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Partial Loss (partial + loss)
Selected AbstractsGenetic basis of rett syndromeDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2002Ignatia B. Van den Veyver Abstract The origin of Rett syndrome has long been debated, but several observations have suggested an X-linked dominant inheritance pattern. We and others have pursued an exclusion-mapping strategy using DNA from a small number of familial Rett syndrome cases. This work resulted in the narrowing of the region likely to harbor the mutated gene to Xq27.3-Xqter. After systematic exclusion of several candidate genes, we discovered mutations in MECP2, the gene that encodes the transcriptional repressor, methyl-CpG-binding protein 2. Since then, nonsense, missense, or frameshift mutations have been found in at least 80% of girls affected with classic Rett syndrome. Sixty-four percent of mutations are recurrent C > T transitions at eight CpG dinucleotides mutation hotspots, while the C-terminal region of the gene is prone to recurrent multinucleotide deletions (11%). Most mutations are predicted to result in total or partial loss of function of MeCP2. There is no clear correlation between the type and position of the mutation and the phenotypic features of classic and variant Rett syndrome patients, and XCI appears to be a major determinant of phenotypic severity. Further research focuses on the pathogenic consequences of these mutations along the hypothesis of loss of transcriptional repression of a small number of genes that are essential for neuronal function in the maturing brain. MRDD Research Reviews 2002;8:82,86. © 2002 Wiley-Liss, Inc. [source] Calmodulin and profilin coregulate axon outgrowth in DrosophilaDEVELOPMENTAL NEUROBIOLOGY, Issue 1 2001You-Seung Kim Abstract Coordinated regulation of actin cytoskeletal dynamics is critical to growth cone movement. The intracellular molecules calmodulin and profilin actively regulate actin-based motility and participate in the signaling pathways used to steer growth cones. Here we show that in the developing Drosophila embryo, calmodulin and profilin convey complimentary information that is necessary for appropriate growth cone advance. Reducing calmodulin activity by expression of a dominant inhibitor (KA) stalls axon extension of pioneer neurons within the CNS, while a partial loss of profilin function decreases extension of motor axons in the periphery. Yet, surprisingly, when calmodulin and profilin are simultaneously reduced, the ability of both CNS pioneer axons and motor axons to extend beyond the choice points is restored. In the CNS, at the time when growth cones must decide whether to cross or not to cross the midline, a reduction in calmodulin and/or roundabout signaling causes axons to cross the midline inappropriately. These inappropriate crossings are suppressed when profilin activity is simultaneously reduced. Interestingly, the mutual suppression of calmodulin and profilin activity requires a minimal level of profilin. In KA combinations with profilin null alleles, defects in axon extension and midline guidance are synergistically enhanced rather than suppressed. Together, our data indicate that the growth cone must coordinate the activity of both calmodulin and profilin in order to advance past selected choice points, including those dictating midline crossovers. © 2001 John Wiley & Sons, Inc. J Neurobiol 47: 26,38, 2001 [source] Altered membrane glycoprotein targeting in cholestatic hepatocytesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 5 2010Giuseppa Esterina Liquori Eur J Clin Invest 2010; 40 (5): 393,400 Abstract Background, Hepatocytes are polarized epithelial cells with three morphologically and functionally distinct membrane surfaces: the sinusoidal, lateral and canalicular surface domains. These domains differ from each other in the expression of integral proteins, which concur to their polarized functions. We hypothesize that the cholestasis-induced alterations led to partial loss of hepatocyte polarity. An altered expression of membrane proteins may be indicative of functional disorders. Alkaline liver phosphatase (ALP), one of the most representative plasma membrane glycoproteins in hepatocytes, is expressed at the apical (canalicular) pole of the cell. Because the release of ALP protein in the bloodstream is significantly increased in cholestasis, the enzymatic levels of plasma ALP have major relevance in the diagnosis of cholestatic diseases. Here we assess the cholestasis-induced redistribution of membrane glycoproteins to investigate the ALP release. Materials and methods, We performed enzymatic histochemistry, immunohistochemistry, lectin histochemistry, immunogold and lectin-and immunoblotting studies. Experimental cholestasis was induced in rats by ligation of common bile duct (BDL). Results, The BDL led to altered membrane sialoglycoprotein targeting as well as to ultrastructural and functional disorders. Disarrangement of the microtubular system, thickening of the microfilamentous pericanalicular ectoplasm and disturbance of the vectorial trafficking of membrane glycoprotein containing vesicles were found. Conclusions, Altogether, results indicate that the cholestasis-induced partial loss of hepatocyte cell polarity leads to mistranslocation of ALP to the sinusoidal plasma membrane from where the enzyme is then massively released into the bloodstream. [source] A narrow deletion of 7q is common to HCL, and SMZL, but not CLLEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2004Claus Lindbjerg Andersen Abstract: To further characterise the genetic background of the two closely related B-lymphocytic malignancies hairy cell leukaemia (HCL), and splenic marginal zone lymphoma (SMZL) we have identified characteristic copy number imbalances by comparative genomic hybridisation (CGH). Based on these findings, areas of special interest were fine mapped, and relevant probes constructed for use in interphase-fluorescence in situ hybridisation (FISH) investigations. Thus, using the CGH data from 52 HCL and 61 SMZL patients, we identified the characteristic profiles of copy number imbalances for both diseases. These were a gain of 5q13-31 (19%) and loss of 7q22-q35 (6%) for HCL, and gain of 3q25 (28%), loss of 7q31 (16%), and gain of 12q15 (16%) for SMZL. A partial loss of 7q unsual for low-malignant B-cell diseases was found to be common to the two