Effect of aerobic exercise intervention on markers of insulin resistance in breast cancer women.

Insulin may affect breast cancer (BC) risk and prognosis. Exercise reduces insulin in obese BC survivors. We designed a randomised controlled trial to test the effect of an aerobic exercise intervention (AEI) on insulin parameters and body composition in non-obese BC women without insulin resistance. Thirty-eight BC women were randomised into an intervention group (IG = 18) or control group (CG = 20). IG participated in a structured AEI for 3 months, while CG received only the Word Cancer Research Fund/American Institute Cancer Research (WCRF/AICR) recommendation to be physically active. Fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) index, metabolic parameters and body composition were collected at baseline and after the AEI. IG reduced insulin and HOMA-IR index by 15% and 14%, while CG increased these parameters (+12% and +16%). Insulin changed differently over time in the two randomised groups (pinteraction  = .04). The between-group differences in the change of insulin (IG = -1.2 µU/ml versus CG = +0.8 µU/ml) and HOMA-IR index (IG = -0.26 versus CG = +0.25) were respectively significant (p = .04) and non-significant (p = .06). IG significantly improved lower limb muscle mass in comparison with CG (p = .03). A structured AEI may improve insulin, HOMA-IR index and body composition in non-obese BC survivors without insulin resistance.

Circulating fractures-related microRNAs distinguish primary hyperparathyroidism-related from estrogen withdrawal-related osteoporosis in postmenopausal osteoporotic women: A pilot study.

Primary hyperparathyroidism (PHPT) represents a common cause of secondary osteoporosis in postmenopausal women, where the negative effect of estrogen withdrawal and that of hyperparathyroidism on bone mineralization coexist. Circulating microRNAs (miRNAs) expression profile has been correlated to both osteoporosis and fragility fractures. The study aimed to profile a set of miRNAs associated with osteoporotic fractures, namely miR-21-5p, miR-23a-5p, miR-24-2-5p, miR-24-3p, miR-93-5p, miR-100-5p, miR-122-5p, miR-124-3p, miR-125b-5p and miR-148-3p, in the plasma of 20 postmenopausal PHPT women. PHPT miRNAs profiles were compared with those detected in 10 age-matched postmenopausal non-PHPT osteoporotic women (OP). All the 10 miRNAs were detected in the plasma samples of both PHPT and OP women. The miRNA profiles clearly distinguished PHPT from OP samples, and identified within the PHPT group, two clusters differing for the PHPT severity, in term of ionized calcium and bone mineralization. In particular, miR-93-5p was significantly downregulated in PHPT samples, while miR-24-3p negatively correlated with the T-score at lumbar, femur neck and total hip sites. PHPT women who experienced osteoporotic fractures had plasma miR-24-3p levels higher than those detected in unfractured PHPT women. In conclusion, PHPT may modulate circulating fractures-related miRNAs, in particular, miR-93-5p, which may distinguish estrogen-related from PHPT-related osteoporosis.

Ultrasound elastography is useful to distinguish acute and chronic deep vein thrombosis.

Essentials Ultrasound elastography uses tissue deformation to assess the relative quantification of its elasticity. Compression and duplex ultrasonography may be unable to correctly determine the thrombus age. Ultrasound elastography may be useful to distinguish between acute and chronic deep vein thrombosis. The exact determination of the thrombus age could have both therapeutic and prognostic implications. BACKGROUND: Background Ultrasound elastography (UE) imaging is a novel sonographic technique that is commonly employed for relative quantification of tissue elasticity. Its applicability to venous thromboembolic events has not yet been fully established; in particular, it is unclear whether this technique may be useful in determining the age of deep vein thrombosis (DVT). Thus, the aim of this study was to assess the role of UE in distinguishing acute from chronic DVT. Methods Consecutive patients with a first unprovoked acute and chronic (3 months old) DVT of the lower limbs were analyzed. Patients with recurrent DVT or with a suspected recurrence were excluded. The mean elasticity index (EI) values of acute and chronic popliteal and femoral vein thrombosis were compared. The accuracy of the EI in distinguishing acute from chronic DVT was also assessed by measuring the sensitivity, specificity, positive and negative predictive values, and likelihood ratios. Results One-hundred and forty-nine patients (mean age 63.9 years, standard deviation 13.6; 73 males) with acute and chronic DVT were included. The mean EI of acute femoral DVT was higher than that of chronic femoral DVT (5.09 versus 2.46), and the mean EI of acute popliteal DVT was higher than that of chronic popliteal DVT (4.96 versus 2.48). An EI value of > 4 resulted in a sensitivity of 98.9% (95% confidence interval [CI] 93.3-99.9), a specificity of 99.1% (95% CI 94.8-99.9), a positive predictive value of 91.1% (95% CI 77.9-97.1), a negative predictive value of 98.6% (95% CI 91.3-99.9), a positive likelihood ratio of 13.23 (95% CI 93-653) and a negative likelihood ratio of 0.001 (95% CI 0.008-0.05) for acute DVT. Conclusions UE appears to be a promising technique for distinguishing between acute and chronic DVT. Larger prospective studies are warranted to confirm our preliminary findings.

