ΔNp63α promotes adhesion of metastatic prostate cancer cells to the bone through regulation of CD82.

ΔNp63α is a critical mediator of epithelial development and stem cell function in a variety of tissues including the skin and breast, while overexpression of ΔNp63α acts as an oncogene to drive tumor formation and cancer stem cell properties in squamous cell carcinoma. However, with regards to the prostate, while ΔNp63α is expressed in the basal stem cells of the mature gland, during adenocarcinoma development, its expression is lost and its absence is used to clinically diagnose the malignant state. Surprisingly, here we identify a sub-population of bone metastatic prostate cancer cells in the PC3 cell line that express ΔNp63α. Interestingly, we discovered that ΔNp63α favors adhesion and stem-like growth of these cells in the bone microenvironment. In addition, we show that these properties require expression of the target gene CD82. Together, this work uncovers a population of bone metastatic prostate cancer cells that express ΔNp63α, and provides important information about the mechanisms of bone metastatic colonization. Finally, we identify metastasis-promoting properties for the tetraspanin family member CD82.

ZRF1 controls oncogene-induced senescence through the INK4-ARF locus.

The reactivation of the INK4-ARF locus, which is epigenetically repressed by Polycomb proteins in healthy cells, is a hallmark of senescence. One mechanism of reactivating Polycomb-silenced genes is mediated by the epigenetic factor ZRF1, which associates with ubiquitinated histone H2A. We show that cells undergoing senescence following oncogenic Ras expression have increased ZRF1 levels, and that this binds to the p15INK4b, ARF and p16INK4a promoters. Furthermore, ZRF1 depletion in oncogenic Ras-expressing cells restores proliferation by preventing Arf and p16Ink4a expression, consequently bypassing senescence. Thus, ZRF1 regulates the INK4-ARF locus during cellular proliferation and senescence, and alterations in ZRF1 may contribute to tumorigenesis.

The prevalence of low back pain in the elderly. A systematic review of the literature.

STUDY DESIGN: The prevalence of low back pain in the older population (> = or 65 years) was reviewed in an analysis of the literature from 1966 to the present. OBJECTIVE: To determine the prevalence of low back pain in the geriatric population. SUMMARY OF BACKGROUND DATA: Back pain is one of the most frequently reported conditions affecting the adult population. However, the prevalence of low back pain in the older age population is not accurately known. METHODS: A methodologic search of five computerized bibliographic databases was performed to identify citations on the prevalence of low back pain in the elderly. Data were summarized, and prevalence studies were critically appraised in detail for their quality. RESULTS: There is wide variability in the reported prevalence of back pain. Many factors have been proposed to explain these findings including sample source, study design, definitions of back pain, and use of patient-reported data. Comorbidity among older patients also contributes to the variability in the reporting of prevalence of back pain. CONCLUSION: There is an under-representation of the older population in the back pain literature. The data in the current study suggest that the prevalence of low back pain in this population is not known with certainty and is not comparable with that in the younger population. The authors stress the need for future studies to improve the reporting of age information to make prevalence studies more informative and applicable.

Molybdenum absorption and utilization in humans from soy and kale intrinsically labeled with stable isotopes of molybdenum.

BACKGROUND: Stable-isotope studies of molybdenum metabolism have been conducted in which molybdenum was added to the diet and was assumed to be absorbed and utilized similarly to the molybdenum in foods. OBJECTIVE: Our objective was to establish whether the molybdenum in foods is metabolized similarly to molybdenum added to the diet. DESIGN: We first studied whether sufficient amounts of molybdenum stable isotopes could be incorporated into wheat, kale, and soy for use in a human study. Enough molybdenum could be incorporated into soy and kale to study molybdenum absorption and excretion. Two studies were then conducted, one in women and one in men. In the first study, each meal contained approximately 100 microg Mo from soy, kale, and extrinsic molybdenum. In the second study, soy and extrinsic molybdenum were compared; the meal contained approximately 300 microg Mo. RESULTS: In the first study, molybdenum was absorbed equally well from kale and an extrinsic source. However, the molybdenum in soy was less well absorbed than the molybdenum in kale or that added to the diet. In the second study, absorption of molybdenum from soy was less than from the extrinsic label. Urinary excretion of soy molybdenum was also lower than urinary excretion of the extrinsic label, but excretion as a percentage of the absorbed dose was not significantly different between treatments. CONCLUSIONS: The molybdenum in soy is less available than molybdenum added to the diet, but the molybdenum in kale is as available as molybdenum added to the diet. Once absorbed, excretion is not significantly different for soy, kale, and extrinsic molybdenum.

Cell death in the endocardial cushions of the developing heart.

