Potential rise in iron deficiency due to future anthropogenic carbon dioxide emissions.

Iron deficiency reduces capacity for physical activity, lowers IQ, and increases maternal and child mortality, impacting roughly a billion people worldwide. Recent studies have shown that certain highly consumed crops-C3 grains (e.g., wheat, rice, and barley), legumes, and maize-have lower iron concentrations of 4-10% when grown under increased atmospheric CO2 concentrations (550 ppm). We examined diets in 152 countries globally (95.5% of the population) to estimate the percentage of lost dietary iron resulting from anthropogenic CO2 emissions between now and 2050, specifically among vulnerable age-sex groups: children (1-5 years) and women of childbearing age (15-49 years), holding diets constant. We also cross-referenced these with the current prevalence of anemia to identify most at-risk countries. We found that 1.4 billion children aged 1-5 and women of childbearing age (59% of global total for these groups) live in high-risk countries, where the prevalence of anemia exceeds 20% and modeled loss in dietary iron would be in the most severe tertile (>3.8%). The countries with the highest anemia prevalence also derive their iron from the fewest number of foods, even after excluding countries consuming large amounts of unaccounted wild-harvest foods. The potential risk of increased iron deficiency adds greater incentive for mitigating anthropogenic CO2 emissions and highlights the need to address anticipated health impacts via improved health delivery systems, dietary behavioral changes, or agricultural innovation. Because these are effects on content rather than yield, it is unlikely that consumers will perceive this health threat and adapt to it without education.

Cell cycle regulatory gene abnormalities are important determinants of leukemogenesis and disease biology in adult acute lymphoblastic leukemia.

To test the hypothesis that cell cycle regulatory gene abnormalities are determinants of clinical outcome in adult acute lymphoblastic leukemia (ALL), we screened lymphoblasts from patients on a Southwest Oncology Group protocol for abnormalities of the genes, retinoblastoma (Rb), p53, p15(INK4B), and p16(INK4A). Aberrant expression occurred in 33 (85%) patients in the following frequencies: Rb, 51%; p16(INK4A), 41%; p53, 26%. Thirteen patients (33%) had abnormalities in 2 or more genes. Outcomes were compared in patients with 0 to 1 abnormality versus patients with multiple abnormalities. The 2 groups did not differ in a large number of clinical and laboratory characteristics. The CR rates for patients with 0 to 1 and multiple abnormalities were similar (69% and 54%, respectively). Patients with 0 to 1 abnormality had a median survival time of 25 months (n = 26; 95% CI, 13-46 months) versus 8 months (n = 13; 95% CI, 4-12 months) for those with multiple abnormalities (P <.01). Stem cells (CD34+lin-) were isolated from adult ALL bone marrows and tested for p16(INK4A) expression by immunocytochemistry. In 3 of 5 patients lymphoblasts and sorted stem cells lacked p16(INK4A) expression. In 2 other patients only 50% of sorted stem cells expressed p16(INK4A). By contrast, p16 expression was present in the CD34+ lin- compartment in 95% (median) of 9 patients whose lymphoblasts expressed p16(INK4A). Therefore, cell cycle regulatory gene abnormalities are frequently present in adult ALL lymphoblasts, and they may be important determinants of disease outcome. The presence of these abnormalities in the stem compartment suggests that they contribute to leukemogenesis. Eradication of the stem cell subset harboring these abnormalities may be important to achieve cure.

Critical role of p42/44(MAPK) activation in anisomycin and hepatocyte growth factor-induced LDL receptor expression: activation of Raf-1/Mek-1/p42/44(MAPK) cascade alone is sufficient to induce LDL receptor expression.

