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At least 919 records · Page 51Linked to original sources
PubMed2000

Carbohydrate-deficient glycoprotein syndrome type 1a: a variant phenotype with borderline cognitive dysfunction, cerebellar hypoplasia, and coagulation disturbances.

An 8-year-old boy is described with borderline cognitive impairment, cerebellar hypoplasia, a stroke-like episode, and venous thrombosis of the left leg after a period of immobilization. The pattern of multiple abnormalities in blood coagulation suggested carbohydrate-deficient glycoprotein syndrome type 1a. Isoelectric focusing of serum transferrin was abnormal. The activity of phosphomannomutase in leukocytes and fibroblasts was decreased. Mutation analysis of the PMM2 gene revealed the R141H/E151G genotype. These results confirm the presence of carbohydrate-deficient glycoprotein syndrome type 1a without severe psychomotor retardation.

Blood Coagulation Disorders↗
PubMed2001

Deletion of the Src homology 3 domain and C-terminal proline-rich sequences in Bcr-Abl prevents Abl interactor 2 degradation and spontaneous cell migration and impairs leukemogenesis.

The hematopoietic cells from patients with Bcr-Abl-positive chronic myelogenous leukemia exhibit multiple abnormalities of cytoskeletal function. The molecular events leading to these abnormalities are not fully understood. Previously we showed that Bcr-Abl elicits ubiquitin-dependent degradation of Abl interactor proteins. Because recent studies have suggested a role of Abl interactor proteins in the pathway that regulates cytoskeletal function, we investigated whether mutations in Bcr-Abl that interfere with the signaling to Abl interactor proteins affect its leukemogenic activity. We report here that the Src homology 3 domain and C-terminal proline-rich sequences of Bcr-Abl are required for its binding to Abl interactor 2 as well as for the induction of Abl interactor 2 degradation. Although the deletion of these regions did not affect the ability of the mutant Bcr-Abl to transform hematopoietic cells to growth factor independence, it abrogated its ability to stimulate spontaneous cell migration on fibronectin-coated surfaces. Furthermore, the mutant Bcr-Abl, defective in binding to Abl interactor 2 and inducing its degradation, failed to induce chronic myelogenous leukemia-like disease in mouse. These results are consistent with a role of Abl interactor proteins in the regulation of cytoskeletal function as well as in the pathogenesis of Bcr-Abl-induced leukemogenesis.

Adaptor Proteins, Signal Transducing↗
PubMed2001

The germinal isozyme of angiotensin-converting enzyme can substitute for the somatic isozyme in maintaining normal renal structure and functions.

The angiotensin-converting enzyme (ACE) gene encodes two structurally related isozymes, somatic ACE and germinal ACE, that are uniquely expressed in discrete locations in the body. The importance of ACE in these cell types was revealed by generating Ace -/- mice, which exhibit multiple abnormalities including renal structural defects and functions, hypotension, and male sterility. To test the hypothesis that specific physiological functions of ACE are mediated by isozyme-specific and tissue-specific expression patterns, we have used a transgenic approach to develop mouse strains that express just one ACE isoform in the target tissue of Ace -/- mice. The mice described in this report produce germinal ACE in sperm and serum. These mice were as healthy as wild type mice, and the males were fertile. Interestingly, they had normal kidney structure, fluid homeostasis, and partially restored urine concentration despite having low blood pressure. This result demonstrated that circulating germinal ACE is sufficient for maintaining normal kidney structure and fluid homeostasis but insufficient for restoring blood pressure to normal levels.

Animals↗
PubMed2006

Kindlin-1 is a phosphoprotein involved in regulation of polarity, proliferation, and motility of epidermal keratinocytes.

A novel family of focal adhesion proteins, the kindlins, is involved in attachment of the actin cytoskeleton to the plasma membrane and in integrin-mediated cellular processes. Deficiency of kindlin-1, as a result of loss-of-function mutations in the KIND1 gene, causes Kindler syndrome, an autosomal recessive genodermatosis characterized by skin blistering, progressive skin atrophy, photosensitivity and, occasionally, carcinogenesis. Here we characterized authentic and recombinantly expressed kindlin-1 and show that it is localized in basal epidermal keratinocytes in a polar fashion, close to the cell surface facing the basement membrane, in the areas between the hemidesmosomes. We identified two forms of kindlin-1 in keratinocytes, with apparent molecular masses of 78 and 74 kDa, corresponding to phosphorylated and desphosphorylated forms of the protein. In kindlin-1-deficient skin, basal keratinocytes show multiple abnormalities: cell polarity is lost, proliferation is strongly reduced, and several cells undergo apoptosis. In vitro, deficiency of kindlin-1 in keratinocytes leads to strongly reduced cell proliferation, decreased adhesion, undirected motility, and intense protrusion activity of the plasma membrane. Taken together, these results show that kindlin-1 plays a role in keratinocyte adhesion, polarization, proliferation, and migration. It is involved in organization and anchorage of the actin cytoskeleton to integrin-associated signaling platforms.

