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New steps in the Wnt/beta-catenin signal transduction pathway.

Wnt regulates developmental and oncogenic processes through its downstream effector, beta-catenin, and a set of other intracellular regulators that are largely conserved among species. Wnt family genes encode secreted glycoproteins that act as ligands for membrane receptors belonging to the Frizzled family of proteins. Wnt-1 originally was found as a proto-oncogene that was upregulated in tumors caused by the mouse mammary tumor virus. The Drosophila homologue of Wnt-1, wingless, is a segment polarity gene that regulates body patterning of the fly embryo. In Xenopus, the Wnt pathway regulates formation of the ventral-dorsal axis. Although Wnt proteins are expressed widely in mammals, the function of the Wnt signaling pathway in normal adult mammalian tissues is not understood. Downstream components of the Wnt pathway, APC (adenomatous polyposis coli) and beta-catenin, clearly are involved in human cancer. There are also several reports that Wnt ligands are highly expressed in tumors. Wnt stabilizes cytoplasmic beta-catenin and activates beta-catenin/Lef-1 (lymphoid enhancer factor), Tcf (T-cell factor)-dependent gene transcription. This regulation of cytosolic beta-catenin is mediated by glycogen synthase kinase-3 (GSK-3) activity but in neither case is the mechanism known. The mechanism by which Wnt inhibits GSK-3 is unknown. Recent studies have shown that some of the intracellular signaling molecules that mediate the Wnt pathway are in complexes, including Dishevelled (Dsh or Dvl), GSK-3beta, and APC protein. However, little is known about how Wnt or other upstream stimuli regulate these complexes to stabilize beta-catenin. We took a variety of approaches to identify new components of the Wnt pathway. Using an expression-cloning technique, we isolated casein kinase I (CKI)epsilon as a positive regulator of beta-catenin in the Wnt pathway. Overexpression of CKIepsilon mimics Wnt by stabilizing beta-catenin, thereby increasing expression of beta-catenin-dependent genes. Inhibition of endogenous CKIepsilon attenuated gene transcription stimulated by Wnt or by Dsh. CKIepsilon forms a complex with Axin and the other downstream components of the Wnt pathway. CKIepsilon is a positive regulator of the Wnt pathway and a possible functional link between upstream signals and the intracellular Axin signaling complex that regulates beta-catenin. In separate experiments, we have identified a Dishevelled-associated kinase (DAK) that binds to Dsh and regulates its functions. Dsh is required for two different pathways, the Wnt pathway and planar polarity pathway in Drosophila. DAK dramatically enhances the function of Dsh in the Wnt pathway and inhibits its function in the planar polarity pathway. This chapter will discuss these newly identified components of the Wnt pathway.

Adaptor Proteins, Signal Transducing↗

[Association of lichen planus and discoid lupus erythematosus. A clinical and histopathological study of 2 cases].

Two patients showing features of both lichen planus and lupus erythematosus are described: reticular whitish patches in the oral mucosa coexisting with chronic, partly atrophic LED-like skin lesions located on the face were present in both of them. The histological, histochemical and immunopathological findings allowed to diagnose a "LP-LE coexistence" more than a mixed LP-LE disease. The clinical, histological and immunological relationships between LP and LE are discussed and it is suggested that the pathogenesis of the coexistence of the two diseases could be related to a common pathophysiological pathway. It might be that LP and LE are due to a single aetiological agent (e.g. a virus) interacting with different genetic backgrounds to cause LE in some, LP in others and an intermediate disease in a small group of patients. The histopathological and immunopathological features that distinguish LP from LE are the concentration of lymphocytes in areas of keratinocyte damage, the different colloid bodies patterns and the direct IF findings. The Authors conclude that further studies should be performed on "LP-LE coexistence".

Adult↗

[Urinary incontinence and prolapse. Medical treatment and functional treatment].

Urinary continence implies that the variations of the vesical pressure does not exceed the capacities of the cervico-urethral closure system. The aim of the various methods of treatment is to have a beneficial action on those two parameters: drug therapy will mainly reduce the intra-vesical pressure (parasympatholytics...) and also improve the urethral tone (alpha-adrenergics...), or have a mixed effect on both systems (tricyclic antidepressants, oestrogens...). The side effects are often numerous due to the impact on the vegetative or neuromuscular system. The re-education is complemented by: local and general kinesitherapy, sensorial retrocontrol, associated or not to electrotherapy. Motivation and active participation of the patient are essential. The indications covers all the various pathologies (perineal insufficiency, defects in the body pattern, prolapse, sphincteral insufficiency, transmission problems, vesical instability, urethral instability) and concerns patients of all age groups.

