Differentiation pathways in carcinogenesis and in chemo- and radioresistance

Cancer stem cells (CSCs) share many features with embryonic stem cells (ESCs) such as the ability for self-renewal and differentiation. Signaling pathways that are involved in these processes are also involved in chemo- and radioresistance (e.g. Wnt, Notch and Hedgehog pathways). This review is focused on the influence of three important differentiation pathways on carcinogenesis and on chemo- and radioresistance in ESCs and CSCs.     

Advances in hypertension and diabetes in 2007

This article contains a review of some of the main developments reported in 2007 on the topics of hypertension and diabetes. The most important was the publication of the European Society of Cardiology's clinical practice guidelines on the two conditions, both of which have been adopted by the Spanish Society of Cardiology. Elsewhere, we have recently been witnessing crucial debates on the use of rosiglitazone for the treatment of diabetes and on the drug's effect on cardiovascular outcomes. The evidence available up to the present time is assessed. Finally, we will review the results of the most recent large clinical trial on the prevention of vascular complications in diabetics, which employed an antihypertensive approach.     

Oxytocin and vasopressin immunoreactivity in hypothalamic and extrahypothalamic sites in late pregnant and postpartum rats

This study examines immunoreactive levels of oxytocin (OT) and arginine-vasopressin (AVP) from acid extracts of the paraventricular nucleus (PVN), supraoptic nucleus (SON), anterior commissural nucleus (ACN) and the suprachiasmatic nucleus (SCN) as well as selected extrahypothalamic sites in pregnant or postpartum (PP) rats. Animals are sacrificed between 08.30 and 10.30 h 16 or 22 days after sperm is detected in their vaginal smears or on the morning after parturition. Peptide levels of pregnant or PP animals are compared to levels of ovariectomized (OVXed) rats sacrificed and assayed simultaneously. OT immunoreactive levels in the PVN and SON are significantly elevated in late pregnancy and PP. OT content of the ACN is elevated on day 16, but drops to control levels by day 22 of pregnancy and day 1 PP. Concomitant with the falling OT content in the ACN at the end of pregnancy, samples from the ventral septum have significantly increased OT content on day 1 PP. In extracts including the nucleus of the tractus solitarius (NTS) and dorsal motor nucleus of the vagus (dMX) OT is also elevated on the day after parturition. AVP levels peak on the day before parturition in all hypothalamic nuclei examined. These increases are significantly greater than in OVXed controls in the PVN and SON. AVP levels in the lateral habenula are elevated both on day 16 of pregnancy and on the first day PP. From these data we conclude that nonapeptide levels are altered across late pregnancy and early postpartum in some hypothalamic synthesis sites and in certain limbic and brainstem sites. We also postulate that OT is transported out of the ACN to extrahypothalamic sites around the time of parturition.     

Danazol: in vitro effects on human hemopoiesis and in vivo activity in hypoplastic and myelodysplastic disorders

Abstract: We examined the effects of danazol on in vitro growth of human bone marrow and peripheral blood progenitor cells from 15 normal donors and 5 myelodysplastic patients, and on in vivo hemopoiesis in 30 patients with hypoplastic or myelodysplastic disorders. At concentrations similar to that reported as the plasma level after oral administration, danazol significantly increased CFU-GM colony growth in all normal donors, while the influence on CFU-E, BFU-E, CFU-MK and CFU-GEMM colony growth was less evident. The stimulatory effect on CFU-GM was observed even after accessory cell depletion. No stimulatory effect either in vitro on the growth of all hemopoietic progenitors or in vivo was observed in 15 myelodysplastic patients, while 7 complete and 3 partial hematological responses occurred in 15 patients with hypoplastic disorders. In conclusion, our results suggest that danazol exerts a direct stimulatory activity in vitro at least on CFU-GM, and a hemopoietic stimulatory effect in vivo in hypoplastic but not in myelodysplastic disorders.     

Subjective and objective learning effects dissociate in space and in time

Perceptual learning not only improves sensitivity, but it also changes our subjective experience. However, the question of how these two learning effects relate is largely unexplored. Here we investigate how subjects learn to see initially indiscriminable metacontrast-masked shapes. We find that sensitivity and subjective awareness increase with training. However, sensitivity and subjective awareness dissociate in space: Learning effects on performance are lost when the task is performed at an untrained location in another quadrant, whereas learning effects on subjective awareness are maintained. This finding indicates that improvements in shape sensitivity involve visual areas up to V4, whereas changes in subjective awareness involve other brain regions. Furthermore, subjective awareness dissociates from sensitivity in time: In an early phase of perceptual learning, subjects perform above chance on trials that they rate as subjectively invisible. Later, this phenomenon disappears. Subjective awareness is thus neither necessary nor sufficient for achieving above-chance objective performance.     