The incidence of apoptotic cells in the hearts of chick embryos between days 4 and 8 of development was examined using an in situ technique for the detection of DNA fragmentation. Using this method it was possible to demonstrate foci of apoptotic cells primarily in two locations: the outflow tract cushions and the atrioventricular cushions. Both occurred only during narrow time windows: between embryonic days 4.5 and 6.5 in the outflow tract, and between embryonic days 5.5 and 7.5 in the atrioventricular canal. This is a much more restricted distribution of dying cells than previously thought, with reproducible cell death notably absent from the atrial and ventricular walls. Dying cells were also unexpectedly absent from the fusion seam of apposed cushions. In a complementary study, cell proliferation in these tissues was examined over the same time period using the expression of proliferating cell nuclear antigen as a marker for dividing cells. Cell proliferation occurred throughout the region of the cushions at these stages, including the myocardium and the fusion points of the apposed cushions. It is concluded that cells undergoing programmed cell death at this time in the developing chick heart are abundant in, and largely restricted to, the cushion tissue, and that cushion morphogenesis is regulated by the co-ordination of cell transformation, cell proliferation and, during a narrow time window, cell death.

Copper absorption, excretion, and retention by young men consuming low dietary copper determined by using the stable isotope 65Cu.

A study was conducted in young men to evaluate the effect of a low-copper diet on copper absorption, excretion, and retention. Eleven young men were confined to a metabolic research unit for 90 d. The study was divided into three periods, with dietary copper as the only variable. Dietary copper intake was 0.66 mg/d for 24 d, 0.38 mg/d for 42 d, and 2.49 mg/d for 24 d. The stable isotope 65Cu was fed to five of the subjects once during the first and last dietary period and twice, early and late, in the second period to determine copper absorption. 65Cu was infused into an arm vein of the other six subjects once during each dietary period to estimate excretion of endogenous copper. Total copper and 65Cu were determined by isotope dilution with thermal-ionization mass spectrometry. Fractional absorption was significantly higher during the low-copper period than in either period with higher dietary copper and excretion of the infused isotope was significantly lower in the low-copper period. Subjects were in negative balance early in the first two periods but achieved balance by the end of those periods. They retained copper during the highest dietary copper period (third period). The results suggest that endogenous copper excretion is a major point of regulation of the body's copper stores. Regulation of absorption and of endogenous excretion in response to dietary copper intake helps to protect against deficiency and toxicity. However, this regulation was not sufficient to maintain copper status at the lowest intake of dietary copper, 0.38 mg/d.

On becoming a parasite: evaluating the role of wall oxidases in parasitic plant development.

BACKGROUND: The temporal and spatial control of the transition from vegetative to parasitic growth is critical to any parasite, but is essential to the sessile parasitic plants. It has been proposed that this transition in Striga spp. is controlled simply by an exuded oxidase that converts host cell-surface phenols into benzoquinones which act as developmental signals that mediate the transition. An understanding of this mechanism may identify the critical molecular events that made possible the evolution of parasitism in plants. RESULTS: PoxA and PoxB are identified as the only apoplastic phenol oxidases in Striga asiatica seedlings, and the genes encoding them have been cloned and sequenced. These peroxidase enzymes are capable of oxidizing the 60 known inducing phenols into a small set of benzoquinones, and it is these quinones that induce parasitic development. Analysis of the reaction requirements and comparisons to host enzymes, however, lead us to argue that PoxA and PoxB are not necessary for host recognition. CONCLUSIONS: A new model is proposed where constitutive production of an activated oxygen species (in the case of Striga, H2O2) mediates host recognition. This strategy would allow a parasite to exploit abundant host enzymes to produce the diffusible recognition signals by converting a standard host defense into a parasitic offense.

Copper status of young men consuming a low-copper diet.

A study was conducted in 11 young men to evaluate the effect of a low-copper diet on indexes of copper status and to define an amount of dietary copper at which adequate copper status could not be maintained. The young men were confined to a metabolic research unit for 90 d. The study was divided into three periods, with dietary copper as the only variable. Dietary copper was 0.66 mg/d for 24 d, 0.38 mg/d for 42 d, and 2.49 mg/d for 24 d. Plasma copper, ceruloplasmin activity, ceruloplasmin concentration, and erythrocyte superoxide dismutase (SOD) were measured at selected time points during each dietary copper period. Urine was collected throughout the study. Plasma copper, ceruloplasmin concentration and activity, and urinary copper declined significantly during the lowest dietary copper period. Plasma copper, ceruloplasmin concentration, and urinary copper increased in response to repletion. The average erythrocyte SOD concentration was lower during the depletion period than in the periods before or after depletion, but it did not decline significantly over time in the depletion period. The results suggest that these indexes are sensitive to copper depletion; that 0.38 mg Cu/d is not sufficient to maintain copper status in normal, healthy young men; and that the minimum dietary copper requirement is between 0.4 and 0.8 mg/d.