Biofeedback, Psychology↗

Subtypes in major depression without melancholia.

Using the Diagnostic and Statistical Manual of Mental Disorders (DSM III, 1980) criteria to diagnose major depression without melancholia, 70 adult patients were selected for further detailed clinical and neuro-endocrinological evaluation. Two subtypes emerged; changes in sleeping patterns, body mass and thyrotrophin response to thyrotrophin-releasing hormone constituted the distinguishing features between the two categories (P = 0.012).

Adult↗

General pharmacology of brotizolam in animals.

Brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-1,2,4-triazolo [4,3-a]-1,4-diazepine, We 941, Lendormin) is a thienotriazolo-diazepine with profound sedative and hypnogenic properties. The side effects of the drug on general behavior, motocoordination, feeding pattern, body temperature, uropoietic and gastrointestinal functions, cardiovascular system, and respiration, as well as interactions with some biogenic amines are reported and discussed. The findings correlate with those known for other diazepines. Accordingly, effects on motocoordination were prominent, but were limited to an ataxia, whereas even extremely high doses scarcely eliminated the postural reflexes. Sleeping animals could invariably be woken and were capable of locomotion; thus, no comatose condition developed. The cardiovascular functions were not appreciably altered by brotizolam in anesthetized cats, while in conscious dogs minor fluctuations of blood pressure and heart rate occurred. Respiration was clearly inhibited when brotizolam was given intravenously. The cardiovascular effects of acetylcholine, norepinephrine, epinephrine, isoprenaline, and histamine were only slightly modulated. The orexigenic and hypothermic effects equalled those of other diazepines. The functions of kidney, stomach, and intestines were not affected. The entirety of the observations procured in ten different species suggest that brotizolam is well tolerated when given orally.

Animals↗

[Quantity of DNA, sex chromatin bodies and nucleoli in the nuclei of the muscle cells of normal and hypertrophied human atria].

Nuclei of myocytes of normal and hypertrophied human heart atrium were studied on squash preparations. Judging by the sex chromatin body pattern, it is the polyploidization that is responsible for the increased DNA contents in these nuclei. The cytophotometric DNA measurements demonstrated the up to 93% occurrence of polyploid nuclei even in myocytes of normal atrium. Myocytes of hypertrophied atrium contained nuclei of higher ploidy degrees. The total area of nucleoli per nucleus was shown to be proportional to a degree of ploidy.

Adult↗

[Hemophilia: evaluation of the nutritional status and growth in childhood].

Haemophilia is a bleeding disorder characterized by decreased activity of the circulating antihemophilic factor, with different degrees of severity. The prognosis of the disease for an useful normal life is good, providing an adeguate follow-up. We think that the auxological determinants of growth and nutritional status must enter as points of a multicentre follow-up sheet of haemophilia in the pediatric age. We have tried such an approach in 13 patients; preliminary results have shown that all patients are growing well with some degrees of discrete malnutrition (arm circumference less than -1.6 SD). From costitutional point of view, haemophilic boys show a discrete "lean" body pattern (W/H2 less than or equal to O SD(with their trunk longer than legs. Data from other studies are wellcome for confirming our first impressions.

Anthropometry↗

Cancer of the prostate: treatment and nursing implications.

PURPOSE/OBJECTIVES: To review the clinical manifestations, current treatment, and nursing management of prostate cancer. DATA SOURCES: Published articles, book chapters, American Cancer Society booklets. DATA SYNTHESIS: Prostate cancer is a slow-growing malignancy and usually is asymptomatic in its early stages. It causes acute urinary obstruction at more advanced stages, and patients may present with metastatic disease. Diagnosis is made by biopsy, and treatment options include periodic observation, surgery, radiotherapy hormonal manipulation, and chemotherapy with standard or investigational drugs or combination therapy. The major complications associated with surgery and radiation therapy are transient or permanent incontinence and impotence. CONCLUSIONS: Because no definitive method for identifying clinically important lesions exists, much controversy surrounds prostate cancer treatment. Issues significant to the diagnosis and treatment of all stages of prostate cancer are identified, and nursing care concerns focusing on treatment and disease-related problems are presented. IMPLICATIONS FOR NURSING PRACTICE: Nursing care focuses on providing patients with accurate information to make informed decisions regarding treatment for early stage disease, on promoting comfort, and on preventing and managing treatment and disease-related complications. Nursing diagnoses include knowledge deficit; altered sexual patterns, body image disturbance, altered urinary elimination, diarrhea, impaired skin integrity, and pain, fatigue, bleeding, and infection, all of which are related to surgery, pathologic fractures, spinal cord compression, and edema of the scrotum/lower extremities.