diseases. This loss was therefore fine mapped with BAC/PAC clones. Fine mapping revealed that in SMZL the minimal lost region covers 11.4 Mb spanning from 7q31.33 to 7q33 located between sequence tagged site (STS)-markers SHGC-3275 and D7S725. This area was distinct from the commonly deleted 7q region of myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML). A FISH probe specific for the 7q region was constructed. Using this probe in an interphase-FISH investigation we showed the minimal lost 7q-region of HCL and SMZL to be one and the same. In one HCL case, this investigation furthermore showed the extent of the deleted region to be below the detection limit of CGH, whereas interphase-FISH screening of 36 chronic lymphocytic leukaemia (CLL) cases showed no deletion of the 7q area. In conclusion, we have identified characteristic profiles of copy number imbalances in HCL and SMZL and fine mapped the minimal extent of a commonly lost 7q area of special interest. We hypothesise that this region may contain (a) gene(s) important for the pathology of HCL and SMZL. [source] PPAR-gamma-mediated neuroprotection in a chronic mouse model of Parkinson's diseaseEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2009Nicoletta Schintu Abstract Rosiglitazone is a commonly prescribed insulin-sensitizing drug with a selective agonistic activity on the peroxisome proliferator-activated receptor-gamma (PPAR-,). PPAR-, can modulate inflammatory responses in the brain, and agonists might be beneficial in neurodegenerative diseases. In the present study we used a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine plus probenecid (MPTPp) mouse model of progressive Parkinson's disease (PD) to assess the therapeutic efficacy of rosiglitazone on behavioural impairment, neurodegeneration and inflammation. Mice chronically treated with MPTPp displayed typical features of PD, including impairment of motor and olfactory functions associated with partial loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc), decrease of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) content and dynorphin (Dyn) mRNA levels in the caudate-putamen (CPu), intense microglial and astroglial response in the SNc and CPu. Chronic rosiglitazone, administered in association with MPTPp, completely prevented motor and olfactory dysfunctions and loss of TH-positive cells in the SNc. In the CPu, loss of striatal DA was partially prevented, whereas decreases in DOPAC content and Dyn were fully counteracted. Moreover, rosiglitazone completely inhibited microglia reactivity in SNc and CPu, as measured by CD11b immunostaining, and partially inhibited astroglial response assessed by glial fibrillary acidic protein immunoreactivity. Measurement of striatal MPP+ levels 2, 4, 6 h and 3 days after chronic treatment indicated that MPTP metabolism was not altered by rosiglitazone. The results support the use of PPAR-, agonists as a putative anti-inflammatory therapy aimed at arresting PD progression, and suggest that assessment in PD clinical trials is warranted. [source] Lactosamine modulates the rate of migration of GnRH neurons during mouse developmentEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2006Elizabeth Bless Abstract Gonadotropin-releasing hormone (GnRH) neurons are derived from progenitor cells in the olfactory placodes and migrate from the vomeronasal organ (VNO) across the cribriform plate into the forebrain. At embryonic day (E)12 in the mouse most of these neurons are still in the nasal compartment but by E15 most GnRH neurons have migrated into the forebrain. Glycoconjugates with carbohydrate chains containing terminal lactosamine are expressed by neurons in the main olfactory epithelium and in the VNO. One of the key enzymes required to regulate the synthesis and expression of lactosamine, ,1,3-N-acetylglucosaminyltransferase-1 (,3GnT1), is strongly expressed by neurons in the olfactory epithelium and VNO, and on neurons migrating out of the VNO along the GnRH migratory pathway. Immunocytochemical analysis of lactosamine and GnRH in embryonic mice reveals that the percentage of lactosamine+,GnRH+ double-labeled neurons decreases from >,80% at E13, when migration is near its peak, to ,,30% at E18.5, when most neurons have stopped migrating. In ,3GnT1,/, mice, there is a partial loss of lactosamine expression on GnRH neurons. Additionally, a greater number of GnRH neurons were retained in the nasal compartment of null mice at E15 while fewer GnRH neurons were detected later in embryonic development in the ventral forebrain. These results suggest that the loss of lactosamine on a subset of GnRH neurons impeded the rate of migration from the nose to the brain. [source] The essential haematopoietic transcription factor Scl is also critical for neuronal developmentEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2006Cara K. Bradley Abstract The basic helix-loop-helix (bHLH) transcription factor Scl displays tissue-restricted expression and is critical for the establishment of the haematopoietic system; loss of Scl results in embryonic death due to absolute anaemia. Scl is also expressed in neurons of the mouse diencephalon, mesencephalon and metencephalon; however, its requirement in those sites remains to be determined. Here we report conditional deletion of Scl in neuronal precursor cells using the Cre/LoxP system. Neuronal-Scl deleted mice died prematurely, were growth retarded and exhibited an altered motor phenotype characterized by hyperactivity and circling. Moreover, ablation of Scl in the nervous system affected brain morphology with abnormal neuronal development in brain regions known to express Scl under normal circumstances; there was an almost complete absence of Scl-null neurons in the hindbrain and partial loss of Scl-null neurons in the thalamus and midbrain from early neurogenesis onwards. Our results demonstrate a crucial role for Scl in the development of Scl-expressing neurons, including ,-aminobutyric acid (GABA)ergic interneurons. Our study represents one of the first demonstrations of functional overlap of a single bHLH protein that regulates neural and haematopoietic cell development. This finding underlines Scl's critical function in cell fate determination of mesodermal as well as neuroectodermal tissues. [source] Functional characterization of compound heterozygosity for GlyR,1 mutations in the startle disease hyperekplexiaEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2002Ruth Rea Abstract The human disease hyperekplexia is characterized by excessive startle reactions to auditory and cutaneous stimuli. In its familial form, hyperekplexia has been associated with both dominant and recessive mutations of the GLRA1 gene encoding the glycine receptor ,1 subunit (GlyR,1), which mediates inhibitory transmission in the spinal cord and brainstem. Here we have examined the functional consequences of two amino acid substitutions found in a compound heterozygous family, R252H and R392H, to investigate the mechanisms determining this inheritance pattern. When expressed in Xenopus laevis oocytes, both mutations were non-functional. Neither mutant affected the electrophysiological properties of wild type GlyR,1 when co-expressed. We introduced a green fluorescent protein tag to mutant subunits and found that both mutant proteins were detectable. Evidence that subcellular localization differed from wild type was significant for one of the mutants. Thus, an effective loss of functional GlyR,1-mediated current underlies hyperekplexia in this family, whereas a partial loss is asymptomatic. [source] Flammability studies of sodium thiosulphate or metabisulphite impregnated wood using cone calorimeterFIRE AND MATERIALS, Issue 2 2007imkovic Abstract Spruce wood boards impregnated with Na2S2O3 or Na2S2O5 were studied with the cone calorimeter. The presence of Na2S2O3 lowered the average heat release rate in comparison to untreated material. The total amounts of CO and CO2 production were reduced by the treatment and also the specific extinction area and mass loss rate decreased. Washing of the salt from the material with water caused partial loss of the properties. Addition of the second impregnation step using acids (HCOOH, H3BO3 or H3PO4) resulted in the fixation of the sulphur in wood, but gave not the results of single-step modification for thiosulphate. With Na2S2O5 and without acid, the CO and time-to-ignition values were higher and average heat release rate smaller in comparison to unmodified material. Combined one step Na2S2O5/H3BO3 treatment lowered the CO, CO2 and specific extinction area values in comparison to the modification with Na2S2O5, similarly like it was observed for Na2S2O3/H3BO3 two-step-treatment. According to time-to-ignition values, Na2S2O5 alone at 5% addition is a better flame retardant than Na2S2O3 at 7%, but the effect is diminished at 10% amount or presence of acids. The total smoke release curves showed decrease due to modification in both phases of the process. Introduction of water washing as well as the acid treatment further lowered the values. The best results were achieved with 15% Na2S2O3,2% H3PO4,H2O system. According to the total smoke release curve the specimen produced more than five times smaller amount of smoke than untreated material in the first phase of the process. It seams that the concentration of Na2S2O5 is less affecting the properties than the synergistic effect of the Na2S2O3 or Na2S2O5/H3BO3 system. Although the level of smoke is low, the presence of elemental sulphur causes smaller times-to-ignition than on starting material. Copyright © 2006 John Wiley & Sons, Ltd. [source] Survival of DA neurons is independent of CREM upregulation in absence of CREBGENESIS: THE JOURNAL OF GENETICS AND DEVELOPMENT, Issue 10 2006R. Parlato Abstract cAMP response element binding protein (CREB) and the related factors CREM (cAMP response element modulator) and ATF1 (activation transcription factor 1) are bZIP-domain-containing transcription factors activated through cAMP and other signaling pathways. The disruption of CREB function in developing and mature neurons affects their development and survival when associated with loss of CREM. Since dopaminergic (DA) neurons are affected in several neurological diseases, we generated CREB conditional mutants in DA neurons by using a newly generated transgenic Cre line targeting the dopaminergic system (DATCre). Here we report the generation and analysis of mutant mice lacking CREB in DA neurons (CREBDATCre mutants). During adulthood, lack of CREB leads to a partial loss of DA neurons. Since CREM is upregulated in absence of CREB, we have introduced this mutation in a CREM,/, genetic background to assess a compensatory role of CREM. Additional inactivation of CREM does not lead to a more severe phenotype. genesis 44:454,464, 2006. © 2006 Wiley-Liss, Inc. [source] Zygomaticomaxillary buttress reconstruction of midface defects with the osteocutaneous radial forearm free flapHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 10 2008Patricio Andrades MD Abstract Background. The purpose of this study was to evaluate morbidity, functional, and aesthetic outcomes in midface zygomaticomaxillary buttress reconstruction using the osteocutaneous radial forearm free flap (OCRFFF). Methods. A retrospective review of 24 consecutive patients that underwent midface reconstruction using the OCRFFF was performed. All patients had variable extension of maxillectomy defects that requires restoration of the zygmatico-maxillary buttress. After harvest, the OCRFFF was fixed transversely with miniplates connecting the remaining zygoma to the anterior maxilla. The orbital support was given by titanium mesh when needed that was fixed to the radial forearm bone anteriorly and placed on the remaining orbital floor posteriorly. The skin paddle was used for intraoral lining, external skin coverage, or both. The main outcome measures were flap success, donor-site morbidity, orbital, and oral complications. Facial contour, speech understandability, swallowing, oronasal separation, and socialization were also analyzed. Results. There were 6 women and 18 men, with an average age of 66 years old (range, 34,87). The resulting defects after maxillectomy were (according to the Cordeiro classification; Disa et al, Ann Plast Surg 2001;47:612,619; Santamaria and Cordeiro, J Surg Oncol 2006;94:522,531): type I (8.3%), type II (33.3%), type III (45.8%), and type IV (12.5%). There were no flap losses. Donor-site complications included partial loss of the split thickness skin graft (25%) and 1 radial bone fracture. The most significant recipient-site complications were severe ectropion (24%), dystopia (8%), and oronasal fistula (12%). All the complications occurred in patients with defects that required orbital floor reconstruction and/or cheek skin coverage. The