Tissue-specific expression of human CD4 in transgenic mice.

The gene for the human CD4 glycoprotein, which serves as the receptor for human immunodeficiency virus type 1, along with approximately 23 kb of sequence upstream of the translational start site, was cloned. The ability of 5' flanking sequences to direct tissue-specific expression was tested in cell culture and in transgenic mice. A 5' flanking region of 6 kb was able to direct transcription of the CD4 gene in NIH 3T3 cells but did not result in detectable expression in the murine T-cell line EL4 or in four lines of transgenic mice. A larger 5' flanking region of approximately 23 kb directed high-level CD4 transcription in the murine T-cell line EL4 and in three independent lines of transgenic mice. Human CD4 expression in all tissues analyzed was tightly correlated with murine CD4 expression; the highest levels of human CD4 RNA expression were found in the thymus and spleen, with relatively low levels detected in other tissues. Expression of human CD4 protein in peripheral blood mononuclear cells was examined by flow cytometry in these transgenic animals and found to be restricted to the murine CD4+ subset of lymphocytes. Human CD4 protein, detected with an anti-human CD4 monoclonal antibody, was present on the surface of 45 to 50% of the peripheral blood mononuclear cells from all transgenic lines.

Possible role of nutrients in neoplasia.

The relationship between cancer and diet is supported by epidemiological evidence suggesting that diet is a factor in the development of cancer of various organs including the esophagus, stomach, liver, and large bowel. The role of depressed immunocompetency, especially during critical periods of growth and development, is stressed as a possible important consequence of nutritional insults leading to carcinoma. Study of the relationships among nutritional factors, host-defense mechanisms, and carcinogens to carcinogenesis is significant since, theoretically, manipulation of diet could suppress or prevent chemically induced cancers. The distinction should be emphasized, however, between "nutrients," those elements of one's intake that are essential because the body is unable to synthesize them de novo, and "diet," which refers to everything that is ingested. It is the components of diet, chemicals in particular, that are most convincingly implicated as carcinogens, while it is doubtful that nutrient deficiencies or excesses have a direct causal relationship with the onset or development of cancer. Rather, nutrition probably exerts its carcinogenic effects indirectly; nutrients possibly enhance chemical carcinogenesis multifactorially by mechanisms linked to their ability to: (a) act as carriers of carcinogens or their precursors; (b) alter intestinal flora so that carcinogenic reactions are facilitated; (c) enhance levels and reactivity of cocarcinogens; (d) influence absorptive properties or morphology of tissues so that carcinogenic activity is enhanced; and/or (e) modify host-defense mechanisms that normally protect the organism.

Alcohol and alcohol-related deficiencies as carcinogens.

From the available evidence, alsohol ingestion per se does not appear to be carcinogenic. While alcoholism constitutes a major and serious social problem, it is not clear to what extent it constitutes a major health problem. We suggest that excessive alcohol ingestion coupled with a nutritional deficiency or some other insult (e.g., smoking) may be carcinogenic. Alcohol and/or several nutritional deficiencies usually associated with alcoholism have been shown to be immunosuppressive. The relationship between immunoincompetency and neoplasia has long been appreciated, and the exact role that alcohol and/or nutritional insults have in this relationship requires further investigation.

Lipids and immune function.

There is in vitro and in vivo evidence to suggest that dietary lipids play a role in modulating immune function. A review of the current literature on the interrelationships among dietary lipids, blood cholesterol levels, immunosuppression, and tumorigenesis makes for a very strong argument that (a) immunosuppression may be causally related to lymphoproliferative disorders, as well as to tumorigenesis and (b) diets high in polyunsaturated fat, relative to diets high in saturated fat, are more immunosuppressive and are better promotors of tumorigenesis. The effects of dietary fat on immune function seem to be mediated though its component parts, the unsaturated fatty acids, specially linoleic, linolenic, and arachidonic. It is not clear how these components affect immune function. Several studies suggest that one effect is mediated by altering the lipid component of the cell membrane and thus its fluidity; the more fluid the membrane, the less responsive it is. Thus, fluidity of both immune cells and those to be destroyed or protected may be affected. The effects of saturated as well as unsaturated fatty acids may be mediated by modulating serum lipoprotein levels, prostaglandin metabolism, and cholesterol concentrations and metabolism.

