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At least 163 records · Page 9Linked to original sources
PubMed1994

Hox11 controls the genesis of the spleen.

Many homeobox genes are clustered in a linear array along a chromosome, reflecting their ordered expression along the anterior-posterior axis of the embryo. Expression patterns as well as grafting, ectopic expression and loss-of-function experiments suggest that the Hox genes encode a combinatorial system of positional specification along that axis. In contrast, the function of orphan homeobox genes located at sites outside the four mammalian Hox clusters is less well understood. To assess the functional role of the orphan homeobox gene Hox11, we have generated Hox11-deficient mice through gene targeting. Hox11-/- mice have no spleen, but otherwise appear normal. Hox11 is normally expressed in the splenic anlage arising from the splanchnic mesoderm. Hox11-/- embryos have no cellular organization at the site of splenic development but all other splanchnic derivatives develop normally. Hox11 controls the genesis of a single organ, providing new insight into the genetic regulation of morphogenesis.

Animals↗
PubMed1997

Macrophage prostaglandin production contributes to the age-associated decrease in T cell function which is reversed by the dietary antioxidant vitamin E.

The aging process is associated with a decline in T cell-mediated immunity, including decreased interleukin (IL)-2 production and mitogen-induced T cell proliferation. Because macrophages (M phi) from old mice have higher production of prostaglandin (PG) E2 than young mice, and PGE2 has been shown to suppress T cell-mediated function, we hypothesized that increased production of PGE2 would contribute to decreased T cell function with aging and that decrease in PGE2 production by dietary antioxidants would enhance T cell-mediated function. Experiments were conducted in which combinations of purified M phi and T cells (> 95% pure) from young or old C57BL/6N1A mice were cultured together. Co-cultures containing T cells and M phi from old mice had reduced ConA-stimulated proliferation and IL-2 secretion than those consisting of T cells and M phi from young mice. Addition of M phi from old mice suppressed proliferation and IL-2 secretion by T cells from young mice. Likewise, T cells from old mice secreted more IL-2 when cultured with M phi from young mice compared to those cultured with M phi from old mice. Addition of PGE2, at concentrations produced by old M phi, decreased proliferation and IL-2 production by young but not old T cells. Neither addition of H2O2 at physiological levels, nor catalase changed the response of cultures from young or old mice. However, addition of indomethacin and the antioxidant nutrient vitamin E, both of which decreased PGE2 production, improved T cell proliferation and IL-2 production. These experiments demonstrate that increased production of PGE2 by M phi contributes to the age-associated decline in T cell function. Vitamin E improves T cell responsiveness in old mice mostly by reducing M phi PGE2 production, although a direct effect of vitamin E on T cells was also observed.

Aging↗
PubMed1990

On the cost functions for the control of the human arm movement.

The aim of our investigation is to understand the mechanisms which control the movement of the human arm. The arm is here considered as a redundant system: the shoulder, elbow and wrist joints, which provide three degrees of freedom, combine to move the hand in a horizontal plane, i.e. a two dimensional space. Thus the system has one extra degree of freedom. Earlier investigations of the static situation led to the hypothesis that independent cost functions were attached to each of the three joints and that the configuration chosen for a given target position is that which provides the minimum total cost (Cruse 1986). The aim of the current investigation was to look for measurable values corresponding to the hypothetical cost functions. Experiments using pointers of different lengths attached to the hand showed that the strategy in choosing the joint angles are independent of the limb length. The muscle force necessary to reach a given angle is increased by a spring mounted across a joint. In this situation the angles of the loaded joint are changed for a given target point to give way to the force effect. This leads to the conclusion that the hypothetical cost functions are not independent of the physiological costs necessary to hold the joint at a given angle. The cost functions seem to depend on joint angle and on the force which is necessary to hold the joint in a given position. Cost functions are measured by psychophysical methods. The results show U-shaped curves which can be approximated by parabolas. The position of minimum cost (maximum comfort) for one joint showed no or weak dependency on the angles of the other joints. For each subject these "psychophysical" cost functions are compared with the hypothetical cost functions. The comparison showed reasonable agreement. This supports the assumption that the psychophysically measured "comfort functions" provide a measure for the hypothetical cost functions postulated to explain the targeting movements. Targeting experiments using a four joint arm which has two extra degrees of freedom showed a much larger scatter compared to the three joint arm. Nevertheless, the results still conform to the hypothesis that also in this case the minimum cost principle is applied to solve the redundancy problem. As the cost function for the whole arm shows a large minimum valley, quite a large range of arm positions is possible of about equal total costs.(ABSTRACT TRUNCATED AT 400 WORDS)

