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The retinal pigmented epithelium is required for development and maintenance of the mouse neural retina.

BACKGROUND: During development of the vertebrate eye, there is a series of reciprocal cellular interactions that determine the fate of the eye components. Although evidence from organ culture suggests that the retinal pigmented epithelium (RPE) organizes the laminar structure of the differentiated neural retina, no role has been identified for the RPE in early eye development, nor has the later function of RPE been demonstrated in vivo. RESULTS: To investigate the role of RPE cells in eye development, we generated transgenic mice that carry the attenuated diphtheria toxin-A gene; this transgene was driven by the promoter of the gene encoding the tyrosinase-related protein-1, which is specifically expressed in pigment cells. Depending on the expression level of the transgene, the retinal epithelium was ablated before or after its differentiation into a pigmented cell layer. We show that an early ablation (embryonic day E10-11) resulted in disorganization of the retinal layer, immediate arrest of eye growth and subsequent eye resorption. A later ablation (E11.5-12.5) allowed the eye to be maintained during embryogenesis, but the laminar structure of the retina became disrupted by the end of gestation, the vitreous failed to accumulate the adults were anophthalmic or severely microphthalmic. In some microphthalmic eyes, a number of RPE cells escaped ablation and formed patches of pigmented cells; the laminar structure of the retina was maintained immediately adjacent to such pigmented areas but disrupted elsewhere. In both cases--early or late ablation of the RPE--the retina appears to be the primary affected tissue. CONCLUSIONS: We conclude that presence of the RPE is required for the normal development of the eye in vivo. Its presence early in development is necessary for the correct morphogenesis of the neural retina. After the neural retina has started to differentiate, the RPE is still necessary, either directly or indirectly, to maintain the organization of the retinal lamina.

Animals↗

Double-blind procedure: an assessment in a study of lithium prophylaxis.

Fifty-seven patients with primary affective disorder who were in a double-blind outpatient study to evaluate the prophylaxis of lithium were questioned as to whether they believed they were receiving lithium or placebo. Research nurses who were 'blind' to the patients' medication and a close relative living with each patient were also questioned. Nearly all patients (96%) said they beleived they were receiving lithium, ascribing this belief in 63% of the cases to a perceived improvement in condition. In only 14% of the cases on lithium was the presence of side-effects implicated in the patients' beliefs. One of the three nurses had a correct guess rate in excess of chance expectancy. All nurses tended to be more accurate in their guesses in the cases of patients who had been in prophylactic trials of over 15 months' duration than for patients with briefer periods in the study. Patients' relatives were, as a group, extremely accurate, their correct guess rate exceeding chance expectancy at the 0-001 level.

Affective Symptoms↗

Lateral ventricular size in schizophrenia: relationship to the disease process and its clinical manifestations.

Using computed tomography, lateral ventricular size was studied in a sample of 112 institutionalized chronic schizophrenic patients (selected from 510 cases to investigate the correlates of the defect state and intellectual decline and the effects of insulin, electroconvulsive and neuroleptic treatment), and compared with matched groups of non-institutionalized schizophrenics, patients with first schizophrenic episodes, institutionalized and non-institutionalized patients with primary affective disorder, and neurotic out-patients. Age was significantly correlated (P less than 0.0002) with lateral ventricular size, but the institutionalized schizophrenic patients had significantly larger (P less than 0.025) lateral ventricles than the neurotics when age was taken into account. Ventricular enlargement was unrelated to past physical treatment (neuroleptics, insulin coma and electroconvulsive therapy). Within the group of institutionalized schizophrenic patients few correlates of ventricular enlargement were identified; thus in this population increased ventricular size was not clearly associated with the features of the defect state (negative symptoms and intellectual impairment). However, there was a curvilinear (inverted-U) relationship between intellectual function and ventricular size. Increased ventricular size was significantly related to absence of hallucinations, impairment of social behaviour, inactivity and the presence of abnormal involuntary movements. The findings confirm that structural brain changes do occur in chronic schizophrenia, but illustrate some of the difficulties in elucidating the clinical significance of ventricular enlargement. Lateral ventricular size is strongly age-related and the distribution in chronic schizophrenia is skewed and not bimodal; the relationship to particular features of the disease is complex and likely to emerge only in studies with a large sample size.