average follow-up was 11.5 months, and over 80% of the patients had adequate swallowing, speech, and reincorporation to normal daily activities. Conclusions. The OCRFFF is an excellent alternative for midface reconstruction of the zygomaticomaxillary buttress. Complications were more common in patients who underwent resection of the orbital rim and floor (type III and IV defects) or external cheek skin. © 2008 Wiley Periodicals, Inc. Head Neck, 2008 [source] Pretibial epidermolysis bullosa: is this case a new subtype with loss of types IV and VII collagen?INTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 8 2009Hong-sun Lee MD Pretibial epidermolysis bullosa (PEB) is an extremely rare subtype of dominant dystrophic epidermolysis bullosa (DDEB), in which recurrent blistering with scarring predominantly involves the pretibial skin. Nail dystrophy, albopapuloid lesions, and hypertrophic scars may also occur. In PEB, immunohistochemical and electron microscopic studies demonstrate the complete or partial loss of the anchoring fibril (AF) in the basement membrane zone, suggesting disturbed synthesis or excessive degradation of collagen VII, the main component of AF. Interestingly, we report a case of PEB with unusual results of joint loss of types IV and VII collagen. [source] Nonstationary spatio-temporal small rodent dynamics: evidence from long-term Norwegian fox bounty dataJOURNAL OF ANIMAL ECOLOGY, Issue 3 2009John-André Henden Summary 1The geographical pattern in Fennoscandian small rodent population dynamics with a southern noncyclic and a northern cyclic region, and with latitudinal gradients in density-dependent structure, cycle period length and spatial synchrony within the northern cyclic region, has been widely publicized and interpreted in the ecological literature. However, the time-series data on which these inferences have been established are relatively short and originate from a specific time period (mostly around 1970,90). Hence, it can be questioned whether the geographical population dynamics patterns are consistent over time (i.e. whether they are stationary). 2Here we analyse an almost century long (1880,1976) panel of fox bounty time series including 18 counties of Norway, thus spanning the whole range of latitudes of Fennoscandia (i.e. 15 latitudinal degrees). These fox time series mirror the dynamics of their dominant small rodent prey, in particular, with respect to cycle period length and spatial synchrony. 3While we found some evidence consistent with previous analyses showing a clearly patterned dynamics according to latitude, such patterns were not stationary on a longer time-scale. In particular, we observed a shift from an extensively synchronous (i.e. regionalized) 4-year cycle north of 60°N just after the ,Little Ice Age' (1880,1910) to a diversification of cycle period length (3,5 years) and eventually, partial loss of cyclicity and synchronicity in later periods. Incidents of loss of cyclicity appeared to be preceded by changes in cycle period (i.e. period lengthening and shortening). 4These results show that the dynamics of Fennoscandian small rodents, and their associated guild of predators, are more prone to change than previously acknowledged. [source] Intrinsic and acquired resistance to quaternary ammonium compounds in food-related Pseudomonas spp.JOURNAL OF APPLIED MICROBIOLOGY, Issue 4 2003S. Langsrud Abstract Aims: To determine the sensitivity of a strain used for disinfectants testing (Pseudomonas aeruginosa ATCC 15442) and food-associated isolates to benzalkonium chloride and didecyl dimethylammonium chloride (DDAC). To determine whether the increase in bacterial resistance after adaptation to DDAC can be associated with phenotypic changes. To test the activity of alternative disinfectants to eliminate resistant Pseudomonas spp. Methods and Results:Pseudomonas aeruginosa ATCC 15442 was among the most resistant strains tested using a bactericidal suspension test. Growth of a sensitive Ps. fluorescens in gradually higher concentrations of DDAC resulted in stable higher resistance and to some cross-resistance to several antibacterial agents, with the exception of disinfectants containing chloramine T, glutaraldehyde or peracetic acid. It was shown by microscopy that adaptation was followed by loss of flagella, and slime formation. Removal of the slime by sodium dodecyl sulphate resulted in partial loss of the acquired resistance. Conclusions:Pseudomonas spp. may adapt to survive against higher concentrations of quaternary ammonium compounds (QACs), but resistant strains can be eliminated with chemically unrelated disinfectants. Significance and Impact of the Study: The work supports the rotation of disinfectants in food processing environments for avoiding the development of bacterial resistance to QACs. The alternating disinfectants should be chosen carefully, because of possible cross-resistance. [source] Alteration of RANKL-Induced Osteoclastogenesis in Primary Cultured Osteoclasts From SERCA2+/, Mice,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2009Yu-Mi Yang Abstract RANKL is essential for the terminal differentiation of monocytes/marcrophages into osteoclasts. RANKL induces long-lasting oscillations in the intracellular concentration of Ca2+ ([Ca2+]i) only after 24 h of stimulation. These Ca2+ oscillations play a switch-on role in NFATc1 expression and osteoclast differentiation. Which Ca2+ transporting pathway is induced by RANKL to evoke the Ca2+ oscillations and its specific role in RANKL-mediated osteoclast differentiation is not known. This study examined the effect of a partial loss of sarco/endoplasmic reticulum Ca2+ ATPase type2 (SERCA2) on osteoclast differentiation in SERCA2 heterozygote mice (SERCA2+/,). The BMD in the tibias of SERCA2+/, mice increased >1.5-fold compared with wildtype mice (WT). RANKL-induced [Ca2+]i oscillations were generated 48 h after RANKL treatment in the WT mice but not in the SERCA2+/, bone marrow,derived macrophages (BMMs). Forty-eight hours after RANKL treatment, there was a lower level of NFATc1 protein expression and markedly reduced translocation of NFATc1 into the nucleus during osteoclastogenesis of the SERCA2+/, BMMs. In addition, RANKL treatment of SERCA2+/, BMMs incompletely induced formation of multinucleated cells, leading to reduced bone resorption activity. These results suggest that RANKL-mediated induction of SERCA2 plays a critical