Cloning of the goat beta-casein-encoding gene and expression in transgenic mice.

The goat beta-casein-encoding gene (CSN2), which encodes the most abundant protein of goat milk, has been cloned and sequenced. The intron/exon organization of the 9.0-kb goat CSN2 gene is similar to that of other CSN2 genes. Expression of the goat gene was principally restricted to the mammary gland of lactating transgenic animals. A low level of expression was also observed in skeletal muscle and skin. In contrast to a rat CSN2 transgene [Lee et al., Nucleic Acids Res. 16 (1988) 1027-1041], the goat gene was expressed to a high degree in the lactating mammary gland. Differences in the content or context of regulatory elements may account for the enhanced performance of the goat relative to the rat CSN2 gene in transgenic mice.

The impact of infection on vitamin metabolism: an unexplored area.

Very little work has been done to answer the question: What is the effect of an infectious process on vitamin metabolism? The few studies that have been done would indicate that in the acute phase of an infection there is a redistribution of vitamins as well as other nutrients; these changes can be interpreted as indicating an adaptive and perhaps beneficial response of the host in meeting the challenges imposed by the infectious agent. It is accepted that chronic infection may lead to nutrient depletion, but it is not clear that in the normal healthy individual the administration of vitamins during an acute infections is of any benefit. One can certainly argue that during the infectious process the administration of vitamins and perhaps other nutrients could conceivably afford some protection were the infectious process to continue for some time. This raises other questions concerning the effects of chronic infection and whether or not they occur in well or malnourished individuals.

Surface lipid composition in children with protein-calorie malnutrition.

The composition of skin surface lipid has been measured in a group of 21 children with the diagnosis of marasmic-kwashiokor. When compared to the values for healthy children of comparable age, the squalene content was significantly decreased (3.1% +/- 3.2% versus 9.8% +/- 3.6%) and the squalene/wax ester ratio was also significantly decreased (0.57 +/- 0.55 versus 2.13 +/- 0.91). Measurements of skin surface lipid also were made in five of these children after treatment. The altered values reverted towards normal. Since changes in the squalene content and the squalene/wax ester ratio of skin surface lipid can be correlated with other biochemical changes of protein-calorie malnutrition, the analysis of surface lipid, a procedure that is both convenient and non-invasive, can be of use in determining the nutritional status in field studies of malnourished subjects.

Effects of oral soy phosphatidylcholine on phagocytosis, arachidonate concentrations, and killing by human polymorphonuclear leukocytes.

A dietary supplement of linoleic acid (LA) as soy phosphatidylcholine (PC) or as triglyceride on polymorphonuclear leukocyte (PMNL) functions, arachidonate (AA) concentrations, AA release, and leukotriene B4 (LTB4) generation was studied in normal adults. Study 1: Eight subjects were fed PC (27 g) or placebo for 3 d in a blinded crossover experiment with PMNL assays at baseline and 4, 7, and 14 d. Study 2: Subjects were fed equal quantities of LA as PC (18 g, n = 8), safflower (SF, n = 4), or soybean oil (SY, n = 4) with PMNL assays at baseline and 48 h. Study 1: PC increased PMNL phagocytosis and killing of Candida albicans twofold (P less than 0.001) and PMNL phospholipid AA content threefold (P less than 0.001); AA release after Candida albicans stimulation increased 5.3-fold, correlating with PMNL killing (r = 0.932) and phagocytosis (r = 0.872). Study 2: PC, but not SF or SY, produced changes similar to those of study 1. With PMNL exposure to calcium ionophore A23187 or N-formyl-methionyl-leucyl-phenylalanine, PC increased LTB4 generation. Phospholipid LA, in contrast to triglyceride LA, enhanced PMNL phospholipid AA, phagocytosis, and killing.

Extrapulmonary silicosis: a clinical, morphologic, and ultrastructural study.