Adult↗

Basic and translational advances in cancer metastasis: Nm23.

Cancer metastasis is a significant contributor to breast cancer patient morbidity and mortality. To develop new anti-metastatic therapies, we need to understand the biological and biochemical mechanisms of metastasis. Toward these efforts, we and others have studied metastasis suppressor genes, which halt metastasis in vivo without affecting primary tumor growth. The first metastasis suppressor gene confirmed was nm23, also known as NDP kinase. Using in vitro assays, nm23 overexpression resulted in reduced anchorage-independent colonization in response to TGF-beta, reduced invasion and motility in response to multiple factors, and increased differentiation. We hypothesize that the mechanism of action of Nm23 in metastasis suppression involves diminished signal transduction, downstream of a particular receptor. We hypothesize that a histidine protein kinase activity of Nm23 underlies its suppression of metastasis, and identify candidate substrates. This review also discusses therapeutic options on the basis of reexpression of metastasis suppressors.

Animals↗

Lithium elimination half-life and duration of therapy.

The elimination half-life (t1/2E) of lithium carbonate in red blood cells, plasma, and urine was measured in 30 patients hospitalized for primary affective disorder. Duration of Li treatment at time of sampling was found to have a direct effect on lengthening time course. Patients on their initial course of Li had the lowest t1/2s: 1.12 (urine), 1.28 (plasma), and 1.22 days (red blood cells); those less than 1 yr on Li had intermediate values: 1.85, and 1.65, and 1.75 days; and those more than 1 continuous year on Li had the longest mean t1/2s: 2.40, 2.43, and 2.24 days. These results for urine (p less than 0.01) and plasma (p less than 0.05) are further evidence that Li may stimulate the production of an endogenous regulator of Li efflux. This regulator may prove to be an important factor in planning of long-term Li prophylaxis.

Female↗

Functional balance between T cell chimeric receptor density and tumor associated antigen density: CTL mediated cytolysis and lymphokine production.

Genetically engineered expression of tumor-specific single chain antibody chimeric receptors (ch-Rec) on human T lymphocytes endow these cells with the parental monoclonal antibody (mAb) dictated tumor specificity and may be useful for clinical immuno-genetherapy. Therefore it was of importance to assess how the densities of tumor-specific receptors and tumor associated antigens (TAA), respectively, affect primary human T lymphocyte functions in relation to target cell susceptibilities to lysis. We therefore studied the functional balance between ch-Rec densities on human T lymphocytes and TAA on tumor cells. The gene construct encoding a ch-Rec derived from (1) a renal carcinoma cell (RCC) specific mouse mAb (G250), and (2) the human signal transducing Fc(epsilon)RI gamma-chain was used. To obtain ch-RecHIGH-POS and ch-RecLOW-POS T lymphocytes, two distinct retroviral vectors were used to introduce the gene constructs into primary human T lymphocytes. Levels of ch-Rec-redirected T lymphocyte mediated tumor cell lysis, as well as lymphokine production were determined using RCC lines as target/stimulator cells, which express either no or increasing densities of the TAA. A functional and dynamic balance between ch-Rec densities on cytotoxic T lymphocytes (CTLs) on the one hand and TAA densities on RCCs on the other, was found. In short, ch-RecHIGH-POS CTLs are triggered by TAAHIGH-POS as well as TAALOW-POS RCCs to lyse tumor cells and produce (IFN-gamma and TNF-alpha) lymphokine. In contrast, ch-RecLOW-POS T lymphocytes are only triggered for cytolysis and lymphokine production by relatively TAAHIGH-POS RCCs. In conclusion, (1) the activation of T lymphocyte responses is co-determined by the expression levels of the ch-Rec on T lymphocytes and the TAA on tumor cells and (2) at relatively high T lymphocyte ch-Rec expression levels the CTLs lyse tumor cells with a wide range of TAA densities. Gene Therapy (2000) 7, 35-42.

Antigens, Neoplasm↗

Human patellar articular proportions: recent and Pleistocene patterns.