role in the RANKL-induced [Ca2+]i oscillations that are essential for osteoclastogenesis. [source] Accentuated Ovariectomy-Induced Bone Loss and Altered Osteogenesis in Heterozygous N-Cadherin Null Mice,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2006Chung Fang Lai Abstract Ovariectomy-induced bone loss is accentuated in mice with germline Cdh2 haploinsufficiency, the result of a decreased osteoblastogenesis in the face of normal osteoclast number. Reduced N-cadherin abundance in these mice decreases cell,cell adhesion and alters signaling pathways important for osteoblast commitment and differentiation, thus providing in vivo evidence that N-cadherin,mediated cell,cell interactions are involved in homeostatic responses to increased bone remodeling. Introduction: We have shown that targeted expression of a dominant negative truncated form of N-cadherin (Cdh2) delays acquisition of peak bone mass in mice and retards osteoblast differentiation. We tested the role of this molecule in the skeletal homeostatic response to ovariectomy in mice with germline Cdh2 haploinsufficiency. Materials and Methods: Heterozygous Cdh2 null (Cdh2+/,) and wildtype mice were ovariectomized and followed up to 13 weeks by in vivo radiodensitometric and ex vivo histologic assessment of bone mass and turnover. Cells isolated from wildtype and Cdh2+/, mice were used to determine the alterations in bone cell function produced by partial loss of N-cadherin. Results: Bone mass was not significantly different between Cdh2+/, and wildtype littermates, but on ovariectomy, bone loss in Cdh2+/, mice was initially slower, but with time it became significantly greater than in wildtype mice. This accentuated bone loss was associated with lower osteoblast number and serum osteocalcin levels, with no differences in bone resorption. Although development of calcified nodules was faster in calvaria cells isolated from Cdh2+/, mice relative to Cdh2+/+ cells, bone marrow osteogenic precursors were lower in the former than in the latter genotypes. Cdh2 expression was downregulated with differentiation in wildtype calvaria cells, whereas cadherin-11 abundance remained unchanged. Furthermore, cell,cell adhesion (postconfluence) was decreased among heterozygous calvaria cells, as was cell proliferation (preconfluence), relative to wildtype cells. Finally, the abundance and cellular distribution of ,-catenin was minimally decreased in Cdh2+/, cells, whereas mitogen-activated protein kinase (MAPK) signaling was more active in Cdh2 insufficient cells. Conclusions:Cdh2 is involved in the homeostatic bone formation response to ovariectomy, presumably by regulating osteoprogenitors number and differentiation through stabilization of cell,cell adhesion and/or signaling modulation. [source] If pemphigus vulgaris IgG are the cause of acantholysis, new IgG-independent mechanisms are the concauseJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2007Nicola Cirillo Pemphigus vulgaris (PV) is a disease of epidermal adhesion. Its pathogenesis is currently traced back to the action of autoantibodies against antigens located within the intercellular substance of keratinocytes, such as desmogleins and acetylcholine receptors. In the present paper, we sought to elucidate the non-IgG-mediated effects of PV sera on keratinocytes. Results showed that PV sera depleted of IgG were able to induce well-defined changes on keratinocyte morphology and metabolic activity. Indeed, PV IgG-free sera determined marked alterations on cell shape, accompanied by partial loss of keratinocyte,keratinocyte interactions within 48 h after treatment. Furthermore, PV IgG-depleted sera caused a sharp reduction of cell viability along with a less sustained weakening of intercellular adhesion strength. In light of the above findings, loss of cell,cell adhesion in PV occurs as a result of the cooperating action of both IgG and non-IgG-mediated mechanisms. These data have remarkable consequences on experimental models of PV and might open new "biological" approaches to its therapy. Thus, researchers are well advised that PV pathophysiology cannot be faithfully reproduced by leaving non-IgG serum factors out of consideration. J. Cell. Physiol. 212:563,567, 2007. © 2007 Wiley-Liss, Inc. [source] MAIN FACTORS CONTROLLING THE COMPOSITIONAL VARIABILITY OF SEEPAGE OILS FROM TRUJILLO STATE, WESTERN VENEZUELAJOURNAL OF PETROLEUM GEOLOGY, Issue 3 2010F. Galarraga The organic geochemistry of eighteen samples of seepage oils from Trujillo State, Western Venezuela, was investigated. These oils are probably derived from the predominantly marine Cretaceous La Luna Formation which is near peak maturity for oil generation. A range of biomarkers (n-alkanes, acyclic isoprenoids, phenanthrene and alkyl-phenanthrenes, as well as dibenzothiophene and alkyl-dibenzothiophenes) were analysed by gas chromatography - mass spectrometry (GC-MS). The seepage oils have been modified as a result of water washing and biodegradation. A first group of samples were slightly biodegraded with the partial loss of n- and iso-alkanes. Other samples fall into two groups: those that are moderately degraded, with partial depletion of acyclic isoprenoids; and those that are severely altered, as indicated by the partial or total absence of hopanes. One objective of this work was to evaluate the factors influencing the compositional differences of the three samples sets. In-situ measurements, together with the interpretation of the geochemical data, suggest that diverse factors were responsible for these variations. These included different degrees of alteration due to biodegradation and water washing, as well as differences in flow rate towards the surface. [source] Differential Effects of Ethanol on Insulin-Like Growth Factor-I Receptor SignalingALCOHOLISM, Issue 2 2000Andrea E.M. Seiler Background: Activation of the insulin-like growth factor I receptor (IGF-IR) by its ligands IGF-I and IGF-II induces cell proliferation and protects against apoptosis. Ethanol inhibits IGF-IR tyrosine autophosphorylation, which subsequently interferes with the activation of key downstream signaling mediators including insulin-receptor substrate-1, phosphatidylinositol 3-kinase, and mitogen-activated protein (MAP) kinase. The ethanol-induced inhibition of IGF-IR signaling reduces mitogenesis and enhances apoptosis. In the current study, we demonstrate that the antiproliferative action of ethanol