into durum cultivars. The cost of Cd selection in a breeding program is initially large both in terms of Cd determination and reduced progress towards development of other economic traits, but declines as more breeding lines in the program carry the low-Cd trait and are utilized in new crosses. Production of low-Cd crop cultivars can be used as a tool to reduce the risk of movement of Cd into the human diet.

Flow dependence of valve area in aortic stenosis: relation to valve morphology.

OBJECTIVES: We sought to develop an index of flow dependence of valve area in aortic valve (AoV) stenosis and to determine whether this index is related to structural characteristics of the diseased valve. BACKGROUND: Many studies of AoV stenosis using Gorlin or continuity equation methods have demonstrated flow dependence (an increase in valve area with increased flow). Variation in flow dependence between patients despite similar flow rates remains unexplained. METHODS: Dobutamine Doppler echocardiography was used to calculate flow rate and valve area by the continuity equation in 27 patients with aortic stenosis. For each patient the slope of the regression line of valve area to flow rate was determined (slope of flow dependence). Transesophageal echocardiography was used to evaluate features of valve morphology potentially related to the etiology of AoV stenosis and the mechanism of flow dependence. RESULTS: Mean slope of flow dependence was 0.28 cm2/100 ml per s (range -0.06 to 0.53); flow dependence was significantly >0 in 21 patients and was lower for bicuspid valves (slope 0.21 cm2/100 ml per s) than for tricuspid valves with <10% commissural fusion (slope 0.35, p < 0.01). Off-center/ovoid orifices demonstrated the least flow dependence (slope 0.19), whereas star-shaped orifices showed the most (slope 0.36, p < 0.01). Greater flow dependence was related to a lower percentage of commissural fusion (r = -0.46, p = 0.02) as well as diffuse sclerosis, primarily involving the cusp bodies, rather than localized sclerosis, with involvement of cusp margins. CONCLUSIONS: The slope of flow dependence of valve area in AoV stenosis differs markedly between patients. More flow dependence was associated with tricuspid valves and the morphologic features characteristic of calcific AoV stenosis, whereas less flow dependence was associated with bicuspid valves and the features of rheumatic disease.

Cu2+ Reduction by Tomato Root Plasma Membrane Vesicles.

Reduction of Cu2+ by plasma membrane vesicles isolated from tomato (Lycopersicon esculentum Mill.) roots was investigated. Plants were grown in hydroponic culture with complete nutrition for 4 weeks or were deprived of Fe for the last 7 d. Plasma membrane vesicles were prepared by aqueous two-phase partitioning. Reduction of Cu, Fe, and ferricyanide by plasma membrane vesicles was measured. An increase in the activity of all three pyridine-nucleotide-dependent activities was noted in plasma membrane preparations from Fe-deficient, compared to Fe-sufficient, plants. Solubilization and chromatographic separation of two plasma membrane electron transport systems indicated that the Fe-chelate reductase was probably responsible for reduction of Cu. Assays used a variety of Cu chelates, and for each the Cu activity in the assay was determined by the program Geochem PC. The rate of reduction of Cu correlated with the level of Cu activity, and results support the idea that free Cu2+ and not Cu chelates may serve as the true substrate for reduction. Reduction was observed only in assays in which Cu activity was equivalent to Cu-enriched or Cu-toxic soils. These results suggest that reduction of Cu by tomato root may have little or no physiological relevance under conditions experienced by the root in the soil.

Direct Measurement of 59Fe-Labeled Fe2+ Influx in Roots of Pea Using a Chelator Buffer System to Control Free Fe2+ in Solution.

Fe2+ transport in plants has been difficult to quantify because of the inability to control Fe2+ activity in aerated solutions and non-specific binding of Fe to cell walls. In this study, a Fe(II)-3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine-4[prime]4"-disulfonic acid buffer system was used to control free Fe2+ in uptake solutions. Additionally, desorption methodologies were developed to adequately remove nonspecifically bound Fe from the root apoplasm. This enabled us to quantify unidirectional Fe2+ influx via radiotracer (59Fe) uptake in roots of pea (Pisum sativum cv Sparkle) and its single gene mutant brz, an Fe hyperaccumulator. Fe influx into roots was dramatically inhibited by low temperature, indicating that the measured Fe accumulation in these roots was due to true influx across the plasma membrane rather than nonspecific binding to the root apoplasm. Both Fe2+ influx and Fe translocation to the shoots were stimulated by Fe deficiency in Sparkle. Additionally, brz, a mutant that constitutively exhibits high ferric reductase activity, exhibited higher Fe2+ influx rates than +Fe-grown Sparkle. These results suggest that either Fe deficiency triggers the induction of the Fe2+ transporter or that the enhanced ferric reductase activity somehow stimulates the activity of the existing Fe2+ transport protein.