The protein synthesis inhibitor anisomycin activates stress-related mitogen-activated protein kinases (MAPKs), namely, c-jun NH(2)-terminal kinase (p46/54(JNK)) and p38(MAPK) in mammalian cells. In this paper, we show that although exposure to anisomycin resulted in rapid and strong activation of p46/54(JNK) and p38(MAPK), with a delayed low level dual-phosphorylation of mitogen/extracellular protein kinase (p42/44(MAPK)), low density lipoprotein (LDL) receptor induction depends solely on the mild activation of p42/44(MAPK) signaling cascade in HepG2 cells. Unlike hepatocyte growth factor (HGF) which caused LDL receptor induction via rapid, strong, and Ras-dependent p42/44(MAPK) activation, anisomycin-induced p42/44(MAPK) activity and increased LDL receptor expression in a Ras-independent manner. Finally, we examined the role of the p42/44(MAPK) signaling cascade in LDL receptor induction by activating this kinase independently of anisomycin or HGF. By using estrogen-dependent human Raf-1 protein kinase in transient transfection assays, we show that the exclusive activation of the Raf-1/MEK-1/p42/44(MAPK) signaling cascade with antiestrogen ICI 182, 780 caused induction of LDL receptor expression to the same level as observed with either HGF or anisomycin. Consistent with the role of p42/44(MAPK), induction was strongly inhibited by pretreatment with the MEK-1/2 inhibitor PD98059. Our observation that anisomycin can use p42/44(MAPK) signaling cascade is a departure from established thinking, and the results presented shows that activation of the p42/44(MAPK) alone is sufficient to fully induce LDL receptor transcription.

One-way cross-talk between p38(MAPK) and p42/44(MAPK). Inhibition of p38(MAPK) induces low density lipoprotein receptor expression through activation of the p42/44(MAPK) cascade.

In this paper, we report that SB202190 alone, a specific inhibitor of p38(MAPK), induces low density lipoprotein (LDL) receptor expression (6-8-fold) in a sterol-sensitive manner in HepG2 cells. Consistent with this finding, selective activation of the p38(MAPK) signaling pathway by expression of MKK6b(E), a constitutive activator of p38(MAPK), significantly reduced LDL receptor promoter activity. Expression of the p38(MAPK) alpha-isoform had a similar effect, whereas expression of the p38(MAPK) betaII-isoform had no significant effect on LDL receptor promoter activity. SB202190-dependent increase in LDL receptor expression was accompanied by induction of p42/44(MAPK), and inhibition of this pathway completely prevented SB202190-induced LDL receptor expression, suggesting that p38(MAPK) negatively regulates the p42/44(MAPK) cascade and the responses mediated by this kinase. Cross-talk between these kinases appears to be one-way because modulation of p42/44(MAPK) activity did not affect p38(MAPK) activation by a variety of stress inducers. Taken together, these findings reveal a hitherto unrecognized one-way communication that exists between p38(MAPK) and p42/44(MAPK) and provide the first evidence that through the p42/44(MAPK) signaling cascade, the p38(MAPK) alpha-isoform negatively regulates LDL receptor expression, thus representing a novel mechanism of fine tuning cellular levels of cholesterol in response to a diverse set of environmental cues.

Effects of vasoactive and inflammatory mediators on endothelin-1 expression in pulmonary endothelial cells.

Endothelin-1 (ET-1) is known to be involved in a variety of pathophysiologic conditions, especially of the pulmonary vasculature. The aim of this study was to investigate physiologic mediators potentially involved in the pathogenesis of pulmonary hypertension, for their effects on ET-1 gene expression at both the transcriptional and translational level. Rat microvascular and pulmonary artery endothelial cells grown in culture were exposed to vasoactive mediators (thrombin or an anoxic gas mixture) and inflammatory mediators (lipopolysaccharide, interleukin 1 alpha, interleukin 1 beta, or tumor necrosis factor alpha) for various time periods. The change in prepro-ET-1 (ppET-1) mRNA levels in these cells in response to stimuli was a time-dependent phenomenon. The inflammatory mediators caused an acute rise in ppET-1 mRNA levels whereby peak induction occurred after 1 h with a rapid decline to control levels by 4 h. The vasoactive mediators elicited a more sustained response whereby a significant elevation in ppET-1 mRNA expression occurred quickly and remained elevated through 4 h. The pattern of induction was more rapid for thrombin than for anoxic gas exposure. Radioimmunoassay analysis demonstrated a similar response for thrombin and the inflammatory mediators in ET-1 mature peptide release, whereas the effect of anoxic gas exposure was divergent. Significant elevations were noted after 6 h for thrombin as well as each of the inflammatory mediators except IL-1 alpha. In response to the anoxic gas exposure, however, a significant rise in ET-1 peptide release was not evident until after 24 h. To determine the level at which ppET-1 mRNA induction is regulated, cells were cotreated with each of the stimuli and actinomycin D or cycloheximide. Results indicate that the induction of ppET-1 mRNA levels is likely due to de novo transcription, as well as mRNA stabilization. In summary, inflammatory and vasoactive agents are important regulators of ET-1 gene expression in rat pulmonary endothelial cells; most important, we observed a differential response at the mRNA or peptide level depending on the mediator involved.