can be modulated by differential sensitivity of the autophosphorylation of the IGF-IR to ethanol. Methods: A series of subclones was generated from 3T3 cells that express the human IGF-IR. Results: There was considerable variability in the ability of ethanol to inhibit IGF-I-dependent IGF-IR tyrosine autophosphorylation and MAP kinase activation, despite equivalent IGF-IR expression. The IGF-IR was completely resistant to a high concentration of ethanol (150 mM) in several subclones. The sensitivity of IGF-IR autophosphorylation to ethanol correlated directly with the inhibition of IGF-I-mediated MAP kinase activation and cell proliferation. Resistant subclones exhibited features of the transformed phenotype including high MAP kinase activity, partial loss of contact inhibition, and the development of foci at confluency. The IGF-IR isolated from ethanol-resistant cells was similarly resistant to ethanol in autophosphorylation reactions in vitro, whereas ethanol inhibited the autophosphorylation of IGF-IR obtained from sensitive cells. Conclusions: Our findings are the first to demonstrate the modulation of ethanol sensitivity of a tyrosine kinase receptor, and they provide a molecular basis for differential effects of ethanol on cell proliferation. [source] Aesthetic reconstruction of thumb or finger partial defect with trimmed toe-flap transferMICROSURGERY, Issue 2 2007Guoliang Cheng M.D. A new concept of esthetic reconstruction for partial loss of distal finger segment was introduced. In a series of 77 patients, 80 thumb or finger partial defects of lateral, dorsal, or volar half, or composite tissue defect of the finger body were reconstructed with lateral skin-nail flap, dorsal skin-nail flap, pulp flap, or composite tissue transplant taken from corresponding part of the toes. The blood circulations were reestablished by anastomosing digit arteries of the toe transplants and fingers. Seventy-eight fingers in 75 patients of this series were successfully reconstructed. The overall survival rate was 97.5%. Follow-up examinations made half to 12 years postoperatively showed normal length, outward appearance, and function of the reconstructed digits. Their nails are preserved or reconstructed. The pulps are full. Sweating is present. 2-PD was 4,6 mm. Esthetic reconstruction can achieve the goal of mending any part of tissue loss precisely with good result. © 2007 Wiley-Liss, Inc. Microsurgery, 2007. [source] Septic, CD-30 Positive Febrile Ulceronecrotic Pityriasis Lichenoides et Varioliformis AcutaPEDIATRIC DERMATOLOGY, Issue 4 2005Mark D. Herron M.D. Hemorrhagic-crusted papules and plaques covered over 90% of the patient's body, leaving her susceptible to Pseudomonas aeruginosa and Staphylococcus epidermidis bacteremia as well as Candida parapsilosis fungemia. Sepsis delayed definitive treatment of the underlying cutaneous disease for 2 weeks. Combined therapy with methotrexate and cyclosporin caused remission of the process. Although immunohistochemistry revealed CD-30 positive cells, suggesting the diagnosis of lymphomatoid papulosis, the histopathology was most compatible with pityriasis lichenoides et varioliformis acuta. A partial loss of CD2 and CD5 in the predominant CD3 T-cell lymphocytes suggested a clonal proliferation. Elevated soluble interleukin-2 receptor levels reflected marked T-cell activation, and the downward trend of the levels during treatment coincided with clinical regression of this inflammatory dermatosis. [source] Update on the clinical features and natural history of Wolf,Hirschhorn (4p-) syndrome: Experience with 87 patients and recommendations for routine health supervision,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 4 2008Agatino Battaglia Abstract Wolf,Hirschhorn syndrome (WHS) is a well-known multiple congenital anomalies/mental retardation syndrome, firstly described in 1961 by Cooper and Hirschhorn. Its frequency is estimated as 1/50,000,1/20,000 births, with a female predilection of 2:1. The disorder is caused by partial loss of material from the distal portion of the short arm of chromosome 4 (4p16.3), and is considered a contiguous gene syndrome. No single gene deletions or intragenic mutations have been shown to confer the full WHS phenotype. Since the disorder was brought to the attention of geneticists, many additional cases have been published. Only in 1999, however, were the first data on the natural history brought to the attention of the medical community. The purpose of the present study is to help delineate in more detail and over a longer period of time, the natural history of WHS, in order to establish appropriate health supervision and anticipatory guidance for individuals with this disorder. We have collected information on 87 patients diagnosed with WHS (54 females and 33 males) both in USA and Italy. Age at first observation ranged between newborn and 17 years. Twenty patients have been followed from 4 months to 23 years. The deletion proximal breakpoint varied from 4p15.32 to 4p16.3, and, by FISH, was terminal and included both WHSCR. Deletion was detected by standard cytogenetics in 44/87 (50.5%) patients, whereas FISH was necessary in the other 43 (49.5%). Array-CGH analysis at 1 Mb resolution was performed in 34/87 patients, and, in 15/34 (44%), showed an unbalanced translocation leading to both a 4p monosomy and a partial trisomy for another chromosome arm. Six more patients had been previously shown to have an unbalanced translocation by karyotype analysis or FISH with a WHS-specific probe. Sixty-five of 87 patients had an apparent pure, de novo, terminal deletion; and 1/87 a tandem duplication of 4p16.1p16.3 associated with 4p16.3pter deletion. Age at diagnosis varied between 7 months gestation and 16 years. Ninety-three percent had a seizure disorder with a good outcome; 80% had prenatal onset growth deficiency followed by short stature and slow weight gain; 60% had skeletal anomalies; 50% had heart lesions; 50% had abnormal tooth development; and 40% had hearing loss. Distinctive EEG findings were seen in 90%. Structural CNS anomalies were detected in 80%. Global developmental delay of varying degrees was present in all patients. Almost 50% was able to walk either alone or with support. Hypotonia was present in virtually all patients. A global improvement was observed in all individuals, over time. Our survey has also shown how the characteristic facial phenotype tends to