Fibrin Monomer and Platelet Aggregation in Vitro and in Vivo

S ummary . The effect of fibrin monomer or fibrinogen-fibrin monomer complexes (FFMC) on platelet aggregation was studied in vitro and in vivo . FFMC produced by limited action of thrombin in vitro did not cause spontaneous platelet aggregation and neither accelerated nor inhibited platelet aggregation induced by ADP or collagen. If FFMC were converted to gels by treatment with ethanol, platelets aggregated spontaneously. When purified rabbit fibrin monomer was infused into rabbits pretreated with heparin to block the intravascular generation of thrombin, platelet counts did not decrease significantly, indicating the lack of a plateletaggregating effect of FFMC. It is concluded that FFMC, derived from thrombin action on fibrinogen, do not initiate or accelerate platelet aggregation.     

Justice and HIV care in Africa--antiretrovirals in perspective

The immense burden of HIV disease in sub-Saharan Africa has focused international interest on HIV care, especially on the lack of access to antiretroviral therapy (ART). Difficulties in implementing ART in Africa include drug costs, adequate long-term funding sources, assurance of drug quality, and rapid development of the human resources and healthcare infrastructure needed to deliver ART. Important questions requiring study are the minimum level of laboratory monitoring and clinical support consistent with good treatment outcomes, the impact of antiretroviral drug resistance on treated individuals and communities, and the effect of ART on transmission at a community level. There are some concerns and risks. First, a focus on treatment could compromise the commitment of individuals to risk-reduction, and of governments to prevention. Second, health equity could be reduced, by diverting scarce public funds from basic care for the poorest, to costly disease-suppressive care for a small and probably elite group. In conclusion, while prevention must be the first priority, care is also essential. The vast prevailing economic inequity between the world's rich and poor is the fundamental determinant of inequities in health and healthcare, including care for HIV. The global community of healthcare workers must focus its substantial influence on changing political and economic policies that foster injustice and AIDS.     

Comparative airway and vascular activities of leukotrienes C-1 and D in vivo and in vitro.

The pharmacologic activities of leukotrienes C-1 and D(LTC-1 and LTD), constituents of slow reacting substance of anaphylaxis (SRS-A), were evaluated in vitro on airway contractile tissues and in vivo on pulmonary mechanical function, mean systemic arterial pressure, and cutaneous microcirculation. In vitro both LTC-1 and LTD were potent and selective peripheral airway agonists, being more active than histamine; furthermore, LTD was active on peripheral airways at concentrations 1/100th those of LTC-1. The concentration-effect relationship for LTD and the profile of antagonism by FPL 55712 are consistent with the activity of this molecule at two separate peripheral airway receptors. In vivo, LTC-1 and LTD were nearly equally active in their effects on pulmonary mechanics, and the pattern of alterations was consistent with the predominant site of action being in the lung periphery. Furthermore, both agents had a direct systemic arterial hypotensive effect and were vasoactive on the cutaneous microcirculation. Thus, these compounds are likely to be major mediators of the pathologic alterations in immediate type hypersensitivity reactions in which peripheral airway constriction and hypotension are prominent features.     

Differences in measured and self-reported height and weight in Dutch adolescents

BACKGROUND/AIMS: Monitoring overweight prevalence and its trends in Dutch youth is frequently based on self-reported data. The validity of self-reported data especially in young adolescents is not sufficiently known. The purpose of this study is to study the validity of self-reported height and weight in 12- to 13-year-olds, to identify sociodemographic correlates and to explore whether correction factors can be developed to estimate the prevalence of overweight in youth. METHODS: 5,525 12- to 13-year-old pupils in the Rotterdam area filled in a confidential questionnaire on health topics, including their height and weight. In a sub-sample of 499 pupils both self-reported and measured height and weight were available. RESULTS: Self-reported data led to a considerable underestimation of Body Mass Index and consequently the prevalence of overweight. Underestimation was higher in pupils who regarded themselves as more fat, were of non-Dutch origin and in lower education levels. CONCLUSION: Self-reported height and weight appeared to be inappropriate to estimate the overweight prevalence in 12- to 13-year-olds, unless the figures were adjusted. Using adjusted self-reported BMI on an individual level is questionable. Actual measurements of height and weight are necessary to draw up valid correction formulas in new samples.     