Animals↗
PubMed1979

Syndrome delineation. 1. Malformations and dysplasias.

A practical classification of genetic disorders and birth defects divides them into five categories: malformations, dysplasias, inborn errors of metabolism, deformities, and variant familial developmental patterns. The first two categories are discussed here. The last three will be discussed next month in part 2.

Abnormalities, Drug-Induced↗
PubMed1987

Nonimmunologic hydrops fetalis: a clinicopathological study of 50 autopsy cases.

Fifty cases of nonimmunologic hydrops fetalis found in Japanese infants are reported. Nonimmunologic hydrops fetalis is associated with various pathological conditions, twin transfusion syndrome including acardiac monsters, fetal heart diseases, congenital cystic adenomatoid malformation, pulmonary sequestration, pulmonary lymphangiectasia, intrauterine infections such as cytomegalovirus infection and neonatal hepatitis, congenital neuroblastoma, Kasabach-Merritt syndrome, cystic hygroma, and chromosomal aberrations. The mechanism of hydrops fetalis found in these conditions is discussed from various viewpoints. Despite a careful examination, no causative conditions were found in 14 cases. The placenta showed a proliferation of Hofbauer cells that were strongly positive for immunoreactive alpha 1-antichymotrypsin and there were other common findings such as edema of terminal villi and fibrin thrombi.

Abnormalities, Multiple↗
PubMed2004

Peripheral and spinal motor reorganization after nerve injury and repair.

Functional recovery after peripheral nerve injury depends on the amount as well as on the accuracy of reinnervation by regenerative axons. In this study, the rat sciatic nerve was subjected to crush injury or complete transection repaired by either (1) straight nerve suture, (2) crossed nerve suture of tibial and peroneal fascicles, or (3) silicone tubulization leaving a gap of 4 mm. The compound muscle action potentials (CMAP) of gastrocnemius, tibialis anterior and plantar muscles were recorded 90 days post operation to assess functional reinnervation and Fast Blue, Fluoro Gold and DiI were applied to the nerve branches projecting into these muscles to quantify morphological reinnervation. The CMAP amplitude achieved in gastrocnemius, tibialis anterior and plantar muscles was higher after nerve crush (86%, 82%, 65% of control) than after any surgical nerve repair (straight suture: 49%, 53%, 32%; crossed suture: 56%, 50%, 31%; silicone tube: 42%, 44%, 25%). The total number of labeled motoneurons, however, did not significantly differ between groups (control: 1238 +/- 82, crush: 1048 +/- 49, straight suture: 1175 +/- 106, crossed suture: 1085 +/- 84, silicone tube: 1250 +/- 182). The volume occupied by labeled motoneurons within the spinal cord was larger after surgical nerve repair than in crush or normal control animals, and fewer neurons showed abnormal multiple projections after crush (2.5%) or straight suture (2.2%) than following crossed suture (5%) or silicone tube (6%). In conclusion, nerve repair with a silicone tube leaving a short gap does not increase accuracy of reinnervation.

Action Potentials↗
PubMed1978

Protein restriction in the conservative management of uremia.