Arm↗
PubMed1988

Correlation of immunoregulatory function with cell phenotype in cord blood lymphocytes.

The strong suppressor activity of cord T lymphocytes contrasts markedly with their mainly CD4 (helper) rather than CD8 (suppressor) phenotype. We studied the phenotype of cord CD3, CD4 and CD8 cells compared to adult cells using the monoclonal antibodies, 2H4, 4B4, and UCHL1. Almost all cord CD4 lymphocytes carried the suppressor-inducer marker 2H4, whereas 4B4+ UCHL1+ helper-inducer cells were virtually absent; CD8 cord cells were also of the 2H4+ 4B4- UCHL1- phenotype. In contrast in adult peripheral blood, half of the T cells, whether CD4 or CD8, were 2H4+ and half 4B4/UCHL1+. The suppressor-inducer phenotype of cord T cells was shown, in parallel functional experiments, to correlate with their enhanced proliferation to lectin and poor production of immunoglobulin and with the ability of cord mononuclear cells to suppress proliferation and immunoglobulin production by adult cells in co-culture experiments. These results indicate that the major imbalance in the cord CD4 subset in favour of 2H4 cells can explain many of the functional differences from adult cells. However, involvement of other cell types, in particular of the monocyte lineage, is necessary to explain other properties of immunocompetent cord cells.

Adult↗
PubMed1990

The epithelium of the human endolymphatic sac: immunohistochemical characterization.

A panel of monoclonal and polyclonal antibodies has been used to study the epithelium of the extraosseous part of the human endolymphatic sac (ES) by immunohistochemistry. The ES epithelium reacted with several epithelial markers such as Lu-5, different anticytokeratins, antiepithelial membrane antigen, and anticarcinoembryonic antigen. Unexpectedly, all epithelial cells also revealed a strong positive reaction for the mesenchymal marker vimentin and for S-100 protein. 'Neuroendocrine', a neurosecretory antigen, and neuron-specific enolase reactivity was detected in a few epithelial cells. The results support the assumption that the ES epithelium is metabolically active and capable of secretion and resorption. These findings are in keeping with results of functional experiments in animals. The demonstration of neurosecretory antigen and neuron-specific enolase in some cells indicate that the epithelium may also have paracrine functions.

Antibodies, Monoclonal↗
PubMed1992

Different types of receptor interaction of peptide and nonpeptide angiotensin II antagonists revealed by receptor binding and functional studies.