The profile elevation scale and the impairment scale: two new summary scales for the Luria-Nebraska Neuropsychological Battery.

Two new clinical summary scales have been developed for the Luria-Nebraska Neuropsychological Battery. The scales were constructed in a derivation/ crossvalidation design with a sample of 459 mixed brain impaired patients and 135 non-brain impaired persons. Preliminary evidence suggests that the Profile Elevation scale and the Impairment scale are psychometrically viable, produce additional information to what is offered by the current clinical summary scales, and deserve further investigation. Interpretations are suggested for the two new scales and supported by two neurosurgical case examples. The scales are also expected to offer the possibility of quick screening devices.

Urinary alkalinization and smoking cessation.

Previous studies have shown that large doses of a urinary alkalinizing agent reduced cigarette consumption spontaneously among smokers. After establishing a safe daily dose of an alkalinizing agent, sodium bicarbonate, its effect upon smoking cessation rates among 72 enrollees in a smoking cessation program was studied. In the first study, we determined that sodium bicarbonate (3900 mg per day) significantly increased urinary pH (from 6.0 to 6.7) and lowered titratable acidity. Ascorbic acid (1500 mg per day) had no effect of pH or acidity. In a second study, a group given sodium bicarbonate surpassed a placebo control group (who were given 1500 mg per day ascorbic acid) in total daily cigarette reduction after 5 weeks and in week-to-week smoking reduction. The groups did not, however, differ in the number who achieved total abstinence.

Effect of viral infections on pulmonary function in patients with chronic obstructive pulmonary diseases.

The effect of 100 separate viral infections of the respiratory tract on pulmonary function was evaluated prospectively over an eight-year period in 84 patients with chronic obstructive pulmonary diseases and in eight normal subjects. Some viral infections were associated with small acute declines in forced vital capacity and/or 1-sec forced expiratory volume of 25-300 ml. These declines were detectable only during the 90-day period after infection. The greatest abnormalities of pulmonary function followed infections with influenza virus, and the mean acute changes in 1-sec forced expiratory volume (-118.5 ml) were significantly greater than expected (-15.2 ml; P = 0.03). Smaller, statistically insignificant declines followed infections with parainfluenza virus, rhinovirus, adenovirus, and respiratory syncytial virus, and no changes were detectable after infections with coronavirus, herpes simplex virus, Mycoplasma pneumoniae, and Haemophilus influenzae. Long-term effects of influenza or other viral infections on the course of chronic obstructive pulmonary disease were not detected in this study population.

Variables associated with changes in spirometry in patients with obstructive lung diseases.

One hundred fifty subjects were enrolled in a long-term study of obstructive lung diseases; 84 of these were subjected to five or more spirometric studies over a period of two or more years. Stepdown regression analysis was performed to determine the association between many different variables and the annual rates of change in the forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). The following associations were noted to be significant (p less than 0.03); more favorable rates of change of the FVC and FEV1 were associated with a higher alpha1-antitrypsin level and older age. Less favorable changes were associated with more years of cigarette smoking, more airway reactivity and more frequent lower respiratory tract illnesses.

Prediction of neurosurgical results by psychological evaluation.