Molybdenum absorption, excretion, and retention studied with stable isotopes in young men at five intakes of dietary molybdenum.

A study of molybdenum absorption, excretion, and balance was conducted in four young men fed five amounts of dietary molybdenum, ranging from 22 to 1490 micrograms/d, for 24 d each. The study was conducted to obtain scientific data on which to base a recommendation on dietary molybdenum intake for healthy young men. Stable isotopes of molybdenum were used as tracers. 100Mo was fed five times during the study and 97Mo was infused three times. 94Mo was used to quantify the molybdenum isotopes and total molybdenum in urine, fecal collections, and diets by isotope dilution. Adverse effects were not observed at any of the dietary intakes. Molybdenum was very efficiently absorbed, 88-93%, at all dietary molybdenum intakes, and adsorption was most efficient at the highest amounts of dietary molybdenum. The amount and percentage of molybdenum excreted in the urine increased as dietary molybdenum increased, suggesting that molybdenum turnover is slow when dietary molybdenum is low and increases as dietary molybdenum increases. We conclude from these results that dietary intakes between 22 and 1500 micrograms/d by adult men are safe for > or = 24 d and that molybdenum retention is regulated by urinary excretion. Molybdenum is conserved at low intakes and excess molybdenum is rapidly excreted in the urine when intake is high.

Molybdenum absorption, excretion, and retention studied with stable isotopes in young men during depletion and repletion.

A study of molybdenum absorption, excretion, and balance was conducted in four young men fed a low-molybdenum diet (22 micrograms/d) for 102 d followed by 18 d of the same diet supplemented to contain 467 micrograms/d. The study was conducted to determine the minimum dietary molybdenum requirement of healthy young men. Stable isotopes of molybdenum were used as tracers. 100Mo was fed four times during the study, 97Mo was infused twice, and 94Mo was used as an isotopic diluent to quantify the molybdenum isotopes and total molybdenum in complete urine and fecal collections and in the diets. The study demonstrated that subjects could not consistently attain balance with the low-molybdenum diet, but balance improved with time, and no signs of molybdenum deficiency were observed. Molybdenum was very efficiently absorbed at both intakes of dietary molybdenum and urinary excretion increased as dietary molybdenum increased. Molybdenum turnover was significantly slower when dietary molybdenum was low. We estimate from these results that the minimum dietary molybdenum requirement is approximately 25 micrograms/d or possibly less. This suggests that the lower end of the recommended range could be less than the current recommended amount of 75 micrograms/d.

Isotope ratios of molybdenum determined by thermal ionization mass spectrometry for stable isotope studies of molybdenum metabolism in humans.

Methods were developed to separate and purify Mo from biological samples and to measure isotopic ratios in 1 microgram of Mo. A magnetic sector, thermal ionization mass spectrometer was used with simultaneous collection of five isotopes. Isotopic ratios were corrected for mass fractionation by iterative normalization using the 96/98 ratio. Ion beam intensity was enhanced by using a double-filament configuration, loading samples onto evaporation filaments with silica gel and boric acid. A triple-isotope-dilution approach was used, so the method could be applied to two-tracer studies of Mo metabolism in human subjects. 94Mo was added to samples prior to purification to quantify the total Mo content of samples and to determine the amounts of enriched 97Mo and 100Mo appearing in urine and fecal samples of study participants. The three ratios, 94/98, 97/98, and 100/98, were determined with within-run precision of from 0.06 to 0.10% (RSD). Precision of the ratios between replicates was from 0.05 to 0.08%.

Oxygen free radicals and the cerebral arteriolar response to group B streptococci.

We used a cranial window preparation to observe the effects of direct application of group B streptococci to the surface of the brain in the adult rat. Continuous exposure to group B streptococci at concentrations of 10(3) and 10(5) organisms/mL caused progressive dilation of surface (pial) cerebral arterioles that became statistically significant (p less than 0.05) after 2.5 h. These results were reproduced with heat-killed organisms at the same concentration, but not with a bacteria-free filtrate of the growth medium. In separate studies, we found that infusion of alkaline cerebrospinal fluid (pH = 7.8) into the window did not reverse vasodilation, suggesting that it was not due to progressive cerebrospinal fluid acidosis. A solution of nitroblue tetrazolium infused into the window at the end of a 3-h exposure to the organism was promptly reduced, suggesting the presence of oxygen free radicals. Treatment with i.v. polyethylene glycol-superoxide dismutase and polyethylene glycol-catalase in doses of 10,000 and 20,000 U/kg, respectively, was itself without effect on pial arterioles, but treatment with these compounds before exposure to group B streptococci eliminated the vasodilation. These data support a role for oxygen free radicals in the pathogenesis of pial arteriolar dysfunction induced by exposure to group B streptococci.