Neridronate inhibits angiogenesis in vitro and in vivo

The effects of the amino-bisphosphonate neridronate on endothelial cell functions involved in angiogenesis, namely, proliferation and morphogenesis on Matrigel were tested in vitro, whereas its effects on angiogenesis were studied in vivo, by using the chick embryo chorioallantoic membrane (CAM) assay. In vitro, neridronate inhibited endothelial cell proliferation in a dose-dependent fashion, peaking at 30 μM. At the same concentration, neridronate inhibited fibroblast growth factor-2 (FGF-2)-induced capillary-like tube formation in the morphogenesis assay on Matrigel. In vivo, when tested in the CAM assay, neridronate again displayed the capability to inhibit FGF-2-induced angiogenesis. Overall, these results suggest that anti-angiogenesis by neridronate could be used to treat a wide spectrum of angiogenesis-dependent diseases, including certain chronic inflammatory diseases and cancer.     

ADH Genotypes and Alcohol Use and Dependence in Europeans

We have tested for effects of alcohol dehydrogenase ( ADH ) genotypes on self-reported alcohol consumption and symptoms of alcohol dependence, recorded on three occasions up to 15 years apart, in 377 male and female subjects of European descent. ADH2 genotype had significant effects on both consumption and dependence in the men, but not in the women. The effects of ADH3 genotype were considerably less than those of ADH2 , but significant results could be demonstrated when the combined genotypes were considered. The direction of the effects on alcohol consumption and dependence risk were consistent with reports on Asian subjects, and with the in vitro properties of ADH isoenzymes. As with previous studies on the relationship between ADH type and alcohol use, population stratification cannot be excluded as a contributing factor in these results.     

Gastric motor effects of peptide and non-peptide ghrelin agonists in mice in vivo and in vitro

BACKGROUND AND AIMS: The gastroprokinetic activities of ghrelin, the natural ligand of the growth hormone secretagogue receptor (GHS-R), prompted us to compare the effect of ghrelin with that of synthetic peptide (growth hormone releasing peptide 6 (GHRP-6)) and non-peptide (capromorelin) GHS-R agonists both in vivo and in vitro. METHODS: In vivo, the dose dependent effects (1-150 nmol/kg) of ghrelin, GHRP-6, and capromorelin on gastric emptying were measured by the 14C octanoic breath test which was adapted for use in mice. The effect of atropine, N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME), or D-Lys3-GHRP-6 (GHS-R antagonist) on the gastroprokinetic effect of capromorelin was also investigated. In vitro, the effect of the GHS-R agonists (1 microM) on electrical field stimulation (EFS) induced responses was studied in fundic strips in the absence and presence of L-NAME. RESULTS: Ghrelin, GHRP-6, and capromorelin accelerated gastric emptying in an equipotent manner, with bell-shaped dose-response relationships. In the presence of atropine or l-NAME, which delayed gastric emptying, capromorelin failed to accelerate gastric emptying. D-Lys3-GHRP-6 also delayed gastric emptying but did not effectively block the action of the GHS-R agonists, but this may be related to interactions with other receptors. EFS of fundic strips caused frequency dependent relaxations that were not modified by the GHS-R agonists. L-NAME turned EFS induced relaxations into cholinergic contractions that were enhanced by ghrelin, GHRP-6, and capromorelin. CONCLUSION: The 14C octanoic breath test is a valuable technique to evaluate drug induced effects on gastric emptying in mice. Peptide and non-peptide GHS-R agonists accelerate gastric emptying of solids in an equipotent manner through activation of GHS receptors, possibly located on local cholinergic enteric nerves.     

Pet- and pollen-induced upper airway symptoms in farmers and in nonfarmers.

The effect of farming on the risk of upper airway symptoms is not clear. In this cross-sectional, population-based study, 198 female farmers, 50 nonfarmers living on a farm, and 218 nonfarmers not living on a farm, filled in a symptom questionnaire and underwent skin-prick testing with common and agricultural allergens. In the logistic regression analysis, the latter group served as a control. Several adjustments were made, including childhood farming environment. Current farming was found to decrease the risks of pet- and pollen-induced upper airway symptoms, dose-dependently with the intensity and duration of animal husbandry. Including skin-test positivity to pets in the regression models did not affect the negative association between farming and pet-induced symptoms. In contrast, animal husbandry increased the risk of farm work-induced upper airway symptoms. Animal husbandry often induces work-related upper airway symptoms. However, the present study among female adults suggests that it may also decrease the risk of pet- and pollen-induced upper airway symptoms.     