Humans↗

Frequency of feeding, weight reduction and energy metabolism.

A study was conducted to investigate the effect of feeding frequency on the rate and composition of weight loss and 24 h energy metabolism in moderately obese women on a 1000 kcal/day diet. During four consecutive weeks fourteen female adults (age 20-58 years, BMI 25.4-34.9 kg/m2) restricted their food intake to 1000 kcal/day. Seven subjects consumed the diet in two meals daily (gorging pattern), the others consumed the diet in three to five meals (nibbling pattern). Body mass and body composition, obtained by deuterium dilution, were measured at the start of the experiment and after two and four weeks of dieting. Sleeping metabolic rate (SMR) was measured at the same time intervals using a respiration chamber. At the end of the experiment 24 h energy expenditure (24 h EE) and diet-induced thermogenesis (DIT) were assessed by a 36 h stay in the respiration chamber. There was no significant effect of the feeding frequency on the rate of weight loss, fat mass loss or fat-free mass loss. Furthermore, fat mass and fat-free mass contributed equally to weight loss in subjects on both gorging and nibbling diet. Feeding frequency had no significant effect on SMR after two or four weeks of dieting. The decrease in SMR after four weeks was significantly greater in subjects on the nibbling diet. 24 h EE and DIT were not significantly different between the two feeding regimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

[Embryonic induction and role of activins during early amphibian development].

Growth factors are known to act for the formation of the animal tissues and organs. We showed that activins, members of the TGF-beta family growth factors, exist in early amphibian embryos and induce mesoderm tissues and organs in undifferentiated blastomeres (animal cap). Activins are characteristic in that they can establish embryonic body axis, by inducing different mesoderm and endoderm organs depending on their dose. The action of activin seems to be a primary important phenomenon which commonly create the body pattern of vertebrate embryos.

Activins↗

Loss of function of the homeobox gene Hoxa-9 perturbs early T-cell development and induces apoptosis in primitive thymocytes.

Hox homeobox genes play a crucial role in specifying the embryonic body pattern. However, a role for Hox genes in T-cell development has not been explored. The Hoxa-9 gene is expressed in normal adult and fetal thymuses. Fetal thymuses of mice homozygous for an interruption of the Hoxa-9 gene are one eighth normal size and have a 25-fold decrease in the number of primitive thymocytes expressing the interleukin-2 receptor (IL-2R, CD25). Progression to the double positive (CD4+CD8+) stage is dramatically retarded in fetal thymic organ cultures. This aberrant development is associated with decreased amounts of intracellular CD3 and T-cell receptor beta (TCRbeta) and reduced surface expression of IL-7R and E-cadherin. Mutant thymocytes show a significant increase in apoptotic cell death and premature downregulation of bcl-2 expression. A similar phenotype is seen in primitive thymocytes from adult Hoxa-9-/- mice and from mice transplanted with Hoxa-9-/- marrow. Hoxa-9 appears to play a previously unsuspected role in T-cell ontogeny by modulating cell survival of early thymocytes and by regulating their subsequent differentiation.

Animals↗

Stature and body weight growth patterns from longitudinal data of Japanese children born during World War II.

Stature and body weight data of 100 boys and 100 girls from 7 to 17 years of age in Shimodate City who were born during World War II were longitudinally analyzed. The children were significantly smaller and lighter throughout their growth period than those born 11 years after the end of the war. The correlation coefficient between statures at each age and at age 17 showed a gradual increase with increasing age, while that between statures at each age and at age 7 decreased with age. However, a drop in the correlation coefficient was found during puberty, at age 11 for girls and at age 13 for boys. Comparing the normalized distance from mean values of stature and body weight at age 7, at puberty, and at age 17, only 51% of the children continued to be in the same relative position for both height and weight, 6% of boys and 4% of girls showing a decreasing pattern for both and 4% of boys and 7% of girls showing an increasing pattern for both. Thus, about 60% of the children of either sex presented parallel stature and body weight growth patterns for ages from 7 to 17.