A stable-isotope study of zinc, copper, and iron absorption and retention by young women fed vitamin B-6-deficient diets.

A 98-d study was conducted in young women to determine the effect of vitamin B-6-deficient diets on zinc, copper, and iron metabolism. Young women were fed vitamin B-6-deficient formula initially, followed by food diets containing four increasing amounts of vitamin B-6. Zinc, copper, and iron absorption, retention, and status were determined at intervals throughout the study. Zinc absorption and retention were greater during vitamin B-6 depletion but serum zinc declined, suggesting that absorbed zinc was not available for utilization. Copper absorption was lower during vitamin B-6 depletion but serum copper was not affected and balance was positive. Iron absorption was not impaired significantly by vitamin B-6-deficient diets but status may have declined. The results suggest that vitamin B-6 depletion of young women may alter zinc metabolism, inhibit copper absorption, and affect iron status. The effects of vitamin B-6 depletion differ markedly among these elements.

Randomized comparative trial of indomethacin and ritodrine for the long-term treatment of preterm labor.

A randomized prospective trial was performed to compare the efficacy and safety of ritodrine and indomethacin in the long-term treatment of preterm labor. Forty patients with intact membranes in preterm labor at 23 to 34 weeks' gestation were randomized to receive either intravenous ritodrine or oral indomethacin as the first-line tocolytic agent. Successful intravenous ritodrine therapy was followed by oral terbutaline therapy, and indomethacin-treated patients continued to receive oral indomethacin. Treatment failures were defined as progressive preterm labor or patient intolerance, and these patients were treated with intravenous magnesium sulfate. Ritodrine and indomethacin were equally successful in delaying preterm birth as defined by interval to delivery, gestational age at delivery, delivery delayed greater than 7 days, attainment of 35 weeks of gestation, percentage of patients who required magnesium sulfate therapy, percentage of patients who were readmitted with premature rupture of membranes, absence of recurrent preterm labor, and infant birth weight. More than 80% of mothers who received ritodrine voiced complaints of beta-sympathomimetic side effects, and one patient discontinued treatment as the result of intolerance. There were minimal patient complaints with indomethacin use. No statistically significant differences were noted in neonatal outcome as defined by Apgar scores, umbilical cord pH, intensive care days, ventilator days, or neonatal deaths. However, three cases of primary pulmonary hypertension were observed in the indomethacin group. We had not previously observed this problem with short-term (24 to 48 hours) indomethacin therapy.

Milk's effect on the bioavailability of iron from cereal-based diets in young women by use of in vitro and in vivo methods.

A study was conducted in healthy young women to measure and compare the availability of iron from cereal-based diets with and without milk by use of in vivo and in vitro methods. In vitro iron-bioavailability tests demonstrated that the amounts of soluble and ionizable iron in cereal-based diets were increased two- and three-fold, respectively, when milk was added. 54Fe, a stable isotope of iron, and fecal monitoring were used to determine iron absorption in eight young women. Iron absorption was higher with milk than without milk in seven of the eight subjects but did not differ significantly between the two treatments. The results suggest that in vivo and in vitro effects differ and that the absorption of iron from cereal-based diets is neither enhanced nor inhibited by the addition of milk.

Assessing the need for transfusion of premature infants and role of hematocrit, clinical signs, and erythropoietin level.

There are no clear criteria for administration of blood to premature infants. In the past, indications for transfusion have included tachypnea, tachycardia, poor weight gain, apnea, bradycardia, pallor, lethargy, decreased activity, or poor feeding. Some have suggested that erythropoietin levels may also be useful in determining the need for transfusion. Data were studied from 11 premature infants with birth weights less than 1500 g collected throughout 469 hospital days. During that period the infants received a total of 37 blood transfusions. No overall relationship was found between hematocrit of 19% to 64% and heart rate, respiratory rate, or the occurrence of bradycardia; ie, these variables proved to be clinically unreliable as indicators of hematocrit. Furthermore, no predictable effect of transfusion could be identified on heart rate, respiratory rate, or on the incidence of apnea or bradycardia. It was anticipated that frequent episodes of apnea or bradycardia might increase serum erythropoietin concentration. To the contrary, more frequent bradycardia was associated with the low erythropoietin levels because those infants tended to receive transfusions for "symptomatic" anemia. The data are consistent with the concept that "anemia of prematurity" is not predictably associated with symptoms classically attributed to anemia. Possible reasons for this are that the premature infant has a different inherent response to anemia; that it is inappropriate to extrapolate symptoms of severe acute anemia to persons with mild or moderate chronic anemia; or, most likely, that other determinants of heart rate, respiratory rate, and apnea/bradycardia are of more importance than mild or moderate anemia.