The pharmacological effects of angiotensin II (AII) are potently inhibited by several peptide and recently synthesized nonpeptide AII receptor antagonists. The interaction of sarcosine1, isoleucine8-AII (sarile), sarcosine1,O-methyltyrosine4-AII (sarmesin), and the nonpeptide AII antagonists 2-n-butyl-4-chloro-5- hydroxymethyl-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)- methyl]imidazole (DuP 753, Losartan potassium) and its metabolite 2-n-butyl-4-chloro-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl]imidaz ole - 5-carboxylic acid (EXP3174) with AII binding sites was investigated in radioligand binding and functional studies. Sarile, sarmesin, DuP 753, and EXP3174 inhibited 125I-AII binding to rat lung tissue, with Ki values of 3.5, 16.1, 23.7, and 10.4 nM, respectively. The Hill coefficients of all displacement curves, except for sarile (nH, 1.45), were not significantly different from unity. In functional experiments using rabbit aorta, sarmesin and DuP 753 competitively inhibited the contractile response to AII, with pA2 values of 6.75 and 8.01, respectively. Sarile, in contrast, revealed noncompetitive antagonism, i.e., the maximum contractile force and the slope of the concentration-contractile force curve were significantly and concentration-dependently depressed. The concentration-contractile response curve for AII was shifted to the right in a parallel fashion in the presence of EXP3174 (3 nM to 1 microM); however, the maximum contractile force was significantly decreased, by 24%. The marked noncompetitive antagonism of sarile (3 nM) was reversed in the presence of increasing concentrations of sarmesin (30 nM to 30 microM) or DuP 753 (10 nM to 1 microM), whereas in the presence of increasing concentrations of EXP3174 (3-300 nM) a 25% depression in maximum contractile force persisted. Moreover, the reduction of the maximum contractile force by EXP3174 (10 nM) was concentration-dependently restored in the presence of increasing concentrations of DuP 753 (10 nM to 1 microM), indicating interaction with the same binding site. Whereas sarile (0.3-10 nM) did not affect the 125I-AII binding capacity in radioligand saturation experiments, a 54% reduction of Bmax was observed in the presence of 100 nM EXP3174. The data provide evidence that all antagonists inhibit the functional response to AII by interacting with a common binding site at the receptor. The noncompetitive behavior of sarile seems to be due to slow dissociation from this receptor site. An additional mechanism must be postulated for EXP3174. An allosteric interaction with the receptor, as suggested by the reduction in Bmax, may be, at least in part, responsible for the nonclassical antagonism of this compound.

Angiotensin II↗
PubMed1996

Biochemical evidence of functional interaction between mu- and delta-opioid receptors in SK-N-BE neuroblastoma cell line.

Radioligand binding assays and functional experiments revealed that the SK-N-BE neuroblastoma cell line expresses a similar ratio of mu- and delta-opioid receptors, both negatively coupled to adenylyl cyclase through pertussis toxin-sensitive G proteins. Our findings also indicate that some functional interaction occurred between the two opioid subtypes; in fact, long-term exposure to [D-Ala2-N-methyl-Phe4-Gly-ol5]enkephalin (DAMGO), a mu-selective agonist, sensitized the functional response of the delta-selective agonist but not vice versa. It is interesting that in acute interaction experiments, we observed a shift to the right of the concentration-effect curve of either DAMGO or [D-Pen2,5]enkephalin (DPDPE), a delta-selective agonist, as a result of DPDPE or DAMGO administration, respectively. In addition, low doses of naloxone, an antagonist selective for mu receptors, increased the inhibitory effect [D-Ala2-D-Met5]enkephalinamide (DAME), a mixed mu/delta agonist, on adenylyl cyclase activity. Taken overall, these data support the hypothesis of the existence of a cross talk between mu and delta receptors in the SK-N-BE cell line.

Adenylyl Cyclases↗
PubMed1993

Neurosurgical intensive care unit organization and function: an American experience.

This article describes the organization and function of a university-based neurosurgical intensive care unit. The unit's success has been based in part on its physical structure and in larger part on its organization. Patients are comanaged by a team of neurosurgeons and anesthesiologist intensive care specialists, who receive twice-weekly input from all other participating patient care specialists, including nurses, physical therapists, social workers, and others. This type of approach promotes teamwork and fosters mutual respect among the team. It also improves patient care and, frequently, outcome.

Critical Care↗
PubMed2026

Integrative Genomic and Functional Investigation of the Multi-Layered Genetic Architecture Between Anorexia Nervosa and Bone Loss.