be less pronounced in those patients with a smaller deletion, and microcephaly is not observed in the patients with certain cryptic unbalanced translocations. © 2008 Wiley-Liss, Inc. [source] Study of PfMyb1 Transcription Factor Regulation Network during Plasmodium falciparum Erythrocytic CycleTHE JOURNAL OF EUKARYOTIC MICROBIOLOGY, Issue 2 2005M. GISSOT During the complex life cycle of Plasmodium falciparum, the regulation of events that occur during the erythrocytic cycle, such as proliferation and differentiation, implies a fine control of transcriptional activities governing the expression profiles of each gene. However, transcriptional regulation and notably its actors, transcription factors and regulation motifs, are poorly described in Plasmodium. In order to decipher the mechanisms implicated in transcriptional regulation, we studied a transcription factor belonging to the trytophan family and showed that the PfMyb1 protein contained in nuclear extracts has a specific DNA binding activity. We took advantage of long pfmyb1 double stranded RNA (dsRNA) to inactivate the cognate messenger and understand the role of PfMyb1 during the erythrocytic cycle. Culture treated with pfmyb1 dsRNA exhibited a 40% growth inhibition and mortality during trophozoite to schizont transition when compared to either untreated control or culture treated with unrelated long dsRNA. We have further demonstrated that pfmyb1 transcript and protein decreased up to 80% in treated trophozoite culture at the time of pfmyb1 expression peak. Thus, we investigated the effect of this partial loss of transcript and protein using a thematic DNA microarray containing PCR products, representative of P. falciparum genes involved in cell cycle and transcriptional regulation. SAM software enabled us to identify several genes over and under-expressed, potentially directly or indirectly regulated by PfMyb1. These alterations of expression were verified by qPCR and Western blotting. We are currently working on the promoters of those genes to decode determinants of gene regulation by Pfmyb1. [source] Reconstruction of the Through-and-Through Anterior Mandibulectomy Defect: Indications and Limitations of the Double-Skin Paddle Fibular Free Flap,THE LARYNGOSCOPE, Issue 8 2008Frederic W.-B. Abstract Objectives/Hypothesis: The purpose of this report is to describe our recent experience using a double-skin paddle fibular free flap (DSPFFF) for reconstruction of the through-and-through anterior mandibulectomy defect and to present a reconstructive algorithm based on the extent of lip and mental skin resection. Study Design: Retrospective review of 10 consecutive patients with through-and-through anterior mandibulectomy defects. Methods: Outcomes that were examined included methods of reconstruction based on the cutaneous defect, flap complications, fistula rate, and donor site complications. Results: Seven patients were reconstructed with a DSPFFF. For lip reconstruction, two patients were also concomitantly reconstructed with Karapandzic or lip advancement flaps. Three patients were reconstructed with both a fibular free flap and a second free flap (1 radial forearm fasciocutaneous flap and 2 anterolateral thigh flaps). The transverse dimensions of the DSPFFFs were as great as 15 cm. None of the patients developed a fistula. All free tissue transfers were successful. One patient developed partial loss of the fibular skin paddle used for submental skin replacement. Conclusions: DSPFFF is a safe and reliable way to reconstruct an anterior through-and-through mandibular defect. Indications for using a DSPFFF are 1) a cutaneous defect that lies at or below the plane of the reconstructed mandible, 2) a transverse width of the oral mucosa and cutaneous defect that does not exceed 15 cm (the approximate distance from the mid-calf to the anterior midline), and 3) a lip defect that, if present, can be reconstructed with local flaps. [source] Loss of hypocretin (orexin) neurons with traumatic brain injury,ANNALS OF NEUROLOGY, Issue 4 2009Christian R. Baumann MD Chronic, daytime sleepiness is a major, disabling symptom for many patients with traumatic brain injury (TBI), but thus far, its etiology is not well understood. Extensive loss of the hypothalamic neurons that produce the wake-promoting neuropeptide hypocretin (orexin) causes the severe sleepiness of narcolepsy, and partial loss of these cells may contribute to the sleepiness of Parkinson disease and other disorders. We have found that the number of hypocretin neurons is significantly reduced in patients with severe TBI. This observation highlights the often overlooked hypothalamic injury in TBI and provides new insights into the causes of chronic sleepiness in patients with TBI. Ann Neurol 2009;66:555,559 [source] Serum biomarker for progranulin-associated frontotemporal lobar degeneration,ANNALS OF NEUROLOGY, Issue 5 2009Kristel Sleegers MD Objective Mutations that lead to a loss of progranulin (PGRN) explain a considerable portion of the occurrence of frontotemporal lobar degeneration. We tested a biomarker allowing rapid detection of a loss of PGRN. Methods We used an enzyme-linked immunosorbent assay to measure in serum the PGRN protein levels of six affected and eight unaffected carriers from within an extended Belgian founder family segregating the null mutation IVS1+5G>C. Further, we measured serum PGRN levels in 2 patients with another null mutation (a Met1 and a frameshift mutation), in 4 patients carrying a predicted pathogenic missense mutation and in 5 patients carrying a benign missense polymorphism, in 9 unaffected noncarrier relatives, and in 22 community controls. Results Serum PGRN levels were reduced in both affected and unaffected null mutation carriers compared with noncarrier relatives (pexact < 0.0001), and allowed perfect discrimination between carriers and noncarriers (sensitivity: 1.0; 1 , specificity: 0.0). Serum PGRN levels in Cys139Arg and Arg564Cys mutation carriers were significantly lower than in controls, but greater than in null mutation carriers, fitting the hypothesis of partial loss of function caused by these missense mutations. As expected, levels for carriers of benign missense polymorphisms were not significantly different from controls. Interpretation Our results indicate that the serum PGRN level is a reliable biomarker for diagnosing and early detection of frontotemporal lobar degeneration caused by