The degrees of mediolateral asymmetry of the patellar articular facet, as well as the median and lateral articular angles of the facet, were compared across samples of recent humans and of Pleistocene archaic and modern fossil humans. All samples exhibit considerable variability in these patellar proportions. The articular angles are similar across the different samples, but there is a trend towards decreasing lateral angles with decreasing robusticity. The archaic humans exhibit significantly more symmetry of the medial and lateral facets than do any of the recent human samples. However, given the variability in medial versus lateral patellofemoral contact forces documented for extant humans and the roles of the distal oblique portions of vastus medialis and vastus lateralis in patellar stabilisation, it is unclear to what extent this variation in patellar articular proportions may affect knee kinesiology. The contrasts may be related to different levels of patellar stability and/or musculoskeletal hypertrophy, but they appear unlikely to have affected primary knee function.

Animals↗

Effectiveness of a skin cancer control educational intervention for internal medicine housestaff and attending physicians.

OBJECTIVES: To evaluate the effects of a brief educational program on beliefs, knowledge, and behaviors related to skin cancer control among internal medicine housestaff and attending physicians. DESIGN: Randomised controlled trial. SETTING: Urban academic general medicine practice. PARTICIPANTS: Internal medicine housestaff and attending physicians with continuity clinics at the practice site. INTERVENTION: Two 1-hour educational seminars on skin cancer control conducted jointly by a general internist and a dermatologist. MEASUREMENTS AND MAIN RESULTS: Self-reported attitudes and beliefs about skin cancer control, ability to identify and make treatment decisions on 18 skin lesions, and knowledge of skin cancer risk factors were measured by a questionnaire before and after the teaching intervention. Exit surveys of patients at moderate to high risk of skin cancer were conducted 1 month before and 1 month after the intervention to measure physician skin cancer control practices reported by patients. Eighty-two physicians completed baseline questionnaires and were enrolled in the study, 46 in the intervention group and 36 in the control group. Twenty-five physicians attended both sessions, 11 attended one, and 10 attended neither. Postintervention, the percentage of physicians feeling adequately trained increased from 35% to 47% in the control group (p = .34) and from 37% to 57% in the intervention group (p = .06). Intervention physicians had an absolute mean improvement in their risk factor identification score of 6.7%, while control physicians' mean score was unchanged (p = .06). Intervention and control physicians had similar increases in their postintervention lesion identification and management scores. Postintervention, the mean proportion of patients per physician stating they were advised to watch their moles increased more among intervention physicians than control physicians (absolute difference of 19% vs -8%, p = .04). Other changes in behavior were not significant. CONCLUSIONS: Although we observed a few modest intervention effects, overall this brief skin cancer education intervention did not significantly affect primary care physicians' skin cancer control attitudes, beliefs, knowledge, or behaviors. A more intensive intervention with greater participation may be necessary to show a stronger impact on attitudes and knowledge about skin cancer control among primary care physicians.

Clinical Competence↗

Australian and New Zealand mammal species considered to be pests or problems.

In New Zealand and Australia, 25 and 16 introduced mammals are viewed as pests, respectively, as well as a further 17 native mammals in Australia. Most introductions were deliberate and the deleterious effects became apparent later. These pests affect primary production, act as a sylvatic reservoir of disease, cause degradation of natural ecosystems, or threaten rare or endangered native animals and plants. Many species have multiple impacts. In Australia, some native mammals, particularly kangaroos and wallabies, are also controlled because of their adverse impacts on primary production. In both countries, current control depends largely on the use of poisons, shooting, the spread of disease (in the case of rabbits), trapping, habitat alteration, and commercial or recreational hunting. Methods of control by interfering with fertility (immunocontraception) are currently being investigated for rabbits, house mice, foxes, and kangaroos in Australia, and for the brushtail possum in New Zealand. If these methods prove effective, they may be applied to other mammal pests, but the need to tailor the particular approach to the ecology and behaviour of the species means that there will be a necessarily long lead time.

Animals↗

Advertising and obesity: a behavioral perspective.

Concern over the levels of obesity observed in Western countries has grown as researchers forecast a rapid growth in the medical care that a progressively more obese population will require. As health workers deal with increased incidences of diabetes and other obesity-related disorders, policymakers have examined the factors contributing to this problem. In particular, advertising that promotes high fat and high sugar products to children has come under increasing scrutiny. Advertisers have rejected claims that advertising contributes to obesity by arguing that it cannot coerce people into purchasing a product, and does not affect primary demand. This reasoning overlooks the role advertising plays in reinforcing and normalising behavior, however, and it assumes that only direct causal links merit regulatory attention. Ehrenberg's "weak" theory suggests advertising will support unhealthy eating behaviors, while the wide range of sales promotions employed will prompt trial and reward continued consumption. This article presents an alternative analysis of how marketing contributes to obesity and uses behavior modification theory to analyse the "fast-food" industry's promotions. We also review the New Zealand government's response to obesity and suggest policy interventions that would foster healthier eating behaviors.