OBJECTIVE: Bone loss is a severe and often irreversible complication of anorexia nervosa (AN), yet the genetic mechanisms underlying this comorbidity remain underexplored. This study focuses on constructing a comprehensive genetic architecture between AN and estimated calcaneal bone mineral density (eBMD). METHOD: We applied an integrative framework incorporating genetic correlation, pleiotropic association, and causal inference across single-variant, multi-variant, and gene expression levels. Functional validation was conducted in vitro to investigate the biological role of the key candidate gene. RESULTS: Local genetic correlation analysis identified significant signals at 8p21.2 and 10q26.3, despite the lack of significant global correlation. Mendelian randomization analysis pointed to a suggestive negative causal effect of genetically predisposed AN on eBMD. Extensive pleiotropic signals were detected, particularly at 3p21.31 and 10q26.3, loci enriched with genes associated with both traits. Notably, we identified a novel pleiotropic signal near NCAM1 at 11q23.2, which was supported by multi-layered genetic evidence and confirmed through in vitro functional experiments. NCAM1, a well-established neural-associated gene, promoted osteoclastic differentiation and bone resorption when overexpressed in osteoclast precursor cells, indicating that NCAM1 possesses distinct functional roles in both neural and skeletal tissues. DISCUSSION: This study constructs a comprehensive genetic architecture underlying AN and eBMD and highlights NCAM1 as a key pleiotropic gene.

anorexia nervosa↗
PubMed2026

Brain perivascular macrophages regulate endothelial cell function via a cMAF-dependent transcriptional program in mouse and human.

Brain perivascular macrophages maintain brain physiology, yet their transcriptional regulators and functions in health and disease remain unclear. Using single-cell multi-omics and functional experiments, we identify cellular musculoaponeurotic fibrosarcoma oncogene (cMAF) as a key transcription factor for brain perivascular macrophages, and conditional deletion of cMAF disrupts their phenotype in vivo. Functionally, cMAF drives insulin-like growth factor-1 (IGF1) expression in perivascular macrophages, enabling communication with endothelial cells. Consistently, cMAF deletion in perivascular macrophages causes transcriptional alterations in cerebral arteries, affecting vascular functions. Notably, cMAF emerges as the main transcription factor for human perivascular macrophages, suggesting conservation of this transcriptional module. During Alzheimer's disease (AD), human perivascular macrophages upregulate cMAF and IGF1 to enhance communication with vascular cells, and this response is abrogated in APOE4 carriers. Lastly, we explore an uncharacterized polymorphism in cMAF, providing evidence that the cMAF program is protective against AD. Targeting cMAF in perivascular macrophages may offer new therapeutic strategies for neurodegenerative and cerebrovascular diseases.

APOE4↗
PubMed1986

In vivo treatment with anti-I-A antibodies: differential effects on Ia antigens and antigen-presenting cell function of spleen cells and epidermal Langerhans cells.

The in vivo activation of T cells by a variety of antigens can be inhibited by the administration of anti-I-A antibodies (Ab) at the time of antigen priming. This inhibition can partially be explained by the temporary loss of Ia molecules from Ia-bearing antigen-presenting cells (APC) in the spleen. In this study, the effects of i.p. injected monoclonal Ab specific for I-A glycoproteins of different H-2 haplotypes on Ia antigen expression and APC function of spleen cells and epidermal Langerhans cells were compared. It was found that anti-I-A Ab quickly bound to both spleen cell and Langerhans cell Ia antigens. Although spleen cell Ia antigens were modulated and thus temporarily disappeared, Ia antigen expression by epidermal Langerhans cells was not modulated. In functional studies, the capacity of spleen cells and epidermal cells from anti-I-A Ab treated vs control animals to function as APC for antigen-specific, I-A- or I-E-restricted T cell clones was tested. A single injection of anti-I-A Ab completely abolished the APC function of spleen cells as shown in several inbred mouse strains, F1 animals, and with the use of several different Ab and T cell clones. In contrast, Langerhans cell-dependent APC function of epidermal cells remained completely unaltered. Even multiple injections of high doses of Ab never caused any inhibition of Langerhans cell function. Experiments with anti-I-Ak or anti-I-Ad Ab in an (H-2k X H-2d)F1 animal showed abrogation of APC function of spleen cells, but again not of Langerhans cells. Thus in vivo anti-I-A Ab administration appears to differentially affect Ia antigen expression and APC function from spleen and epidermis: Ia antigens are modulated from spleen cells but not from epidermis, and APC function disappears in the spleen but not in the epidermis. The abrogation of splenic but not of Langerhans cell APC function with anti-I-A Ab will facilitate the dissection of the relative contributions of Langerhans cells as compared with other APC in the generation of cutaneous immune responses.