Protein-restricted diets are widely used in the dietary management of uremia. These diets are undoubtedly effective in ameliorating many aspects of the uremic syndrome. However, there is no consensus as to whether diets providing less than 0.6 g/kg per day of protein are nutritionally adequate and capable of preventing the wasting syndrome. Wasting is common in the adult patient with renal insufficiency as is growth failure in the uremic child. There is some evidence that wasted patients do less well on hemodialysis and are more prone to infection. Experimental studies in uremic animals point ot diminihsed efficiency of utilization of protein, increased gluconeogenesis from animo acids, and increased catabolism of protein in the fasting state; in addition, the metabolism of a number of individual amino acids is altered in uremia. In view of these multiple abnormalities, it would seem unwise to routinely provide less than the Recommended Daily Allowances of protein. More recent developments, i.e., supplementation of essential amino acids and perhaps alpha keto acids, may provide useful alternatives. One important aspect of dietary management, i.e. prevention of hyperlipidemia, has attracted surprisingly little attention so far. Therapy with protein restricted diets in nondialyzed uremic patients has to compete with other modalities of treatment currently available, i.e., hemodialysis and transplantation, in providing optimal medical rehabilitaiton of the patient.

Adult↗
PubMed2004

Immune function is impaired in iron-deficient, homebound, older women.

BACKGROUND: Aging is often associated with a dysregulation of immune function. Iron deficiency may further impair immunity in older adults. Published reports on iron deficiency and immune response in humans are inconsistent. Most studies are focused on young children in developing countries and are often confounded by comorbid conditions, infections, and nutrient deficiencies. OBJECTIVE: Our objective was to determine the relation of iron status with immune function in homebound older women, who often have impairments in both iron status and immune response. The subjects were selected according to rigorous exclusion criteria for disease, infection, and deficiencies in key nutrients known to affect immunocompetence. DESIGN: Seventy-two homebound elderly women provided blood for comprehensive evaluation of iron status and cell-mediated and innate immunity. Women were classified as iron-deficient or iron-sufficient on the basis of multiple abnormal iron status test results. Groups were compared with respect to lymphocyte subsets, phagocytosis, oxidative burst capacity, and T cell proliferation upon stimulation with mitogens. RESULTS: In iron-deficient women, T cell proliferation upon stimulation with concanavalin A and phytohemagglutinin A was only 40-50% of that in iron-sufficient women. Phagocytosis did not differ significantly between the 2 groups, but respiratory burst was significantly less (by 28%) in iron-deficient women than in iron-sufficient women. CONCLUSIONS: Iron deficiency is associated with impairments in cell-mediated and innate immunity and may render older adults more vulnerable to infections. Further prospective studies using similar exclusion criteria for disease, infection, and concomitant nutrient deficiencies are needed for simultaneous examination of the effects of iron deficiency on immune response and morbidity.

Aged↗
PubMed1991

The primacy of membrane microviscosity in genetic hypertension.

Because of the known influence of the lipid bilayer on membrane transport systems, the characteristics of the bilayer from vascular smooth muscle and from platelets were studied in genetically hypertensive and in normotensive rats. Membrane microviscosity was measured by the degree of polarization of embedded fluorophores. Both the core of the bilayer in which diphenylhexatriene (DPH) was embedded and the surface in which the trimethyl-ammonium derivative of DPH (TMA-DPH) was embedded evidence a greater microviscosity (less fluid) in the hypertensive than in the normotensive rat. We had previously observed that monovalent cation fluxes were elevated in hypertension. We now observe that an increase in calcium concentration reverses both the elevated microviscosity and the increased cation fluxes. Conversely an increased incorporation of cholesterol in the membrane increases both the microviscosity and the cation fluxes. We hypothesize that the greater microviscosity of the lipid bilayer in hypertension constitutes a generalized defect of the matrix in which the transport proteins function. We further hypothesize that this defect is responsible for the multiple abnormalities of membrane transport systems and the increase in vascular reactivity that have been described in genetic hypertension.

Animals↗
PubMed2002

Essential role of PDK1 in regulating cell size and development in mice.

PDK1 functions as a master kinase, phosphorylating and activating PKB/Akt, S6K and RSK. To learn more about the roles of PDK1, we generated mice that either lack PDK1 or possess PDK1 hypomorphic alleles, expressing only approximately 10% of the normal level of PDK1. PDK1(-/-) embryos die at embryonic day 9.5, displaying multiple abnormalities including lack of somites, forebrain and neural crest derived tissues; however, development of hind- and midbrain proceed relatively normally. In contrast, hypomorphic PDK1 mice are viable and fertile, and insulin injection induces the normal activation of PKB, S6K and RSK. Nevertheless, these mice are 40-50% smaller than control animals. The organ volumes from the PDK1 hypomorphic mice are reduced proportionately. We also establish that the volume of a number of PDK1-deficient cells is reduced by 35-60%, and show that PDK1 deficiency does not affect cell number, nuclear size or proliferation. We provide genetic evidence that PDK1 is essential for mouse embryonic development, and regulates cell size independently of cell number or proliferation, as well as insulin's ability to activate PKB, S6K and RSK.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2004

N-glycan branching requirement in neuronal and postnatal viability.