Adolescent↗

Dichogamy and sexual dimorphism in floral traits in the andromonoecious Euphorbia boetica.

BACKGROUND AND AIMS: Euphorbia boetica (Euphorbiaceae) is a functional andromonoecious species that shows both intra- and interfloral dichogamy, hermaphrodite cyathia being protogynous. Sexual dimorphism of the cyathia of E. boetica is examined according to their gender and arrangement on the inflorescence. METHODS: Data were obtained from two natural populations, where the distribution of male and hermaphrodite cyathia in the inflorescence was recorded. The size, pollen production and viability, and nectar secretion were measured in both types of cyathia. KEY RESULTS: Most cyathia were male at the first levels of the inflorescence, then hermaphrodite cyathia predominated at the successive levels, although at the last levels the proportion of male cyathia increased. Male cyathia at basal positions lack ovaries, whereas those at distal positions showed vestigial ovaries. The size of the cyathia varied significantly depending on the level of the inflorescence where they were produced: those of the last levels were usually smaller. The hermaphrodites were significant bigger than males; however, these differences were due to the differential distribution of each cyathium type in the inflorescence. Male cyathia produced significantly more pollen and nectar than hermaphrodites. CONCLUSIONS: In Euphorbia boetica, basal male cyathia could be explained by the presence of protogyny, and apical male cyathia seem to respond to a preemption of resources. A true dimorphism affecting primary sexual characters and related to gender function appears at lower levels of the inflorescence, whereas an apparent size dimorphism due to positional effects occurs at upper positions. Longevity and distribution of cyathia, and their pattern of nectar production, could improve both male and female fitness.

Euphorbia↗

Effects of gelatin-based resuscitation fluids on platelet aggregation.

Fluid resuscitation aims to maintain intravenous volume without significant effects on haemostasis. Several different types of i.v. fluid are available for use in a patient who has suffered trauma, but there is evidence that some resuscitation fluids may affect primary haemostasis. We have compared the effects of two resuscitation fluids, Haemaccel and Gelofusin, on platelet aggregation in vitro. These resuscitation fluids are both based on gelatin but Haemaccel contains a high concentration of Ca2+ whereas Gelofusin does not. Their effects on platelet aggregation in whole blood, induced by a range of different agents, were determined using a platelet-counting technique. Both Haemaccel and Gelofusin prevented platelet aggregation induced by ristocetin (P < 0.05, Mann-Whitney). In addition, Haemaccel proved to be a potent inhibitor of the platelet aggregation that occurred in response to all of the other agonists investigated: adenosine diphosphate, platelet-activating factor, collagen, a thromboxane A2 mimetic (U46619) and epinephrine. The additional inhibitory effects of Haemaccel were largely, but not completely, attributable to its high Ca2+ content. Inhibition of platelet aggregation by ristocetin may indicate a mechanism by which Haemaccel or Gelofusin may contribute to impaired haemostasis. The presence in Haemaccel of high concentrations of Ca2+, which is largely responsible for inhibition of the aggregation induced by other agents, may provide an additional means by which haemostasis could be impaired.

Gelatin↗

Illusory persistence of touch after right parietal damage: neural correlates of tactile awareness.

We studied a patient who experienced 'palinaesthesia', an illusion of persistent touch following tactile stimulation on the left hand, subsequent to a right parietal meningioma affecting primary somatosensory regions in the postcentral gyrus (SI) and superior parietal gyrus (Brodmann area 7), but preserving the secondary somatosensory cortex (SII) in the upper lateral sulcus. This subjective sensation was accompanied by transient increases in objective measures of tactile threshold. The patient had mild deficits in superficial tactile perception, but showed severe left-sided extinction for offsets of tactile stimuli during bilateral stimulation, but not for onsets of stimuli. Functional MRI revealed increased neural activity during palinaesthesia selectively arising within the ipsilesional-right SI cortex, but no abnormality within left SI and bilateral SII. Right SI responded to the onset of new tactile stimuli on the left hand but not to their offset. By contrast, any tactile events on either hand modulated activity in contralateral SII regions, even undetected left-sided offsets. These data demonstrate that illusory persistence of touch following stimulation on the hand may result from sustained neural activity in a restricted region of the SI cortex outlasting the offset of the actual tactile stimuli. These findings also provide direct evidence for a critical role of SI in mediating conscious somatosensory experience on contralateral parts of the body.