Animals↗
PubMed1995

Psychosocial functioning and subjective experience in schizophrenia: a reanalysis.

Data collected by Brekke et al. (1993) on the symptomatology, psychosocial functioning, and subjective experience of schizophrenia outpatients were reanalyzed using LISREL to elucidate a causal model that would depict the functional relationships between the variables. The model that best fit the data parallels another model tested previously on cardiac patients and shows that subjective experience is much more influenced by symptomatology than by social functioning. This confirms Brekke et al.'s main finding. The implications of these results for intervention and for future research are considered.

Activities of Daily Living↗
PubMedDate not supplied

Interleukin-2-induced proliferation of CD4-CD8- human thymocytes. In vitro expression of CD3 and CD8 antigens and cytolytic activity.

Human thymocytes lacking both CD4 and CD8 differentiation antigens were prepared by treating total thymocyte suspensions with a mixture of anti-CD4 and anti-CD8 monoclonal antibodies and complement. The resulting populations contained less than 2% CD4+, CD8+ or WT31+ cells and variable percentages (less than 20%) of CD3+ cells. These cell populations were cultured in recombinant IL-2 in the presence of peripheral blood mononuclear cells as feeder cells. Cells underwent extensive proliferation accompanied by a progressive increase of CD3+ and CD8+ cells. On the other hand, appearance of neither WT31+, alpha/beta-positive T cell receptor (TCR), nor CD4+ cells could be observed in several independent experiments. Functional analyses revealed the appearance and the progressive increase of cytolytic activity against the natural killer (NK)-sensitive K562 cells as well as the NK-resistant fresh melanoma cells. Experiments of T cell cloning indicated that both the expression of CD8 and CD3 antigens and the appearance of cytolytic activity were consequent to cell maturation occurring at the level of CD4-CD8- non-cytolytic cell precursors. In these experiments, more than 30% of cells underwent clonal expansion and all the clonal progenies obtained displayed cytolytic activity and expressed the CD3+WT31- surface phenotype. The expression of CD8 was variable, whereas no CD4+ clones could be obtained. Cells expressing such surface phenotype are known to belong to the TCR gamma-positive T lymphocyte subset lacking the typical alpha/beta TCR and thus appear to be the only T cell type capable of in vitro proliferation and maturation under easily reproducible culture conditions.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1994

CD27: marker and mediator of T-cell activation?

CD27 is a lymphocyte-specific member of the tumour necrosis factor receptor (TNF-R) family, expression of which is tightly regulated during T-cell ontogeny. Recently, the ligand for CD27 was identified and was shown to be identical to CD70, a novel member of the TNF family. Functional experiments show that the interaction between CD27 and its ligand generates a co-stimulatory signal for T-cell activation. Here, Rogier Hintzen and colleagues integrate the phenotypic and functional data available on CD27 and its ligand, and propose a role for CD27 in the amplification of T-cell responses.

Animals↗
PubMed1990

Functional impairment in Mexican Americans and non-Hispanic whites with diabetes.