Independent impact of obesity and fat distribution in hypertension prevalence and control in the elderly

BACKGROUND: Studies on the impact of weight excess and fat distribution on blood pressure are usually limited to young and middle-aged population, and data on the elderly are scarce. METHODS AND RESULTS: We performed an analysis of the Prevencion de Riesgo de Ictus, a population-based study on individuals aged 60 years or more in Spain, to assess the impact of weight excess, stratified by body mass index (normal <25; overweight 25-29.9; obesity > or =30 kg/m), and waist circumference [increased if > or =88 cm (women) or > or =102 (men)] on the prevalence on hypertension and lack of blood pressure control. In 6263 individuals (mean age 71.9 years old, 53.3% women; 73.0% with diagnosed hypertension), prevalence of obesity was 35.0%, and 65.6% showed an increased waist circumference. Body mass index and waist circumference showed an independent impact on the prevalence and absence of hypertension control. In a multivariate model including age, sex, body mass index, and waist circumference, prevalence of hypertension was higher in the overweight and obesity groups (odds ratio 1.41 and 1.96, respectively, compared to normal weight), and in those with increased waist circumference (odds ratio 1.25) compared with normal waist circumference. After further adjustment for antihypertensive therapy, overweight, and obesity (odds ratio 1.40 and 1.59, respectively) as well as increased waist circumference (odds ratio 1.39) were independently related to absence of blood pressure control. The impact of waist circumference on hypertension and blood pressure control was shown in each category of body mass index. CONCLUSION: In this cross-sectional study in an elderly population, body mass index and waist circumference showed an independent and direct impact on the prevalence of hypertension and on the absence of blood pressure control.     

Influence of cortisol on the larval bullfrog thyroid axis in vitro and in vivo and on plasma and ocular melatonin

Adrenal (interrenal) steroids have an important role in amphibian development, antagonizing the metamorphic changes induced by the thyroid at first and then synergizing with the thyroid hormones as their level rises during metamorphosis. Because most of the studies of corticoids at metamorphosis have focused on peripheral tissues, we investigated the effect of cortisol (hydrocortisone; HC) in vitro and in vivo on the thyroid of Rana catesbeiana (bullfrog) tadpoles on 12:12 light/dark (LD) cycles. Plasma and ocular melatonin, which is altered by changes in thyroxine (T(4)) levels, were also assayed in some experiments. Thyroids from premetamorphic tadpoles secreted less T(4) into culture media when incubated with 10 micrograms/ml HC and 0.2 micrograms/ml ovine thyrotropin (TSH) than with TSH alone and when cultured in the absence of TSH following 5 days of 10-micrograms HC injections, indicating that HC inhibited the thyroid at young stages. The effect of 10 micrograms/ml HC at older stages was investigated by culturing thyroids and pituitaries separately on the first day in control or HC media and then incubating the thyroids on the second day in homologous pituitary-conditioned media as a bioassay for pituitary TSH. HC had no effect on baseline T(4) secretion by the thyroids of prometamorphic or climax tadpoles on the first day but increased T(4) secretion over the control on the second day. Thyroids cultured with TSH and HC showed no increase in T(4) secretion over the control TSH group on the second day, indicating that, in the previous experiments, HC had enhanced pituitary secretion of TSH, rather than the response of the thyroid to TSH. In vivo, 5 days of injections of 10 micrograms HC increased plasma T(4) at prometamorphosis and decreased it at climax. There was no marked effect of HC on plasma or ocular melatonin levels. The findings showed that the nature of the effect of HC on the thyroid axis changes during metamorphosis from inhibition at early stages to a positive influence at prometamorphosis and finally to a negative effect on the T(4) level in the plasma at climax.     

Changes in blood pressure in the lying and sitting positions in normotensive, borderline and hypertensive subjects

This study attempted to determine the occurrence rate of blood pressure reduction after stroke by reviewing 100 patients with stroke diagnosed by clinical and laboratory studies. Retrospectively, blood pressures were noted on admission, 2nd hospital day and on discharge. Hypertension was defined as readings over 160 mmHg systolic and 90 mmHg diastolic. Pre-stroke and stroke blood pressures along with pressures during hospitalization for other diseases were also studied, totaling 252 admissions. Patients with congestive heart failure, myocardial infarction, coma and those who died were not counted. Of the 100 stroke patients, 47 hypertensives, consisting of 28 females and 19 males with a mean age of 69 years, were used. At the time of their stroke, 6 hypertensive patients were normotensive, 31 were normotensive from the 2nd hospital day and an additional 7 were normotensive on the day of discharge. One patient had labile blood pressures and 3 patients remained hypertensive. This study documents stroke as having a blood pressure lowering effect occurring in 13% of stroke patients on admission and in 64% by the 2nd hospital day. These observations in the hypertensive patient, rendered normotensive with stroke, suggests stroke has its own blood pressure lowering effect.     