Aged↗

Fucose in alpha(1-6)-linkage regulates proliferation and histogenesis in reaggregated retinal spheroids of the chick embryo.

We have used the lectin from Aleuria aurantia (AAL) which is highly specific for alpha(1-6)-linked fucose, to examine its effect on chicken retinogenesis in a reaggregation culture system. When dispersed cells of the embryonic chick retina are reaggregated to form histotypic retinospheroids, AAL elicits strong inhibition of spheroid growth. The action of AAL is specific, since its effect is dose-dependent, saturable, and inhibited by an excess of fucose. Fucosidase treatment entirely abolishes reaggregation. In contrast, Anguilla anguilla agglutinin (AAA) binding to fucose in alpha(1-2)-linkage does not show any effects. Incubation with CAB4-a specific monoclonal antibody for fucose in alpha(1-6)-linkage-reduces spheroid size and shape. AAL does not much affect primary aggregation, but rather subsequent processes of cell proliferation and histogenesis. In particular, AAL inhibits uptake of bromo-desoxyuridine (BrdU), most efficiently so during days in vitro 2 (div2) and div3. As a consequence, the histological differentiation is entirely disturbed, as evidenced by vimentin immunostaining; particularly, rosettes are not forming and the radial glia scaffold is disorganized. We conclude that glycoproteins exhibiting fucose in alpha(1-6)-linkage may play major roles in early processes of retinal tissue formation.

Animals↗

Platelet monoamine oxidase and plasma amine oxidase in psychiatric patients.

Platelet monoamine oxidase (MAO) and plasma amine oxidase (PAO) activities were determined in 70 normal controls and 76 psychiatric patients. Platelet MAO activity did not differ between the normal controls and patients diagnosed as schizophrenic or primary affective illness, although there was a strong trend for chronic schizophrenics to have lower MAO activity. Schizophrenic patients with Schneiderian-type hallucinatiions had significantly lower MAO activity than normal controls or schizophrenic patients who did not hallucinate. There was no relationship between hallucinations and platelet MAO activity in patients with affective psychoses. Paranoid schizophrenics did not have significantly different MAO activity from nonparanoid schizophrenics. PAO activity was generally lower in all diagnostic groups than in normal controls, but the results were statistically significant only for acute schizophrenics.

Affective Disorders, Psychotic↗

Neutralization of endogenous vascular endothelial growth factor depletes primordial follicles in the mouse ovary.

The regulation of early follicular growth and development involves a complex interaction of autocrine, paracrine, and endocrine signals. The ability of these factors to regulate follicle growth may depend in part on the extent of vascular delivery to and perfusion of the ovary. Vascular endothelial growth factor A (VEGFA) is a major regulator of vascular physiology in the ovary. VEGFA is produced in numerous ovarian compartments and likely plays a role in the regulation of all phases of follicular growth, from preantral through preovulatory. The aim of the present study was to further evaluate the role of VEGF in early follicle growth by neutralization of endogenous VEGF or VEGF receptors. Adult mice were injected systemically and prepubertal mice were injected directly under the ovarian bursa with antibodies designed to neutralize VEGF or block interaction with its receptors in the ovary. Both systemic and intrabursal injections of VEGF antibody significantly reduced the number of primordial follicles within 1-3 days after administration without affecting primary or secondary follicle numbers. Primordial follicle numbers were not different from control levels by 30 days after VEGFA antibody administration. Administration of antibodies to the kinase domain receptor (KDR), but not the FMS-like tyrosine receptor (FLT1), for VEGF also resulted in a significant decrease in primordial follicles. These data suggest that VEGF plays a vital role in the maintenance and growth of the primordial follicle pool.

Animals↗

Alcohol consumption promotes body weight loss in melanoma-bearing mice.