Phytoremediation of soil metals.

The phytoremediation of metal-contaminated soils offers a low-cost method for soil remediation and some extracted metals may be recycled for value. Both the phytoextraction of metals and the phytovolatilization of Se or Hg by plants offer great promise for commercial development. Natural metal hyperaccumulator phenotype is much more important than high-yield ability when using plants to remove metals from contaminated soils. The hypertolerance of metals is the key plant characteristic required for hyperaccumulation; vacuolar compartmentalization appears to be the source of hypertolerance of natural hyperaccumulator plants. Alternatively, soil Pb and Cr6+ may be inactivated in the soil by plants and soil amendments (phytostabilization). Little molecular understanding of plant activities critical to phytoremediation has been achieved, but recent progress in characterizing Fe, Cd and Zn uptake by Arabidopsis and yeast mutants indicates strategies for developing transgenic improved phytoremediation cultivars for commercial use.

Trace element chemistry in residual-treated soil: key concepts and metal bioavailability.

Trace element solubility and availability in land-applied residuals is governed by fundamental chemical reactions between metal constituents, soil, and residual components. Iron, aluminum, and manganese oxides; organic matter; and phosphates, carbonates, and sulfides are important sinks for trace elements in soil-residual systems. The pH of the soil-residual system is often the most important chemical property governing trace element sorption, precipitation, solubility, and availability. Trace element phytoavailability in residual-treated soils is often estimated using soil extraction methods. However, spectroscopic studies show that sequential extraction methods may not be accurate in perturbed soil-residual systems. Plant bioassay is the best method to measure the effect of residuals on phytoavailability. Key concepts used to describe phytoavailability are (i) the salt effect, (ii) the plateau effect, and (iii) the soil-plant barrier. Metal availability in soil from metal-salt addition is greater than availability in soil from addition of metal-containing residuals. Plant metal content displays plateaus at high residual loadings corresponding to the residual's metal concentration and sorption capacity. The soil-plant barrier limits transmission of many trace elements through the food chain, although Cd (an important human health concern) can bypass the soil-plant barrier. Results from many studies that support these key concepts provide a basis of our understanding of the relationship between trace element chemistry and phytoavailability in residual-treated soils. Research is needed to (i) determine mechanisms for trace element retention of soil-residual systems, (ii) determine the effect of residuals on ecological receptors and the ability of residuals to reduce ecotoxicity in metal-contaminated soil, and (iii) predict the long-term bioavailability of trace elements in soil-residual systems.

Towards practical cadmium phytoextraction with Noccaea caerulescens.

A series of field trials were conducted to investigate the potential of Noccaea caerulescens F.K. Mey [syn. Thlaspi caerulescens J &C Presl. (see Koch and Al-Shehbaz 2004)] populations (genotypes) derived from southern France to phytoextract localized Cd/Zn contamination in Thailand. Soil treatments included pH variation and fertilization level and application of fungicide. N. caerulescens populations were transplanted to the field plots three months after germination and harvested in May, prior to the onset of seasonal rains. During this period growth was rapid with shoot biomass ranging from 0.93-2.2 g plant(-1) (280-650 kg ha(-1)) DW. Shoot Cd and Zn concentrations for the four populations evaluated ranged from 460-600 and 2600-2900 mg kg(-1) DW respectively. Cadmium and Zn Translocation Factors (shoot/root) for the populations tested ranged from 0.91-1.0 and 1.7-2.1 and Bioaccumulation Factors ranged from 12-15 and 1.2-1.3. We conclude that optimizing the use of fungicidal sprays, acidic soil pH, planting density and increasing the effective cropping period will increase rates of Cd and Zn removal enough to facilitate practical Cd phytoextraction from rice paddy soils in Thailand.

Blood pressure at rest and during maximal dynamic and isometric exercise as predictors of systemic hypertension.