Achalasia in father and son

Achalasia has not been previously reported in father and son. A man, age 38, and his father, age 66, presented two years apart with symptoms of dysphagia and aspiration. The diagnosis of achalasia was made on the basis of x-ray and endoscopic findings and on esophageal motility studies performed on the father. Both responded well to pneumatic dilatation and have been asymptomatic for 24 months and 6 months, respectively. These cases again suggest a genetic basis for achalasia.     

Abnormalities in apo B-containing lipoproteins in diabetes and atherosclerosis

Atherosclerosis is the major cause of death in patients with diabetes. Low-density lipoprotein (LDL) being the most important cholesterol-carrying lipoprotein has been studied extensively in both diabetes and non-diabetes. This paper reviews the literature but also focuses on the precursors of LDL and in particular the postprandial apo B-containing lipoproteins. Abnormalities in the postprandial lipoproteins and alteration in chylomicron assembly and clearance are discussed and the evidence presented suggesting the importance of dysregulation of these lipoproteins in atherosclerotic progression. The relationship between chylomicron production in the intestine and hepatic release of very low-density lipoproteins (VLDL) is explored, as is the interrelationship between clearance rates of these lipoproteins. The size of LDL influences its atherogenicity. VLDL composition and size in relation to its influence on LDL is discussed. The effect of diet on the composition of lipoproteins and the relationship between fatty acid composition and clearance is reviewed. Evidence that diabetic control beneficially alters lipoprotein composition is presented suggesting how improved diabetic control may reduce atherosclerosis. The review concludes with a discussion on the effect of the apo B-containing lipoproteins and their modification through glycation and oxidation on macrophage and endothelial function.     

Trends and patterns in research and development expenditures in the United States

This paper is a review of recent trends in United States expenditures on research and development (R&D). Real expenditures by both the government and the private sector increased rapidly between the mid-1970s and the mid-1980s, and have since leveled off. This is true of both overall expenditures and expenditures on basic research, as well as funding of academic research. Preliminary estimates indicate that about $170 billion was spent on R&D in the United States in 1995, with ≈60% of that funding coming from the private sector and about 35% from the federal government. In comparison to other countries, we have historically spent more on R&D relative to our economy than other advanced economies, but this advantage appears to be disappearing. If defense-related R&D is excluded, our expenditures relative to the size of the economy are considerably smaller than those of other similar economies.     

In vitro and in vivo detection of somatostatin receptors in pheochromocytomas and paragangliomas.

Fifty-one adrenal pheochromocytomas and 14 paragangliomas were evaluated for somatostatin (SRIH) receptor content with in vitro autoradiography on tissue sections from surgically removed tumors, using iodinated 125I[Tyr]3 octreotide as radioligand. Thirty-seven of 51 pheochromocytomas were SRIH receptor positive (73%), as well as 13 of 14 paragangliomas (93%). These SRIH receptors were of high affinity, pharmacologically specific for SRIH and localized on the tumor tissue. Using in vivo imaging techniques with radiolabeled SRIH analogs, paragangliomas could be visualized in five patients, as well as pheochromocytomas in two of three patients. All tumors tested subsequently in vitro (n = 7) were shown to contain SRIH receptors. A majority of pheochromocytomas were also shown to have a high tumoral SRIH content as measured by immunohistochemical techniques. Detection of SRIH messenger RNA in pheochromocytomas by in situ hybridization indicated that the SRIH was produced in the tumors. A weak inverse correlation was observed between SRIH receptor status and tumoral SRIH content, suggesting that SRIH receptors may be down-regulated by high levels of endogenous SRIH in some tumors. There was no correlation between the SRIH receptor status and sex, age, tumor size, benign vs. malignant tumor, or urinary metanephrine excretion. These tumors were also analyzed for allelic losses on various chromosomes and showed significant loss of heterozygosity (LOH) on chromosomes 1p, 3p, 17p, and 22q. All eight tumors with LOH on chromosome 1p were SRIH receptor positive (100%), whereas only 6 of 11 tumors without LOH on 1p (55%) were SRIH receptor positive, suggesting a correlation between LOH on 1p and SRIH receptor positive status. SRIH receptors thus represent a consistent pathobiochemical marker for most of these adrenal and extra-adrenal tumors. In addition, these receptors may be of potential interest for the in vivo localization of these tumors.