Adolescent↗

Insulin sensitivity, glucose effectiveness, and body fat distribution pattern in nondiabetic offspring of patients with NIDDM.

OBJECTIVE: To determine the relationship of insulin sensitivity (SI), glucose effectiveness (glucose-dependent glucose transport [SG]), and body fat distribution patterns in glucose-tolerant offspring of patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: Ten glucose-tolerant offspring of patients with NIDDM and 10 age-, sex-, and weight-matched healthy control subjects without family history of diabetes were studied with the minimal model method of Bergman et al. Body fat composition and distribution pattern were assessed by the bioelectrical impedance analyzer and waist-hip circumference ratios (WHR), respectively, in each subject. RESULTS: Mean fasting serum glucose (4.39 +/- 0.17 vs. 3.94 +/- 0.17 mM) and postglucose peak (18.50 +/- 1.50 vs. 13.20 +/- 1.06 mM) levels were significantly greater (P less than 0.05) in the offspring than in the control subjects. Mean fasting serum insulin levels were slightly greater but not significantly different in the offspring versus control subjects (64 +/- 14 vs. 29 +/- 7 pM). After intravenous stimulation with glucose and tolbutamide, the mean serum insulin rose to significantly greater (P less than 0.05) levels at t = 5 and 25 min in the offspring compared with the control subjects. Mean SI was significantly reduced by 45% in the offspring compared with the control subjects (4.77 +/- 0.67 vs. 8.37 +/- 1.24 x 10(-4) min-1.mU-1.L-1). However, SG was not different in the offspring versus control subjects (1.92 +/- 0.12 vs. 2.10 +/- 0.17 x 10(-2) min-1). SI correlated significantly and inversely with the percentage of body fat mass (r = -0.580, P less than 0.05) but not with the WHR (r = -0.019) in the offspring. We found a negative association between SI and basal serum insulin (r = -0.798, P less than 0.01) but not with the poststimulation incremental insulin responses in the offspring. Family history of diabetes independently accounted for at least 27% of variance in the SI in our subjects. CONCLUSIONS: Our study confirmed that insulin insensitivity but not a reduced glucose effectiveness exists in young glucose-tolerant offspring of patients with NIDDM. The reduced S1 appears to be causally related to the total body fat content and may be a familial and/or genetic trait in the offspring.

Adipose Tissue↗

The alpha beta T-cell receptor repertoire in inclusion body myositis: diverse patterns of gene expression by muscle-infiltrating lymphocytes.

Inclusion body myositis (IBM) is one member of a group of disorders known as idiopathic inflammatory myopathies (IIM) in which autoreactive T cells directed against muscle are thought to play a primary role in disease pathogenesis. We have utilized the polymerase chain reaction to determine the pattern of alpha beta T-cell receptor (TCR) variable (V) gene expression in muscle biopsies from 13 IBM patients. In the majority of biopsies, we detected oligoclonal patterns of TCR V gene expression by muscle-infiltrating lymphocytes; an average of six out of the 22 TCR V alpha gene families surveyed and seven out of 24 TCR V beta gene families surveyed were detected per biopsy. While no TCR V alpha gene families were over-represented in our survey, TCR V beta 3 and V beta 6 gene usage was a prominent feature of IBM muscle biopsies. TCR gene expression was characterized further by analysing the junctional sequence composition of both V beta 3 and V beta 6 clones from muscle biopsies of the IBM patients. A large number of structurally diverse V beta 3 and V beta 6 clonotypes were identified from these patients demonstrating a polyclonal pattern of T cell infiltration. These data, while describing prominent TCR V beta 3 and V beta 6 gene detection, do not suggest that a common antigen-driven T-cell response promotes chronic inflammation in muscle of IBM patients.

Adult↗

Continuous exposure to dim illumination uncouples temporal patterns of sleep, body temperature, locomotion and drinking behavior in the rat.