The structural variations among extracellular N-glycans reflect the activity of glycosyltransferases and glycosidases that operate in the Golgi apparatus. More than other types of vertebrate glycans, N-glycans are highly branched oligosaccharides with multiple antennae linked to an underlying mannose core structure. The branching patterns of N-glycans consist of three types, termed high-mannose, hybrid, and complex. Though most extracellular mammalian N-glycans are of the complex type, some cells variably express hybrid and high-mannose forms. Nevertheless, a requirement for hybrid and complex N-glycan branching exists in embryonic development and postnatal function among mice and humans inheriting defective Mgat1 or Mgat2 alleles. The resulting defects in formation N-glycan branching patterns cause multiple abnormalities, including neurologic defects, and have inferred the presence of distinct functions for hybrid and complex N-glycan branches among different cell lineages. We have further explored N-glycan structure-function relationships in vivo by using Cre-loxP conditional mutagenesis to abolish hybrid and complex N-glycan branching specifically among neuronal cells. Our findings show that hybrid N-glycan branching is an essential posttranslational modification among neurons. Loss of Mgat1 resulted in a unique pattern of neuronal glycoprotein deficiency concurrent with caspase 3 activation and apoptosis. Such animals exhibited severe locomotor deficits, tremors, paralysis, and early postnatal death. Unexpectedly, neuronal Mgat2 deletion resulting in the loss of complex but not hybrid N-glycan branching was well tolerated without phenotypic markers of neuronal or locomotor dysfunction. Structural features associated with hybrid N-glycan branching comprise a requisite posttranslational modification to neuronal glycoproteins that permits normal cellular function and viability.

Acyltransferases↗
PubMed2003

Inactivation of ether lipid biosynthesis causes male infertility, defects in eye development and optic nerve hypoplasia in mice.

Although known for almost 80 years, the physiological role of plasmalogens (PLs), the major mammalian ether lipids (ELs), is still enigmatic. Humans that lack ELs suffer from rhizomelic chondrodysplasia punctata (RCDP), a peroxisomal disorder usually resulting in death in early childhood. In order to learn more about the functions of ELs, we generated a mouse model for RCDP by a targeted disruption of the dihydroxyacetonephosphate acyltransferase gene. The mutant mice revealed multiple abnormalities, such as male infertility, defects in eye development, cataract and optic nerve hypoplasia, some of which were also observed in RCDP. Mass spectroscopic analysis demonstrated the presence of highly unsaturated fatty acids including docosahexaenoic acid (DHA) in brain PLs and the occurrence of PLs in lipid raft microdomains (LRMs) isolated from brain myelin. In mutants, PLs were completely absent and the concentration of brain DHA was reduced. The marker proteins flotillin-1 and F3/contactin were found in brain LRMs in reduced concentrations. In addition, the gap junctional protein connexin 43, known to be recruited to LRMs and essential for lens development and spermatogenesis, was down-regulated in embryonic fibroblasts of the EL-deficient mice. Free cholesterol, an important constituent of LRMs, was found in these fibroblasts to be accumulated in a perinuclear compartment. These data suggest that the EL-deficient mice allow the identification of new phenotypes not related so far to EL-deficiency (male sterility, defects in myelination and optic nerve hypoplasia) and indicate that PLs are required for the correct assembly and function of LRMs.

Acyltransferases↗
PubMed1998

The cobweb syndrome: first trimester sonographic diagnosis of multiple amniotic bands confirmed by fetoscopy and pathological examination.

Amniotic band syndrome is a well described clinical entity presenting with deformities of the limbs, thorax, craniofacial skeleton, soft tissues and umbilical cord, but it still lacks a precise definition and a coherent hypothesis for its pathogenesis. We report on a case of first trimester diagnosis of amniotic band syndrome by sonography and fetoscopy. This revealed multiple abnormalities including facial cleft, brain and limb deformities; the appearance of the amniotic cavity was that of a cobweb containing the fetus. Post-mortem examination and histopathological studies confirmed the diagnosis of amniotic band syndrome. These results may enhance the knowledge of its natural course. In addition, based on histological and newly identified ultrastructural features, we present a hypothesis which could help to explain the aetiopathogenesis of the amniotic band syndrome.