There has been an increasing interest in the role of personality factors in the outcome of medical treatment. The present study examined the role of personality measures in predicting the outcome of neurosurgery for patients with a well-documented disruption of one or more discs. Each of 15 male and 16 female patients whose average age was 40.8 yr. received the Minnesota Multiphasic Personality Inventory before surgery and received a follow-up at least one year after surgery or until a final, stable level of recovery was attained. A multiple correlation of .64 between the personality measures and treatment outcome suggested that even in cases with a well-documented need for surgery, psychological factors can play a major influence in the eventual outcome. Possible psychological interventions before surgery which might increase the likelihood of a good outcome are briefly outlined.

Ultrasonic extraction of total particulate aromatic hydrocarbons (TpAH) from airborne particles at room temperature.

A superior enrichment procedure for the extraction of TpAH from airborne particles collected on glass fiber filter paper is described. The sample is suspended in a solvent and subjected to ultrasonic waves at room temperature with glass powder to adsorb polar coextractives. The TpAH in the filtered extracts are separated from other compounds by high speed liquid chromatography. Sensitivity is in the nanogram range, and the procedure is highly reproducible. Significantly larger amounts of TpAH are recovered than with Soxhlet extraction for 6 to 8 hours, and the percentage of pAH in the extracts is much higher. The entire procedure requires approximately 40 minutes, most of which is waiting time.

Immunological nature of antimycobacterial phenomenon in macrophages.

Heptane-extractable fractions (HEF) prepared from immune-activated macrophages (IA-M) of tubercle bacilli or bovine gamma globulin-sensitized and -challenged guinea pigs inhibited the growth of tubercle bacilli whereas HEF of normal macrophages exerted no antibacterial activity. In distinction to the strong antibacterial activity of HEF of IA-M, HEF of immune macrophages exerted weak or no antimycobacterial activity. HEF of alveolar macrophages exerted stronger antibacterial activity than HEF of peritoneal macrophages. The degree of the antibacterial activity of HEF was determined primarily by the time of macrophage collection from antigenically stimulated animals. The antibacterial activity gradually increased and peaked at 2 weeks after the antigenic stimulation of sensitized animals; subsequently, the activity declined and disappeared in about 5 weeks. Similar to other immunological reactions, the stimulation of sensitive animals with specific antigen induced an anamnestic reaction which was characterized by a rapid recall of the macrophage antimycobacterial phenomenon (MAP). The antibacterial strength of the recalled phenomenon in sensitized animals was dependent upon the intensity of the sensitizing regimen; the phenomenon was much stronger in three times-sensitized animals than in once- and twice-sensitized animals. The time of appearance and the specificity of induction and of recall of the MAP indicate that the phenomenon is associated with the activated state in macrophages and, as a consequence of this association, it has a well-defined immunological nature.

Antimycobacterial effect of lysates prepared from immunologically activated macrophages.

Lysates or heptane extracts of peritoneal (P) and alveolar (A) normal macrophages (N-M), immune macrophages (I-M), and immune-activated macrophages (IA-M) were examined for antimycobacterial activity by the agar-plate diffusion test. This test has been found suitable to reveal the antibacterial activity in 3-day incubated, but not in freshly prepared, lysates. Results showed that materials of IA-AM or I-AM and of IA-PM exerted antimycobacterial effects, whereas materials of N-PM, I-PM, and of N-AM were usually inactive. Antimycobacterial activity of lysates of AM was stronger than that of PM. The formation of antibacterial factors during an incubation of M lysates, the solubility of the factors in heptane, and various other characteristics suggested that the antimycobacterial effect was caused by the formation of toxic levels of non-esterified fatty acids. M lysates exerted equal activities against BCG, H(37)Ra, and H(37)Rv strains of tubercle bacilli. The presence of antimycobacterial activity in lysates prepared from IA-M of either BCG- or BCG-sensitized animals indicated that the potential to generate antimycobacterial activity is associated with the state of delayed hypersensitivity and the state of activation of M.