Dissociable circadian rhythms of sleep and body temperature in primates are thought to be regulated by independent oscillators whereas the uncoupling of circadian rhythms has not been well described in other mammals. Therefore, we made simultaneous recordings of non-rapid-eye-movement-sleep (NREMS), rapid-eye-movement-sleep (REMS), brain temperature, intraperitoneal temperature, locomotion and drinking activity under light-dark (LD) and continuous dim illumination (dim LL) and analyzed their interrelations. The rhythmic patterns of body temperature, locomotion and drinking were modified on the 12th circadian day of dim LL, while the mean body temperature as well as mean occurrence of drinking and locomotor activities did not change significantly. In contrast, dim LL exposure significantly increased the total time spent in NREMS during the resting phase of dim LL and increased REMS episodes during the active phase of dim LL. The diverse effects of dim LL exposure on the recorded phenomena suggest that temporal patterns of sleep were the most sensitive to perturbations of lighting and that differential oscillatory mechanisms may regulate sleep and other circadian rhythms in the rat.

Animals↗

California ground squirrel body temperature regulation patterns measured in the laboratory and in the natural environment.

Body temperature (Tb) was measured by telemetry in both laboratory maintained and natural environment California ground squirrels, Spermophilus beecheyi. Laboratory animals had a mean diurnal Tb of 37.5 degrees C under conditions of LD 14:10, 20 degrees C and 36.5 degrees C under conditions of LD 10:14, 20 degrees C (P < 0.01). Nocturnal mean Tbs were 37.1 and 35.2 degrees C, respectively (P < 0.05). Mean diurnal Tbs for each animal in the natural environment ranged from 39.3 to 40.1 degrees C (mean = 39.6 degrees C) during both study seasons which included the hot season months of March through August and the cool season months of December through February. Natural environment hot season mean Tb was not significantly different from cool season mean Tb but both mean Tbs were significantly different from the diurnal mean Tbs measured in the laboratory (P < 0.05). California ground squirrels exhibit an open-field stress induced hyperthermia in the laboratory which can be extended for periods up to 6 h. The hyperthermic response is blocked by L-propranolol at a dosage of 15 mg kg-1. Laboratory animals do not habituate to repeated open-field exposures over a five consecutive day period. It is suggested that stress hyperthermia might be a normal component of thermoregulation in some free-living ground squirrels because of the openness of the habitat in which they exist.

Animals↗

The impact of nutritional status on body fat distribution patterns in pre- and postmenopausal females.

This study examines the impact of nutritional status, classified by body mass index, on sex specific fat distribution patterns dependent on menopausal status in 467 pre-, peri- or postmenopausal females. Absolute and relative amounts of upper and lower body fat were estimated by means of dual energy X-ray absorptiometry. It was found that low weight, independent of menopausal status, leads to the typical gynoid pattern of fat distribution while excess weight and obesity result in the android pattern of distribution in pre- and postmenopausal women.

Adipose Tissue↗

Circulating leptin in patients with anorexia nervosa, bulimia nervosa or binge-eating disorder: relationship to body weight, eating patterns, psychopathology and endocrine changes.

A decreased production of leptin has been reported in women with anorexia nervosa (AN) and has been attributed merely to the patients' reduced body fat mass. The extent to which eating patterns, purging behaviors, psychopathology and endocrine changes may contribute to the genesis of leptin alterations has not been deeply investigated. Therefore, we measured plasma levels of leptin, glucose and other hormones in three groups of eating disorder patients with different body weight (BW), eating patterns and purging behaviors. Sixty-seven women, 21 with AN, 32 with bulimia nervosa (BN), 14 with binge-eating disorder (BED) and 25 healthy females volunteered for the study. We found that circulating leptin was significantly reduced in AN and BN patients, but significantly enhanced in women with BED. In anorexics, plasma glucose was decreased, whereas plasma cortisol was enhanced; blood concentrations of 17beta-estradiol and prolactin (PRL) were reduced in both AN, BN and BED patients. In all subject groups, a strong positive correlation emerged between plasma levels of leptin and the subjects' BW or body mass index, but not between leptin and psychopathological measures, plasma glucose, cortisol, PRL and 17beta-estradiol. Since leptin was reduced in both underweight anorexics and normal weight bulimics, but increased in overweight BED women, who compulsively binge without engaging in compensatory behaviors, we suggest that factors other than BW may play a role in the determination of leptin changes in eating disorders.

Adult↗