BACKGROUND: Alcohol consumption is an important risk factor for cancer. Little is known about its effects on cancer progression. Previously, we showed that high ethanol consumption inhibited metastasis of B16BL6 melanoma-bearing mice without affecting primary tumor growth. On the other hand, ethanol-consuming tumor-bearing (TE) mice exhibited decreased survival and decreased body weight as compared to water-drinking, tumor-bearing (TW) mice. The focus of this study was to determine how alcohol promotes weight loss in melanoma-bearing mice. METHODS: Female, C57BL/6 mice were given water or 20% w/v ethanol in the drinking water for 3 weeks to 6 months before subcutaneous inoculation of 1 x 10(6) B16BL6 melanoma cells. Mice continued to receive the same fluids. Biochemical parameters were evaluated at various times after tumor inoculation. Body weight, water content, tumor weight and carcass fat content were determined at necropsy. RESULTS: TW mice elicted a modest weight loss. This response was magnified 2-fold by alcohol consumption. The weight loss in TE mice is not caused by dehydration, decreased energy intake, or loss of skeletal muscle mass. It resulted specifically from loss in body fat. Other alterations associated with the fat loss in TE mice were: (1) decreased glucose, (2) elevated fatty acids, (3) elevated beta-hydroxybutyrate, (4) elevated glucagon, and (5) increased leptin levels in plasma. Body temperature decreased about 2.9 degrees C in TE mice. Metabolic rate increased in TW mice. The fat loss due to alcohol consumption in tumor-bearing mice was not due to increased metabolic rate. CONCLUSIONS: The response elicited by alcohol consumption in tumor-bearing mice is complex and associated with alterations in metabolism and hormones. These findings suggest that alcohol abuse could be a risk factor for cancer patients because it invokes a strong depletion of body fat. This could facilitate wasting and shorten survival time.

Alcohol Drinking↗

Propofol has both enhancing and suppressing effects on human platelet aggregation in vitro.

BACKGROUND: Volatile anesthetics are known to suppress platelet aggregation. In contrast, there is conflicting information regarding the effect of propofol on platelet function. The present study was designed to clarify the effects of propofol on platelet function and the mechanisms underlying these effects. METHODS: Propofol or an equivalent volume of 10% Intralipos (as a control) was added to test tubes 5 min before the induction of each reaction. Platelet aggregation induced by epinephrine, arachidonic acid (AA), prostaglandin G2 (PGG2), or STA2 (a thromboxane A2 [TXA2] analog) was measured using an eight-channel aggregometer. To determine type 1 cyclooxygenase activity, AA (0.5 mM) was added to an assay mixture containing type 1 cyclooxygenase, and the concentration of the final product, malonaldehyde, was measured by spectrophotometry. Epinephrine-, adenosine diphosphate-, AA-, and PGG2-induced TXA2 formation was measured using a commercially available radioimmunoassay kit. To estimate TXA2 receptor-binding affinity, 3H-S145, a specific TXA2 receptor antagonist, was added, and the radioactivity of receptor-bound 3H-S145 was determined using a liquid scintillation analyzer. Inositol 1,4,5-triphosphate formation was measured in STA2-stimulated platelets using a commercially available inositol 1,4,5-triphosphate assay kit. RESULTS: Propofol (40 microM) enhanced, whereas 100 microM suppressed, adenosine diphosphate- and epinephrine-induced secondary aggregation without affecting primary aggregation. Propofol (40 microM) also enhanced, but 100 microM suppressed, AA-induced aggregation. Propofol (100 microM) enhanced PGG2- and STA2-induced aggregation. Propofol (100 microM) suppressed AA-induced TXA2 formation but did not alter that induced by PGG2. Propofol (30-100 microM) suppressed AA-induced malonaldehyde formation, indicating inhibition of type 1 cyclooxygenase activity. Propofol did not alter TXA2 receptor-binding affinity. Propofol (30 and 100 microM) augmented inositol 1,4,5-triphosphate formation in STA2-stimulated platelets. CONCLUSIONS: The present findings clearly indicate that high concentrations of propofol suppress the activity of type 1 cyclooxygenase, the enzyme that converts AA to PGG2. Furthermore, propofol also enhanced STA2-induced inositol 1,4,5-triphosphate formation. These results may explain the inconsistent findings of previous investigators.

Adult↗