There are virtually no data available describing the functional status of diabetic individuals. We therefore measured functional status using the Sickness Impact Profile (SIP) in 393 diabetic subjects and 486 nondiabetic control subjects identified from the San Antonio Heart Study, a population-based study of diabetes among Mexican Americans and non-Hispanic whites. The SIP is a validated instrument that assesses the presence of health-related behavior changes and activity restrictions in 12 different categories. Functional impairment, defined as a SIP score of 2.0% or greater, was present among 36.6% of diabetic subjects. Following adjustments for age, Mexican Americans were 1.63 times more likely to experience functional impairment that non-Hispanic whites, although this difference was not statistically significant (95% confidence interval: 0.92-2.89). The categories in which subjects experienced impairment varied widely, but the category with the highest prevalence of impairment was "eating" (greater than 40%). The prevalence of functional impairment was 45.9% among diabetic subjects with vascular complications, 31.8% among diabetic subjects without complications, and 16.7% among nondiabetic control subjects. Among all diabetic subjects impairment increased with age, duration of diabetes, fasting glucose, and BMI, and with insulin use and the presence of hypertension. In a multiple logistic regression model these factors (with the exception of insulin use) remained associated with the presence of functional impairment even after adjustment for the presence of vascular complications. If the factors responsible for this excess of functional impairment can be identified, an intervention might be designed which can lead to improvement in the quality of life for diabetic individuals.

Adult↗
PubMed1995

Pharmacological implications of inward rectifier K+ channels regulation by cytoplasmic polyamines.

The powerful combination of molecular biology and electrophysiology has allowed extraordinary progress in the field of ion channel structure-function. In fact, only 10 years have passed since the first amino acid sequence of a voltage-dependent ion channel, the Na+ channel, was deduced [1], and already the structural domains involved in ion channel permeation, block and gating have been identified in many channel types. Despite this progress, in most cases the correlation between specific domains and ion channel function is still speculative at present, due to the absence of direct structural information [2]. In this review we will describe recent progress in the field of structure-function of one class of K+ channels, the inward rectifiers (IRKs). In particular, we will review the sequences of structure-function experiments which have led to the discovery of a novel regulation of IRKs by cytoplasmic organic polycationic substances like polyamines (PAs). This discovery represents a paradigm for how structure-function information has preceded and made possible the identification of physiological mechanisms of ion channel regulation. Owing to the important role played by IRKs in the regulation of resting membrane potential, a major determinant of cellular transport and volume [3], and to the established link between PAs and cell growth and division, the direct regulation of IRKs by PAs assumes a critical importance for the pharmacological control of cell growth and neoplastic transformation.

Animals↗
PubMed1996

Simultaneous activation of granulocytes and extrathymic T cells in number and function by excessive administration of nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) sometimes show serious side effects such as damage to the gastroduodenal mucosa and dysfunction of the liver. Although many investigators have focused on some types of leukocytes, a comprehensive study concerning all types of leukocytes, especially recently identified extrathymic T cells, remains to be done. When mice were treated with an intraperitoneal injection of indomethacin (50 or 300 microg/mouse), the number of thymocytes decreased while the number of MNC in various peripheral organs increased. This increase in MNC was due mainly to the increase in the numbers of granulocytes and extrathymic T cells. Reflecting thymic atrophy, the proportion of thymus-derived T cells distributed in the periphery decreased. The use of other NSAIDs revealed that granulocytosis seen in the periphery arose from a selective activation of myelomonocytic cells in the bone marrow. Some functional experiments using the Ca2+ influx, iNOS mRNA expression, and autoreactive cytotoxicity as indicators suggested that granulocytes and extrathymic T cells were in activated states not only in number but also in function. Since both granulocytes and extrathymic T cells become cytotoxic effectors against self-tissues or self-cells when overactivated, these activated leukocytes may be intimately related to the etiology of the tissue damage inducible by NSAIDs (i.e., adverse drug reaction).

Animals↗
PubMedDate not supplied

[The effect of the removal of the pancreas and its resection on prostatic function].

Endogenic and/or exogenic pancreatic dysfunction as a result of chronic diseases or surgery have been detected in 87 patients with prostatic lesions. To specify the effect of hypo- and apancreatic conditions on prostatic structure and function experiments have been performed on 71 dogs. The animals were subjected to radical or partial pancreatectomy. The postoperative histological and histometric examination of the prostate provided evidence for the dependence of prostatic morphology and function on pancreatic performance. Both endo- and exogenic disorders of the pancreas can give rise to prostatopathy, carbohydrate dystrophy, formation of cysts, prostatic sclerosis. The above facts should be taken into consideration by clinicians.

Animals↗