A variety of silicotic lesions derived from thoracic silicosis via lymphohematogenous spread to the liver, spleen, bone marrow, and extrathoracic lymph nodes are described. The morphologic features of these lesions depend on the extent of macrophage aggregation, the occurrence of fibrogenesis, and the development of necrosis and degradative changes in macrophages and adjacent extracellular matrix, presumably caused by lysosomal enzymes released from macrophages. Ultrastructurally, the degenerative alterations of matrix material include longitudinal splitting and breakage of collagen fibrils into segments one and three quarters the length of the original fibrils and deposition of flocculent electron-dense material either focally or diffusely around collagen fibrils. The corresponding changes viewed light microscopically are those of fibrinoid necrosis. The sclerohyaline nodule, the characteristic lesion of silicosis, includes all of these features as it evolves through nodular histiocytic and subsequent fibrohistiocytic phases. Its ultimate morphology appears to be determined by the reassembly of the degraded matrix into non-native, fibrous long-spacing collagen via a spiny collagen intermediary. The sclerohyaline nodule occurs infrequently in the spleen and liver, although less typical lesions caused by silica alone or admixed with other dusts seem to occur more commonly in these organs. These lesions appeared as loose or nodular histiocytic or fibrohistiocytic aggregates. Nonspecific fibrous nodules or more extensive fibrosis, as seen in portal triads, may represent advanced stages of such lesions. Acute or healed focal segmental glomerulonephritis occurred in 40 per cent of the cases, suggesting that it may be an important remote effect of silicosis. Continuous destruction of lymphocytes adjacent to silicotic nodules may be an antigenic source of the high concentration of autoimmune reactants described in silicosis.

The effect of alcohol intoxication on inflammation of the cornea.

New Zealand albino rabbits received daily intraperitoneal injections of alcohol (ethyl alcohol), 1.6 g/kg and the effect of short-term (three days) and long-term (six weeks) administration on corneal inflammation was studied. Both regimens produced an average peak serum concentration of more than 0.200 g/dL, a level consistent with gross intoxication in the majority of humans. Clinical signs of intoxication were present in all animals, manifested by a gross disturbance of equilibrium and gait. Neither regimen produced measurable liver damage. Nonetheless, following both regimens of alcohol administration, significantly fewer polymorphonuclear leukocytes invaded the corneas of animals receiving alcohol than invaded the corneas of simultaneously run controls receiving intraperitoneal saline. These data provide a mechanism to explain why an alcoholic individual might not cope with a corneal infection as well as a nonalcoholic person, an observation long thought to be true clinically.

Steroid section patterns of a hilus cell tumor of the ovary.

Steroidogenic function of a locally invasive hilus cell tumor of the ovary was studied. Serum levels of testosterone, androstenedione, dihydrotestosterone, 17 alpha-hydroxyprogesterone, progesterone, and estradiol were measured in blood samples from the peripheral and the ovarian vein. The tumor was secreting all but estradiol. Concentrations of progesterone and 17 alpha-hydroxyprogesterone were greatly elevated. Testosterone and dihydrotestosterone were the predominant androgens secreted by the tumor. Estradiol concentrations were elevated but without a significant peripheral-ovarian gradient. Concentrations of all the steroids coming from the tumor were increased paradoxically in the peripheral circulation after administration of dexamethasone, and the tumor was responsive to stimulation by human chorionic gonadotropin.

Increases in heart rate and blood pressure produced by injections of dermorphin into discrete hypothalamic sites.

Central cardiovascular sites of action for dermorphin were determined by injecting 40 pmol of the peptide into discrete sites within the hypothalamus of halothane anesthetized rats. Blood pressure and heart rate in 101 rats were 88 +/- 1 mm Hg and 338 +/- 3 beats/min, respectively, prior to 100 nl intrahypothalamic injections of either vehicle or dermorphin. In the caudal anterior hypothalamic nucleus (A5800-5300), dermorphin, but not vehicle, increased blood pressure 8% and heart rate 26%, without changing respiration rate. The peak response was at 32 +/- 5 min, the duration greater than 90 min. Injections of naloxone (30 nmol) into the same anterior hypothalamic site, or 3 mg/kg naloxone administered i.m., completely reversed the cardiovascular actions. Similar increases in heart rate and blood pressure occurred at A6600-6300, the region between medial preoptic and anterior hypothalamic nuclei. Small increases in heart rate, but not blood pressure, resulted from dermorphin injections into the septal area, medial preoptic nucleus, paraventricular hypothalamic nucleus and the lateral ventricle, while injections in the posterior and dorsomedial hypothalamic nuclei were without effect on blood pressure and heart rate. These data provide support for anterior hypothalamic and medial preoptic sites for the cardiovascular actions of the opiate receptor agonist, dermorphin, and indicate greatest effects with this dose (primarily on heart rate) are produced at discrete sites (A6600-6300 and A5800-5300) within these nuclei.