This study sought to verify evidence that transient high blood pressure (BP) at rest and during dynamic and isometric exercise is often predictive of later hypertension. In addition these 3 predictors were compared. One hundred office patients (all men) with BPs less than 140/90 mm Hg, ages 28 to 79 years, who had little or no heart disease and were not taking medication, had BPs taken at rest and during treadmill and handgrip dynamometer. Within 14 years, 16 subjects developed hypertension and 84 remained normotensive. Multivariate statistical comparisons for systolic and diastolic BPs and their interactions were used to discriminate between later hypertensive and normotensive subjects. The best single predictor was resting diastolic BP, classifying 88% of hypertensive and 69% of normotensive subjects correctly, followed closely by handgrip and treadmill diastolic BP and resting, treadmill and handgrip systolic BP. The best prediction was by the interaction between resting diastolic BP X handgrip diastolic BP; this classified 88% of hypertensive and 80% of normotensive subjects correctly. Of the few known precursors of hypertension, high BP at rest and during dynamic and isometric stress provides a means of alerting to careful follow-up and early treatment.

Predictability of blood pressure response to isometric stress.

Isometric exercise causes transient systemic hypertension, but with individual differences. An attempt was made to delineate predictors of those differences by analyzing the blood pressure (BP) response in terms of variables readily measured in clinical practice. For each of 270 office patients, we determined blood pressure, heart rate (HR), electrocardiographic findings, and symptoms in response to maximal isometric and maximal dynamic exercise. For systolic BP response as the predicted measure, 4 predictor variables in combination, including age, sex, resting systolic BP, and maximal treadmill systolic BP, yielded 70% predictability. For diastolic BP, 5 predictors in combination, including handgrip strength, resting diastolic BP, treadmill HR, systolic BP, and diastolic BP, allowed 66% prediction. Not predictive of either were resting HR, abnormality of treadmill test, presence of heart disease, and certain other medical diagnoses.

Cadmium Resistance Screening in Nitrilotriacetate-Buffered Minimal Media.

Media used to determine the MICs of heavy metals for bacteria are unreliable because organic components in the media bind or chelate most of the metal being studied. To define specific metal activity in media and to maintain metal activity at a constant level, HEPES-MES [N-2-hydroxyethylpiperazine-N' -2-ethanesulfonic acid-2-(N-morpholine)ethanesulfonic acid] salts medium with arabinose medium was modified, and the modified medium was used to examine the MIC of cadmium for Rhizobium fredii USDA 201. Arabinose-HEPES-MES was modified by addition of the chelator nitrilotriacetate to buffer the supply of free Cd ion to maintain a constant Cd activity and by the use of only MES to buffer pH (buffered arabinose-MES medium [BAM]). Ca and Mg were supplied at the normal levels for soil solutions, and other trace elements were supplied at the levels required for normal growth of plants. The concentration of free Cd ion was calculated by using the computer program GEOCHEM-PC with a corrected data base. The Cd MIC in BAM was 14.0 muM, while that in a tryptone-yeast extract medium was 107 muM. The results indicate that substantial free Cd is removed from solution in most standard media, resulting in falsely high MICs. The new BAM medium allows for the precise determination of MICs, thus avoiding the uncertainties associated with other media.

Inorganic arsenic: a need and an opportunity to improve risk assessment.

This paper presents views on the current status of (inorganic) arsenic risk assessment in the United States and recommends research needed to set standards for drinking water. The opinions are those of the Arsenic Task Force of the Society for Environmental Geochemistry and Health, which has met periodically since 1991 to study issues related to arsenic risk assessment and has held workshops and international conferences on arsenic. The topic of this paper is made timely by current scientific interest in exposure to and adverse health effects of arsenic in the United States and passage of the Safe Drinking Water Act Amendment of 1996, which has provisions for a research program on arsenic and a schedule mandating the EPA to revise the maximum contaminant level of arsenic in drinking water by the year 2001. Our central premise and recommendations are straightforward: the risk of adverse health effects associated with arsenic in drinking water is unknown for low arsenic concentrations found in the United States, such as at the current interim maximum contaminant level of 50 microg/l and below. Arsenic-related research should be directed at answering that question. New epidemiological studies are needed to provide data for reliable dose-response assessments of arsenic and for skin cancer, bladder cancer, or other endpoints to be used by the EPA for regulation. Further toxicological research, along with the observational data from epidemiology, is needed to determine if the dose-response relationship at low levels is more consistent with the current assumption of low-dose linearity or the existence of a practical threshold. Other recommendations include adding foodborne arsenic to the calculation of total arsenic intake, calculation of total arsenic intake, and encouraging cooperative research within the United States and between the United States and affected countries.

Pharmacokinetics, tolerability, and clinical effectiveness of quetiapine fumarate: an open-label trial in adolescents with psychotic disorders.