PGRN null mutations, and provided the first in vivo evidence that at least some missense mutations in PGRN may lead to a (partial) loss of PGRN. Ann Neurol 2009 [source] Chromogranins as markers of altered hippocampal circuitry in temporal lobe epilepsyANNALS OF NEUROLOGY, Issue 2 2001Susanne Pirker MD Chromogranins are polypeptides which are widely expressed in the central nervous system. They are stored in dense core vesicles of nerve terminals, from where they are released upon stimulation. Using immunocytochemistry, we investigated the distribution of chromogranin A, chromogranin B, secretoneurin, and, for comparison, dynorphin in hippocampal specimens removed at routine surgery from patients with drug-resistant mesial temporal lobe epilepsy and in autopsy tissues from nonneurologically deceased subjects. In post mortem controls (n = 21), immunoreactivity for all four peptides (most prominently for chromogranin B and dynorphin) was observed in the terminal field of mossy fibers. For chromogranins, staining was observed also in sectors CA1 to CA3 and in the subiculum. Chromogranin B immunoreactivity was found in the inner molecular layer of the dentate gyrus, the area of terminating associational-commissural fibers. Secretoneurin and dynorphin immunoreactivity labeled the outer molecular layer and the stratum lacunosum moleculare of sectors CA1 to CA3, where projections from the entorhinal cortex terminate. In specimens with Ammon's horn sclerosis (n = 25), staining for all three chromogranins and for dynorphin was reduced in the hilus of the dentate gyrus. Instead, intense staining was observed in the inner molecular layer, presumably delineating terminals of sprouted mossy fibers. Specimens obtained from temporal lobe epilepsy patients without Ammon's horn sclerosis (n = 4) lacked this pronounced rearrangement of mossy fibers. In the stratum lacunosum moleculare of sector CA1, secretoneurin and dynorphin immunoreactivity was reduced in sclerotic, but not in nonsclerotic, specimens, paralleling the partial loss of fibers arising from the entorhinal cortex. Instead, presumably sprouted secretoneurin-immunoreactive fibers were found in the outer dentate molecular layer in sclerotic specimens. These changes in staining patterns for chromogranins and dynorphin mark profound plastic and functional rearrangement of hippocampal circuitry in temporal lobe epilepsy. [source] PYPAF1 nonsense mutation in a patient with an unusual autoinflammatory syndrome: Role of PYPAF1 in inflammationARTHRITIS & RHEUMATISM, Issue 2 2006I. Jéru Objective To gain insight into the pathophysiology of an unusual autoinflammatory syndrome, in a patient of Armenian origin, that mimicked familial Mediterranean fever (FMF) but with episodes triggered by generalized exposure to cold, and to further elucidate the controversial function of the protein encoded by PYPAF1, whose mutations (exclusively missense to date) have been identified in 3 hereditary recurrent fever syndromes. Methods The patient's DNA was screened for mutations in both MEFV, the gene responsible for FMF, and PYPAF1. The ability of different recombinant PYPAF1 isoforms, expressed in HEK 293 cells, to regulate NF-,B signaling was subsequently assessed. Results No disease-causing mutation was found in MEFV. However, a nonsense mutation (p.Arg554X) was identified in PYPAF1; this defect resulted in a truncated protein lacking all leucine-rich repeats. Study of the wild-type and mutant PYPAF1 recombinant proteins revealed that PYPAF1 inhibited NF-,B proinflammatory pathways, and that the identified nonsense mutation impaired this property. Conclusion These molecular and clinical findings, together with the clinical manifestations in the patient, which call into question the current nosology of the hereditary recurrent fever syndromes, are consistent with the hypothesis that PYPAF1 acts as an inhibitor of NF-,B signaling. They also provide a clear elucidation of the functional consequences of this nonsense PYPAF1 mutation not previously described in the literature, which result in a partial loss of function and may thereby explain the pathophysiology of the autoinflammatory syndrome observed in this patient. [source] Genome-Wide Analysis of Subependymomas Shows Underlying Chromosomal Copy Number Changes Involving Chromosomes 6, 7, 8 and 14 in a Proportion of CasesBRAIN PATHOLOGY, Issue 4 2008Kathreena M. Kurian Abstract Subependymomas (SE) are slow-growing brain tumors that tend to occur within the ventricles of middle-aged and elderly adults. The World Health Organization classifies these tumors within the ependymoma group. Previous limited analysis of this tumor type had not revealed significant underlying cytogenetic abnormalities. We have used microarray comparative genomic hybridization to study a series of SE (n = 12). A whole-genome array at 0.97-Mb resolution showed copy number abnormalities in five of 12 cases (42%). Two cases (17%) showed regions of loss on chromosome 6. More detailed analysis of all cases using a chromosome 6 tile-path array confirmed the presence of overlapping regions of loss in only these two cases. One of these cases also showed trisomy chromosome 7. Monosomy of chromosome 8 was seen in a further two cases (17%), and a partial loss on chromosome 14 was observed in one additional case. This is the first array-based, genome-wide study of SE. The observation that five of 12 cases examined (42%) at 0.97-Mb resolution showed chromosomal copy number abnormalities is a novel finding in this tumor type. [source] Purpura fulminans as a sequel to erythema nodosum in a child with homozygous Leiden mutation and acquired protein S deficiencyACTA PAEDIATRICA, Issue 8 2005Cathrine Foyn Bruun Abstract A 6-y-old boy presented with generalized, bruise-like swelling of both legs. Three weeks later, he developed purpura fulminans in one of the affected feet. Histology of the leg swelling was in accordance with erythema nodosum. The boy proved to be homozygous for the Factor V Leiden mutation and to have acquired protein S deficiency. He recovered, with partial loss of two toes. Conclusion: In contrast to what is often stated, erythema nodosum is not always a benign condition. On the basis of this report, we suggest that if extensive erythema nodosum develops in an individual without any known thrombophilic disorder, investigations with respect to the latter should be performed. [source] | ||||||||||||||||