Response perseveration in psychopathic women.

Recent attempts to validate the Psychopathy Checklist-Revised (PCL-R) as a measure of psychopathy in female offenders have been limited by a failure to examine laboratory correlates of the syndrome. We assessed 112 incarcerated women by using the PCL-R and examined their performance on a card perseveration task that has been used to demonstrate response perseveration in psychopathic men. Contrary to prediction, psychopathic women did not perseverate responding when the PCL-R was used either dimensionally or categorically. The authors discuss the implications of the results for the PCL-R and for female psychopathy more generally.

Long-term nutritional support as an adjunct to chemotherapy for breast cancer.

In recent years, the concept of nutritional support as a part of a comprehensive cancer management program has gained increasing acceptability. However, little data is available in regard to the effect of nutritional support programs on the chronic disease state represented by recurrent or persistent cancer that characterizes patients undergoing systemic chemotherapy. In 1977 we undertook to study this problem in a randomized prospective study designed to evaluate the effects of long-term (12 months) enteral nutritional support in a group of ambulatory breast cancer patients undergoing a standard cytotoxic chemotherapy treatment program, in an adjuvant or therapeutic setting. The results of this study suggest that patients with breast cancer are overweight as compared to the general population and that any significant change in initial body weight, either a gain or a loss, is associated with an increased risk of recurrent disease. Data are presented which show little or no correlation between standard parameters of nutritional assessment and risk of disease recurrence and/or response to chemotherapy. These data also suggest that until we better understand the relationship between tumor and host in breast cancer patients, we offer nutritional support programs only in situations where there are specific clinical indications for such interventions.

A possible role of iron deficiency in gastric cancer in Colombia.

Through the efforts of Correa, Cuello, Haenszel, Tannenbaum and others it was learned that the incidence of gastric cancer in certain areas of Narino (Colombia) was among the highest in the world. These areas of high risk for gastric cancer were adjacent to an area of substantially lower risk. Gastric biopsies from healthy volunteers residing in the "high risk" area exhibited a greater incidence of superficial gastritis and chronic atrophic gastritis with and without intestinal metaplasia than those from the low risk area. The latter pathological finding is considered to be a precursor lesion to gastric cancer. Volunteers from the "low risk" area as well as individuals from Cali in the coastal region and Cartegena on the coast, also exhibited a similar spectrum of pathology but at a substantially reduced frequency. Natives of both cities were also at lower risk for gastric cancer than inhabitants of Narino. It was found that the water supply of the "high risk" area contained a higher concentration of nitrate than water in the "low risk" area. Correa et al. hypothesized that the high nitrate concentrations of well water contributed to the formation of N-nitroso compounds in the stomachs of these individuals early in life. The occurrence of this putative carcinogen in combination with the abrasive action of dietary grains contributed to a series of mutations in the gastric epithelium progressing through a sequence of pathologic changes, loss of gastric acid and culminating in gastric cancer. In the current report individuals in a Medellin population who were admitted with abdominal complaints and were found to be iron deficient exhibited the same spectrum of gastric pathology described by previous investigators. Superficial gastritis, chronic atrophic gastritis and achlorhydria have also been described in association with chronic iron deficiency (and/or associated nutritional defects) per se. The development of these lesions are likely to occur within the first two decades of life when iron requirements are maximal. It is suggested that these changes preceed the development of gastric cancer. Bacterial colonization of the achlorhydric stomach may facilitate nitrate reduction and the formation of a putative carcinogen N-nitroso compound(s) from nitrate in the water supply. Additionally, the effects of chronic iron deficiency on host immune defense may compromise these mechanisms and permit tumor growth with minimal immune intervention.

Behavior modification in a residence and school for adolescent boys: a team approach.

A behavior modification program emphasizing close communication and cooperation between educators and child care workers has proved effective in a school for adolescent boys with learning and behavior problems.

Transgenic production of a variant of human tissue-type plasminogen activator in goat milk: generation of transgenic goats and analysis of expression.

We report the first successful production of transgenic goats that express a heterologous protein in their milk. The production of a glycosylation variant of human tPA (LAtPA--longer acting tissue plasminogen activator) from an expression vector containing the murine whey acid promoter (WAP) operatively linked to the cDNA of a modified version of human tPA was examined in transgenic dairy goats. Two transgenic goats were identified from 29 animals born. The first animal, a female, was mated and allowed to carry the pregnancy to term. Milk was obtained upon parturition and was shown to contain enzymatically active LAtPA at a concentration of 3 micrograms/ml.