BACKGROUND: This is the first investigation of the pharmacokinetics, tolerability, and efficacy of quetiapine fumarate in adolescents with chronic or intermittent psychotic disorders. METHOD: Ten patients with DSM-IV chronic or intermittent psychotic disorders (ages 12.3 through 15.9 years) participated in an open-label, rising-dose trial and received oral doses of quetiapine twice daily (b.i.d.), starting at 25 mg b.i.d. and reaching 400 mg b.i.d. by day 20. The trial ended on day 23. Key assessments were pharmacokinetic analysis of plasma quetiapine concentrations and neurologic, safety, and efficacy evaluations. RESULTS: No statistically significant differences were observed between 100-mg b.i.d. and 400-mg b.i.d. quetiapine regimens for total body clearance, dose-normalized area under the plasma concentration-time curve, or dose-normalized premorning- or postmorning-dose trough plasma values obtained under steady-state conditions after multiple-dose regimens. No unexpected side effects occurred with quetiapine therapy, and no statistically significant changes from baseline were observed for the UKU Side Effect Rating Scale items that were rated. No serious adverse events or clinically important changes in hematology or clinical chemistry variables were reported. The most common adverse events were postural tachycardia and insomnia. Extrapyramidal side effects improved, as evidenced by significant (p < .05) decreases from baseline to endpoint in the mean Simpson-Angus Scale total scores and Barnes Akathisia Scale scores. Quetiapine improved positive and negative symptoms, as shown by significant (p < .05) decreases from baseline to endpoint in the mean Brief Psychiatric Rating Scale total score, the Clinical Global Impressions-Severity of Illness scale, and the Modified Scale for the Assessment of Negative Symptoms summary score. CONCLUSION: Quetiapine pharmacokinetics were dose proportional in adolescents and were similar to those previously reported for adults. Quetiapine was well tolerated and effective in the small number of adolescents studied.

Birth injury as the cause of mental retardation.

Mental retardation, on initial impression, may appear to be caused by the birth process, but may be disproved by later clinical or autopsy examination. However, information often is lacking as to the basic pathology that may have been responsible for attributing the cause of the mental retardation to traumatic birth. From a 39-year period (1944 to 1983) 1146 records were evaluated at a state hospital for mentally retarded persons to determine how the intake impression compared with the final clinical and autopsy diagnoses of perinatal damage. Clinical evaluations provided some corrections of the intake diagnoses; autopsies provided more, but a combination provided the most reliable final diagnoses. Of 258 patients diagnosed as birth injury on intake, only 49.2% were confirmed by the best clinical and/or autopsy diagnoses. Although the cause of mental retardation was not ascertainable by either clinical or autopsy studies in 14.8% of cases, 31.4% were corrected to prenatal influences, and 4.6% to postnatal brain damage. Patients with perinatal cause of mental retardation usually were institutionalized at a young age and died young. If they do not require institutionalization until they are older, their life expectancy is longer, although still much less than that of normal persons.

Absolute bioavailability of lead acetate and mining waste lead in rats.

The primary purpose of this study was to generate data that could be used to determine the absolute bioavailability of lead using data from a previous study in which soil containing lead from mining waste was mixed with feed. Young male and female Sprague-Dawley rats (7-8 weeks of age, five/sex/group) were given either soluble lead acetate mixed in a purified diet (AIN-76) at three different dose levels (1, 25, and 250 ppm Pb for 30 consecutive days) or intravenously at doses of 0.02, 0.20, and 2.0 mg Pb/kg BW for 29 days. A control group (purified diet only) was also included. The intravenous groups were used to provide maximal absorption (lead presumed to be 100% bioavailable) and accumulation data for lead in blood, bone, and liver. The lead acetate groups were used to evaluate the comparability of the present study with a previous study that compared bioavailable lead from ingested soil and lead acetate. Group mean whole blood, bone and liver lead concentration values increased with increasing dose levels for all treatment groups. A linear relationship was observed between blood lead concentration and dose following intravenous administration of lead and this provided empirical support for using blood lead concentrations at supposed steady state (approximately 30 days) to compute the bioavailability of lead administered by different routes and from different sources. The absolute bioavailability values of mining waste lead in soil were low based on the results for all tissue types. Absolute bioavailability values for lead acetate in dosed feed for blood, bone, and liver were approximately 6-, 19-, and 20-fold greater, respectively, than mining waste lead. Based on the current design and test system used, the absolute bioavailability of mining waste lead in soil administered in feed was approximately 3% based on blood data and less than 1% based on bone and liver data. These data are consistent with the low solubility of the constituent lead mineral phases in Butte soils.