Adult↗
PubMed1994

Infection determinants at extremes of age.

The immune defence of the full-term neonate is compromised in several ways. Although adequate numbers of B lymphocytes are present, antibody production may be delayed compared with the adult. Decreased levels of complement components contribute to the impaired opsonization potential of newborn sera and in turn, to impaired chemotactic responses of neonatal polymorphonuclear leucocytes (PMN). Multiple abnormalities in neonatal PMN function, coupled with deficient bone marrow supplies during stress, contribute greatly to the increased vulnerability to infection of neonates. Infection is a major problem for infants born before 28 weeks. Their serum IgG antibody levels are extremely low and the deficiencies in complement levels and PMN chemotatic responses noted in full-term neonates are even more marked and persist for longer. Opsonic activity decreases with decreasing gestational age and septicaemic pre-term infants are liable to develop neutrophil storage pool exhaustion. In contrast to neonates, the effect of ageing on the immune response is more variable but the changes in cell-mediated immunity have the greatest clinical impact. This decline in T cell function alters the balance between the immune system and intracellular organisms and leads to reactivation of previously controlled infections. Impaired function of immunoregulatory cells contributes to the poor and unsustained antibody responses of the elderly to primary and booster immunizations. Immunosenescence contributes to the morbidity and mortality of old age by several mechanisms, but mainly through an increased susceptibility to infection.

Aged↗
PubMed2003

A protein kinase from Colletotrichum trifolii is induced by plant cutin and is required for appressorium formation.

When certain phytopathogenic fungi contact plant surfaces, specialized infection structures (appressoria) are produced that facilitate penetration of the plant external barrier; the cuticle. Recognition of this hydrophobic host surface must be sensed by the fungus, initiating the appropriate signaling pathway or pathways for pathogenic development. Using polymerase chain reaction and primers designed from mammalian protein kinase C sequences (PKC), we have isolated, cloned, and characterized a protein kinase from Colletotrichum trifolii, causal agent of alfalfa anthracnose. Though sequence analysis indicated conserved sequences in mammalian PKC genes, we were unable to induce activity of the fungal protein using known activators of PKC. Instead, we show that the C. trifolii gene, designated LIPK (lipid-induced protein kinase) is induced specifically by purified plant cutin or long-chain fatty acids which are monomeric constituents of cutin. PKC inhibitors prevented appressorium formation and, to a lesser extent, spore germination. Overexpression of LIPK resulted in multiple, abnormally shaped appressoria. Gene replacement of lipk yielded strains which were unable to develop appressoria and were unable to infect intact host plant tissue. However, these mutants were able to colonize host tissue following artificial wounding, resulting in typical anthracnose lesions. Taken together, these data indicate a central role in triggering infection structure formation for this protein kinase, which is induced specifically by components of the plant cuticle. Thus, the fungus is able to sense and use host surface chemistry to induce a protein kinase-mediated pathway that is required for pathogenic development.

Amino Acid Sequence↗
PubMed1997

Glutathione oxidation is associated with altered microtubule function and disrupted fertilization in mature hamster oocytes.

We hypothesized that depletion of glutathione (GSH) with diamide, a relatively specific GSH oxidant, may alter the meiotic spindle apparatus in mature hamster oocytes. Immunofluorescent analysis of oocytes exposed to diamide for 1.5 or 3 h revealed time- and concentration-dependent disruption of spindle morphology accompanied by chromosome clumping. In oocytes first cultured in diamide for 1.5 h and then in diamide-free medium for 1.5 or 3 h, microtubules appeared to repolymerize, but normal spindle structure was not regained. HPLC confirmed that diamide oxidized oocyte GSH under conditions identical to those associated with spindle-related abnormalities. Exposure of oocytes to 25 or 50 microM diamide before in vitro fertilization did not affect their ability to undergo fertilization. A significant proportion of the fertilized oocytes that had been exposed to 50 microM diamide before insemination exhibited abnormal multiple female pronuclei with an apparently normal male pronucleus. These observations indicate that mature hamster oocytes are susceptible to oxidative stress during the critical period that precedes fertilization and provide further evidence that GSH plays important roles in oocyte spindle function and pronucleus development.

Animals↗